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WO2023185763A1 - Composé peptidomimétique, procédé de préparation, composition pharmaceutique et utilisation associée - Google Patents

Composé peptidomimétique, procédé de préparation, composition pharmaceutique et utilisation associée Download PDF

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Publication number
WO2023185763A1
WO2023185763A1 PCT/CN2023/084172 CN2023084172W WO2023185763A1 WO 2023185763 A1 WO2023185763 A1 WO 2023185763A1 CN 2023084172 W CN2023084172 W CN 2023084172W WO 2023185763 A1 WO2023185763 A1 WO 2023185763A1
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substituted
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unsubstituted
alkyl
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Chinese (zh)
Inventor
柳红
胡树雷
李建
张磊砢
戴文豪
谢雄
蒋华良
陈凯先
肖庚富
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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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the field of medicine. Specifically, the present invention relates to a peptidomimetic compound that blocks the replication of coronaviruses including SARS-CoV-2 and other RNA viruses, as well as its preparation method, pharmaceutical composition and use.
  • RNA viruses are prone to mutation, and some coronaviruses, small RNA viruses, and noroviruses have caused serious disease problems to human society.
  • Coronaviruses belong to the subfamily Coronavirinae of the family Coronaviridae of the order Nidovirales. Based on early serological and subsequent genomic evidence, the subfamily Coronavirus is divided into 4 major genera: ⁇ , ⁇ , ⁇ and ⁇ , among which the genus ⁇ coronavirus can be further divided into 4 genera: A, B, C and D. pedigree.
  • HCoVs human coronaviruses
  • HCoV-229E and HCoV-NL63 belong to the genus Alphacoronavirus.
  • HCoV-OC43 and HCoV-HKU1 belong to lineage A
  • SARS-CoV belongs to lineage B
  • MERS-CoV belongs to lineage C
  • SARS-CoV-2 belongs to lineage B of the genus Coronavirus in the family Coronaviridae.
  • the coronavirus genome is an unsegmented, positive-sense single-stranded RNA. After the positive strand enters the host cell, it can directly serve as an mRNA chain to guide protein synthesis; it can also generate a negative strand through the action of RNA-dependent RNA polymerase (RDRP), and then use the negative strand as a template to generate a positive strand under the action of RDRP. chain. This achieves the purpose of replication. At the same time, the generated positive strand can also be used as mRNA to guide protein synthesis.
  • the coronavirus genome is 27-32kb in size, is capped at the 5'-end, polyadenylated at the 3'-end, and contains multiple open reading frames (ORFs).
  • coronavirus replicase is encoded by two large overlapping ORFs (ORF1a and ORF1b) occupying approximately two-thirds of the genome and is translated directly from genomic RNA.
  • ORF1a and ORF1b two large overlapping ORFs
  • structural and auxiliary proteins are translated from subgenomic RNAs (sgRNAs) produced during genome transcription/replication.
  • SARS-CoV-2 belongs to the genus Coronavirus in the family Coronaviridae. At present, it has affected most countries in the world. home influence.
  • Targeting the replication process of SARS-CoV-2 coronavirus, the main protease (Mpro), also known as 3C-like protease (3CL) is a key target for drug development. Inhibition of 3CL protease can effectively block the cleavage of viral polyprotein precursors, block viral replication, and inhibit the production of progeny viruses. Because it does not have the same enzyme in the human body, it has good safety and is currently recognized as an ideal target for the development of anti-coronavirus drugs.
  • the acute coronavirus has caused serious social impact, and the virus has produced multiple variants, increasing the social pressure to fight COVID-19.
  • Developing low-toxic, highly effective drugs with independent intellectual property rights to meet the needs of patients is of great social significance.
  • An object of the present invention is to provide a peptidomimetic compound that blocks the replication of coronaviruses including SARS-CoV-2 and other RNA viruses and its preparation method, pharmaceutical composition and use.
  • a first aspect of the present invention provides a peptidomimetic compound represented by general formula I, or its racemate, cis-trans isomer, enantiomer, diastereomer, pharmaceutically active compound Use of metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof for the preparation of (a) SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV and /or 3CL protease inhibitors of norovirus; (b) 3C protease inhibitors of RNA viruses EV71 and/or EV68; and (c) treatment and/or prevention, mitigation of SARS-CoV-2 and/or SARS-CoV and/or drugs for diseases caused by MERS-CoV and/or FIPV, and/or RNA viruses EV71 and/or EV68 and/or norovirus:
  • R 1 is selected from the following group:
  • R 5 is selected from the following group: substituted or unsubstituted C1 ⁇ C10 alkyl, substituted or unsubstituted C2 ⁇ C10 alkenyl, substituted or unsubstituted C2 ⁇ C10 alkynyl, substituted or unsubstituted C1 ⁇ C10 Alkoxy group, substituted or unsubstituted C3-C10 cycloalkyl group, substituted or unsubstituted 3-10 membered heterocyclyl group, substituted or unsubstituted C6 ⁇ C14 aryl group, substituted or unsubstituted 5 ⁇ 12 membered heterocyclic group Aryl; the substitution refers to being substituted by 1 to 3 substituents selected from the following group: halogen, C1-C4 alkyl, C3-C6 cycloalkyl, C6-10 aryl;
  • X is O or S
  • Y is selected from O, NH, N-Boc, N, or NR 5a ; wherein, when Y is NR 5a , NR 5a and R 5 together form a 5-7 membered nitrogen-containing heterocycle;
  • R 6 is selected from the group consisting of: H, halogen or cyano
  • R 7 is selected from the following group: substituted or unsubstituted 3-10-membered heterocyclyl, substituted or unsubstituted 5-12-membered heteroaryl; the substitution refers to 1 to 3 groups selected from the following group Substitution: halogen, C1-C4 alkyl;
  • R 8 is selected from the following group: hydrogen, C1 ⁇ C6 alkyl or -CO-C1 ⁇ C6 alkyl;
  • R 9 is H, NH4 + , or a metal ion selected from the following group: Na + , K + , Li + ;
  • R 10 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, or substituted or unsubstituted C3-C10 ring Oxygen group; the substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;
  • R 11 and R 12 are each independently selected from the following group: hydrogen, substituted or unsubstituted C1 to C10 alkyl, substituted or unsubstituted C2 to C10 alkenes, substituted or unsubstituted C2 to C10 alkynes; Substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;
  • R 11 and R 12 are connected to connected oxygen atoms to form a ring, forming a 5-8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen;
  • R 13 and R 14 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C10 alkylene Alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3- C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20
  • R 2 ' is selected from the following group: hydrogen, substituted or unsubstituted C1 ⁇ C10 alkyl, substituted or unsubstituted C2 ⁇ C10 alkenyl, substituted or unsubstituted C2 ⁇ C10 alkynyl, substituted or unsubstituted C3 ⁇ C10 cycloalkyl; the substitution means substitution by 1 to 2 groups selected from the following group: halogen, C1-C4 alkyl;
  • R 2 is selected from the following group: substituted or unsubstituted C1 ⁇ C10 alkyl, substituted or unsubstituted C2 ⁇ C10 alkenyl, substituted or unsubstituted C2 ⁇ C10 alkynyl, substituted or unsubstituted C1 ⁇ C10 alkoxy base, substituted or unsubstituted C3 ⁇ C10 cycloalkyl group, substituted or unsubstituted 3 ⁇ 10 membered heterocyclyl group, substituted or unsubstituted C6 ⁇ C14 aryl group, substituted or unsubstituted 5 ⁇ 12 membered heteroaryl group ;
  • the substitution refers to substitution with a group selected from the following group: halogen, C1-C6 alkyl, C6 ⁇ C10 aryl;
  • substitution means substitution by 1-3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;
  • R 4 is selected from the following group: substituted or unsubstituted C1 ⁇ C10 alkyl, substituted or unsubstituted C2 ⁇ C10 alkenyl, substituted or unsubstituted C2 ⁇ C10 alkynyl, substituted or unsubstituted C1 ⁇ C10 alkoxy base, substituted or unsubstituted C3 ⁇ C10 cycloalkyl, substituted or unsubstituted C6 ⁇ C14 aryl, substituted or unsubstituted 5 ⁇ 12-membered heteroaryl; the substitution refers to being substituted by 1-3 Substitution with groups independently selected from the following group: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkyl ketone carbonyl, cyano, nitro group, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, mercapto
  • R 4 ' is selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, the substitution refers to being substituted by 1-3 halogens;
  • R 4 and R 4 ' are connected to form a ring, the ⁇ carbon atom, ⁇ carbon atom connected to R 4 , and the ⁇ nitrogen atom connected to R 4 ' form a substituted or unsubstituted 5-10 membered heterocyclic ring, 5 -12-membered heteroaromatic ring; the substitution refers to being substituted by 1-3 Substituted with a group from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;
  • R 3 is selected from the following group: substituted or unsubstituted C1 ⁇ C10 alkyl, substituted or unsubstituted C2 ⁇ C10 alkenyl, substituted or unsubstituted C2 ⁇ C10 alkynyl, substituted or unsubstituted C3 ⁇ C10 cycloalkyl , substituted or unsubstituted 3 to 10-membered heterocyclyl, substituted or unsubstituted C6 to C14 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl; the substitution means 1 to 3 members selected from the following group Group substitution: halogen, C1 ⁇ C6 alkyl, C2 ⁇ C6 alkenyl, C2 ⁇ C6 alkynyl, C1 ⁇ C6 alkoxy, C6 ⁇ C10 aryl, halogenated C6 ⁇ C10 aryl, C1 ⁇ C6 alkyl Carbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl
  • heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
  • the virus is infected by SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA virus EV71 and/or EV68 and/or norovirus.
  • the disease caused is selected from the group consisting of: respiratory tract infection, pneumonia and its complications, or a combination thereof.
  • R 1 is selected from the following group:
  • R 1 is selected from the following group:
  • R 1 is selected from the following group:
  • R5 is selected from the following group: substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted C2 ⁇ C6 alkenyl, substituted or unsubstituted C2 ⁇ C6 alkynyl, substituted or unsubstituted C1 ⁇ C6 Alkoxy group, substituted or unsubstituted C3-C7 cycloalkyl group, substituted or unsubstituted 3-7 heterocyclyl group, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted A 5- to 10-membered heteroaryl group; the substitution refers to being substituted by 1 to 3 substituents selected from the following group: halogen, C1-C4 alkyl, C3-C6 cycloalkyl, C6-10 aryl;
  • X is O or S
  • Y is selected from O, NH, N-Boc, N, or NR 5a ; wherein, when Y is NR 5a , NR 5a and R 5 together form a 5-7 membered nitrogen-containing heterocycle;
  • R 6 is selected from the following group: H, F, Cl or cyano
  • R 7 is selected from the following group: substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to being substituted by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;
  • R 8 is selected from the following group: hydrogen or -CO-C1 ⁇ C4 alkyl
  • R 9 is Na + ;
  • R 10 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C3-C6 ring Oxygen group; the substitution means substitution by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;
  • R 11 and R 12 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkene, substituted or unsubstituted C2-C6 alkyne; or R 11
  • the oxygen atom connected to R 12 constitutes a 5-6 membered heterocyclic group; the substitution refers to being substituted by 1 to 3 groups selected from the following group: halogen, C1-C4 alkyl;
  • R 13 and R 14 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 heteroaryl, substituted or unsubstituted C6-C14 aryl C1-C5 alkylene, substituted or unsubstituted C3-C10 heteroaryl C1-C5 Alkylene, substituted or unsubstituted C6-C10 aryl
  • R 2 ' is selected from the following group: hydrogen, substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted C2 ⁇ C6 alkenyl, substituted or unsubstituted C2 ⁇ C6 alkynyl, substituted or unsubstituted C3 ⁇ C6 cycloalkyl; the substitution means substitution by 1 to 2 groups selected from the following group: halogen, C1-C4 alkyl;
  • R 2 is selected from the following group: substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted C2 ⁇ C6 alkenyl, substituted Or unsubstituted C2 ⁇ C6 alkynyl, substituted or unsubstituted C1 ⁇ C6 alkoxy, substituted or unsubstituted C3 ⁇ C6 cycloalkyl, substituted or unsubstituted 3 ⁇ 7 membered heterocyclyl, substituted or unsubstituted Substituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substitution refers to substitution with a group selected from the following group: halogen, C1-C6 alkyl, C6-C10 aryl ;
  • substitution means substitution by 1-3 groups selected from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl or C3-C4 cycloalkyl;
  • R 4 is selected from the following group: substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted C2 ⁇ C6 alkenyl, substituted or unsubstituted C2 ⁇ C6 alkynyl, substituted or unsubstituted C1 ⁇ C6 alkoxy base, substituted or unsubstituted C3 ⁇ C7 cycloalkyl, substituted or unsubstituted C6 ⁇ C10 aryl, substituted or unsubstituted 5 ⁇ 10 membered heteroaryl; the substitution refers to being substituted by 1-3 respective Substitution with groups independently selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or two adjacent substituents together with the Carbon atoms form a 5- to 7-membered ring;
  • R 4 ' is selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, the substitution refers to being substituted by 1-3 halogens;
  • R 4 and R 4 ' are connected to form a ring, the ⁇ carbon atom, ⁇ carbon atom connected to R 4 , and the ⁇ nitrogen atom connected to R 4 ' form a substituted or unsubstituted 5 to 10-membered heterocyclic ring, 5 -10-membered heteroaromatic ring; the substitution means substitution by 1-3 halogens;
  • R 3 is selected from the following group: substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted C2 ⁇ C6 alkenyl, substituted or unsubstituted C2 ⁇ C6 alkynyl, substituted or unsubstituted C3 ⁇ C10 cycloalkyl , substituted or unsubstituted 3 to 7-membered heterocyclyl, substituted or unsubstituted C6 to C10 aryl, substituted or unsubstituted 5 to 10-membered heteroaryl; the substitution means 1 to 3 members selected from the following group Group substitution: halogen, C1 ⁇ C6 alkyl, C2 ⁇ C6 alkenyl, C2 ⁇ C6 alkynyl, C1 ⁇ C6 alkoxy, C6 ⁇ C8 aryl, halogenated C6 ⁇ C8 aryl, or two phases The adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring
  • heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
  • the ring formed by R 2 and R 2 ' and the connected and adjacent atoms has a structure selected from the following group:
  • the ring formed by R 4 and R 4 ' and the connected and adjacent atoms has a structure selected from the following group:
  • R 1 is selected from the following group:
  • R 1 is selected from the following group:
  • R 5 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to being substituted by 1 to 3 substituents selected from the following group Substitution: C1-C4 alkyl, C6-10 aryl;
  • R 10 is selected from the following group: substituted or unsubstituted C2 ⁇ C6 alkenyl, substituted or unsubstituted C2 ⁇ C6 alkynyl, or substituted or unsubstituted C3 ⁇ C6 epoxy group; the substitution refers to substituted by 1 ⁇ 3 groups selected from the following group are substituted: halogen, C1-C4 alkyl;
  • R 11 and R 12 are each independently selected from the following group: hydrogen, C1-C6 alkyl, or the oxygen atoms to which R 11 and R 12 are connected constitute a 5-6-membered heterocyclic group;
  • R 13 and R 14 are each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1 -C5 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C6-C14 aryl C1-C5 alkylene, substituted or unsubstituted C6-C10 Aryl C2-C5 alkenylene; the substitutions each independently refer to substitution with 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C
  • R 2 ' is selected from hydrogen and C1 ⁇ C6 alkyl
  • R 2 is selected from the group consisting of substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted C1 ⁇ C6 alkoxy, substituted or unsubstituted C3 ⁇ C6 cycloalkyl, or substituted or unsubstituted C6 ⁇ C8 aryl; the substitution refers to substitution with a group selected from the following group: halogen, C1-C4 alkyl, C6 ⁇ C8 aryl;
  • R 2 and R 2 ' are connected to form a ring, the ⁇ carbon atom and ⁇ carbon atom connected to R 2 and the ⁇ nitrogen atom connected to R 2 ' form a substituted or unsubstituted 5 to 10-membered heterocyclic ring, 5 -10-membered heteroaromatic ring; the substitution means substitution by 1-3 halogens;
  • R 4 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to 1-3 groups independently selected from the following group Group substitution: halogen, C1 ⁇ C6 alkyl;
  • R 4 ' is hydrogen
  • R 3 is selected from the following group: substituted or unsubstituted C2 to C6 alkenyl, substituted or unsubstituted 5 to 10-membered heteroaryl; the substitution refers to being substituted by 1 to 3 groups selected from the following group: Halogen, C1 ⁇ C4 alkyl, C1 ⁇ C6 alkoxy, halogenated C6 ⁇ C8 aryl, or two adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;
  • heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
  • R 5 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl; the substitution refers to being substituted by 1 to 3 selected from The following group of substituents are substituted: C1-C4 alkyl, C6-10 aryl;
  • R 3 is selected from the following group: substituted or unsubstituted C2 to C6 alkenyl, substituted or unsubstituted 5 to 10-membered heteroaryl; the substitution refers to being substituted by 1 to 3 groups selected from the following group: Halogen, C1 ⁇ C4 alkyl, C1 ⁇ C6 alkoxy, halogenated C6 ⁇ C8 aryl, or two adjacent substituents together with the carbon atoms connected to them form a 5-7 membered ring;
  • heterocyclyl group and the heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O, and S.
  • R 1 is selected from the following group:
  • R 1 is selected from the following group:
  • R 1 is selected from the following group:
  • R 2 and R 2 ' do not form a ring and R 2 ' is not hydrogen, R 2 ' is methyl.
  • R 3 is a substituted or unsubstituted benzoheteroaromatic ring; the substitution refers to being substituted by 1-3 groups selected from the following group: halogen, C1-C4 alkyl or C1 -C4 alkoxy.
  • R 3 is selected from the following group: substituted or unsubstituted indole aromatic heterocycle, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted quinoline aromatic heterocycle, substituted or unsubstituted Furan aromatic heterocycle, substituted or unsubstituted thiazole, substituted or unsubstituted quinoxaline, substituted or unsubstituted quinoline aromatic heterocycle, the substitution means that 1, 2 or 3 are selected from the following group Group substitution: halogen, C1 ⁇ C4 alkyl, C1 ⁇ C6 alkoxy, halogenated C6 ⁇ C8 aryl.
  • R 3 is selected from the following group: benzodioxole, indole, isoxazole, 2-hydropyran, pyridine, pyrazole, dihydroimidazopyridine, imidazo Pyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, benzofuran, indazole, benzimidazole or quinoline.
  • R 3 has a structure selected from the following group:
  • R 3 has a structure selected from the following group:
  • the compound is selected from the following group:
  • the compound is compound 5-11, 15-16, 56-62, 65, 67-171 in Table 1.
  • a second aspect of the present invention provides a method for preparing the peptidomimetic compound described in the first aspect of the present invention, including the steps:
  • Step (1) react compound Ia and compound Ib in an inert solvent in the presence of a condensing agent to obtain compound Ic;
  • Step (2) react compound Ic in a mixed solution of an inert solution and an acidic solution to obtain compound Id;
  • Step (3) react compound Ie and compound Id in an inert solvent in the presence of a condensing agent to obtain compound If;
  • Step (4) react compound If in a mixed solution of an inert solution and an acidic solution to obtain compound Ig;
  • Step (5) react compound Ih and compound Ig in an inert solvent in the presence of a condensing agent to obtain compound Ii;
  • Step (6) In an inert solvent, compound Ii undergoes a reduction reaction with a reducing agent to obtain compound Ij;
  • Step (7) In an inert solvent, compound Ij undergoes an oxidation reaction with an oxidizing agent to obtain compound Ik;
  • Step (8) In an inert solvent, compound Ik and compound IL are reacted in the presence of triphenylphosphine to obtain compound Im;
  • Step (9) In an inert solvent, compound Ik and compound In are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Io;
  • Step (10) In an inert solvent, compound Ik and compound Ip are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Iq;
  • Step (11) In an inert solvent, compound Ik and compound Ir are reacted in the presence of a base to obtain compound Is;
  • Step (13) In a polar solvent, compound Ii is reacted with ammonia water to obtain compound Iv; in an anhydrous inert solvent, compound Iv is reacted with an acid anhydride to obtain compound Iw;
  • Step (14) In a polar solvent, compound Ii is hydrolyzed under alkaline conditions to obtain compound Ix; in an inert solvent, compound Ix is condensed with N-methyl-N-methoxyamine hydrochloride. React to obtain compound Iy; in an inert solvent, compound Iy reacts with Grignard reagent to obtain compound Iz;
  • the definitions of m, n, X and Y are the same as those in the first aspect of the present invention.
  • the inert solvent is selected from the following group: C1-C6 alkane solvents, C2-C6 nitrile solvents, C2-C6 ether solvents, or combinations thereof.
  • the inert solvent is selected from the following group: dichloromethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or a combination thereof.
  • the condensation agent is HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate).
  • the acidic solution is selected from the following group: 4M hydrochloric acid.1,4-dioxane solution.
  • the polar solvent is selected from the following group: water, C1-C6 alcohol solvents, C2-C6 ester solvents, or combinations thereof.
  • the polar solvent is selected from the following group: water, ethanol, ethyl acetate, or a combination thereof.
  • the reducing agent is borohydride.
  • the oxidizing agent is selected from the following group: Dess-Martin oxidizing agent, sulfur trioxide, pyridine oxidizing agent, or a combination thereof.
  • the base is selected from the following group: piperidine, NaH, lithium hexamethyldisilazide, or a combination thereof.
  • the alcohol solvent is a C1-C6 alcohol solvent selected from the following group: methanol, ethanol, propanol, isopropyl alcohol, n-butanol, ethylene glycol, propylene glycol, or a combination thereof .
  • the catalytic amount of acid is p-toluenesulfonic acid.
  • the acid anhydride is trifluoroacetic anhydride.
  • the third aspect of the present invention provides a pharmaceutical composition, including (a) a therapeutically effective amount of a peptidomimetic compound represented by general formula (I), or its racemate, cis-trans isomer, para enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof, and (b) a pharmaceutically acceptable carrier or excipient, Among them, the peptidomimetic compound represented by general formula (I) is as described in the first aspect of the present invention.
  • the fourth aspect of the present invention provides a use of the pharmaceutical composition according to the third aspect of the present invention for preparing (a) SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/ or 3CL protease inhibitors of FIPV and/or norovirus; (b) 3C protease inhibitors of RNA viruses EV71 and/or EV68; and (c) treatment and/or prevention, mitigation of SARS-CoV-2 and/or Drugs for diseases caused by SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA viruses EV71 and/or EV68 and/or norovirus.
  • the virus is infected by SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA virus EV71 and/or EV68 and/or norovirus.
  • the associated disease caused is selected from the group consisting of: respiratory tract infection, pneumonia and its complications, or a combination thereof.
  • the fifth aspect of the present invention provides a method for treating and/or preventing and alleviating SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or RNA virus EV71 and/or EV68 and/or a method for related diseases caused by norovirus infection, comprising the steps of: administering a safe and effective amount of a peptidomimetic compound represented by general formula I, or its racemate, cis-trans isomer, to a subject in need , enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvates, prodrugs, or combinations thereof, wherein the peptoid represented by the general formula I Compounds are as described above.
  • a sixth aspect of the present invention provides a method for inhibiting the activity of 3CL protease of SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV and/or norovirus, including the steps:
  • the peptoid compounds of general formula I, or their racemates, cis-trans isomers, enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, and solvates , prodrugs or combinations thereof contact SARS-CoV-2 and/or SARS-CoV and/or MERS-CoV and/or FIPV, and/or 3CL protease of norovirus, thereby inhibiting SARS-CoV-2 and/or The activity of 3CL protease of SARS-CoV and/or MERS-CoV and/or FIPV, and/or norovirus, wherein the peptidomimetic compound of general formula I is as described above.
  • the seventh aspect of the present invention provides a method for inhibiting the activity of 3C protease of RNA virus EV71 and/or EV68, including the steps of: adding the peptidomimetic compound represented by general formula I, or its racemate, cis Anti-isomers, enantiomers, diastereomers, pharmaceutically active metabolites, pharmaceutically acceptable salts, solvation
  • the substance, prodrug, or combination thereof contacts the 3C protease of RNA virus EV71 and/or EV68, thereby inhibiting the activity of the 3C protease of RNA virus EV71 and/or EV68, wherein the peptidomimetic compound of general formula I is as described above narrate.
  • the eighth aspect of the present invention provides a peptidomimetic compound according to the first aspect of the present invention, or its racemate, cis-trans isomer, enantiomer, diastereomer, A drug's active metabolite, pharmaceutically acceptable salt, solvate, prodrug, or combinations thereof,
  • R 1 , R 2 , R 2 ', R 3 , R 4 , R 4 ', m, n are as defined in the first aspect of the invention.
  • the active ingredients of coronavirus, and/or EV71 and/or EV68 and/or norovirus and other RNA virus infections that is, the compound represented by general formula (I) or its pharmaceutically acceptable salts, enantiomers, Diastereomers or racemates, or combinations thereof.
  • Tests have shown that the active ingredient of the present invention can effectively inhibit the activity of 3CL or 3C protease of coronaviruses such as SARS-CoV-2 and other small RNA viruses, thereby inhibiting coronaviruses such as SARS-CoV-2 and other small RNA viruses. replication and activity. On this basis, the present invention was completed.
  • substituted means that one or more hydrogen atoms on a group are replaced by Substituted with substituents selected from the following group: C1 to C10 alkyl, C3 to C10 cycloalkyl, C1 to C10 alkoxy, halogen, hydroxyl, carboxyl (-COOH), C1 to C10 aldehyde, C2 to C10 acyl, C2 ⁇ C10 ester group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group with 1-3 substituents, the substituent group is selected from: halogen, C1 ⁇ C10 alkyl group, Cyano group, hydroxyl group, nitro group, C3 ⁇ C10 cycloalkyl group, C1 ⁇ C10 alkoxy group, amino group.
  • each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.
  • C1-C10 alkyl refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms, preferably a straight-chain or branched alkyl group having 1 to 6 carbon atoms; for example, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
  • C2-C10 alkenyl refers to a straight-chain or branched alkyl group having 2 to 10 carbon atoms, preferably a straight-chain or branched alkyl group having 2 to 6 carbon atoms; for example, ethylene, propylene, Butene, or similar groups.
  • C2-C10 alkynyl refers to a straight-chain or branched alkyl group having 2 to 10 carbon atoms, preferably a straight-chain or branched alkyl group having 2 to 6 carbon atoms; for example, acetylene, propyne , butyne, or similar groups.
  • heterocyclyl refers to a saturated or partially saturated cyclic group with heteroatoms selected from N, S and O, which can be a single ring or a bicyclic ring, for example, a bridged ring or a bridged ring. Spiral form.
  • the heterocyclyl group is preferably a 4- to 10-membered heterocyclyl group, more preferably a 5- to 7-membered heterocyclyl group, and even more preferably a 5 to 6-membered heterocyclyl group.
  • heterocyclyl include, but are not limited to: azetidine, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, and the like.
  • the heterocyclyl group can be fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring (such as forming [5+3], [5+5], [5+6], [6+5 ] or [6+6] fused ring system, etc.), in which the ring connected to the parent structure is a heterocyclic group.
  • Five-membered heterocycle is intended to include a five-membered heterocycle and a 3-7-membered ring, a spiro ring formed by a five-membered heterocycle and a 3-7-membered ring, and a bridged ring formed by a five-membered heterocycle and a 4-7-membered ring.
  • Six-membered heterocyclic ring is intended to include a six-membered heterocyclic ring and a 3-7-membered ring, a spiro ring formed by a six-membered heterocyclic ring and a 3-7-membered ring, and a bridged ring formed by a six-membered heterocyclic ring and a 4-7-membered ring.
  • aryl refers to an aromatic ring group that does not contain heteroatoms on the ring.
  • the aryl group can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, which is related to the parent structure.
  • the rings joined together are aryl rings.
  • phenyl ie C6 aryl or six-membered aryl
  • naphthyl ie C10 aryl or [6+6] aryl
  • the six-membered aryl is also intended to include six-membered aryl and 5-6 One-membered cycloalkyl and six-membered aryl and 5-6-membered heterocyclyl.
  • aryl refers to a fused 6,5 bicyclic ring system.
  • the aryl group is preferably a C6-C14 aryl group, more preferably a C6-C10 aryl group.
  • Examples of aryl groups include phenyl, naphthyl.
  • Aryl groups may be optionally substituted or Not superseded.
  • heteroaryl refers to a cyclic aromatic group having 1 to 3 heteroatoms selected from the group consisting of N, S and O, which may be a single ring or a condensed ring.
  • the heteroaryl group is preferably a 5- to 6-membered heteroaryl group.
  • heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • [5+6]heteroaryl refers to a fused 6,5 bicyclic ring system, such as benzothienyl, benzofuranyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzene Thiadiazolyl, benzoxazolyl, etc.
  • the term "5- to 12-membered heteroaryl” refers to a group formed by losing one hydrogen atom from a 5- to 12-membered aryl group having 1 to 3 heteroatoms selected from the following group: N, S, O, where each heteroaryl
  • the cyclic system of the base can be monocyclic or polycyclic: for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinolyl or similar groups.
  • C1-C10 alkoxy refers to a straight-chain or branched alkoxy group having 1 to 10 carbon atoms; preferably, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms; for example, methoxy group, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, or similar groups.
  • C2-C6 alkenyl refers to a group formed by losing one or two hydrogen atoms from an alkene with 2 to 6 carbon atoms.
  • halogen refers to F, Cl, Br and I.
  • the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, double bond (Z), (E) isomers and (Z), (E) conformational isomers. Therefore, the single stereochemical isomers of the compounds of the present invention or their enantiomers Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the present invention.
  • tautomers means that structural isomers with different energies can cross a low energy barrier and thus convert into each other.
  • proton tautomers i.e. proton transfer
  • interconversion through proton migration such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
  • valency tautomers include interconversion through some bonding electron recombination.
  • C1-C6 is formed to mean that the group may have from 1 to 6 carbon atoms, such as 1, 2, 3, 4 or 5.
  • an active ingredient that can effectively inhibit the replication of SARS-CoV-2 is provided.
  • the active ingredient is a compound represented by general formula I, which can effectively prevent, treat and/or alleviate COVID-19 related diseases.
  • the active ingredients of the present invention include peptidomimetic compounds represented by general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, or Its prodrug. It should be understood that the active ingredient of the present invention also includes the crystalline form, amorphous compound, deuterated compound and other forms of the compound of general formula (I).
  • the "pharmaceutically acceptable salt” is a conventional non-toxic salt formed by the reaction of a compound of general formula (I) with an inorganic acid or organic acid.
  • conventional non-toxic salts can be prepared by reacting compounds of general formula (I) with inorganic acids or organic acids.
  • the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid and phosphoric acid, etc.
  • Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, propylene glycol Acid, fumaric acid, succinic acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, parapic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p- Aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, etc.; or compounds of general formula (I) with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • the present invention also provides peptidomimetic compounds represented by general formula (I), or their pharmaceutically acceptable salts, enantiomers, diastereomers or racemates and prodrugs.
  • One or more mixtures of active ingredients are prepared to treat and/or prevent and alleviate coronaviruses caused by SARS-CoV-2 and/or SARSCoV and/or MERS-CoV and/or FIPV, and/or EV71 and/or RNA such as EV68 and/or norovirus Used in medicines for respiratory tract infections, pneumonia and other related diseases caused by viral infections.
  • the pharmaceutical composition provided by the present invention preferably contains active ingredients in a weight ratio of 0.001 to 99wt%.
  • the preferred ratio is that the compound of general formula (I) as the active ingredient accounts for 0.1wt% to 90wt% of the total weight, and the rest is pharmaceutically acceptable.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents. Neutralize suitable for use in sterile equipment for injection or infusion.
  • the unit dosage of the dosage form formula usually contains 0.05 to 400 mg of the compound of general formula (I).
  • the unit dosage of the preparation formula contains 1 mg to 500 mg of the compound of general formula (I).
  • the compounds and pharmaceutical compositions of the present invention can be used clinically on mammals, including humans and animals, and can be administered through the oral, nasal, skin, lung or gastrointestinal tract. Oral administration is most preferred.
  • the most preferred daily dose is 0.01 to 400 mg/kg body weight, taken at one time, or 0.01 to 200 mg/kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for the individual will depend on the specific treatment. Usually, you start with a small dose and gradually increase the dose until you find the most suitable dose.
  • the drugs or inhibitors of the present invention can be administered in various ways, for example, through injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method, such as muscle, intradermal, subcutaneous, intravenous introduction into the body. , mucosal tissue; or mixed or wrapped with other substances and introduced into the body.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) retarding solvents, such as paraffin; (f) absorption Accelerators, such as quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol, such
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form 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 employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, 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.
  • the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, 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 contain 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 excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds 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 that may be required.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as other antiviral drugs).
  • the treatment method of the present invention can be administered alone or in combination with other treatment methods or therapeutic drugs.
  • the compound of formula I of the present invention can be prepared by the following method.
  • the conditions of the method such as reactants, solvents, bases, amounts of compounds used, reaction temperature, reaction time required, etc. are not limited to the following solutions: release.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • Step (1) In an inert solvent, compound Ia and compound Ib are reacted in the presence of a condensing agent to obtain compound Ic; wherein the condensing agent is preferably HATU (2-(7-azabenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate);
  • Step (2) react compound Ic in a mixed solution of an inert solution and a hydrochloric acid solution to obtain compound Id; wherein the hydrochloric acid solution is preferably 4M hydrochloric acid.1,4-dioxane solution;
  • Step (3) In an inert solvent, compound Ie and compound Id are reacted in the presence of a condensing agent to obtain compound If; wherein the condensing agent is preferably HATU (2-(7-azabenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate);
  • Step (4) react compound If in a mixed solution of an inert solution and a hydrochloric acid solution to obtain compound Ig; wherein the hydrochloric acid solution is preferably 4M hydrochloric acid.1,4-dioxane solution;
  • Step (5) In an inert solvent, compound Ih and compound Ig are reacted in the presence of a condensing agent to obtain compound Ii; wherein the condensing agent is preferably HATU (2-(7-azabenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate);
  • Step (6) In an inert solvent, compound Ii is subjected to a reduction reaction under certain conditions to obtain compound Ij; wherein the reducing agent is preferably borohydride;
  • Step (7) In an inert solvent, compound Ij is subjected to an oxidation reaction under certain conditions to obtain compound Ik; wherein the oxidizing agent is preferably Dess-Martin oxidizing agent or sulfur trioxide-pyridine oxidizing agent;
  • Step (8) In an inert solvent, compound Ik and compound IL are reacted in the presence of triphenylphosphine to obtain compound Im;
  • Step (9) In an inert solvent, compound Ik and compound In are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Io;
  • the base is preferably piperidine;
  • Step (10) In an inert solvent, compound Ik and compound Ip are subjected to Knoevenagel condensation reaction in the presence of a base to obtain compound Iq; the base is preferably NaH;
  • Step (11) In an inert solvent, compound Ik and compound Ir react in the presence of a base to obtain compound Is;
  • the base is preferably lithium hexamethyldisilazide;
  • Step (13) In a polar solvent, compound Ii is reacted with ammonia water to obtain compound Iv; in an anhydrous inert solvent, compound Iv is reacted with an acid anhydride to obtain compound Iw; the acid anhydride is preferably trifluoroacetic anhydride;
  • Step (14) In a polar solvent, compound Ii is hydrolyzed under alkaline conditions to obtain compound Ix; in an inert solvent, compound Ix is condensed with N-methyl-N-methoxyamine hydrochloride. React to obtain compound Iy; in an inert solvent, compound Iy reacts with Grignard reagent to obtain compound Iz;
  • the definitions of m, n, X and Y are the same as those in the first aspect of the present invention.
  • Figure 1 Data on the inhibition of EV71 3C protease activity of compound 72 tested in RD cells.
  • Figure 2 CC50 data of compound 72 tested in RD cells.
  • Figure 3 The corresponding blood drug concentration change curves over time after oral administration (10 mg/kg) and intravenous administration (5 mg/kg) of compound 68 in mice.
  • Figure 4 RI-PCR method detects the inhibitory effect of compound 10, compound 21, and compound 172 on FIPV in CRFK cells.
  • Figure 5 IFA method to detect the ability of compound 172 to inhibit FIPV replication in CRFK cells.
  • Figure 6 IFA method to detect the ability of compound 21 to inhibit FIPV replication in CRFK cells.
  • Figure 7 IFA method to detect the ability of compound 10 to inhibit FIPV replication in CRFK cells.
  • Nuclear magnetic resonance was measured by GEMINI-300, Brucker AMX-400 and INVOA-600 nuclear magnetic resonance instruments. TMS (tetramethylsilyl) was used as the internal standard, the chemical shift unit was ppm, and the coupling constant unit was Hz; mass spectrometry Measured by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.
  • the silica gel used for column chromatography is 200-300 mesh (produced by Qingdao Ocean Chemical); the TLC silica gel plate is a HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Factory; the boiling range of petroleum ether is 60-90°C; a UV lamp is used. Color development in iodine cylinder.
  • the conventional reagents and drugs used in the following examples were purchased from Sinopharm Group. The reagents and solvents used in the experiment were handled according to the specific conditions of the reaction.
  • N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester 1-1 (6g, 21.8mmol) was dissolved in 60mL anhydrous tetrahydrofuran, and LiHMDS (1M in THF) in tetrahydrofuran (47 mL, 47 mmol). Keep the temperature stable at -78°C during the dropwise addition, which lasts for 1 hour. After completion of dropping, stir at -78°C for 1 hour. Bromoacetonitrile (2.79g, 23.3mmol) was dissolved in 20 mL of tetrahydrofuran, and then the solution was slowly added dropwise to the reaction system, and the dropping process continued for 1 to 2 hours.
  • Intermediate 1-3 (1g, 3.5mmol) was dissolved in dichloromethane (40mL), 4M HCl dioxane solution (9mL, 35mmol) was added at 0°C, the reaction was continued to stir at room temperature for 12h, and then The solution is evaporated to dryness to obtain intermediate 1-4, which can be directly used for the next reaction without purification.
  • Dissolve compound 1-5 (1.1g, 3.5mmol) in dichloromethane (40mL), cool the reaction solution to -20°C, then add HATU (1.9g, 4.9mmol) to the reaction solution, and stir for 20 minutes.
  • Intermediate 1-4 obtained in the previous step was added to the reaction solution, stirred again at -20°C for 30 minutes, and then DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution.
  • Compound 2-1 was used to replace maleimide 1-12 in Example 1, and the synthesis method was based on the synthesis of compound 1 to obtain compound 2.
  • Compound 4-1 was used to replace maleimide 1-12 in Example 1, and the synthesis method was based on the synthesis of compound 1 to obtain compound 4.
  • Dissolve compound 1-3 (1g, 3.5mmol) in 10mL of methanol, add 5mL of water, add lithium hydroxide monohydrate (290mg, 7.0mmol) while stirring at room temperature, react at room temperature overnight, and monitor the reaction with a spot plate after the reaction is complete.
  • the synthesis of compound 27 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 27-1.
  • the synthesis of compound 28 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 28-1.
  • the synthesis of compound 29 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 29-1.
  • the synthesis of compound 30 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 30-1.
  • the synthesis of compound 31 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 31-1.
  • the synthesis of compound 32 refers to the synthesis of compound 26, and the corresponding intermediate 26-1 is replaced by 32-1.
  • Dissolve compound 34-1 (29 mg, 0.24 mmol) in anhydrous tetrahydrofuran (5 mL), add NaH (10 mg, 60% dispersion in mineral oil) in batches at 0°C, and after 20 minutes, slowly add dissolved Compound 1-11 (100 mg, 0.22 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), reacted for 2 hours, and monitored by spot plate.
  • Add 5 mL saturated ammonium chloride solution and 5 mL ethyl acetate separate the organic phase, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure and then separate by column chromatography to obtain white solid compound 34 (60 mg), yield 49%.
  • the synthesis of compound 35 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by 35-1.
  • the synthesis of compound 36 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-5 is replaced by 35-1.
  • the synthesis of compound 37 refers to the synthesis of compound 1-11 and compound 5, and the corresponding intermediate 1-5 is replaced by 35-1.
  • the synthesis of compound 38 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 35-1 and 38-1.
  • the synthesis of compound 39 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 38-1.
  • the synthesis of compound 40 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 40-1.
  • the synthesis of compound 41 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 40-1.
  • the synthesis of compound 42 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-5 is replaced by 42-1.
  • the synthesis of compound 43 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by 42-1.
  • the synthesis of compound 44 refers to the synthesis of compound 1-8 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 42-1 and 44-1.
  • the synthesis of compound 45 refers to the synthesis of compound 1-8 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 42-1 and 45-1.
  • the synthesis of compound 46 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 46-1.
  • the synthesis of compound 48 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 48-1.
  • the synthesis of compound 49 refers to the synthesis of compound 1-11 and compound 19, and the corresponding intermediate 1-8 is replaced by 49-1.
  • the synthesis of compound 50 refers to the synthesis of compound 1-11 and compound 5, and the corresponding intermediate 1-8 is replaced by 50-1.
  • the synthesis of compound 51 refers to the synthesis of compound 1-11 and compound 5, and the corresponding intermediate 1-8 is replaced by 51-1.
  • the synthesis of compound 53 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 53-1.
  • the synthesis of compound 54 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 54-1.
  • the synthesis of compound 55 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-8 is replaced by 56-1.
  • the synthesis of compound 56 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 56-1.
  • the synthesis of compound 57 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 57-1.
  • the synthesis of compound 58 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 58-1.
  • the synthesis of compound 59 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 59-1.
  • the synthesis of compound 60 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 60-1.
  • the synthesis of compound 61 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 61-1.
  • the synthesis of compound 62 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-8 is replaced by 62-2.
  • the synthesis of compound 63 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by 63-1.
  • the synthesis of compound 64 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-5 is replaced by 63-1.
  • Intermediate 1-3 (1g, 3.5mmol) was dissolved in dichloromethane (40mL), 4M HCl dioxane solution (9mL, 35mmol) was added at 0°C, the reaction was continued to stir at room temperature for 12h, and then The solution is evaporated to dryness to obtain intermediate 1-4, which can be directly used for the next reaction without purification.
  • Dissolve compound 1-8 (0.47g, 2.9mmol) in dichloromethane (40mL), and cool the reaction solution to -20°C, then add HATU (1.3g, 3.5mmol) to the reaction solution, stir for 20 minutes, add the intermediate 1-7 obtained in the previous step to the reaction solution, stir again at -20°C for 30 minutes, and then add DIPEA (1.7mL, 10.5mmol) was added dropwise to the reaction solution.
  • the synthesis of compound 66 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 66-1.
  • the synthesis of compound 67 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 67-1.
  • the synthesis of compound 68 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 68-1.
  • the synthesis of compound 69 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 69-1.
  • the synthesis of compound 70 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 70-1.
  • the synthesis of compound 71 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 71-1.
  • the synthesis of compound 72 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 72-1.
  • the synthesis of compound 73 refers to the synthesis of compound 1-11 and compound 18, and the corresponding intermediate 1-5 is replaced by 68-1.
  • the synthesis of compound 74 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 74-1.
  • the synthesis of compound 75 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 75-1.
  • the synthesis of compound 76 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 76-1.
  • the synthesis of compound 77 refers to the synthesis of compound 65, and the corresponding intermediate 65-1 is replaced by 77-1.
  • the synthesis of compound 78 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by compound 72-1.
  • the synthesis of compound 79 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediate 1-5 is replaced by 68-1.
  • the synthesis of compound 80 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 68-1 and 80-1.
  • the synthesis of compound 81 refers to the synthesis of compound 1-11 and compound 5, and the corresponding intermediates 1-5 and 5-1 are replaced by 68-1 and 6-1.
  • the synthesis of compound 83 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 70-1 and 80-1.
  • the synthesis of compound 84 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 70-1 and 84-1.
  • the synthesis of compound 85 refers to the synthesis of compound 1-9 and compound 21, and the corresponding intermediates 1-5 and 1-8 are replaced by 70-1 and 85-1.
  • the synthesis of compound 86 refers to the synthesis of compound 65, and the corresponding intermediates 65-1 and 1-8 are replaced by 70-1 and 85-1.
  • the synthesis of compound 87 refers to the synthesis of compound 65, and the corresponding intermediates 65-1 and 1-8 are replaced by 72-1 and 85-1.
  • the synthesis of compound 88 refers to the synthesis of compound 65, and the corresponding intermediates 65-1 and 1-8 are replaced by 68-1 and 85-1.
  • Compound 90 was synthesized with reference to compound 65, and the corresponding intermediates 65-1 and 1-8 were replaced by 74-1 and 85-1.
  • intermediate 93-7 refers to 1-8; dissolve compound 93-8 (2.0g, mmol) in 45mL methanol and 15mL water, add lithium hydroxide monohydrate (523mg, 12.46mmol), and react at room temperature for 2h; monitor the raw materials After the reaction is completed, add 1M HCl to adjust the pH to 9.0, add ethyl acetate for extraction (50mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride (50mL ⁇ 2), dry over anhydrous sodium sulfate, and rotary evaporate to remove the solvent to obtain a white solid. 93-9, used directly for the next step.
  • Dissolve compound 93-10 (800 mg, 1.45 mmol) in 20 mL tetrahydrofuran and 10 mL water, add Oxone (1.0 g, 2.91 mmol), react at room temperature for 30 min, add an appropriate amount of water to dilute, extract with dichloromethane (30 mL ⁇ 2), and combine Dichloromethane, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a white solid 93-11, which was directly used in the next step.
  • ESI-MS m/z 496.2[M+H] +
  • Compound 100 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 100-1 and 100-2.
  • Compound 102 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 102-1 and 102-2.
  • Compound 104 was synthesized with reference to compound 103, and the corresponding intermediates 93-1 and 93-12 were replaced by 104-1 and 104-2.
  • Compound 106 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 106-1 and 106-2.
  • Compound 110 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-12 were replaced by 110-1 and 110-2.
  • Compound 120 was synthesized with reference to compound 93, and the corresponding intermediates 93-1 and 93-6 were replaced by 120-1 and 120-2.
  • Compound 122 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 122-1, 122-2 and 122-3.
  • Compound 123 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 123-1, 123-2 and 123-3.
  • Compound 124 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6, 93-12 and 93-3 were replaced by 124-1, 124-2, 124-3 and 124-4.
  • Compound 125 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6, 93-12 and 93-3 were replaced by 125-1, 125-2, 125-3 and 125-4.
  • Compound 126 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6, 93-12 and 93-3 were replaced by 126-1, 126-2, 126-3 and 126-4.
  • Compound 127 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6, 93-12 and 93-3 were replaced by 127-1, 127-2, 127-3 and 127-4.
  • Compound 129 was synthesized with reference to compound 93, and the corresponding intermediates 93-6, 93-12 and 93-3 were replaced by 129-1, 129-2 and 129-3.
  • Compound 131 was synthesized with reference to compound 93, and the corresponding intermediates 93-6, 93-12 and 93-3 were replaced by 131-1, 131-2 and 131-3.
  • Compound 132 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 132-1 and 132-2.
  • Compound 134 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 134-1 and 134-2.
  • Compound 136 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 136-1 and 136-2.
  • Compound 137 was synthesized with reference to compound 93, and the corresponding intermediates 93-6 and 93-3 were replaced by 137-1 and 137-2.
  • Compound 138 was synthesized with reference to compound 93, and the corresponding intermediates 93-6, 93-3 and 93-12 were replaced by 138-1, 138-2 and 138-3.
  • Compound 139 was synthesized with reference to compound 93, and the corresponding intermediates 93-6, 93-3 and 93-12 were replaced by 139-1, 139-2 and 139-3.
  • Compound 140 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 140-1, 140-2 and 140-3.
  • Compound 141 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 141-1, 141-2 and 141-3.
  • Compound 142 was synthesized with reference to compound 93, and the corresponding intermediates 93-1, 93-6 and 93-12 were replaced by 142-1, 142-2 and 142-3.
  • Compound 146 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-15 were replaced by 146-1 and 146-2.
  • Compound 147 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-15 were replaced by 147-1 and 147-2.
  • Compound 148 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-15 were replaced by 148-1 and 148-2.
  • Compound 149 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-15 were replaced by 149-1 and 149-2.
  • Compound 150 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-6 were replaced by 150-1 and 150-2.
  • Compound 151 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-6 were replaced by 151-1 and 151-2.
  • Compound 152 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-6 were replaced by 152-1 and 152-2.
  • Compound 153 was synthesized with reference to compound 143, and the corresponding intermediates 143-9, 143-6 and 143-15 were replaced by 153-1, 153-2 and 153-3.
  • Compound 154 was synthesized with reference to compound 143, and the corresponding intermediates 143-9, 143-6 and 143-15 were replaced by 154-1, 154-2 and 154-3.
  • Compound 158 was synthesized with reference to compound 143, and the corresponding intermediates 143-9, 143-3 and 143-15 were replaced by 158-1, 158-2 and 158-3.
  • Compound 159 was synthesized with reference to compound 143, and the corresponding intermediates 143-3 and 143-15 were replaced by 159-1 and 159-2.
  • Compound 160 was synthesized with reference to compound 143, and the corresponding intermediates 143-9, 143-3 and 143-15 were replaced by 160-1, 160-2 and 160-3.
  • compound 161 refers to compound 143, and the corresponding intermediates 143-9 and 143-3 are replaced by 161-1 and 161-2.
  • Compound 162 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-3 were replaced by 162-1 and 162-2.
  • Compound 164 was synthesized with reference to compound 143, and the corresponding intermediates 143-9 and 143-3 were replaced by 164-1 and 164-2.
  • compound 165 refers to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 are replaced by 68-1 and 165-1.
  • Compound 166 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 166-1.
  • Compound 167 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 167-1.
  • Compound 168 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 168-1.
  • the synthesis method refers to the synthesis of compound 5, except that compound 172-1 is used to replace compound 5-1 in Example 5 to obtain compound 172.
  • the synthesis method refers to the synthesis of compound 5, except that compound 173-1 is used to replace compound 5-1 in Example 5 to obtain compound 173.
  • the synthesis method refers to the synthesis of compound 12, except that compound 173 is used to replace compound 9 in Example 12 to obtain compound 174.
  • the synthesis method refers to the synthesis of compound 5, except that compound 175-1 is used to replace compound 5-1 in Example 5 to obtain compound 175.
  • the synthesis method refers to the synthesis of compound 5, except that compound 176-1 is used to replace compound 5-1 in Example 5 to obtain compound 176.
  • the synthesis method refers to the synthesis of compound 12, except that compound 177 is used to replace compound 9 in Example 12 to obtain compound 178.
  • Compound 180 was synthesized with reference to compound 1 and compound 5, and the corresponding intermediates 1-5 and 5-1 were replaced by 68-1 and 176-1.
  • the synthesis of compound 181 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 181-2, 181-1 and 181-3.
  • the synthesis of compound 182 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 182-2, 181-1 and 181-3.
  • the synthesis of compound 183 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 183-2, 183-1 and 183-3.
  • the synthesis of compound 184 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 184-2, 184-1 and 184-3.
  • the synthesis of compound 185 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-8 and 5-1 are replaced by 185-1 and 184-3.
  • the synthesis of compound 186 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 184-2, 186-1 and 184-3.
  • the synthesis of compound 187 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 187-2, 187-1 and 187-3.
  • the synthesis of compound 188 refers to the synthesis of compound 1 and compound 5, and the corresponding intermediates 1-5, 1-8 and 5-1 are replaced by 187-2, 188-1 and 187-3.
  • Recombinant SARS-CoV-2 3CL protease (final concentration 30 nM) was mixed with serial concentrations of compound in 80 ⁇ L assay buffer (50 mM Tris–HCl, pH 7.3, 1 mM EDTA) and incubated for 10 min. Start the reaction by adding 40 ⁇ L of fluorogenic substrate to a final concentration of 20 ⁇ M. Afterwards, a fluorescence signal (emission) was generated at 320nm (excitation)/405nm and measured immediately with a Bio-Tek Synergy4 plate reader every 30 seconds for 10 minutes. Compared with the blank control of adding DMSO, calculate the Vmax of the reaction of adding different concentrations of compounds to obtain the IC50 curve.
  • assay buffer 50 mM Tris–HCl, pH 7.3, 1 mM EDTA
  • the anti-SARS-CoV-2 3CL protease IC50 was measured at 9 concentrations and 3 independent experiments.
  • the anti-SARS-CoV-2 3CL protease inhibitory activity is expressed by three concentration gradient inhibition rate levels. All experimental data were analyzed using GraphPad Prism software. The experimental results are shown in Table 2.
  • African green monkey kidney Vero E6 cells were obtained from the American Type Culture Collection Center (ATCC) and stored in DMEM medium containing 10% fetal bovine serum (FBS), 1% antibiotic/antifungal (Gibco Invitrogen), at 37 degrees Place in a humidified incubator containing 5% CO2.
  • the strain used for the initial screening test was clinically isolated SARS-CoV-2 (nCoV-2019BetaCoV/Wuhan/WIV04/2019).
  • the EC 50 test strain is the Delta strain. Test experiments were conducted in the P3 laboratory.
  • SARS-CoV-2 EC50 of compound 9 1.088 ⁇ M.
  • Anti-SARS-CoV-2 (Vero E6 cells) activity data of some other compounds at 1 ⁇ M level
  • test results show that some compounds have the ability to inhibit the activity of SARS-CoV-2.
  • the SARS-CoV-2 EC50 of compound 9 is 1.088 ⁇ M.
  • Compound 5, compound 19 and compound 116 have an inhibitory rate of SARS-CoV-2 greater than 98% at a concentration of 10 ⁇ M.
  • mice There were 6 male ICR (SD-1) mice, weighing 22-25g. Randomly divide into 2 groups, 3 animals in each group. Administer according to gavage and intravenous regimens respectively.
  • the subjects were fasted for 12 h before the experiment and had free access to water. Eat at the same time 2 hours after administration.
  • the vehicle solution for intragastric administration was DMSO/0.5% HPMC (5/95, v/v) and was prepared to the final concentration.
  • the intravenous administration vehicle protocol is DMSO/EtOH/PEG300/0.9% NaCl (5/5/40/50, v/v/v/v) to prepare to the final concentration.
  • the evaluation scheme of compound 69 is consistent with that of compound 68, and the experimental results are shown in Table 7 and Table 8. Among them, the oral exposure of compound 68 is 1288h*ng/mL, the injection exposure is 6178h*ng/mL, and the oral bioavailability is 10.4%. The oral exposure of compound 69 was 615h*ng/mL, the injection exposure was 3484h*ng/mL, and the oral bioavailability was 8.83%.
  • the evaluation of the FIPV replication inhibitory activity of the compounds of the present invention is carried out through the CPE method for the first screening, the qPCR method for the second screening, and the IFA method for the third screening.
  • the test cells used for the initial screening of the CPE method are CRFK cells, the virus infection dose is 1000TCID 50 , the drug action dose is 30 ⁇ m, and the drug action time is 72 hours.
  • the second screening test conditions of the qPCR method are the same as the CPE method, and the test concentration is 50 ⁇ m.
  • the third screening test conditions of the IFA method are the same as the CPE method.
  • the initial test concentration is 30 ⁇ m, and the test concentration gradient is 20 ⁇ m, 10 ⁇ m, 5 ⁇ m, 2.5 ⁇ m, 1.25 ⁇ m, and 0.1625 ⁇ m.

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Abstract

L'invention concerne un composé peptidomimétique, un procédé de préparation, une composition pharmaceutique et une utilisation associée. Plus particulièrement, l'invention concerne un composé peptidomimétique représenté par la formule générale (I), ou un racémate, un isomère cis-trans, un énantiomère, un diastéréomère ou un mélange de ceux-ci, ou un métabolite de celui-ci, ou un sel, solvate ou promédicament pharmaceutiquement acceptable de celui-ci. L'invention concerne également une utilisation du composé dans l'inhibition de coronavirus notamment le SARS-CoV-2, le SARS-CoV, le MERS-CoV, le FIPV, ainsi que d'autres comprenant des virus à ARN tels que EV71, EV68 et norovirus.
PCT/CN2023/084172 2022-04-01 2023-03-27 Composé peptidomimétique, procédé de préparation, composition pharmaceutique et utilisation associée Ceased WO2023185763A1 (fr)

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JP2023000996A (ja) * 2021-06-18 2023-01-04 ラクオリア創薬株式会社 プロテアーゼ阻害剤としてのケトアミド誘導体

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