WO2023048151A1 - Peptide cyclique présentant une activité inhibitrice de la prolifération virale - Google Patents

Peptide cyclique présentant une activité inhibitrice de la prolifération virale Download PDF

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WO2023048151A1
WO2023048151A1 PCT/JP2022/035043 JP2022035043W WO2023048151A1 WO 2023048151 A1 WO2023048151 A1 WO 2023048151A1 JP 2022035043 W JP2022035043 W JP 2022035043W WO 2023048151 A1 WO2023048151 A1 WO 2023048151A1
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substituted
hydrogen atom
group
unsubstituted alkyl
unsubstituted
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PCT/JP2022/035043
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Japanese (ja)
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祥正 川口
太一 上田
徹 山田
善史 楠本
将之 佐野
孝央 佐名木
晋輔 鳥羽
道仁 佐々木
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塩野義製薬株式会社
国立大学法人北海道大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the present invention relates to a compound exhibiting coronavirus growth-inhibitory activity and/or a pharmaceutical composition containing a compound exhibiting coronavirus growth-inhibitory activity.
  • the coronavirus which belongs to the subfamily Orthocoronavirus subfamily, Coronaviridae, order of the Nidoviridae, has a genome size of about 30 kilobases, and is the largest single-stranded + stranded RNA virus among known RNA viruses.
  • Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, and there are two types of coronaviruses that infect humans: Alphacoronavirus (HCoV-229E, HCoV-229E, HCoV -NL63) and five members of the genus Betacoronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2).
  • HCoV-229E HCoV-NL63, HCoV-HKU1, HCoV-OC43
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome coronavirus
  • SARS-CoV novel coronavirus
  • Non-Patent Document 1 The novel coronavirus disease (COVID-19) that broke out in Wuhan, China in December 2019 spread rapidly throughout the international community, and was declared a pandemic by the WHO on March 11, 2020. As of September 10, 2021, the number of confirmed infected people will reach 220 million or more, and the number of deaths will reach 4.6 million or more (Non-Patent Document 1). Droplet infection, contact infection and aerosol infection have been reported as the main infection routes of SARS-CoV-2. (Non-Patent Document 2). The incubation period is about 2 to 14 days, and cold-like symptoms such as fever (87.9%), dry cough (67.7%), malaise (38.1%), and phlegm (33.4%) are typical. (Non-Patent Document 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, etc. occurs. Multiple organ failure such as renal failure and liver failure has also been reported.
  • the spike (S) protein expressed on the surface of the coronavirus is an essential molecule for virus entry into cells.
  • the S protein is composed of S1 and S2 regions, and the S1 region is an essential region for binding to angiotensin-converting enzyme 2 (ACE2) expressed on the surface of host cells.
  • the S2 region contains multiple cleavage sites by host proteases such as transmembrane protease, serine 2 (TMPRSS2), furin and cathepsin, and is an essential region for the fusion of the viral membrane and the cell membrane.
  • TMPRSS2 transmembrane protease
  • furin and cathepsin is an essential region for the fusion of the viral membrane and the cell membrane.
  • EUA Emergency Use Authorization
  • the object of the present invention is to provide a compound having coronavirus growth inhibitory activity.
  • the present invention provides a cyclic peptide having an antiviral effect, particularly a coronavirus growth inhibitory effect, and a medicament containing the cyclic peptide.
  • R 1 is a hydrogen atom or substituted or unsubstituted alkyl
  • R 2 is a hydrogen atom, a group represented by the formula: —(CR 2a R 2b )t 2 —Y 2 , or substituted or unsubstituted alkyl
  • R 1 and R 2 together with the attached nitrogen and carbon atoms may form a substituted or unsubstituted non-aromatic heterocyclic ring
  • R 2' is a hydrogen atom or substituted or unsubstituted alkyl
  • R 3 is a hydrogen atom or substituted or unsubstituted alkyl
  • R 4 is substituted or unsubstituted alkyl
  • R 4' is a hydrogen atom
  • R 5 is a hydrogen atom
  • R 6 is a substituted or unsubstituted alkyl or a group represented by the formula: —(CR 6a R 6b )t 6 —
  • R 1 is a hydrogen atom or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof.
  • R 2 is a hydrogen atom of the formula: —(CH 2 )t 2 —Y 2 (where t 2 is 1 or 2, and Y 2 is substituent group a (substituent group a: hydroxy, carboxy and carbamoyl), an aromatic carbocyclic group substituted with one or more substituents, an unsubstituted aromatic carbocyclic group, an unsubstituted aromatic heterocyclic group, or an unsubstituted unsubstituted aromatic carbocyclic group), or alkyl substituted with one or more substituents selected from substituent group b (substituent group b: hydroxy, carboxy, carbamoyl, amino and guanidino) or non substituted alkyl;
  • substituent group b substituted with one or more substituents selected from substituent group b (substituent group b: hydroxy
  • R 6 is unsubstituted alkyl or formula: —(CH 2 )t 6 —Y 6 (where t 6 is 1 or 2 and Y 6 is a substituent group d (substituent Group d: an aromatic or unsubstituted aromatic carbocyclic group substituted with one or more substituents selected from hydroxy, carboxy and carbamoyl), an unsubstituted non-aromatic carbocyclic group, or unsubstituted aromatic heterocyclic group), The compound according to any one of the above items (1) to (7), or a pharmaceutically acceptable salt thereof, wherein R 6' is a hydrogen atom.
  • R 8 is of the formula: -(CH 2 )t 8 -Y 8 (where t 8 is 1 or 2, Y 8 is substituent group e (substituent group e: hydroxy, carboxy and carbamoyl) substituted with one or more substituents selected from aromatic carbocyclic group or unsubstituted aromatic carbocyclic group, unsubstituted non-aromatic carbocyclic group, or unsubstituted aromatic heterocyclic ring.
  • R 10 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f (substituent group f: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 ) t 10 -Y 10 (where t 10 is 1 or 2, and Y 10 is one or more substituents selected from Substituent Group g (Substituent Group g: hydroxy, carboxy and carbamoyl); substituted aromatic carbocyclic group or unsubstituted aromatic carbocyclic group, unsubstituted non-aromatic carbocyclic group, or unsubstituted aromatic heterocyclic group),
  • R 10′ is a hydrogen
  • R 12 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group h (substituent group h: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 ) t 12 -Y 12 (where t 12 is 1 or 2 and Y 12 is one or more substituents selected from substituent group i (substituent group i: hydroxy, carboxy and carbamoyl); a substituted aromatic carbocyclic group or unsubstituted aromatic carbocyclic group, or an unsubstituted non-aromatic carbocyclic group),
  • R 12' is a hydrogen atom or unsubstituted alkyl
  • R 15 is an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group j (substituent group j: carboxy, carbamoyl, amino and guanidino), or the formula:-( CH 2 )t 15 -Y 15 (where t 15 is 1 or 2 and Y 15 is one or more substituents selected from Substituent Group k (Substituent Group k: hydroxy, carboxy and carbamoyl) an aromatic carbocyclic group substituted with a group, or an unsubstituted aromatic heterocyclic group),
  • R 15' is a hydrogen atom or unsubstituted alkyl.
  • R 17 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from Substituent Group l (Substituent Group l: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 ) t 17 -Y 17 (where t 17 is 1 or 2, and Y 17 is one or more substituents selected from substituent group m (substituent group m: hydroxy, carboxy and carbamoyl); or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (16), which is a substituted aromatic carbocyclic group).
  • R 19 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group n (substituent group n: carboxy, carbamoyl and hydroxy); The compound according to any one of the above items (1) to (17), or a pharmaceutically acceptable salt thereof, wherein R 19′ is a hydrogen atom or unsubstituted alkyl.
  • R 21 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group o (substituent group o: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 ) t 21 -Y 21 (where t 21 is 1 or 2, and Y 21 is one or more substituents selected from substituent group p (substituent group p: hydroxy, carboxy and carbamoyl); or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (18), which is a substituted aromatic carbocyclic group).
  • each R U1 is independently a hydrogen atom or a substituted or unsubstituted alkyl; each R U2 is independently a hydrogen atom or a substituted or unsubstituted alkyl; or R U1 and R U2 may each independently, together with the attached nitrogen and carbon atoms, form a substituted or unsubstituted non-aromatic heterocyclic ring;
  • Each R U3 is independently a hydrogen atom, a substituted or unsubstituted alkyl, or a formula: -(C U3a R U3b )t U3 -Y U3 (wherein R U3a and R U3b are each independently , hydrogen atom, halogen, or substituted or unsubsti
  • each R U1 is independently a hydrogen atom or an unsubstituted alkyl; each R U2 is independently a hydrogen atom; or R U1 and R U2 may each independently be taken together with the attached nitrogen and carbon atoms to form an unsubstituted non-aromatic heterocyclic ring; each R U3 is independently substituted with one or more substituents selected from a hydrogen atom and substituent group q (substituent group q: hydroxy, carboxy, carbamoyl, amino, guanidino, acetamido, sulfanyl and methylsulfanyl); or of the formula: —(CH 2 )t U3 —Y U3 , where t U3 is 1 or 2; Y U3 is a substituent group r (substituent group r: hydroxy, carboxy and an aromatic carbocyclic group substituted with one or more substituents selected from carbamo
  • a pharmaceutical composition for preventing and/or treating coronavirus infection containing the compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (23) above.
  • the growth inhibition method according to item (31) above, wherein the coronavirus is SARS-CoV-2.
  • a method for treating and/or preventing coronavirus infection which comprises administering the compound according to any one of the above items (1) to (23), or a pharmaceutically acceptable salt thereof.
  • the preventive and/or therapeutic method according to item (34) above, wherein the coronavirus infection is novel coronavirus infection (COVID-19).
  • the preventive and/or therapeutic method according to item (34) above, wherein the coronavirus infection is an infection caused by SARS-CoV-2.
  • the coronavirus is an alphacoronavirus and/or a betacoronavirus.
  • the coronavirus is SARS-CoV-2.
  • the compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (23) for manufacturing a therapeutic and/or prophylactic agent for coronavirus infection.
  • the coronavirus infection is novel coronavirus infection (COVID-19).
  • the coronavirus infection is an infection caused by SARS-CoV-2.
  • the compound according to the present invention has coronavirus growth inhibitory activity and is useful as a therapeutic and/or preventive agent for coronavirus infections. Preferably, it is useful as a therapeutic and/or prophylactic agent for infections caused by SARS-CoV-2.
  • Figure 1 shows SARS-CoV-2 MA-P10 infected mice (inoculated with 2 ⁇ 10 2 TCID 50 /50 ⁇ L), vehicle and the compound of the present invention 1.5 mg / kg, 0.5 mg / kg, 0.15 mg / kg. Shown are lung virus titers 48 hours post-infection when dosed 24 hours and 36 hours post-infection.
  • the vertical axis indicates the intrapulmonary virus titer (TCID 50 /mL).
  • the horizontal axis indicates each administration group.
  • Figure 2 shows SARS-CoV-2 MA-P10 infected mice (inoculated with 2 ⁇ 10 2 TCID 50 /50 ⁇ L), 24 hours after infection (QD ) or 24 hours and 36 hours after infection (BID), the survival rate up to 10 days after infection is shown.
  • the vertical axis indicates survival rate (%).
  • the horizontal axis indicates the number of days after infection.
  • Figure 3 shows SARS-CoV-2 MA-P10 infected mice (inoculated with 2 ⁇ 10 2 TCID 50 /50 ⁇ L), 24 hours after infection (QD ) or 24 hours and 36 hours after infection (BID), body weight changes up to 10 days after infection.
  • the vertical axis indicates body weight variation (%) when the body weight on the day of infection is taken as 100%.
  • the horizontal axis indicates the number of days after infection.
  • Halogen includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Fluorine and chlorine atoms are particularly preferred.
  • Alkyl includes a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms. do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • alkenyl refers to a group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, still more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. straight or branched chain hydrocarbon groups.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl. More preferred embodiments include ethenyl, n-propenyl, and the like.
  • alkynyl refers to a group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. It includes straight chain or branched hydrocarbon groups. Furthermore, it may have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Preferred embodiments of "alkynyl” include ethynyl, propynyl, butynyl and pentynyl. More preferred embodiments include ethynyl, propynyl and the like.
  • aromatic carbocyclic group means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthryl, phenanthryl and the like. A preferred embodiment of the "aromatic carbocyclic group” is phenyl.
  • Aromatic carbocyclic ring means a ring derived from the above “aromatic carbocyclic group”.
  • Non-aromatic carbocyclic group means a monocyclic or bicyclic or more ring saturated cyclic hydrocarbon group or cyclic non-aromatic unsaturated hydrocarbon group.
  • the "non-aromatic carbocyclic group” having two or more rings also includes a monocyclic or non-aromatic carbocyclic group having two or more rings condensed with the above “aromatic carbocyclic group”.
  • the “non-aromatic carbocyclic group” also includes a group that forms a bridge or a spiro ring as shown below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
  • the bicyclic or more non-aromatic carbocyclic group preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms.
  • Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • Non-aromatic carbocyclic ring means a ring derived from the above “non-aromatic carbocyclic group”.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms which are the same or different and are arbitrarily selected from O, S and N in the ring. do.
  • An aromatic heterocyclic group with two or more rings includes a monocyclic or an aromatic heterocyclic group with two or more rings condensed with the ring in the above "aromatic carbocyclic group", and the bond is Either ring may have it.
  • the monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered.
  • Five-membered aromatic heterocyclic groups include, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
  • the bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered.
  • indolyl isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl.
  • Ryl benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. are mentioned.
  • 9-membered aromatic heterocyclic groups include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazo lyl, benzotriazolyl, benzofuranyl, imidazopyridyl, triazolopyridyl, oxazolopyridyl, thiazolopyridyl and the like.
  • Ten-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, and the like.
  • the aromatic heterocyclic group having 3 or more rings is preferably 13- to 15-membered. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.
  • Aromatic heterocyclic ring means a ring derived from the above “aromatic heterocyclic group”.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more non-aromatic cyclic group having one or more heteroatoms in the ring that are the same or different and arbitrarily selected from O, S and N.
  • a bicyclic or more non-aromatic heterocyclic group is a monocyclic or bicyclic or more non-aromatic heterocyclic group, the above "aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and / Or each ring in the "aromatic heterocyclic group” is condensed, furthermore, the ring in the above "aromatic heterocyclic group” is condensed to a monocyclic or bicyclic or more non-aromatic carbocyclic group and the bond may be in any ring.
  • non-aromatic heterocyclic group also includes a group that forms a bridge or a spiro ring as shown below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3- to 8-membered, more preferably 5- or 6-membered.
  • Three-membered non-aromatic heterocyclic groups include, for example, thiiranyl, oxiranyl, aziridinyl.
  • Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl.
  • Five-membered non-aromatic heterocyclic groups include, for example, oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, and the like. mentioned.
  • 6-membered non-aromatic heterocyclic groups include, for example, dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl and the like.
  • Seven-membered non-aromatic heterocyclic groups include, for example, hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl.
  • the non-aromatic heterocyclic group having two or more rings is preferably 8- to 20-membered, more preferably 8- to 13-membered, still more preferably 8- to 10-membered. Examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
  • Non-aromatic heterocyclic ring means a ring derived from the above “non-aromatic heterocyclic group”.
  • Non-aromatic heterocyclic ring formed by R 1 and R 2 together with the attached nitrogen atom and carbon atom include, for example, the following rings.
  • Trialkylsilyl means a group in which the above three “alkyl” are bonded to a silicon atom.
  • the three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.
  • “Fat-modified residue” means a residue of an organic compound having a molecular weight of 1-1000, including an amino acid residue and/or a chemically modified organic residue.
  • Such amino acid residues include natural amino acids and non-natural amino acids.
  • Non-natural amino acids include commercially available non-natural amino acids and non-natural amino acids that can be synthesized from natural amino acids by conventional methods.
  • substituent group ⁇ means “optionally substituted with one or more groups selected from substituent group ⁇ ".
  • substituent group ⁇ means “optionally substituted with one or more groups selected from substituent group ⁇ ". The same applies to the substituent groups ⁇ , ⁇ , ⁇ ', and the like.
  • a carbon atom at any position may be bonded to one or more groups selected from Substituent Group A below.
  • Substituent group A halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl, alkyloxy optionally substituted with substituent group ⁇ , alkenyloxy optionally substituted with substituent group ⁇ , alkynyloxy optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylcarbonyloxy optionally substituted with substituent group ⁇ , alkenylcarbonyloxy optionally substituted with substituent group ⁇ , alky
  • Substituent group ⁇ halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
  • Substituent group ⁇ halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkynyl, alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylsulfanyl optionally substituted with substituent group ⁇ , alkenylsulfanyl optionally substituted with substituent group ⁇ , alkynylsulfanyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally substituted with substituent group ⁇ , alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇ , alken
  • Substituent Group ⁇ Substituent Group ⁇ , alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.
  • Substituent group ⁇ ' Substituent group ⁇ and oxo.
  • substituents on the ring of the "aromatic carbocyclic ring” and “aromatic heterocyclic ring” of the "substituted aromatic carbocyclic group” and “substituted aromatic heterocyclic group” include the following substituent group B. be done. An atom at any position on the ring may be bonded to one or more groups selected from Substituent Group B below.
  • Substituent group B halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , alkynyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkyloxy, alkenyloxy optionally substituted with substituent group ⁇ , alkynyloxy optionally substituted with substituent group ⁇ , alkylcarbonyloxy optionally substituted with substituent group ⁇ , substituent group ⁇ alkenylcarbonyloxy
  • Substituted non-aromatic carbocyclic group substituted non-aromatic heterocyclic group
  • non-aromatic heterocyclic group substituted non-aromatic heterocyclic group
  • non-aromatic heterocyclic ring formed by R 1 and R 2 together with the nitrogen atom and carbon atom to which they are attached
  • substituents on the ring of "aromatic carbocyclic ring” and “non-aromatic heterocyclic ring” include the following substituent group C. An atom at any position on the ring may be bonded to one or more groups selected from Substituent Group C below.
  • Substituent Group C Substituent Group B and oxo.
  • non-aromatic carbocycle and “non-aromatic heterocycle” are substituted with “oxo” they mean rings in which two hydrogen atoms on the carbon atoms are substituted as follows.
  • R 4′ , R 5 , R 8′ , R 13′ , R 14 , R 16 , R 17′ , R 18 , R 20 and R 21′ are hydrogen atoms; be.
  • R 1 includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as A-1).
  • R 1 includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as A-2).
  • R 1 includes a hydrogen atom (hereinafter referred to as A-3).
  • R 2 is a hydrogen atom, a group represented by the formula: —(CR 2a R 2b )t 2 —Y 2 (where each symbol has the same meaning as in item (1) above), or a substituted or unsubstituted alkyl (hereinafter referred to as B-1).
  • R 2 is a hydrogen atom of the formula: -(CH 2 )t 2 -Y 2 (where t 2 is 1 or 2, Y 2 is a substituent group a (substituent group a: hydroxy, carboxy and carbamoyl) substituted with one or more substituents, an aromatic carbocyclic group or an unsubstituted aromatic carbocyclic group, an unsubstituted aromatic heterocyclic group, or an unsubstituted non-aromatic carbocyclic ring formula group), or alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group b (substituent group b: hydroxy, carboxy, carbamoyl, amino and guanidino).
  • R 2 is a hydrogen atom of the formula: —(CH 2 )—Y 2 (wherein Y 2 is one or more substituents selected from Substituent Group a (Substituent Group a: hydroxy, carboxy and carbamoyl) substituted aromatic carbocyclic group or unsubstituted aromatic carbocyclic group, unsubstituted aromatic heterocyclic group, or unsubstituted non-aromatic carbocyclic group), or a substituent Examples include alkyl or unsubstituted alkyl substituted with one or more substituents selected from group b (substituent group b: hydroxy, carboxy, carbamoyl, amino and guanidino) (hereinafter referred to as B-3).
  • R 2 is represented by the formula: —(CH 2 )—Y 2 (wherein Y 2 is substituted with one or more substituents selected from Substituent Group a (Substituent Group a: hydroxy, carboxy and carbamoyl) (hereinafter, B- 4).
  • R 2 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group b (substituent group b: hydroxy, carboxy, carbamoyl, amino and guanidino) (hereinafter referred to as B- 5).
  • R 2 is represented by the formula: —(CH 2 )—Y 2 (wherein Y 2 is substituted with one or more substituents selected from Substituent Group a (Substituent Group a: hydroxy, carboxy and carbamoyl) or an unsubstituted aromatic carbocyclic group) (hereinafter referred to as B-6).
  • R 2 includes a group represented by the formula: -(CH 2 )-Y 2 (wherein Y 2 is an unsubstituted aromatic carbocyclic group) (hereinafter referred to as B-7).
  • R 2′ includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as C-1).
  • R 2′ includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as C-2).
  • R 2′ includes a hydrogen atom (hereinafter referred to as C-3).
  • R 2′ includes unsubstituted alkyl (hereinafter referred to as C-4).
  • R 1 and R 2 together with the attached nitrogen and carbon atoms form a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as D-1).
  • R 1 and R 2 together with the attached nitrogen and carbon atoms form an unsubstituted, non-aromatic heterocyclic ring (hereinafter referred to as D-2).
  • R 1 and R 2 together with the attached nitrogen and carbon atoms form a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring (hereinafter referred to as D-3).
  • R 1 and R 2 together with the attached nitrogen and carbon atoms form an unsubstituted 5-membered non-aromatic heterocyclic ring (hereinafter referred to as D-4).
  • R 3 includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as E-1).
  • E-2 includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as E-2).
  • E-3 hydrogen atom
  • E-4 includes unsubstituted alkyl (hereinafter referred to as E-4).
  • R 4 includes substituted or unsubstituted alkyl (hereinafter referred to as F-1).
  • R 4 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group c (substituent group c: carboxy, hydroxy and carbamoyl) (hereinafter referred to as F-2).
  • R 4 includes alkyl substituted with one or more substituents selected from substituent group c (substituent group c: carboxy, hydroxy and carbamoyl) (hereinafter referred to as F-3).
  • R 4 includes unsubstituted alkyl (hereinafter referred to as F-4).
  • R 6 is a substituted or unsubstituted alkyl, or a group represented by the formula: —(CR 6a R 6b )t 6 —Y 6 (wherein each symbol has the same meaning as in item (1) above) ( hereinafter referred to as G-1).
  • R 6 is unsubstituted alkyl or formula: -(CH 2 )t 6 -Y 6 (where t 6 is 1 or 2 and Y 6 is substituent group d (substituent group d: hydroxy, carboxy and carbamoyl), an aromatic or unsubstituted aromatic carbocyclic group, an unsubstituted non-aromatic carbocyclic group, or an unsubstituted aromatic heterocyclic group) (hereinafter referred to as G-2).
  • R 6 is unsubstituted alkyl, or formula: —(CH 2 )—Y 6 (wherein Y 6 is one or more selected from substituent group d (substituent group d: hydroxy, carboxy and carbamoyl)
  • Y 6 is one or more selected from substituent group d (substituent group d: hydroxy, carboxy and carbamoyl)
  • An aromatic carbocyclic group or an unsubstituted aromatic carbocyclic group substituted with a substituent of, an unsubstituted non-aromatic carbocyclic group, or an unsubstituted aromatic heterocyclic group) hereinafter referred to as G-3.
  • R 6 includes unsubstituted alkyl (hereinafter referred to as G-4).
  • R 6 is the formula: —(CH 2 )—Y 6 (wherein Y 6 is substituted with one or more substituents selected from Substituent Group d (Substituent Group d: hydroxy, carboxy and carbamoyl) (hereinafter referred to as G- 5).
  • R 6 is the formula: —(CH 2 )—Y 6 (wherein Y 6 is substituted with one or more substituents selected from Substituent Group d (Substituent Group d: hydroxy, carboxy and carbamoyl) or an unsubstituted aromatic carbocyclic group) (hereinafter referred to as G-6).
  • R 6 includes a group represented by the formula: --(CH 2 )--Y 6 (here, Y 6 is an unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as G-7).
  • R 6 includes a group represented by the formula: --(CH 2 )--Y 6 (here, Y 6 is an unsubstituted aromatic heterocyclic group) (hereinafter referred to as G-8).
  • R 6' includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as H-1).
  • R 6' includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as H-2).
  • R 6' includes a hydrogen atom (hereinafter referred to as H-3).
  • R 6′ includes unsubstituted alkyl (hereinafter referred to as H-4).
  • R 7 includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as I-1).
  • R7 includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as I-2).
  • R 7 includes a hydrogen atom (hereinafter referred to as I-3).
  • R 7 includes unsubstituted alkyl (hereinafter referred to as I-4).
  • R 8 examples include groups represented by the formula: -(CR 8a R 8b )t 8 -Y 8 (where each symbol has the same meaning as in item (1) above) (hereinafter referred to as J-1).
  • R 8 is of the formula: -(CH 2 )t 8 -Y 8 (where t 8 is 1 or 2 and Y 8 is Substituent Group e (Substituent Group e: hydroxy, carboxy and carbamoyl) an aromatic carbocyclic group or an unsubstituted aromatic carbocyclic group substituted with one or more substituents selected from, an unsubstituted non-aromatic carbocyclic group, or an unsubstituted aromatic heterocyclic group) (hereinafter referred to as J-2).
  • R 8 has the formula: —(CH 2 )—Y 8 (wherein Y 8 is substituted with one or more substituents selected from Substituent Group e (Substituent Group e: hydroxy, carboxy and carbamoyl) (hereinafter, J- 3).
  • R 8 has the formula: —(CH 2 )—Y 8 (wherein Y 8 is substituted with one or more substituents selected from Substituent Group e (Substituent Group e: hydroxy, carboxy and carbamoyl) (hereinafter referred to as J-4).
  • R 8 includes a group represented by the formula: --(CH 2 )--Y 8 (wherein Y 8 is an unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as J-5).
  • R 8 includes a group represented by the formula: --(CH 2 )--Y 8 (here, Y 8 is an unsubstituted aromatic heterocyclic group) (hereinafter referred to as J-6).
  • R 9 includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as K-1).
  • R 9 includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as K-2).
  • R 9 includes a hydrogen atom (hereinafter referred to as K-3).
  • R 9 includes unsubstituted alkyl (hereinafter referred to as K-4).
  • R 10 is a substituted or unsubstituted alkyl, or a group represented by the formula: —(CR 10a R 10b )t 10 —Y 10 (wherein each symbol has the same meaning as in item (1) above) ( hereinafter referred to as L-1).
  • R 10 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f (substituent group f: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 )t 10 —Y 10 (where t 10 is 1 or 2 and Y 10 is substituted with one or more substituents selected from Substituent Group g (Substituent Group g: hydroxy, carboxy and carbamoyl) (hereinafter, L-2 ).
  • R 10 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f (substituent group f: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 )—Y 10 (here, Y 10 is an aromatic carbocyclic group substituted with one or more substituents selected from substituent group g (substituent group g: hydroxy, carboxy and carbamoyl) or an unsubstituted aromatic carbon (hereinafter referred to as L-3).
  • R 10 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f (substituent group f: carboxy, carbamoyl and hydroxy) (hereinafter referred to as L-4) .
  • R 10 is represented by the formula: —(CH 2 )—Y 10 (wherein Y 10 is substituted with one or more substituents selected from Substituent Group g (Substituent Group g: hydroxy, carboxy and carbamoyl); (Hereinafter, L- 5).
  • R 10 includes alkyl substituted with one or more substituents selected from substituent group f (substituent group f: carboxy, carbamoyl and hydroxy) (hereinafter referred to as L-6).
  • R 10 includes unsubstituted alkyl (hereinafter referred to as L-7).
  • R 10 is represented by the formula: —(CH 2 )—Y 10 (wherein Y 10 is substituted with one or more substituents selected from Substituent Group g (Substituent Group g: hydroxy, carboxy and carbamoyl); or an unsubstituted aromatic carbocyclic group) (hereinafter referred to as L-8).
  • R 10 includes a group represented by the formula: —(CH 2 )—Y 10 (here, Y 10 is an unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as L-9).
  • R 10 includes a group represented by the formula: —(CH 2 )—Y 10 (here, Y 10 is an unsubstituted aromatic heterocyclic group) (hereinafter referred to as L-10).
  • R 10′ includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as M-1).
  • R 10′ includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as M-2).
  • R 10′ includes a hydrogen atom (referred to as M-3).
  • R 10′ includes unsubstituted alkyl (hereinafter referred to as M-4).
  • R 11 includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as N-1).
  • R 11 includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as N-2).
  • R 11 includes a hydrogen atom (hereinafter referred to as N-3).
  • R 11 includes unsubstituted alkyl (hereinafter referred to as N-4).
  • R 12 includes a substituted or unsubstituted alkyl, or a group represented by the formula: —(CR 12a R 12b )t 12 —Y 12 (wherein each symbol has the same meaning as in item (1) above) ( hereinafter referred to as O-1).
  • R 12 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group h (substituent group h: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 )t 12 —Y 12 (where t 12 is 1 or 2 and Y 12 is substituted with one or more substituents selected from substituent group i (substituent group i: hydroxy, carboxy and carbamoyl) (hereinafter referred to as O-2).
  • R 12 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group h (substituent group h: carboxy, carbamoyl and hydroxy), or formula: -(CH 2 )-Y 12 (here, Y 12 is an aromatic carbocyclic group substituted with one or more substituents selected from substituent group i (substituent group i: hydroxy, carboxy and carbamoyl) or an unsubstituted aromatic carbon cyclic group or unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as O-3).
  • R 12 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group h (substituent group h: carboxy, carbamoyl and hydroxy) (hereinafter referred to as O-4) .
  • R 12 is of the formula: —(CH 2 )—Y 12 (wherein Y 12 is substituted with one or more substituents selected from Substituent Group i (Substituent Group i: hydroxy, carboxy and carbamoyl) (hereinafter referred to as O-5).
  • R 12 includes alkyl substituted with one or more substituents selected from substituent group h (substituent group h: carboxy, carbamoyl and hydroxy) (hereinafter referred to as O-6).
  • R 12 includes unsubstituted alkyl (hereinafter referred to as O-7).
  • R 12 is represented by the formula: —(CH 2 )—Y 12 (wherein Y 12 is substituted with one or more substituents selected from Substituent Group i (Substituent Group i: hydroxy, carboxy and carbamoyl) (hereinafter referred to as O-8).
  • R 12 includes a group represented by the formula: --(CH 2 )--Y 12 (wherein Y 12 is an unsubstituted non-aromatic carbocyclic group) (hereinafter referred to as O-9).
  • R 12' includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as P-1).
  • R 12' includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as P-2).
  • R 12′ includes a hydrogen atom (hereinafter referred to as P-3).
  • R 12′ includes unsubstituted alkyl (hereinafter referred to as P-4).
  • R 13 includes substituted or unsubstituted alkyl (hereinafter referred to as Q-1).
  • R 13 includes unsubstituted alkyl (hereinafter referred to as Q-2).
  • R 15 includes a substituted or unsubstituted alkyl, or a group represented by the formula: —(CR 15a R 15b )t 15 —Y 15 (wherein each symbol has the same meaning as in item (1) above) ( hereinafter referred to as R-1).
  • R 15 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group j (substituent group j: carboxy, carbamoyl, amino and guanidino), or formula: —(CH 2 ) t 15 -Y 15 (where t 15 is 1 or 2 and Y 15 is substituted with one or more substituents selected from substituent group k (substituent group k: hydroxy, carboxy and carbamoyl) or an unsubstituted aromatic heterocyclic group) (hereinafter referred to as R-2).
  • R 15 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group j (substituent group j: carboxy, carbamoyl, amino and guanidino), or formula: —(CH 2 ) —Y 15 (where Y 15 is an aromatic carbocyclic group substituted with one or more substituents selected from substituent group k (substituent group k: hydroxy, carboxy and carbamoyl), or non- substituted aromatic heterocyclic group) (hereinafter referred to as R-3).
  • R 15 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group j (substituent group j: carboxy, carbamoyl, amino and guanidino) (hereinafter R-4 and do).
  • R 15 is represented by the formula: —(CH 2 )—Y 15 (wherein Y 15 is substituted with one or more substituents selected from substituent group k (substituent group k: hydroxy, carboxy and carbamoyl); or an unsubstituted aromatic heterocyclic group) (hereinafter referred to as R-5).
  • R 15 includes alkyl substituted with one or more substituents selected from substituent group j (substituent group j: carboxy, carbamoyl, amino and guanidino) (hereinafter referred to as R-6).
  • R 15 includes unsubstituted alkyl (hereinafter referred to as R-7).
  • R 15 is represented by the formula: —(CH 2 )—Y 15 (wherein Y 15 is substituted with one or more substituents selected from substituent group k (substituent group k: hydroxy, carboxy and carbamoyl); aromatic carbocyclic group) (hereinafter referred to as R-8).
  • R 15 includes a group represented by the formula: —(CH 2 )—Y 15 (here, Y 15 is an unsubstituted aromatic heterocyclic group) (hereinafter referred to as R-9).
  • R 15′ includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as S-1).
  • R 15′ includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as S-2).
  • R 15′ includes a hydrogen atom (hereinafter referred to as S-3).
  • R 15′ includes unsubstituted alkyl (hereinafter referred to as S-4).
  • R 17 is a substituted or unsubstituted alkyl or a group represented by the formula: -(CR 17a R 17b )t 17 -Y 17 (hereinafter referred to as T-1).
  • R 17 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from Substituent Group 1 (Substituent Group 1: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 )t 17 -Y 17 (where t 17 is 1 or 2 and Y 17 is substituted with one or more substituents selected from substituent group m (substituent group m: hydroxy, carboxy and carbamoyl) aromatic carbocyclic group) (hereinafter referred to as T-2).
  • R 17 is an alkyl or unsubstituted alkyl substituted with one or more substituents selected from Substituent Group 1 (Substituent Group 1: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 )—Y 17 (here, Y 17 is an aromatic carbocyclic group substituted with one or more substituents selected from substituent group m (substituent group m: hydroxy, carboxy and carbamoyl)) (hereinafter referred to as T-3).
  • R 17 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from Substituent Group 1 (Substituent Group 1: carboxy, carbamoyl and hydroxy) (hereinafter referred to as T-4). .
  • R 17 has the formula: —(CH 2 )—Y 17 (wherein Y 17 is substituted with one or more substituents selected from substituent group m (substituent group m: hydroxy, carboxy and carbamoyl); aromatic carbocyclic group) (hereinafter referred to as T-5).
  • R 17 includes alkyl substituted with one or more substituents selected from Substituent Group 1 (Substituent Group 1: carboxy, carbamoyl and hydroxy) (hereinafter referred to as T-6). R 17 includes unsubstituted alkyl (hereinafter referred to as T-7).
  • R 19 includes substituted or unsubstituted alkyl (hereinafter referred to as U-1).
  • R 19 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group n (substituent group n: carboxy, carbamoyl and hydroxy) (hereinafter referred to as U-2) .
  • R 19 includes alkyl substituted with one or more substituents selected from substituent group n (substituent group n: carboxy, carbamoyl and hydroxy) (hereinafter referred to as U-3).
  • R 19 includes unsubstituted alkyl (hereinafter referred to as U-4).
  • R 19′ includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as V-1).
  • R 19′ includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as V-2).
  • R 19′ includes a hydrogen atom (hereinafter referred to as V-3).
  • R 19′ includes unsubstituted alkyl (hereinafter referred to as V-4).
  • R 21 is a substituted or unsubstituted alkyl or a group represented by the formula: -(CR 21a R 21b )t 21 -Y 21 (hereinafter referred to as W-1).
  • R 21 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group o (substituent group o: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 )t 21 —Y 21 (where t 21 is 1 or 2 and Y 21 is substituted with one or more substituents selected from substituent group p (substituent group p: hydroxy, carboxy and carbamoyl) aromatic carbocyclic group) (hereinafter referred to as W-2).
  • R 21 is alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group o (substituent group o: carboxy, carbamoyl and hydroxy), or formula: —(CH 2 )—Y 21 (here, Y 21 is an aromatic carbocyclic group substituted with one or more substituents selected from substituent group p (substituent group p: hydroxy, carboxy and carbamoyl)) (hereinafter referred to as W-3).
  • R 21 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group o (substituent group o: carboxy, carbamoyl and hydroxy) (hereinafter referred to as W-4) .
  • R 21 is substituted with one or more substituents selected from the formula: —(CH 2 )—Y 21 (wherein Y 21 is substituted with one or more substituents selected from substituent group p (substituent group p: hydroxy, carboxy and carbamoyl) aromatic carbocyclic group) (hereinafter referred to as W-5).
  • R 21 includes alkyl substituted with one or more substituents selected from substituent group o (substituent group o: carboxy, carbamoyl and hydroxy) (hereinafter referred to as W-6).
  • R 21 includes unsubstituted alkyl (hereinafter referred to as W-7).
  • R 22 includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as X-1).
  • R 22 includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as X-2).
  • R 22 includes a hydrogen atom (hereinafter referred to as X-3).
  • R 22 includes unsubstituted alkyl (hereinafter referred to as X-4).
  • each R U1 is independently a hydrogen atom or a substituted or unsubstituted alkyl
  • each R U2 is independently a hydrogen atom or a substituted or unsubstituted alkyl; or R U1 and R U2 may each independently, together with the attached nitrogen and carbon atoms, form a substituted or unsubstituted non-aromatic heterocyclic ring
  • Each R U3 is independently a hydrogen atom, a substituted or unsubstituted alkyl, or a formula: -(C U3a R U3b )t U3 -Y U3 (wherein R U3a and R U3b are each independently , hydrogen atom, halogen, or substituted or unsubstituted alkyl; t U3 is an integer from 1 to 3; Y U3 is a substituted or unsubstituted aromatic carbocyclic group, substituted or unsub
  • X includes —C( ⁇ O)NH 2 (hereinafter referred to as Y-2).
  • X is the formula (L1): (In the formula, each R U1 is independently a hydrogen atom or an unsubstituted alkyl; each R U2 is independently a hydrogen atom; or R U1 and R U2 may each independently be taken together with the attached nitrogen and carbon atoms to form an unsubstituted non-aromatic heterocyclic ring; each R U3 is independently substituted with one or more substituents selected from a hydrogen atom and substituent group q (substituent group q: hydroxy, carboxy, carbamoyl, amino, guanidino, acetamido, sulfanyl and methylsulfanyl); or of the formula: —(CH 2 )t U3 —Y U3 , where t U3 is 1 or 2; Y U3 is a substituent group r (substituent group r: hydroxy, carboxy and an aromatic carbocyclic group substituted with one or more substituents selected from carbamoy
  • X is the formula (L1): (In the formula, each R U1 is independently a hydrogen atom or a substituted or unsubstituted alkyl; each R U2 is independently a hydrogen atom or a substituted or unsubstituted alkyl; or R U1 and R U2 may each independently, together with the attached nitrogen and carbon atoms, form a substituted or unsubstituted non-aromatic heterocyclic ring; each R U3 is independently substituted with one or more substituents selected from a hydrogen atom and substituent group q (substituent group q: hydroxy, carboxy, carbamoyl, amino, guanidino, acetamido, sulfanyl and methylsulfanyl); or of the formula: —(CH 2 )t U3 —Y U3 , where t U3 is 1 or 2; Y U3 is a substituent group r (substituent group r: hydroxy, carboxy and
  • X is of formula (L2):
  • each R V1 is independently a hydrogen atom or a substituted or unsubstituted alkyl
  • each R V2 is independently a hydrogen atom or a substituted or unsubstituted alkyl; or R V1 and R V2 may each independently be taken together with the attached nitrogen and carbon atoms to form an unsubstituted non-aromatic heterocyclic ring
  • R V3 is each independently substituted with one or more substituents selected from a hydrogen atom and substituent group q (substituent group q: hydroxy, carboxy, carbamoyl, amino, guanidino, acetamido, sulfanyl and methylsulfanyl); or of the formula: —(CH 2 )t V3 —Y V3 (where t V3 is 1 or 2; Y V3 is a substituent group r (substituent group r: hydroxy, carboxy and an aromatic carbocycl
  • X is the formula (L3): each R P1 is independently a hydrogen atom or a substituted or unsubstituted alkyl; each R P2 is independently a hydrogen atom or a substituted or unsubstituted alkyl; or R P1 and R P2 may each independently be taken together with the attached nitrogen and carbon atoms to form an unsubstituted non-aromatic heterocyclic ring; R P3 is each independently substituted with one or more substituents selected from a hydrogen atom and substituent group q (substituent group q: hydroxy, carboxy, carbamoyl, amino, guanidino, acetamido, sulfanyl and methylsulfanyl); or an alkyl of the formula: —(CH 2 )t P3 —Y P3 where t P3 is 1 or 2; Y P3 is a substituent group r (substituent group r: hydroxy, carboxy and an aromatic carbocyclic
  • each R X1 is independently a hydrogen atom or a substituted or unsubstituted alkyl; each R X2 is independently a hydrogen atom or a substituted or unsubstituted alkyl; or R X1 and R X2 may each independently be taken together with the attached nitrogen and carbon atoms to form an unsubstituted non-aromatic heterocyclic ring; each R X3 is independently substituted with one or more substituents selected from a hydrogen atom and substituent group q (substituent group q: hydroxy, carboxy, carbamoyl, amino, guanidino, acetamido, sulfanyl and methylsulfanyl); or of the formula: —(CH 2 )t X3 —Y X3 , where t X3 is 1 or 2; Y X3 is a substituent group r (substituent group r:
  • -L- includes -S- or -SO 2 - (hereinafter referred to as Z-1).
  • -L- includes -S- (hereinafter referred to as Z-2).
  • R 4′ , R 5 , R 8′ , R 13′ , R 14 , R 16 , R 17′ , R 18 , R 20 and R 21′ are hydrogen atoms;
  • R 1 is (A-3);
  • R 2 is (B-7);
  • R 2' is (C-3);
  • R 3 is (E-3);
  • R 4 is (F-4);
  • R 6 is (G-8);
  • R 6' is (H-3);
  • R 7 is (I-3);
  • R 8 is (J-6);
  • R 9 is (K-3);
  • R 10 is (L-7);
  • R 10' is (M-3);
  • R 11 is (N-3);
  • R 12 is (O-8);
  • R 12' is (P-3);
  • R 13 is (Q-2);
  • R 15 is (R-6);
  • R 15' is (S-3);
  • R 17 is (T-5);
  • R 19 is (U-4);
  • R 19' is (V-3);
  • R 21 is (W-5);
  • the compounds of formula (I) are not limited to any particular isomer, but include all possible isomers (e.g. keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers , rotamers, etc.), racemates or mixtures thereof.
  • One or more hydrogen, carbon and/or other atoms of the compounds of Formula (I) may be substituted with isotopes of hydrogen, carbon and/or other atoms, respectively.
  • isotopes include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O , 31 P, 32 P, 35 S, 18 F , 123 I and Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included, as is 36 Cl.
  • the compounds of formula (I) also include such isotopically substituted compounds.
  • the isotopically substituted compounds are also useful as pharmaceuticals and include all radiolabeled compounds of formula (I).
  • a "radiolabeling method" for producing the "radiolabel” is also encompassed by the present invention, and the “radiolabel” is useful as a research and/or diagnostic tool in metabolic pharmacokinetic studies, binding assays. is.
  • Radiolabeled compounds of formula (I) can be prepared by methods well known in the art.
  • a tritium-labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) through a catalytic dehalogenation reaction using tritium.
  • This method comprises reacting a suitably halogenated precursor of a compound of formula (I) with tritium gas in the presence or absence of a base, in the presence of a suitable catalyst such as Pd/C.
  • a suitable catalyst such as Pd/C.
  • 14 C-labeled compounds can be prepared by using starting materials with a 14 C carbon.
  • Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, the compound represented by formula (I) and an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid) , trifluoroacetic acid, citric acid, lactic acid, tarta
  • the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form solvates (e.g., hydrates, etc.), co-crystals and/or crystal polymorphs, and the present invention also includes such various solvates, co-crystals and polymorphs.
  • a "solvate” may be coordinated with any number of solvent molecules (eg, water molecules, etc.) to a compound of formula (I).
  • solvent molecules eg, water molecules, etc.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb water, attach adsorbed water, or form a hydrate. Also, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form polymorphs.
  • “Co-crystal” means that a compound or salt of formula (I) and a counter molecule are present in the same crystal lattice, and may contain any number
  • the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs.
  • Prodrugs are derivatives of the compounds of the invention having groups which are chemically or metabolically degradable, and which, upon solvolysis or under physiological conditions, become pharmaceutically active compounds of the invention in vivo.
  • a prodrug is a compound that undergoes enzymatic oxidation, reduction, hydrolysis, or the like under physiological conditions in vivo and is converted into a compound represented by formula (I), or a compound that is hydrolyzed by gastric acid or the like to form formula (I). It includes compounds that are converted to the indicated compounds, and the like. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". A prodrug may itself have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • a compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with sulfonyl anhydrides and mixed anhydrides or by using condensing agents are exemplified.
  • coronaviruses include coronaviruses that infect humans. Coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2.
  • coronaviruses include alphacoronaviruses and/or betacoronaviruses, more preferably betacoronaviruses, and even more preferably sarvecoviruses.
  • alphacoronaviruses include HCoV-229E and HCoV-NL63. Particularly preferred is HCoV-229E.
  • betacoronaviruses include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. HCoV-OC43 or SARS-CoV-2 is preferred, and SARS-CoV-2 is particularly preferred.
  • the betacoronavirus includes betacoronavirus A strain ( ⁇ -coronavirus lineage A), betacoronavirus B strain ( ⁇ -coronavirus lineage B), and betacoronavirus C strain ( ⁇ -coronavirus lineage C). are mentioned. More preferred are ⁇ -coronavirus lineage A and ⁇ -coronavirus lineage B, particularly preferably ⁇ -coronavirus lineage B.
  • Betacoronavirus lineage A includes, for example, HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43.
  • Betacoronavirus lineage B includes, for example, SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2.
  • the beta-coronavirus lineage B preferably includes MERS-CoV.
  • coronaviruses include HCoV-229E, HCoV-OC43 and/or SARS-CoV-2, particularly preferably SARS-CoV-2. It is generally known that viruses mutate during repeated proliferation and infection.
  • the above coronaviruses include not only mutants known in the art but also mutants that will appear in the future, as long as the compounds according to the present invention are strains capable of exhibiting coronavirus 3CL protease inhibitory activity.
  • Known variants of SARS-CoV-2 include, for example, the variants used in the examples herein.
  • Coronavirus infections include infections by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and/or SARS-CoV-2.
  • infections caused by HCoV-229E, HCoV-OC43 and/or SARS-CoV-2 particularly preferably infections caused by SARS-CoV-2.
  • a novel coronavirus infection (COVID-19) is particularly preferred as the coronavirus infection.
  • the compounds represented by formula (I) according to the present invention can be produced, for example, by the general synthetic methods shown below. Extraction, purification, and the like may be carried out in the same manner as in ordinary organic chemistry and peptide synthesis experiments.
  • General Synthetic Method 1 (Wherein, Resin is a resin, -Xa- is -O-, -NH-, etc., PG is a protecting group, is a building block such as an amino acid. )
  • Synthesis can be carried out by the above route based on solid-phase peptide synthesis method (Fmoc method) using Fmoc group as a protective group for ⁇ -amino group. i.e.
  • the compound of the present invention is useful as a medicine, and preferably has one or more of the following excellent characteristics.
  • a) It has a weak inhibitory effect on CYP enzymes eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • coronavirus growth inhibitory activity it has high coronavirus growth inhibitory activity.
  • it has high coronavirus growth inhibitory activity under the addition of human serum (HS) or human serum albumin (HSA).
  • HS human serum
  • HSA human serum albumin
  • examples of coronavirus growth inhibitors include an embodiment in which EC50 is 10 ⁇ M or less, preferably 1 ⁇ M or less, more preferably 100 nM or less in the neutralizing activity evaluation test (Test Example 1) described later.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally.
  • parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear and intravaginal administration.
  • internal solid preparations e.g., tablets, powders, granules, capsules, pills, films, etc.
  • internal liquid preparations e.g., suspensions, emulsions, elixirs, syrups, etc.
  • Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and powders and granules may be dry syrups.
  • the capsules may be soft capsules, microcapsules or sustained release capsules.
  • injections In the case of parenteral administration, injections, drops, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, Any commonly used dosage form such as ointments, plasters, jellies, creams, patches, poultices, powders for external use, suppositories, etc.) can be suitably administered. Injections may be emulsions such as O/W, W/O, O/W/O and W/O/W types.
  • a pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, if necessary. Furthermore, by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention, the pharmaceutical composition can be used as a pharmaceutical composition for children, the elderly, critically ill patients, or for surgery. You can also For example, a pediatric pharmaceutical composition can be used for neonates (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old) infants (1 to 7 years old), children (7 to 15 years old) or 15 Patients between the ages of 18 and 18 can be administered. For example, geriatric pharmaceutical compositions may be administered to patients 65 years of age or older.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, body weight, type and degree of disease, administration route, etc., but when administered orally, it is usually 0.05 to 100 mg / kg/day, preferably within the range of 0.1 to 10 mg/kg/day. In the case of parenteral administration, it is generally 0.005 to 10 mg/kg/day, preferably 0.01 to 5 mg/kg/day, although it varies greatly depending on the route of administration. It may be administered once to several times a day.
  • the compound of the present invention is, for example, a therapeutic drug for other novel coronavirus infections (COVID-19) (the therapeutic drug is not approved It may also be used in combination with drugs received, and drugs under development or to be developed) (hereinafter referred to as concomitant drugs).
  • the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different times.
  • the compound of the present invention and the concomitant drug may be administered as two or more formulations containing each active ingredient, or may be administered as a single formulation containing those active ingredients.
  • the dosage of the concomitant drug can be appropriately selected based on the clinically used dosage.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • Synthesis of cyclic peptide (I-0071) Synthesis of the cyclic peptide (I-0071) was performed according to the above synthesis scheme based on General Synthesis Method 1 and by the following procedure.
  • Step 1 Using Rink Amide Protide resin (CEM, 277 mg, 0.18 mmol/g, 0.05 mmol), a peptide chain elongation reaction was carried out using a Biotage automatic peptide synthesizer Syro I (TM). A resin (equivalent to 0.05 mmol) was added to a reaction vessel, and amino acids were sequentially linked in DMF according to the following 1) to 6) to obtain a peptide intermediate resin x1. 1) Arg: 4 equivalents of Fmoc-Arg(Pbf)-OH, 4 equivalents of HATU and 8 equivalents of DIPEA were added to the resin and reacted at 75°C for 20 minutes.
  • CEM Resink Amide Protide resin
  • TM Biotage automatic peptide synthesizer
  • Third step Transfer the obtained intermediate resin (x2, equivalent to 0.05 mmol) to a tube container with a filter, TFA/TIS/DODT/water (92.5:2.5:2.5:2 by volume .5) was added and reacted at room temperature for 1.5 hours. After removing the resin by filtration, the filtrate was added to 40 ml of MTBE/hexane (1:1 by volume) and the crude cleaved peptide was precipitated by centrifugation. After removing the supernatant, the precipitate was washed twice with MTBE and dried under reduced pressure with a vacuum pump to obtain 85 mg of crude peptide intermediate x3.
  • Synthesis of cyclic peptide (I-0042) Synthesis of the cyclic peptide (I-0042) was performed according to the above synthesis scheme based on General Synthesis Method 2 and by the following procedure.
  • Step 2 500 ml of DCM, Pd(PPh 3 ) 4 (3.47 g, 3 mmol), and phenylsilane (6.49 g, 60 mmol) are added to the resulting intermediate resin (y1, equivalent to 12 mmol) under nitrogen atmosphere. Stir at room temperature for 2 hours. After the solution was discharged, the residue was washed with DMF, MeOH and MTBE, and dried under reduced pressure with a vacuum pump to obtain 21.1 g of peptide intermediate resin y2.
  • 3rd step A peptide chain elongation reaction was carried out using the intermediate resin y2.
  • An intermediate resin y2 equivalent to 0.05 mmol was added to a reaction vessel of an automatic peptide synthesizer Liberty PRIME (TM) manufactured by CEM, and amino acids were sequentially linked in DMF according to the following 1) to 5) to form a peptide intermediate tree.
  • y3 was obtained.
  • 1) Arg: Fmoc-Arg(Pbf)-OH 5 equivalents, DIC 10 equivalents, Oxyma 5 equivalents were added to the resin and reacted at 60° C. for 10 minutes. After distilling off the reaction solution, the same reagent was added again and the reaction was carried out under the same conditions.
  • Synthesis of cyclic peptide (I-0037) Synthesis of the cyclic peptide (I-0037) was performed according to the above synthesis scheme based on General Synthesis Method 2 and by the following procedure.
  • Trp at the 13th residue 5 equivalents of Fmoc-Trp(Boc)-OH, 10 equivalents of DIC, and 5 equivalents of Oxyma were added to the resin and reacted at 105°C for 1 minute. After distilling off the reaction solution, the same reagent was added again and the reaction was carried out under the same conditions.
  • Other amino acids 5 equivalents of Fmoc-protected amino acid, 10 equivalents of DIC, 5 equivalents of Oxyma were added to the resin and reacted at 105°C for 1 minute.
  • 6) For deprotection of Fmoc group 25% pyrrolidine DMF solution was added to the resin and reacted at 110°C for 40 seconds.
  • Second step Subsequently, using an automatic peptide synthesizer Liberty PRIME (CEM), 5 equivalents of 2-chloroacetic acid, 10 equivalents of DIC, and 5 equivalents of Oxyma are added to the resin obtained (equivalent to 0.05 mmol), The reaction was carried out at 90°C for 2 minutes. After the resin was washed with DMF, it was taken out from the reaction vessel, further washed with MeOH and MTBE successively, and dried under reduced pressure with a vacuum pump to obtain a dried peptide intermediate resin.
  • CEM automatic peptide synthesizer Liberty PRIME
  • 3rd step The resulting intermediate resin (equivalent to 0.05 mmol) was transferred to a filter-equipped tube container and mixed with TFA/TIS/DODT/water (92.5:2.5:2.5:2 by volume ratio). 4 ml of 5) was added and reacted at room temperature for 1.5 hours. After removing the resin by filtration, the filtrate was added to 40 ml of MTBE/hexane (1:1 by volume) and the crude cleaved peptide was precipitated by centrifugation. After removing the supernatant, the precipitate was washed twice with MTBE and dried under reduced pressure with a vacuum pump to obtain 98 mg of crude peptide intermediate x.
  • Test Example 1 Neutralizing activity evaluation test using human ACE2- and TMPRSS2-expressing 293T cells (293T-AT cells) ⁇ Material> ⁇ 2% FBS in MEMs It was prepared by adding 10 mL of 8.5% NaHCO 3 , 20 mL of FBS, and 10 mL of L-Glutamine to 1000 mL of Minimum Essential Medium. - 293T-AT cells 2% FBS in MEM was adjusted to an appropriate cell number (1.5 x 10 5 cells/mL).
  • ⁇ Plate reader (Thermo Fisher, PerkinElmer, etc.) ⁇ MTT solution 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (Merck) dissolved in PBS to 5 ⁇ g/mL, 0.45 ⁇ m or 0.22 ⁇ m Filtered.
  • ⁇ Cell lysate (virus inactivation solution) Prepared by adding 50 mL Triton X, 4 mL hydrochloric acid (12 mol/L) in 500 mL isopropanol.
  • DMSO dimethyl sulfoxide
  • ⁇ Operation procedure> ⁇ Dilution and dispensing of test sample
  • the test sample was diluted in advance with DMSO or culture medium (2% FBS in MEM) to an appropriate concentration, and a 2- to 5-fold serial dilution series was prepared in a 96-well plate (50 ⁇ L/well).
  • ⁇ Dilution and dispensing of SARS-CoV-2 In advance, dilute SARS-CoV-2 to an appropriate concentration with culture medium (2% FBS in MEM), and divide 50 ⁇ L / well into a 96 well plate containing the test sample. and left at room temperature for 1 hour. Mixed with a plate mixer every 30 minutes.
  • Dilution and Dispensing of Cells 100 ⁇ L/well of cells prepared to an appropriate number of cells were dispensed into a 96-well plate containing test samples and viruses. Mixed with a plate mixer and cultured in a CO 2 incubator for 2-3 days. ⁇ Dispense of MTT solution and cell lysate The 96-well plate cultured for 2 to 3 days was observed with the naked eye and under a microscope to confirm the morphology of cells and the presence or absence of crystals. 30 ⁇ L of the MTT solution was dispensed into each well and cultured in a CO 2 incubator for 4 to 6 hours. 150 ⁇ L of the supernatant was removed from the plate so as not to absorb the cells.
  • EC50 was calculated from two points A-High (High OD, High conc.) and B-Low (Low OD, Low conc.) sandwiching the 50% OD value on the absorbance and drug concentration curve.
  • the EC50 values of the test substances determined by the MTT method are shown in the table below.
  • the compounds of the invention were tested essentially as described above. The results are shown below.
  • the EC50 value is "A” when less than 0.1 ⁇ M, "B” when 0.1 ⁇ M or more and less than 1 ⁇ M, and "C” when 1 ⁇ M or more and less than 20 ⁇ M.
  • Test Example 2 Neutralizing activity evaluation test using human TMPRSS2-expressing Vero E6 cells (Vero E6-T cells) ⁇ Material> ⁇ 2% FBS in MEMs It was prepared by adding 10 mL of 8.5% NaHCO 3 , 20 mL of FBS, and 10 mL of L-Glutamine to 1000 mL of Minimum Essential Medium. - Vero E6-T cells 2% FBS in MEM was adjusted to an appropriate cell number (1.5 x 105 cells/mL).
  • ⁇ Plate reader (Thermo Fisher, PerkinElmer, etc.) ⁇ MTT solution 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (Merck) dissolved in PBS to 5 ⁇ g/mL, 0.45 ⁇ m or 0.22 ⁇ m Filtered.
  • ⁇ Cell lysate (virus inactivation solution) Prepared by adding 50 mL Triton X, 4 mL hydrochloric acid (12 mol/L) in 500 mL isopropanol.
  • DMSO dimethyl sulfoxide
  • ⁇ Operation procedure> ⁇ Dilution and dispensing of test sample
  • the test sample was diluted in advance with DMSO or culture medium (2% FBS in MEM) to an appropriate concentration, and a 2- to 5-fold serial dilution series was prepared in a 96-well plate (50 ⁇ L/well).
  • ⁇ Dilution and dispensing of SARS-CoV-2 In advance, dilute SARS-CoV-2 to an appropriate concentration with culture medium (2% FBS in MEM), and divide 50 ⁇ L / well into a 96 well plate containing the test sample. and left at room temperature for 1 hour. Mixed with a plate mixer every 30 minutes.
  • Dilution and Dispensing of Cells 100 ⁇ L/well of cells prepared to an appropriate number of cells were dispensed into a 96-well plate containing test samples and viruses. Mixed with a plate mixer and cultured for 3 days in a CO2 incubator. ⁇ Dispense of MTT solution and cell lysate A 96-well plate cultured for 2 to 4 days was observed with the naked eye and under a microscope to confirm the morphology of cells and the presence or absence of crystals. 30 ⁇ L of the MTT solution was dispensed into each well and cultured in a CO 2 incubator for 4 to 6 hours. 150 ⁇ L of the supernatant was removed from the plate so as not to absorb the cells.
  • EC50 was calculated from two points A-High (High OD, High conc.) and B-Low (Low OD, Low conc.) sandwiching the 50% OD value on the absorbance and drug concentration curves.
  • Test Example 3 Efficacy evaluation using a SARS-CoV-2 infected mouse model (confirmation of virus growth inhibitory effect) (1) virus strain SARS-CoV-2 MA-P10 (based on JPN/TY/WK-521 strain, passaged 10 times in mouse lung) (2) Experimental animals BALB/c mice, female, 5 weeks old (3) Evaluation method SARS-CoV-2 MA-P10 was diluted with PBS(-) to 2 ⁇ 10 2 TCID 50 /50 ⁇ L, and 50 ⁇ L of the prepared virus solution was intranasally inoculated to mice. At 24 hours and 36 hours after infection, 50 ⁇ L of the compound of the present invention was intranasally administered to mice, and the lung virus titer was measured at 48 hours after infection.
  • Test Example 4 Efficacy evaluation using SARS-CoV-2 infected mouse model (confirmation of lethality suppressing effect) (1) virus strain SARS-CoV-2 MA-P10 (based on JPN/TY/WK-521 strain, passaged 10 times in mouse lung) (2) Experimental animals BALB/c mice, female, 30-50 weeks old (3) Evaluation method SARS-CoV-2 MA-P10 was diluted with PBS(-) to 2 ⁇ 10 2 TCID 50 /50 ⁇ L, and 50 ⁇ L of the prepared virus solution was intranasally inoculated to mice. At 24 hours after infection (QD) or 24 hours and 36 hours after infection (BID), 50 ⁇ L of the compound of the present invention was intranasally administered to mice.
  • QD 24 hours after infection
  • BID 24 hours and 36 hours after infection
  • the formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.
  • the compounds of the invention can be administered topically by any conventional route, especially enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injection solutions or suspensions.
  • it can be administered as a pharmaceutical composition in the form of lotions, gels, ointments or creams, or in nasal or suppository form.
  • a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable carrier or diluent can be prepared by mixing, mixing, It can be manufactured by a granulation or coating method.
  • oral compositions can be tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients.
  • injectable compositions may be in the form of solutions or suspensions, may be sterilized, and may contain preservatives, stabilizers, buffers and the like.
  • the compounds according to the present invention have coronavirus growth inhibitory activity and are considered useful as therapeutic and/or prophylactic agents for diseases or conditions associated with coronavirus.

Abstract

La présente invention concerne un composé présentant une activité inhibitrice de la prolifération du coronavirus et/ou une composition pharmaceutique contenant le composé présentant une activité inhibitrice de la prolifération du coronavirus. L'invention concerne également un composé représenté par (I) (dans la formule, R1 représente un atome d'hydrogène ou similaire, R2 représente un groupe ou similaire représenté par la formule : -(CR2aR2b)t2-Y2, R2' représente un atome d'hydrogène ou similaire, R3 représente un atome d'hydrogène ou similaire, R4 représente un groupe alkyle substitué ou non substitué, R4' représente un atome d'hydrogène, R5 représente un atome d'hydrogène, R6 représente un groupe ou similaire représenté par la formule : -(CR6aR6b)t6-Y6, R6' représente un atome d'hydrogène ou similaire, R7 représente un atome d'hydrogène ou similaire, R8 représente un groupe représenté par la formule : -(CR8aR8b)t8-Y8, R8' représente un atome d'hydrogène, R9 représente un atome d'hydrogène ou similaire, R10 représente un alkyle substitué ou non substitué ou similaire, R10' représente un atome d'hydrogène ou similaire, R11 représente un atome d'hydrogène ou similaire, R12 représente un groupe ou similaire représenté par la formule : -(CR12aR12b)t12-Y12, R12' représente un atome d'hydrogène ou similaire, R13 représente un alkyle substitué ou non substitué, R13' représente un atome d'hydrogène, R14 représente un atome d'hydrogène, R15 représente un alkyle substitué ou non substitué ou similaire, R15' représente un atome d'hydrogène ou similaire, R16 représente un atome d'hydrogène, R17 représente un groupe représenté par la formule : -(CR17aR17b)t17-Y17, R17' représente un atome d'hydrogène, R18 représente un atome d'hydrogène, R19 représente un alkyle substitué ou non substitué, R19' représente un atome d'hydrogène ou similaire, R20 représente un atome d'hydrogène, R21 représente un groupe ou similaire représenté par la formule : -(CR21aR21b)t21-Y21, R21' représente un atome d'hydrogène, R22 représente un atome d'hydrogène ou similaire, -L- représente -S- ou similaire et X représente un résidu modificateur des lipides), ou un sel pharmaceutiquement acceptable correspondant.
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