WO2023033098A1 - Bicyclic nitrogen-containing heterocyclic derivative having virus growth inhibitory activity and pharmaceutical composition containing same - Google Patents

Bicyclic nitrogen-containing heterocyclic derivative having virus growth inhibitory activity and pharmaceutical composition containing same Download PDF

Info

Publication number
WO2023033098A1
WO2023033098A1 PCT/JP2022/032906 JP2022032906W WO2023033098A1 WO 2023033098 A1 WO2023033098 A1 WO 2023033098A1 JP 2022032906 W JP2022032906 W JP 2022032906W WO 2023033098 A1 WO2023033098 A1 WO 2023033098A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
group
compound
aromatic heterocyclic
Prior art date
Application number
PCT/JP2022/032906
Other languages
French (fr)
Japanese (ja)
Inventor
佑斗 宇納
周平 吉田
健二 中原
栄一 児嶋
義一 佐々木
雅好 宮川
Original Assignee
塩野義製薬株式会社
国立大学法人北海道大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 塩野義製薬株式会社, 国立大学法人北海道大学 filed Critical 塩野義製薬株式会社
Publication of WO2023033098A1 publication Critical patent/WO2023033098A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to compounds exhibiting coronavirus 3CL protease inhibitory activity and pharmaceutical compositions containing compounds exhibiting coronavirus 3CL protease 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 August 22, 2022, the confirmed number of infected people reached 590 million or more, and the number of deaths reached 6,450,000 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 antiviral drug remdesivir, the anti-inflammatory drug dexamethasone, and the rheumatism drug baricitinib were approved as therapeutic agents for COVID-19, and anti-IL-6 receptor antibodies were approved in January 2022.
  • Tocilizumab has been additionally approved.
  • special approval was granted for the antibody cocktail therapy lonaprive
  • September 2021 special approval was granted for sotrovimab
  • December 2021 special approval was granted for molnupiravir.
  • Sufficient evidence has not been obtained regarding the efficacy and safety of these drugs. Therefore, there is an urgent need to create therapeutic drugs, especially oral drugs, against COVID-19.
  • Coronaviruses synthesize two polyproteins when they infect cells. These two polyproteins contain a structural protein for creating new virus particles, a replication complex for creating the viral genome, and two proteases. Protease plays an essential role in cleaving polyproteins synthesized from viruses and allowing each protein to function. Of the two proteases, 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 4). For COVID-19 therapeutics targeting 3CL protease, in June 2021, Pfizer completed a Phase 1b trial of Lufotrelvir (PF-07304814), a prodrug of PF-00835231, at ClinicalTrials.
  • PF-00835231 Lufotrelvir (PF-07304814): PF-07321332: In December 2021, PAXLOVIDTM, a nirmatrelvir (PF-07321332) tablet/ritonavir tablet, was approved for Emergency Use Authorization in the United States, and on February 10, 2022, Pakilovid® pack was launched in Japan. Approved as a special case.
  • Non-Patent Documents 5 to 15 Although compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 5 to 15, none of the documents describe or suggest compounds that are relevant to the present invention. Derivatives having P2X7 receptor inhibitory activity are disclosed in Patent Documents 1 and 2, but 3CL protease inhibitory activity and antiviral effects are neither described nor suggested.
  • An object of the present invention is to provide compounds having coronavirus 3CL protease inhibitory activity.
  • the present invention provides a compound having an antiviral effect, particularly a coronavirus growth-inhibiting effect, and a medicament containing the compound.
  • the present invention relates to the following.
  • R 4a and R 4b together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • R 5 and R 5′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl
  • R 6 is a hydrogen atom or substituted or unsubstituted alkyl
  • R 7 and R 7′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl
  • R 8 is a hydrogen atom or substituted or unsubstituted alkyl) (provided that the following compounds: ), or a pharmaceutically acceptable salt thereof.
  • (3') The compound or a pharmaceutically acceptable salt thereof according to item (1') or (2') above, wherein X is -NH-.
  • each R 4a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic carbocyclic group, above A compound or a pharmaceutically acceptable salt thereof according to any one of items (1′) to (10′).
  • (12') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1') to (11'), wherein R4b is a hydrogen atom.
  • R 4a and R 4b together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • R 5 and R 5′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl
  • R 6 is a hydrogen atom or substituted or unsubstituted alkyl
  • R 7 and R 7′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl
  • R 8 is a hydrogen atom or substituted or unsubstituted alkyl) (provided that the following compounds: ), or a pharmaceutically acceptable salt thereof.
  • Coronavirus 3CL characterized by administering the compound according to any one of the above items (1) to (13) and (1') to (14'), or a pharmaceutically acceptable salt thereof.
  • Coronavirus infection characterized by administering the compound according to any one of the above items (1) to (13) and (1′) to (14′), or a pharmaceutically acceptable salt thereof A method for treating and/or preventing disease.
  • the preventive and/or therapeutic method according to item (26) above, wherein the coronavirus infection is novel coronavirus infection (COVID-19).
  • the preventive and/or therapeutic method according to item (26) above, wherein the coronavirus infection is an infection caused by SARS-CoV-2.
  • coronavirus infection is novel coronavirus infection (COVID-19).
  • coronavirus infection is an infection caused by SARS-CoV-2.
  • the compound according to the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic and/or preventive agent for coronavirus infections.
  • 1 shows a molecular structure diagram of compound (I-0143). 1 shows a molecular structure diagram of compound (I-0252).
  • 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 chain or branched 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”.
  • the "substituted or unsubstituted non-aromatic heterocyclic ring formed by R 2b and R 4a together with the carbon atoms to which they are attached" includes, for example, the following ring. (Wherein, R x is a hydrogen atom, substituted or unsubstituted alkyl, etc., and other symbols are as defined above)
  • 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.
  • substituent group ⁇ means “optionally substituted with one or more groups selected from substituent group ⁇ ". The same applies to the substituent groups ⁇ , ⁇ and ⁇ '.
  • 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” include the following substituent group B. Any atom 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
  • 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.
  • Substituents of “substituted amino”, “substituted imino”, “substituted carbamoyl” and “substituted sulfamoyl” include Substituent Group D below. It may be substituted with one or two groups selected from Substituent Group D.
  • Substituent group D 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 ⁇ , alkeny
  • substituents of "substituted alkyl” for R 1 include: substituted or unsubstituted aromatic heterocyclic group; substituted or unsubstituted non-aromatic heterocyclic groups; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of "substituted alkyl” for R 1 include: substituted aromatic heterocyclic group (substituent: alkyloxy, alkyl) or unsubstituted aromatic heterocyclic group; substituted non-aromatic heterocyclic group (substituent: oxo) or unsubstituted non-aromatic heterocyclic group; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 1 include: substituted or unsubstituted alkyl; halogen; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 1 include: unsubstituted alkyl; halogen; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 3 include: substituted or unsubstituted alkyl; substituted or unsubstituted amino; halogen; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 3 include: substituted alkyl (substituent: halogen, non-aromatic carbocyclic group) or unsubstituted alkyl; substituted amino (substituent: alkyl) or unsubstituted amino; halogen; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" for R 3 include: halogen; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the “substituted or unsubstituted aromatic carbocyclic group” for R 3 include: substituted or unsubstituted alkyloxy; halogen; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the “substituted or unsubstituted aromatic carbocyclic group” for R 3 include: unsubstituted alkyloxy; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 2a include: halogen; Cyano; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 2a include: halogen; Cyano; substituted alkyl (substituent: alkyl-substituted aromatic heterocyclic group, halogen-substituted aromatic carbocyclic group, halogen-substituted aromatic carbocyclic oxy) or unsubstituted alkyl; substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 2a include: halogen; Cyano; Substituted alkyl (substituent: alkyl-substituted aromatic heterocyclic group, halogen-substituted aromatic carbocyclic group, hydroxyalkyl-substituted aromatic carbocyclic group, halogen-substituted aromatic carbocyclic oxy, halogen) or unsubstituted alkyl; substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the “substituted or unsubstituted alkyl” for R 2a include: halogen; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 4a include: halogen; substituted or unsubstituted aromatic carbocyclic oxy; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 4a include: halogen; unsubstituted aromatic carbocyclic oxy; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of "substituted or unsubstituted alkyl" for R 4a include: substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic groups; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; Cyano; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of "substituted or unsubstituted alkyl" for R 4a include: substituted aromatic carbocyclic group (substituent: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino (substituent: alkyl) or unsubstituted amino; halogen; unsubstituted non-aromatic carbocyclic group; substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy; an unsubstituted aromatic heterocyclic group; Cyano; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of "substituted or unsubstituted alkyl" for R 4a include: substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic groups; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; Cyano; hydroxy; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of "substituted or unsubstituted alkyl" for R 4a include: substituted aromatic carbocyclic group (substituent: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino (substituent: alkyl) or unsubstituted amino; halogen; unsubstituted non-aromatic carbocyclic group; substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy; an unsubstituted aromatic heterocyclic group; Cyano; hydroxy; is mentioned. It may be substituted with one or more groups selected from these.
  • Formula (I) For example, as an embodiment in a compound represented by formula (I'): (wherein R 1 , R 2a , R 3 and R 4a are the same as defined in (1) above). Preferred embodiments of R 1 , R 2a , R 3 and R 4a are shown below. As the compound represented by formula (I′), all combinations of specific examples shown below are exemplified.
  • R 1 is substituted alkyl, substituted alkenyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Examples include substituted non-aromatic carbocyclic groups, substituted or unsubstituted amino and substituted or unsubstituted carbamoyl (hereinafter referred to as A-1).
  • R 1 includes a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-2).
  • R 1 includes substituted alkyl (hereinafter referred to as A-3).
  • R 1 includes a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-4).
  • R 1 includes a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-5).
  • R 1 is one or more substituents selected from substituent group a (substituent group a: substituted or unsubstituted aromatic heterocyclic group; and substituted or unsubstituted non-aromatic heterocyclic group) Alkyl or unsubstituted alkyl substituted with, or an aromatic heterocyclic ring substituted with one or more substituents selected from substituent group b (substituent group b: substituted or unsubstituted alkyl; and halogen) and an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-6).
  • substituent group a substituted or unsubstituted aromatic heterocyclic group
  • substituted or unsubstituted non-aromatic heterocyclic group Alkyl or unsubstituted alkyl substituted with, or an aromatic heterocyclic ring substituted with one or more substituents selected from substituent group b (substituent group b: substituted or unsubstitute
  • R 1 is a substituent group a' (substituent group a': substituted aromatic heterocyclic group (substituents: alkyloxy and alkyl) or unsubstituted aromatic heterocyclic group; and substituted non-aromatic heterocyclic ring Alkyl or unsubstituted alkyl substituted with one or more substituents selected from the formula group (substituent: oxo) or unsubstituted non-aromatic heterocyclic group), or substituent group b' (substituent group b ': unsubstituted alkyl and halogen) or an aromatic heterocyclic group substituted with one or more substituents (hereinafter referred to as A-7).
  • A-7 aromatic heterocyclic group substituted with one or more substituents
  • R 1 is one or more substituents selected from substituent group a (substituent group a: substituted or unsubstituted aromatic heterocyclic group; and substituted or unsubstituted non-aromatic heterocyclic group) (hereinafter referred to as A-8).
  • R 1 is an aromatic heterocyclic group or an unsubstituted aromatic heterocyclic group substituted with one or more substituents selected from substituent group b (substituent group b: substituted or unsubstituted alkyl; and halogen)
  • a cyclic group can be mentioned (hereinafter referred to as A-9).
  • R 1 is a substituent group a' (substituent group a': substituted aromatic heterocyclic group (substituents: alkyloxy and alkyl) or unsubstituted aromatic heterocyclic group; and substituted non-aromatic heterocyclic group Alkyl or unsubstituted alkyl substituted with one or more substituents selected from a cyclic group (substituent: oxo) or unsubstituted unaromatic heterocyclic group) (hereinafter referred to as A-10) .
  • R 1 is an aromatic heterocyclic group or an unsubstituted aromatic heterocyclic group substituted with one or more substituents selected from substituent group b' (substituent group b': unsubstituted alkyl and halogen) (hereinafter referred to as A-11).
  • R 1 includes a halogen-substituted aromatic heterocyclic group (hereinafter referred to as A-12).
  • R 1 includes a 6-membered aromatic heterocyclic group substituted with halogen (hereinafter referred to as A-13).
  • R 1 includes alkyl substituted with a substituted aromatic heterocyclic group (substituent: alkyl) (hereinafter referred to as A-14).
  • R 1 includes alkyl substituted with a substituted 5-membered aromatic heterocyclic group (substituent: alkyl) (hereinafter referred to as A-15).
  • R 1 includes a 6-membered aromatic heterocyclic group substituted with halogen, or an alkyl substituted with a substituted 5-membered aromatic heterocyclic group (substituent: alkyl) (hereinafter referred to as A-16 and do).
  • R 2a is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted unsubstituted Examples thereof include aromatic heterocyclic groups, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl (hereinafter referred to as B-1).
  • R 2a includes a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as B-2).
  • R 2a is an aromatic substituted with one or more substituents selected from substituent group c (substituent group c: halogen; cyano; substituted or unsubstituted alkyl; and substituted or unsubstituted alkyloxy)
  • substituent group c substituted or unsubstituted alkyl
  • substituted or unsubstituted alkyloxy A carbocyclic group or an unsubstituted aromatic carbocyclic group can be mentioned (hereinafter referred to as B-3).
  • R 2a is a substituent group c' (substituent group c': halogen; cyano; substituted alkyl (substituent: alkyl-substituted aromatic heterocyclic group, halogen-substituted aromatic carbocyclic group, one or more selected from halogen-substituted aromatic carbocyclic oxy) or unsubstituted alkyl; and substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy)
  • B-4 an aromatic carbocyclic group substituted with a substituent or an unsubstituted aromatic carbocyclic group
  • R 2a includes a halogen-substituted aromatic carbocyclic group (hereinafter referred to as B-5).
  • R 2a includes an aromatic carbocyclic group substituted with 2 or more halogens (hereinafter referred to as B-6).
  • R 2a is 2 or more halogen; and substituted alkyl (substituents: alkyl-substituted aromatic heterocyclic group, halogen-substituted aromatic carbocyclic group, and halogen-substituted aromatic carbon ring oxy) or unsubstituted alkyl; (hereinafter referred to as B-7).
  • R 2a includes an aromatic carbocyclic group substituted with 3 or more halogens (hereinafter referred to as B-8).
  • R 2a includes halogen- and cyano-substituted aromatic carbocyclic groups (hereinafter referred to as B-9).
  • R 3 is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic carbon A cyclic group can be mentioned (hereinafter referred to as C-1).
  • R 3 includes a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as C-2).
  • R 3 is an aromatic heterocyclic substituted with one or more substituents selected from substituent group d (substituent group d: substituted or unsubstituted alkyl; substituted or unsubstituted amino; and halogen) group or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-3).
  • R 3 is substituent group d' (substituent group d': substituted alkyl (substituent: halogen and non-aromatic carbocyclic group) or unsubstituted alkyl; substituted amino (substituent: alkyl) or unsubstituted amino and halogen), or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-4).
  • R 3 includes an aromatic heterocyclic group substituted with alkyl and halogen or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-5).
  • R 3 includes an aromatic heterocyclic group substituted with alkyl and halogen (hereinafter referred to as C-6).
  • R 3 includes an aromatic heterocyclic group substituted with alkyl and halogen or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-7).
  • R 3 includes an aromatic heterocyclic group substituted with alkyl and halogen (hereinafter referred to as C-8).
  • R 3 includes a 9-membered aromatic heterocyclic group substituted with alkyl and halogen or an unsubstituted 9-membered aromatic heterocyclic group (hereinafter referred to as C-9).
  • R 3 includes a 9-membered aromatic heterocyclic group substituted with alkyl and halogen (hereinafter referred to as C-10).
  • R 3 includes indazolyl substituted with alkyl and halogen (hereinafter referred to as C-11).
  • R3 has the formula: (wherein R 3a is a hydrogen atom or halogen; R 3b is a substituted or unsubstituted alkyl) (hereinafter referred to as C-12).
  • R3 has the formula: (wherein R 3a is halogen; R 3b includes groups represented by substituted alkyl (substituent: halogen or non-aromatic carbocyclic group) or unsubstituted alkyl (hereinafter referred to as C-13).
  • R3 has the formula: (wherein R 3a is halogen; R 3b is alkyl or unsubstituted alkyl substituted with halogen) (hereinafter referred to as C-14).
  • R 4a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Examples include an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as D-1).
  • R 4a includes a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as D-2) .
  • R 4a is a hydrogen atom, an aromatic carbocyclic ring substituted with one or more substituents selected from substituent group e (substituent group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy) group or unsubstituted aromatic carbocyclic group, or substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted unsubstituted substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano).
  • D-3 substituent group e
  • R 4a is a hydrogen atom, an aromatic carbocyclic group substituted with one or more substituents selected from substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy) or non- Substituted aromatic carbocyclic group, or substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituent: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino ( halogen; unsubstituted aromatic carbocyclic group; substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy; unsubstituted aromatic and cyano) or alkyl substituted with one or more substituents (hereinafter referred to as D-4).
  • R 4a is a hydrogen atom or an aromatic carbon substituted with one or more substituents selected from substituent group e (substituent group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy)
  • a cyclic group or an unsubstituted aromatic carbocyclic group can be mentioned (hereinafter referred to as D-5).
  • R 4a is a hydrogen atom or an aromatic carbocyclic group substituted with one or more substituents selected from substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy)
  • an unsubstituted aromatic carbocyclic group can be mentioned (hereinafter referred to as D-6).
  • R 4a is a hydrogen atom or a substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic ring substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano). , D-7).
  • R 4a is a hydrogen atom, or substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituents: cyano and halogen) or unsubstituted aromatic carbocyclic group; substituted amino ( halogen; unsubstituted aromatic carbocyclic group; substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy; unsubstituted aromatic and cyano) or alkyl substituted with one or more substituents (hereinafter referred to as D-8).
  • R 4a includes a hydrogen atom (hereinafter referred to as D-9).
  • R 4a is an aromatic carbocyclic group substituted with one or more substituents selected from substituent group e (substituent group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy) or non- and substituted aromatic carbocyclic groups (hereinafter referred to as D-10).
  • R 4a is a substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic group; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano). do).
  • R 4a is an aromatic carbocyclic group or an unsubstituted aromatic group substituted with one or more substituents selected from substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy) carbocyclic groups (hereinafter referred to as D-12);
  • R 4a is a substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituent: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino (substituent: alkyl) or unsubstituted amino; halogen; unsubstituted unaromatic carbocyclic group; substituted alkyloxy (substituent: aromatic carbocyclic group substituted with halogen) or unsubstituted alkyloxy; unsubstituted aromatic heterocyclic group; and cyano) substituted with one or more substituents or un
  • R 4a includes unsubstituted alkyl. (hereinafter referred to as D-14).
  • R 4a includes alkyl substituted with a substituted aromatic carbocyclic group (substituent: cyano, halogen) or an unsubstituted aromatic carbocyclic group (hereinafter referred to as D-15).
  • R 4a includes substituted amino (substituent: alkyl) or alkyl substituted with unsubstituted amino (hereinafter referred to as D-16).
  • R 4a includes halogen-substituted alkyl (hereinafter referred to as D-17).
  • R 4a includes alkyl substituted with an unsubstituted non-aromatic carbocyclic group (hereinafter referred to as D-18).
  • R 4a includes substituted alkyloxy (substituent: aromatic carbocyclic group substituted with halogen) or alkyl substituted with unsubstituted alkyloxy (hereinafter referred to as D-19).
  • R 4a includes alkyl substituted with unsubstituted alkyloxy (hereinafter referred to as D-20).
  • R 4a includes alkyl substituted with an unsubstituted aromatic heterocyclic group (hereinafter referred to as D-21).
  • R 4a includes cyano-substituted alkyl (hereinafter referred to as D-22).
  • Formula (I) For example, as an embodiment in a compound represented by formula (I''): (wherein R 1 , R 2a , R 3 and R 4a are the same as defined in (1) above). Preferred embodiments of R 1 , R 2a , R 3 and R 4a are shown below. As the compound represented by formula (I''), all combinations of specific examples shown below are exemplified.
  • R 1 is the above (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A- 8), (A-9), (A-10), (A-11), (A-12) or (A-13).
  • R 2a is the above (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B- 8) or (B-9).
  • R 3 is the above (C-1), (C-2), (C-3), (C-4), (C-5), (C-6), (C-7), (C- 8), (C-9), (C-10), (C-11), (C-12), (C-13) or (C-14).
  • R 4a is the above (D-1), (D-2), (D-3), (D-4), (D-5), (D-6), (D-7), (D- 8), (D-9), (D-10), (D-11), (D-12), (D-13), (D-14), (D-15), (D-16) , (D-17), (D-18), (D-19), (D-20), (D-21) or (D-22).
  • Embodiments of compounds represented by formula (I′) and formula (I′′) include the following combinations.
  • the compounds of formula (I), formula (I′) and formula (I′′) are not limited to any particular isomer, but all possible isomers (e.g. keto-enol isomers, imine - enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.
  • formula (I') and formula (I'')
  • One or more hydrogen, carbon and/or other atoms of the compounds of Formula (I), Formula (I') and Formula (I'') are isotopes of hydrogen, carbon and/or other atoms, respectively can be replaced with Examples of such 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), Formula (I') and 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), formula (I') and 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), formula (I') and formula (I'') can be prepared by methods well known in the art.
  • the tritium-labeled compounds represented by formula (I), formula (I') and formula (I'') can be converted to formula (I), formula (I') and formula (I') by a catalytic dehalogenation reaction using tritium.
  • It can be prepared by introducing tritium into a specific compound represented by formula (I'').
  • This method suitably comprises compounds of formula (I), formula (I′) and formula (I′′) in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base. It involves reacting the halogen-substituted precursor with tritium gas.
  • 14 C-labeled compounds can be prepared by using starting materials with a 14 C carbon.
  • Pharmaceutically acceptable salts of the compounds represented by formula (I), formula (I') and formula (I'') include, for example, formula (I), formula (I') and formula (I'') with a compound represented by an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metal (e.g., zinc, iron, etc.), ammonia, an organic base (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, odorants).
  • alkali metal e.g., lithium, sodium, potassium, etc.
  • alkaline earth metal e.g.,
  • Hydrochloric acid, phosphoric acid, hydroiodic acid, etc.), and organic acids e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.).
  • organic acids e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid,
  • the compounds represented by formula (I), formula (I′) and formula (I′′) of the present invention or pharmaceutically acceptable salts thereof can be converted into solvates (e.g., hydrates, etc.), co-crystals and/or or may form crystalline polymorphs, and the invention also includes such various solvates, co-crystals and crystalline polymorphs.
  • a "solvate” is a compound of Formula (I), Formula (I') and Formula (I'') coordinated with any number of solvent molecules (e.g., water molecules, etc.) good too.
  • solvent molecules e.g., water molecules, etc.
  • Co-crystal means that a compound or salt of formula (I), formula (I') and formula (I'') and a counter molecule are present in the same crystal lattice, and any number of counter It may contain molecules.
  • 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.
  • Prodrugs are compounds that undergo enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo and are converted into compounds represented by formula (I), formula (I') and formula (I''). , gastric acid, etc. to convert to compounds represented by formula (I), formula (I') and formula (I'').
  • formula (I) and formula (I'') or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • a compound having a hydroxyl group and a suitable acyl halide Prodrugs such as acyloxy derivatives and sulfonyloxy derivatives prepared by reacting with suitable acid anhydrides, suitable sulfonyl chlorides, suitable sulfonyl anhydrides and mixed anhydrides or by using condensing agents is exemplified.
  • the compound according to the present invention has coronavirus 3CL protease inhibitory activity, it is useful as a therapeutic and/or prophylactic agent for diseases associated with coronavirus 3CL protease.
  • the term "therapeutic agent and/or prophylactic agent” also includes symptom improving agents.
  • Diseases involving coronavirus 3CL protease include viral infections, preferably coronavirus infections.
  • 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.
  • 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.
  • coronaviruses include HCoV-229E, HCoV-OC43 and/or SARS-CoV-2, particularly preferably SARS-CoV-2.
  • 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), formula (I') and 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 experiments.
  • the compounds of the present invention can be produced with reference to methods known in the art. For example, it can be manufactured with reference to WO2018/074390 and WO2012/020749.
  • Compound (IA) can be produced by reacting compound (A-5) with trimethylamine hydrochloride and methanesulfonyl chloride in a suitable solvent in the presence of a base according to the synthesis method described in WO2018/074390.
  • the obtained desired compound (IA) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.), if necessary, and SFC fractionation using a chiral column (liquefied carbonic acid-methanol (or ethanol, etc.) ) can be optically resolved.
  • chiral compound (IA) can be produced using chiral compound (A-4).
  • Compound (B-2) can be produced by reacting compound (B-1) with a halogenating reagent in a suitable solvent according to the synthesis method described in WO2018/074390.
  • the compound (B-2) is reacted with a boronic acid or boronate ester (B-3) in the presence of a metal catalyst and a base in an appropriate solvent to give compound (IB ) can be manufactured.
  • the obtained desired compound (IB) can be purified by a conventional method (eg, column chromatography, recrystallization, etc.), if necessary, and subjected to SFC fractionation using a chiral column (liquefied carbonic acid-methanol (or ethanol, etc.) ) can be optically resolved.
  • the compounds according to the present invention have coronavirus 3CL protease inhibitory activity, they are useful as therapeutic and/or prophylactic agents for viral infections. Furthermore, 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.). b) shows good pharmacokinetics such as high bioavailability and moderate clearance; c) high metabolic stability; d) It does not exhibit irreversible inhibitory effects on CYP enzymes (eg CYP3A4).
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc. shows good pharmacokinetics such as high bioavailability and moderate clearance; c) high metabolic stability; d) It does not exhibit irreversible inhibitory effects on
  • coronavirus growth inhibitory activity for example, 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
  • EC 50 is 10 ⁇ M or less, preferably 1 ⁇ M or less, and more preferably 100 nM or less in the CPE suppression effect confirmation test (SARS-CoV-2) 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 200 mg / kg/day, preferably within the range of 0.1 to 100 mg/kg/day. In the case of parenteral administration, it is generally 0.005 to 200 mg/kg/day, preferably 0.01 to 100 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.
  • CDI carbonyldiimidazole
  • DBU 1,8-diazabicyclo[5.4.0]-7-undecene
  • DIEA N,N-diisopropylethylamine
  • FBS fetal bovine serum
  • HCCP hexachlorocyclotriphosphazene
  • MEM Eagle's minimum essential medium
  • SFC Supercritical fluid chromatography mM: mmol/L ⁇ M: ⁇ mol/L nM: nmol/L
  • Step 2 Synthesis of compound 2 Methanol (5 mL) was added to compound 1 (100 mg, 0.455 mmol) and cooled to 0°C.
  • Nickel (II) chloride hexahydrate (108 mg, 0.455 mmol) and sodium borohydride (86.0 mg, 2.28 mmol) were added to the reaction solution and stirred at 0° C. for 5 minutes. After completion of the reaction, water was added to the reaction solution. The resulting insoluble matter was filtered off, and the filtrate was washed with ethyl acetate.
  • Step 3 Synthesis of Compound 5
  • Compound 4 (282 mg, 1.06 mmol), 1,1′-carbonyldiimidazole (206 mg, 1.27 mmol) and THF (2.8 mL) were mixed and heated to reflux for 1 hour, and cooled to room temperature. It was cooled (reaction solution A).
  • reaction solution A potassium tert-butoxide (179 mg, 1.59 mmol) and THF (2.8 mL) were mixed and nitromethane (344 ⁇ L, 6.36 mmol) was slowly added.
  • the reaction solution was stirred at room temperature for 1 hour, and the above reaction solution A was added slowly at room temperature.
  • the reaction solution was stirred at room temperature for 1 hour and then at 50° C. for 1.5 hours.
  • Step 2 Synthesis of Compound 9
  • Compound 8 (4.08 g, 13.41 mmol), THF (20 mL) and methanol (20 mL) were mixed under a nitrogen atmosphere.
  • sodium borohydride (1.02 g, 26.8 mmol) was added little by little to the reaction solution.
  • the reaction solution was stirred at 0° C. for 2 hours and acetone (5 mL) was added.
  • the reaction solution was stirred at 0° C. for 10 minutes, saturated aqueous sodium hydrogencarbonate solution (20 mL) was added, and water (20 mL) was added at room temperature.
  • reaction solution was stirred at room temperature for 3 hours and allowed to stand at room temperature overnight.
  • a 10% aqueous citric acid solution 400 mL was added to the reaction solution in an ice bath, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain compound 17 (36.6 g, 105 mmol, yield 100%).
  • Step 2 Synthesis of Compound 18
  • Compound 17 (37.5 g, 107 mmol) and THF (375 mL) were mixed under a nitrogen atmosphere and cooled in a dry ice-acetone bath. Under an ice bath, diisobutylaluminum hydride (1.02 mol/L hexane solution, 210 mL, 214 mmol) was added dropwise to the reaction solution at -10°C or lower, and the mixture was stirred at -10°C for 15 minutes.
  • Step 2 Synthesis of Compound 12
  • Compound 11 (30.7 g, 108 mmol), dimethylacetamide (307 mL) and 1H-pyrazole-1-carboxamidine hydrochloride (15.8 g, 108 mmol) were mixed at room temperature.
  • DBU (40.6 mL, 269 mmol) was added dropwise to the reaction solution and stirred at 80° C. for 45 minutes.
  • the reaction solution was cooled in an ice bath and CDI (34.9 g, 215 mmol) and DBU (32.5 mL, 215 mmol) were added.
  • the reaction solution was stirred under an ice bath for 3 hours and poured into ice water (300 mL).
  • Step 4 Synthesis of Compound 14
  • Compound 13 (0.45 g, 1.11 mmol) and acetonitrile (14 mL) were mixed.
  • HCCP 0.64 g, 1.34 mmol
  • DIEA 0.53 mL, 1.45 mmol
  • Compound 10 0.52 mL, 3.33 mmol
  • the reaction solution was poured into saturated aqueous sodium hydrogencarbonate solution (20 mL), stirred for 20 minutes, and extracted with ethyl acetate.
  • Step 5 Synthesis of compound 15 (racemic mixture of compound I-0076 and compound I-0064) Methanesulfonyl chloride (0.432 mL, 5.54 mmol) and N, N, N', N '-Tetramethyl-1,3-propanediamine (0.721 mL, 5.54) was added and stirred at 0° C. for 5 minutes. Subsequently, a solution of compound 14 (0.545 g, 0.923 mmol) in DMF (3 mL) was added under ice-cooling, and the mixture was stirred at 0° C. for 5 minutes and then at room temperature for 1 hour.
  • Step 6 Separation and purification of compound (I-0076) and compound (I-0064) Compound 15 obtained in Step 5 was purified by the above SFC preparative method, compound (I-0076, 42.1 mg, 0.073 mmol ) and compound (I-0064, 45.2 mg, 0.079 mmol).
  • Tables 106 and 107 show atomic coordinates of non-hydrogen atoms.
  • U(eq) means an equivalent isotropic temperature factor.
  • Table 108 shows atomic coordinates of hydrogen atoms.
  • U(eq) means an equivalent isotropic temperature factor.
  • the numbers of the hydrogen atoms in Table 108 are associated with the numbers of the non-hydrogen atoms to which they are attached.
  • Tables 109 to 110 show interatomic angles (unit: degree).
  • FIG. 1 shows the molecular structure diagram of the compound (I-0143).
  • Tables 112 and 113 show atomic coordinates of non-hydrogen atoms.
  • U(eq) means an equivalent isotropic temperature factor.
  • Table 114 shows atomic coordinates of hydrogen atoms.
  • U(eq) means an equivalent isotropic temperature factor.
  • the numbers of the hydrogen atoms in Table 114 are associated with the numbers of the non-hydrogen atoms to which they are attached.
  • Tables 115 and 116 show interatomic angles (unit: degrees).
  • FIG. 2 shows the molecular structure diagram of the compound (I-0252).
  • the compound represented by the formula (I) according to the present invention has a coronavirus 3CL protease inhibitory action and may inhibit coronavirus 3CL protease.
  • the IC50 is preferably 50 ⁇ M or less, more preferably 1 ⁇ M or less, and even more preferably 100 nM or less.
  • Test Example 1 Cytopathic effect (CPE) suppression effect confirmation test using human TMPRSS2-expressing Vero E6 cells (Vero E6/TMPRSS2 cells) ⁇ Operating procedure> ⁇ Dilution and dispensing of test sample Dilute the test sample with DMSO in advance to an appropriate concentration, prepare a 2- to 5-fold serial dilution series, and then dispense into a 384-well plate.
  • CPE Cytopathic effect
  • Test Example 2 SARS-CoV-2 3CL protease inhibitory activity test ⁇ Material> ⁇ Commercially available Recombinant SARS-CoV-2 3CL Protease - Commercially available substrate peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1) - Internal Standard peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln (SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln is described in the literature (Atherton, E.; Sheppard, R.C., "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University).
  • an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, 0.01% BSA is used.
  • ⁇ Dilution and dispensing of test sample Dilute the test sample with DMSO in advance to an appropriate concentration, prepare a 2- to 5-fold serial dilution series, and then dispense into a 384-well plate. Addition of Enzyme and Substrate, Enzyme Reaction Add 8 ⁇ M substrate and 6 or 0.6 nM enzyme solution to the prepared compound plate and incubate at room temperature for 3 to 5 hours.
  • reaction stop solution (0.067 ⁇ M Internal Standard, 0.1% formic acid, 10 or 25% acetonitrile) is added to stop the enzymatic reaction.
  • Measurement of Reaction Products Reaction completed plates are measured using a Rapid Fire System 360 and mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a Rapid Fire System 365 and mass spectrometer (Agilent, 6495C Triple Quadrupole).
  • a solution (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate
  • B solution 0.01% trifluoroacetic acid, 0.09% formic acid
  • the reaction product detected by the mass spectrometer is calculated using RapidFire Integrator or a program capable of equivalent analysis and taken as a product area value.
  • the internal standard detected at the same time is also calculated and used as the internal standard area value.
  • ⁇ Calculation of each measurement item value> ⁇ P/IS is calculated by calculating the area value obtained in the item before calculating P/IS using the following formula.
  • P / IS Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC 50 ) calculation
  • x is the logarithmic value of the compound concentration and y is % Inhibition
  • y is % Inhibition
  • the compounds of the invention were tested essentially as described above. The results are shown below.
  • the IC 50 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 10 ⁇ M.
  • Patent Document 1 Compounds I-0089 and I-0189 of International Publication No. 2018/074390 (Patent Document 1) did not exhibit inhibitory activity against SARS-CoV-23CL protease at concentrations up to 9.9 ⁇ M.
  • 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 compound according to the present invention has an inhibitory effect on coronavirus 3CL protease, and is believed to be useful as a therapeutic and/or prophylactic agent for diseases or conditions involving coronavirus 3CL protease.

Abstract

The present invention provides a compound that exhibits an inhibitory activity against coronavirus 3CL protease or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same. A compound represented by formula (I) (in the formula; X represents -NH-, etc.; Y represents =N-, etc.; Z represents -NR1-, etc.; W represents =N-, etc.; R1 represents a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, etc.; R2a represents a substituted or unsubstituted aromatic carbon cyclic group, etc.; R2b represents a hydrogen atom, etc.; n represents 1, etc.; R4a represents a hydrogen atom, a substituted or unsubstituted alkyl, etc.; and R4b represents a hydrogen atom, etc.), or a pharmaceutically acceptable salt thereof.

Description

ウイルス増殖阻害活性を有する二環性含窒素複素環誘導体およびそれらを含有する医薬組成物Bicyclic Nitrogen-Containing Heterocyclic Derivatives Having Virus Growth Inhibitory Activity and Pharmaceutical Compositions Containing Them
　本発明は、コロナウイルス３ＣＬプロテアーゼ阻害活性を示す化合物、およびコロナウイルス３ＣＬプロテアーゼ阻害活性を示す化合物を含有する医薬組成物に関する。 The present invention relates to compounds exhibiting coronavirus 3CL protease inhibitory activity and pharmaceutical compositions containing compounds exhibiting coronavirus 3CL protease inhibitory activity.
　ニドウイルス目コロナウイルス科オルトコロナウイルス亜科に属するコロナウイルスは、約３０キロベースのゲノムサイズを有し、既知のＲＮＡウイルスでは最大級の一本鎖＋鎖ＲＮＡウイルスである。コロナウイルスはアルファコロナウイルス属、ベータコロナウイルス属、ガンマコロナウイルス属およびデルタコロナウイルス属の４つに分類され、ヒトに感染するコロナウイルスとして、アルファコロナウイルス属の２種類（ＨＣｏＶ－２２９Ｅ、ＨＣｏＶ－ＮＬ６３）およびベータコロナウイルス属の５種類（ＨＣｏＶ－ＨＫＵ１、ＨＣｏＶ－ＯＣ４３、ＳＡＲＳ－ＣｏＶ、ＭＥＲＳ－ＣｏＶ、ＳＡＲＳ－ＣｏＶ－２）の計７種類が知られている。この内、４種類（ＨＣｏＶ－２２９Ｅ、ＨＣｏＶ－ＮＬ６３、ＨＣｏＶ－ＨＫＵ１、ＨＣｏＶ－ＯＣ４３）は風邪の病原体であるが、残りの３種類は重症肺炎を引き起こす重症急性呼吸器症候群（ＳＡＲＳ）コロナウイルス（ＳＡＲＳ－ＣｏＶ）、中東呼吸器症候群（ＭＥＲＳ）コロナウイルス（ＭＥＲＳ－ＣｏＶ）および新型コロナウイルス（ＳＡＲＳ－ＣｏＶ－２）である。 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). Of these, four (HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43) are pathogens of the common cold, while the remaining three are severe acute respiratory syndrome (SARS) coronaviruses that cause severe pneumonia ( SARS-CoV), Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) and novel coronavirus (SARS-CoV-2).
　２０１９年１２月に中国武漢で発生した新型コロナウイルス感染症（ＣＯＶＩＤ－１９）は急速に国際社会に蔓延し、２０２０年３月１１日にＷＨＯよりパンデミックが表明された。２０２２年８月２２日時点で確認された感染者数は５．９億人以上、死者数は６４５万人以上に達する（非特許文献１）。ＳＡＲＳ－ＣｏＶ－２の主な感染経路として飛沫感染、接触感染およびエアロゾル感染が報告されており、ＳＡＲＳ－ＣｏＶ－２は３時間程度エアロゾルと共に空気中を漂い続け、感染力を維持することが確認されている（非特許文献２）。潜伏期間は２～１４日程度であり、発熱（８７．９％）、空咳（６７．７％）、倦怠感（３８．１％）、痰（３３．４％）等の風邪様症状が典型的である（非特許文献３）。重症例では、急性呼吸窮迫症候群や急性肺障害、間質性肺炎等による呼吸器不全が起こる。また、腎不全や肝不全などの多臓器不全も報告されている。 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 August 22, 2022, the confirmed number of infected people reached 590 million or more, and the number of deaths reached 6,450,000 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.
　既存薬のドラッグリポジショニングから、抗ウイルス薬であるレムデシビル、抗炎症薬であるデキサメタゾン、リウマチ薬であるバリシチニブがＣＯＶＩＤ－１９に対する治療薬として承認され、２０２２年１月に抗ＩＬ－６受容体抗体であるトシリズマブが追加承認されている。また、２０２１年７月に、抗体カクテル療法であるロナプリーブが特例承認され、２０２１年９月にソトロビマブが特例承認され、２０２１年１２月にモルヌピラビルが特例承認された。これらの薬剤についての有効性や安全性については、十分なエビデンスが得られていない。したがって、ＣＯＶＩＤ－１９に対する治療薬、特に経口薬の創製は急務である。 From the drug repositioning of existing drugs, the antiviral drug remdesivir, the anti-inflammatory drug dexamethasone, and the rheumatism drug baricitinib were approved as therapeutic agents for COVID-19, and anti-IL-6 receptor antibodies were approved in January 2022. Tocilizumab has been additionally approved. In addition, in July 2021, special approval was granted for the antibody cocktail therapy lonaprive, in September 2021, special approval was granted for sotrovimab, and in December 2021, special approval was granted for molnupiravir. Sufficient evidence has not been obtained regarding the efficacy and safety of these drugs. Therefore, there is an urgent need to create therapeutic drugs, especially oral drugs, against COVID-19.
　コロナウイルスは、細胞に感染すると、２つのポリタンパク質を合成する。この２つのポリタンパク質中には、新たなウイルス粒子を作り出すための構造タンパク質、ウイルスゲノムを作る複製複合体、２つのプロテアーゼが含まれている。プロテアーゼは、ウイルスから合成されたポリタンパク質を切断し、それぞれのタンパク質を機能させるために不可欠な働きをする。２つのプロテアーゼのうち、ポリタンパク質の切断のほとんどを担うのが、３ＣＬプロテアーゼ（メインプロテアーゼ）である（非特許文献４）。
　３ＣＬプロテアーゼを標的とした、ＣＯＶＩＤ－１９治療薬としては、２０２１年６月、Ｐｆｉｚｅｒ社によるＰＦ－００８３５２３１のプロドラッグであるＬｕｆｏｔｒｅｌｖｉｒ（ＰＦ－０７３０４８１４）のＰｈａｓｅ１ｂ試験の完了がＣｌｉｎｉｃａｌＴｒｉａｌｓ．ｇｏｖに掲載された（ＮＣＴ０４５３５１６７）。また、２０２１年３月、Ｐｆｉｚｅｒ社は新型コロナウイルス感染症に対する治療薬ＰＦ－０７３２１３３２のＰｈａｓｅ１試験を開始すると発表した。ＰＦ－００８３５２３１、ＬｕｆｏｔｒｅｌｖｉｒおよびＰＦ－０７３２１３３２の構造式は以下に示す通りで、本発明化合物とは化学構造が異なる（非特許文献５、９および１０、ならびに特許文献３および４）。
ＰＦ－００８３５２３１：
Figure JPOXMLDOC01-appb-C000003
Ｌｕｆｏｔｒｅｌｖｉｒ（ＰＦ－０７３０４８１４）：
Figure JPOXMLDOC01-appb-C000004
ＰＦ－０７３２１３３２：
Figure JPOXMLDOC01-appb-C000005
　２０２１年１２月、ニルマトレルビル（ＰＦ－０７３２１３３２）錠／リトナビル錠であるＰＡＸＬＯＶＩＤ（ＴＭ）は、米国で緊急使用許可が承認され、２０２２年２月１０日にパキロビッド（登録商標）パックが日本で特例承認された。 Coronaviruses synthesize two polyproteins when they infect cells. These two polyproteins contain a structural protein for creating new virus particles, a replication complex for creating the viral genome, and two proteases. Protease plays an essential role in cleaving polyproteins synthesized from viruses and allowing each protein to function. Of the two proteases, 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 4).
For COVID-19 therapeutics targeting 3CL protease, in June 2021, Pfizer completed a Phase 1b trial of Lufotrelvir (PF-07304814), a prodrug of PF-00835231, at ClinicalTrials. gov (NCT04535167). Also, in March 2021, Pfizer announced that it will begin Phase 1 trials of PF-07321332, a treatment for COVID-19. The structural formulas of PF-00835231, Lufotrelvir and PF-07321332 are shown below, and differ in chemical structure from the compounds of the present invention (Non-Patent Documents 5, 9 and 10, and Patent Documents 3 and 4).
PF-00835231:
Figure JPOXMLDOC01-appb-C000003
Lufotrelvir (PF-07304814):
Figure JPOXMLDOC01-appb-C000004
PF-07321332:
Figure JPOXMLDOC01-appb-C000005
In December 2021, PAXLOVID™, a nirmatrelvir (PF-07321332) tablet/ritonavir tablet, was approved for Emergency Use Authorization in the United States, and on February 10, 2022, Pakilovid® pack was launched in Japan. Approved as a special case.
　また、３ＣＬプロテアーゼを標的とした、ＣＯＶＩＤ－１９治療薬としては、２０２１年８月、Ｐａｒｄｅｓ　Ｂｉｏｓｃｉｅｎｃｅｓ社によるＰＢＩ－０４５１のＰｈａｓｅ１試験の開始がＣｌｉｎｉｃａｌＴｒｉａｌｓ．ｇｏｖに掲載された（ＮＣＴ０５０１１８１２）。ＰＢＩ－０４５１の構造式は以下に示す通りで、本発明化合物とは化学構造が異なる（非特許文献１１）。
Figure JPOXMLDOC01-appb-C000006
 In addition, as a COVID-19 therapeutic drug targeting 3CL protease, in August 2021, Pardes Biosciences will start a Phase 1 trial of PBI-0451 at ClinicalTrials.com. gov (NCT05011812). The structural formula of PBI-0451 is shown below, and the chemical structure is different from that of the compound of the present invention (Non-Patent Document 11).
Figure JPOXMLDOC01-appb-C000006
　３ＣＬプロテアーゼを標的としたＣＯＶＩＤ－１９治療薬に対する耐性変異については、十分なエビデンスが得られていない。 Sufficient evidence has not been obtained for resistance mutations to COVID-19 therapeutic drugs that target 3CL protease.
　３ＣＬプロテアーゼ阻害活性を有する化合物が非特許文献５～１５に開示されているが、いずれの文献においても本発明に関連する化合物は記載も示唆もされていない。
　Ρ２Ｘ７受容体阻害作用を有する誘導体が特許文献１および２に開示されているが、３ＣＬプロテアーゼ阻害活性および抗ウイルス効果については記載も示唆もされていない。 Although compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 5 to 15, none of the documents describe or suggest compounds that are relevant to the present invention.
Derivatives having P2X7 receptor inhibitory activity are disclosed in Patent Documents 1 and 2, but 3CL protease inhibitory activity and antiviral effects are neither described nor suggested.
国際公開第２０１８／０７４３９０号WO2018/074390 特開２０１９－１８２８０６号公報JP 2019-182806 A 国際公開第２０１２／０２０７４２号WO2012/020742 国際公開第２０１８／１０７１１２号WO2018/107112
　本発明の目的は、コロナウイルス３ＣＬプロテアーゼ阻害活性を有する化合物を提供することにある。好ましくは、本発明は、抗ウイルス作用、特にコロナウイルスの増殖阻害作用を有する化合物、および該化合物を含有する医薬を提供する。 An object of the present invention is to provide compounds having coronavirus 3CL protease inhibitory activity. Preferably, the present invention provides a compound having an antiviral effect, particularly a coronavirus growth-inhibiting effect, and a medicament containing the compound.
　本発明は、以下に関する。
　（１’）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000007
（式中、
　破線は、結合の存在または不存在を示し；
　Ｘは、－ＮＲ５－、－ＣＲ５Ｒ５’－、－Ｏ－または－Ｓ－であり；
　Ｙは、＝Ｎ－または＝ＣＲ６－であり；
　Ｚは、－ＮＲ１－または－ＣＲ１’＝であり；
　Ｗは、＝Ｎ－、－Ｏ－、－ＣＲ７Ｒ７’－または－ＮＲ８－であり；
　Ｒ１は、置換アルキル、置換アルケニル、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換のアミノまたは置換もしくは非置換のカルバモイルであり；
　Ｒ１’は、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換のアミノまたは置換もしくは非置換のカルバモイルであり；
　Ｒ３は、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族炭素環式基であり；
　Ｒ２ａは、水素原子、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり;
　Ｒ２ｂは、水素原子または置換もしくは非置換のアルキルであり；
　ｎは１または２であり；
　Ｒ４ａは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基であり;
　Ｒ４ｂは、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
　ｎが１である場合は、Ｒ２ｂおよびＲ４ａは結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく；
　ｎが１である場合は、Ｒ４ａおよびＲ４ｂは結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく；
　Ｒ５およびＲ５’は、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
　Ｒ６は、水素原子または置換もしくは非置換のアルキルであり；
　Ｒ７およびＲ７’は、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
　Ｒ８は、水素原子または置換もしくは非置換のアルキルである）で示される化合物（ただし、以下の化合物：
Figure JPOXMLDOC01-appb-C000008
を除く）、またはその製薬上許容される塩。
　（２’）Ｙが＝Ｎ－である、上記項目（１’）記載の化合物またはその製薬上許容される塩。
　（３’）Ｘが－ＮＨ－である、上記項目（１’）または（２’）記載の化合物またはその製薬上許容される塩。
　（４’）Ｚが－ＮＲ１－である、上記項目（１’）～（３’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（５’）Ｗが＝Ｎ－である、上記項目（１’）～（４’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（６’）Ｒ１が置換アルキル、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基である、上記項目（１’）～（５’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（７’）Ｒ１が置換もしくは非置換の芳香族複素環式基である、上記項目（１’）～（６’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（８’）Ｒ３が置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基である、上記項目（１’）～（７’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（９’）Ｒ２ａが置換もしくは非置換の芳香族炭素環式基である、上記項目（１’）～（８’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１０’）Ｒ２ｂが水素原子である、上記項目（１’）～（９’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１１’）Ｒ４ａがそれぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族炭素環式基である、上記項目（１’）～（１０’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１２’）Ｒ４ｂが水素原子である、上記項目（１’）～（１１’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１３’）ｎが１である、上記項目（１’）～（１２’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１４’）化合物Ｉ－０００７、Ｉ－００７６、Ｉ－００９７、Ｉ－０１４２、Ｉ－０１４３、Ｉ－０３２６およびＩ－０３３２からなる群から選択される、上記項目（１’）記載の化合物またはその製薬上許容される塩。
　（１）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000009
（式中、
　破線は、結合の存在または不存在を示し；
　Ｘは、－ＮＲ５－、－ＣＲ５Ｒ５’－、－Ｏ－、－Ｓ－または単結合であり；
　Ｙは、＝Ｎ－または＝ＣＲ６－であり；
　Ｚは、－ＮＲ１－または－ＣＲ１’＝であり；
　Ｗは、＝Ｎ－、－Ｏ－、－ＣＲ７Ｒ７’－または－ＮＲ８－であり；
　Ｒ１は、置換アルキル、置換アルケニル、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換のアミノまたは置換もしくは非置換のカルバモイルであり；
　Ｒ１’は、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換のアミノまたは置換もしくは非置換のカルバモイルであり；
　Ｒ３は、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族炭素環式基であり；
　Ｒ２ａは、水素原子、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり;
　Ｒ２ｂは、水素原子または置換もしくは非置換のアルキルであり；
　ｎは１または２であり；
　Ｒ４ａは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基であり;
　Ｒ４ｂは、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
　ｎが１である場合は、Ｒ２ｂおよびＲ４ａは結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく；
　ｎが１である場合は、Ｒ４ａおよびＲ４ｂは結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく；
　Ｒ５およびＲ５’は、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
　Ｒ６は、水素原子または置換もしくは非置換のアルキルであり；
　Ｒ７およびＲ７’は、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
　Ｒ８は、水素原子または置換もしくは非置換のアルキルである）で示される化合物（ただし、以下の化合物：
Figure JPOXMLDOC01-appb-C000010
を除く）、またはその製薬上許容される塩。
　（２）Ｙが＝Ｎ－である、上記項目（１）記載の化合物またはその製薬上許容される塩。
　（３）Ｘが－ＮＨ－である、上記項目（１）または（２）記載の化合物またはその製薬上許容される塩。
　（４）Ｚが－ＮＲ１－である、上記項目（１）～（３）のいずれかに記載の化合物またはその製薬上許容される塩。
　（５）Ｗが＝Ｎ－である、上記項目（１）～（４）のいずれかに記載の化合物またはその製薬上許容される塩。
　（６）Ｒ１が置換アルキル、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基である、上記項目（１）～（５）のいずれかに記載の化合物またはその製薬上許容される塩。
　（７）Ｒ１が置換もしくは非置換の芳香族複素環式基である、上記項目（１）～（６）のいずれかに記載の化合物またはその製薬上許容される塩。
　（８）Ｒ３が置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基である、上記項目（１）～（７）のいずれかに記載の化合物またはその製薬上許容される塩。
　（９）Ｒ２ａが置換もしくは非置換の芳香族炭素環式基である、上記項目（１）～（８）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１０）Ｒ２ｂが水素原子である、上記項目（１）～（９）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１１）Ｒ４ａが水素原子、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族炭素環式基である、上記項目（１）～（１０）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１２）Ｒ４ｂが水素原子である、上記項目（１）～（１１）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１３）ｎが１である、上記項目（１）～（１２）のいずれかに記載の化合物またはその製薬上許容される塩。
　（１４）上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
　（１５）上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩を含有する、コロナウイルス３ＣＬプロテアーゼ阻害剤。
　（１６）上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩を含有する、コロナウイルス増殖阻害剤。
　（１７）コロナウイルスが、アルファコロナウイルスおよび／またはベータコロナウイルスである、上記項目（１６）記載のコロナウイルス増殖阻害剤。
　（１８）コロナウイルスが、ＳＡＲＳ－ＣｏＶ－２である、上記項目（１６）記載のコロナウイルス増殖阻害剤。
　（１９）上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩を含有する、コロナウイルス感染症の予防および／または治療のための、医薬組成物。
　（２０）新型コロナウイルス感染症（ＣＯＶＩＤ－１９）の予防および／または治療のための、上記項目（１９）に記載の医薬組成物。
　（２１）ＳＡＲＳ－ＣｏＶ－２による感染症の予防および／または治療のための、上記項目（１９）に記載の医薬組成物。
　（２２）上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、コロナウイルスの増殖阻害方法。
　（２３）コロナウイルスが、アルファコロナウイルスおよび／またはベータコロナウイルスである、上記項目（２２）に記載の増殖阻害方法。
　（２４）コロナウイルスが、ＳＡＲＳ－ＣｏＶ－２である、上記項目（２２）に記載の増殖阻害方法。
　（２５）上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物、またはその製薬上許容される塩を投与することを特徴とする、コロナウイルス３ＣＬプロテアーゼの関与する疾患の治療および／または予防方法。
　（２６）上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物、またはその製薬上許容される塩を投与することを特徴とする、コロナウイルス感染症の治療および／または予防方法。
　（２７）コロナウイルス感染症が、新型コロナウイルス感染症（ＣＯＶＩＤ－１９）である、上記項目（２６）に記載の予防および／または治療方法。
　（２８）コロナウイルス感染症が、ＳＡＲＳ－ＣｏＶ－２による感染症である、上記項目（２６）に記載の予防および／または治療方法。
　（２９）コロナウイルス３ＣＬプロテアーゼの関与する疾患の治療および／または予防剤を製造するための、上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩の使用。
　（３０）コロナウイルスの増殖阻害剤を製造するための、上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩の使用。
　（３１）コロナウイルスが、アルファコロナウイルスおよび／またはベータコロナウイルスである、上記項目（３０）に記載の使用。
　（３２）コロナウイルスが、ＳＡＲＳ－ＣｏＶ－２である、上記項目（３０）に記載の使用。
　（３３）コロナウイルス感染症の治療および／または予防剤を製造するための、上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩の使用。
　（３４）コロナウイルス感染症が、新型コロナウイルス感染症（ＣＯＶＩＤ－１９）である、上記項目（３３）に記載の使用。
　（３５）コロナウイルス感染症が、ＳＡＲＳ－ＣｏＶ－２による感染症である、上記項目（３３）に記載の使用。
　（３６）コロナウイルス３ＣＬプロテアーゼの関与する疾患の治療および／または予防に使用するための、上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（３７）コロナウイルスの増殖阻害に使用するための、上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（３８）コロナウイルスが、アルファコロナウイルスおよび／またはベータコロナウイルスである、上記項目（３７）に記載の化合物またはその製薬上許容される塩。
　（３９）コロナウイルスが、ＳＡＲＳ－ＣｏＶ－２である、上記項目（３７）に記載の化合物またはその製薬上許容される塩。
　（４０）コロナウイルス感染症の治療および／または予防に使用するための、上記項目（１）～（１３）および（１’）～（１４’）のいずれかに記載の化合物またはその製薬上許容される塩。
　（４１）コロナウイルス感染症が、新型コロナウイルス感染症（ＣＯＶＩＤ－１９）である、上記項目（４０）に記載の化合物またはその製薬上許容される塩。
　（４２）コロナウイルス感染症が、ＳＡＲＳ－ＣｏＶ－２による感染症である、上記項目（４０）に記載の化合物またはその製薬上許容される塩。 The present invention relates to the following.
(1′) Formula (I):
Figure JPOXMLDOC01-appb-C000007
(In the formula,
dashed lines indicate the presence or absence of a bond;
X is -NR 5 -, -CR 5 R 5' -, -O- or -S-;
Y is =N- or =CR 6 -;
Z is —NR 1 — or —CR 1′ =;
W is =N-, -O-, -CR 7 R 7' - or -NR 8 -;
R 1 is substituted alkyl, substituted alkenyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted a substituted non-aromatic carbocyclic group, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl;
R 1′ is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl;
R 3 is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic carbon is a cyclic group;
R 2a is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted unsubstituted an aromatic heterocyclic group, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
R 2b is a hydrogen atom or substituted or unsubstituted alkyl;
n is 1 or 2;
Each R 4a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic ring is a formula group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
each R 4b is independently a hydrogen atom or a substituted or unsubstituted alkyl;
When n is 1, R 2b and R 4a together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. often;
When n is 1, R 4a and R 4b together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. often;
R 5 and R 5′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl;
R 6 is a hydrogen atom or substituted or unsubstituted alkyl;
R 7 and R 7′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl;
R 8 is a hydrogen atom or substituted or unsubstituted alkyl) (provided that the following compounds:
Figure JPOXMLDOC01-appb-C000008
), or a pharmaceutically acceptable salt thereof.
(2') The compound or a pharmaceutically acceptable salt thereof according to item (1') above, wherein Y is =N-.
(3') The compound or a pharmaceutically acceptable salt thereof according to item (1') or (2') above, wherein X is -NH-.
(4') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1') to (3'), wherein Z is -NR 1 -.
(5') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1') to (4'), wherein W is =N-.
(6') Any of the above items (1') to (5'), wherein R 1 is a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group A compound or a pharmaceutically acceptable salt thereof according to claim 1.
(7') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1') to (6'), wherein R 1 is a substituted or unsubstituted aromatic heterocyclic group.
(8') Any one of the above items (1') to (7'), wherein R 3 is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group or a pharmaceutically acceptable salt thereof.
(9') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1') to (8'), wherein R 2a is a substituted or unsubstituted aromatic carbocyclic group.
(10') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1') to (9'), wherein R2b is a hydrogen atom.
(11′) Each R 4a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic carbocyclic group, above A compound or a pharmaceutically acceptable salt thereof according to any one of items (1′) to (10′).
(12') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1') to (11'), wherein R4b is a hydrogen atom.
(13') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1') to (12'), wherein n is 1.
or a pharmaceutically acceptable salt thereof.
(1) Formula (I):
Figure JPOXMLDOC01-appb-C000009
(In the formula,
dashed lines indicate the presence or absence of a bond;
X is -NR 5 -, -CR 5 R 5' -, -O-, -S- or a single bond;
Y is =N- or =CR 6 -;
Z is —NR 1 — or —CR 1′ =;
W is =N-, -O-, -CR 7 R 7' - or -NR 8 -;
R 1 is substituted alkyl, substituted alkenyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted a substituted non-aromatic carbocyclic group, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl;
R 1′ is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl;
R 3 is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic carbon is a cyclic group;
R 2a is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted unsubstituted an aromatic heterocyclic group, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
R 2b is a hydrogen atom or substituted or unsubstituted alkyl;
n is 1 or 2;
Each R 4a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic ring is a formula group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
each R 4b is independently a hydrogen atom or a substituted or unsubstituted alkyl;
When n is 1, R 2b and R 4a together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. often;
When n is 1, R 4a and R 4b together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. often;
R 5 and R 5′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl;
R 6 is a hydrogen atom or substituted or unsubstituted alkyl;
R 7 and R 7′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl;
R 8 is a hydrogen atom or substituted or unsubstituted alkyl) (provided that the following compounds:
Figure JPOXMLDOC01-appb-C000010
), or a pharmaceutically acceptable salt thereof.
(2) The compound or a pharmaceutically acceptable salt thereof according to item (1) above, wherein Y is =N-.
(3) The compound or a pharmaceutically acceptable salt thereof according to item (1) or (2) above, wherein X is -NH-.
(4) The compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (3) above, wherein Z is -NR 1 -.
(5) The compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (4) above, wherein W is =N-.
(6) Any one of the above items (1) to (5), wherein R 1 is a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group. or a pharmaceutically acceptable salt thereof.
(7) The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (6), wherein R 1 is a substituted or unsubstituted aromatic heterocyclic group.
(8) The compound according to any one of the above items (1) to (7), wherein R 3 is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.
(9) The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (8), wherein R 2a is a substituted or unsubstituted aromatic carbocyclic group.
(10) The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (9), wherein R 2b is a hydrogen atom.
(11) Items (1 ) to ( 10) A compound or a pharmaceutically acceptable salt thereof according to any one of items 10).
(12) The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (11), wherein R4b is a hydrogen atom.
(13) The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (12), wherein n is 1.
(14) A pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (13) and (1') to (14') above.
(15) A coronavirus 3CL protease inhibitor containing the compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (13) and (1′) to (14′) above.
(16) A coronavirus growth inhibitor containing the compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (13) and (1′) to (14′) above.
(17) The coronavirus growth inhibitor according to item (16) above, wherein the coronavirus is an alphacoronavirus and/or a betacoronavirus.
(18) The coronavirus growth inhibitor according to item (16) above, wherein the coronavirus is SARS-CoV-2.
(19) Prevention of coronavirus infection and/or containing the compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (13) and (1') to (14') A pharmaceutical composition for therapy.
(20) The pharmaceutical composition according to item (19) above for the prevention and/or treatment of novel coronavirus infection (COVID-19).
(21) The pharmaceutical composition according to item (19) above for the prevention and/or treatment of infections caused by SARS-CoV-2.
(22) Propagation of a coronavirus characterized by administering the compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (13) and (1') to (14') above. inhibition method.
(23) The growth inhibition method according to item (22) above, wherein the coronavirus is an alphacoronavirus and/or a betacoronavirus.
(24) The growth inhibition method according to item (22) above, wherein the coronavirus is SARS-CoV-2.
(25) Coronavirus 3CL, characterized by administering the compound according to any one of the above items (1) to (13) and (1') to (14'), or a pharmaceutically acceptable salt thereof. A method for treating and/or preventing protease-associated diseases.
(26) Coronavirus infection characterized by administering the compound according to any one of the above items (1) to (13) and (1′) to (14′), or a pharmaceutically acceptable salt thereof A method for treating and/or preventing disease.
(27) The preventive and/or therapeutic method according to item (26) above, wherein the coronavirus infection is novel coronavirus infection (COVID-19).
(28) The preventive and/or therapeutic method according to item (26) above, wherein the coronavirus infection is an infection caused by SARS-CoV-2.
(29) The compound according to any one of the above items (1) to (13) and (1') to (14') for producing a therapeutic and/or preventive agent for diseases involving coronavirus 3CL protease. or use of a pharmaceutically acceptable salt thereof.
(30) A compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (13) and (1′) to (14′) for producing a coronavirus growth inhibitor use.
(31) Use according to item (30) above, wherein the coronavirus is an alphacoronavirus and/or a betacoronavirus.
(32) Use according to item (30) above, wherein the coronavirus is SARS-CoV-2.
(33) The compound according to any one of the above items (1) to (13) and (1′) to (14′) for manufacturing a therapeutic and/or prophylactic agent for coronavirus infection, or a pharmaceutical preparation thereof Acceptable use of salt.
(34) Use according to item (33) above, wherein the coronavirus infection is novel coronavirus infection (COVID-19).
(35) Use according to item (33) above, wherein the coronavirus infection is an infection caused by SARS-CoV-2.
(36) The compound according to any one of the above items (1) to (13) and (1′) to (14′) for use in treating and/or preventing diseases involving coronavirus 3CL protease, or a pharmaceutically acceptable salt thereof.
(37) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (13) and (1') to (14') above for use in inhibiting the growth of coronavirus.
(38) The compound or a pharmaceutically acceptable salt thereof according to the above item (37), wherein the coronavirus is alphacoronavirus and/or betacoronavirus.
(39) The compound or a pharmaceutically acceptable salt thereof according to (37) above, wherein the coronavirus is SARS-CoV-2.
(40) The compound according to any one of items (1) to (13) and (1′) to (14′) above for use in treating and/or preventing coronavirus infection, or a pharmaceutically acceptable compound thereof Salt to be served.
(41) The compound or a pharmaceutically acceptable salt thereof according to item (40) above, wherein the coronavirus infection is novel coronavirus infection (COVID-19).
(42) The compound or a pharmaceutically acceptable salt thereof according to item (40) above, wherein the coronavirus infection is an infection caused by SARS-CoV-2.
　本発明に係る化合物は、コロナウイルス３ＣＬプロテアーゼに対する阻害活性を有し、コロナウイルス感染症の治療剤および／または予防剤として有用である。 The compound according to the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic and/or preventive agent for coronavirus infections.
化合物（Ｉ－０１４３）の分子構造図を示す。1 shows a molecular structure diagram of compound (I-0143). 化合物（Ｉ－０２５２）の分子構造図を示す。1 shows a molecular structure diagram of compound (I-0252).
　以下に本明細書において用いられる各用語の意味を説明する。各用語は特に断りのない限り、単独で用いられる場合も、または他の用語と組み合わせて用いられる場合も、同一の意味で用いられる。
　「からなる」という用語は、構成要件のみを有することを意味する。
「含む」という用語は、構成要件に限定されず、記載されていない要素を排除しないことを意味する。
　以下、本発明について実施形態を示しながら説明する。本明細書の全体にわたり、単数形の表現は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。従って、単数形の冠詞（例えば、英語の場合は「ａ」、「ａｎ」、「ｔｈｅ」など）は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。
　また、本明細書において使用される用語は、特に言及しない限り、当上記分野で通常用いられる意味で用いられることが理解されるべきである。したがって、他に定義されない限り、本明細書中で使用される全ての専門用語および科学技術用語は、本発明の属する分野の当業者によって一般的に理解されるのと同じ意味を有する。矛盾する場合、本明細書（定義を含めて）が優先する。 The meaning of each term used in this specification will be explained below. Unless otherwise specified, each term has the same meaning whether it is used alone or in combination with other terms.
The term "consisting of" means having only constituent elements.
The term "comprising" is meant to be open to the elements and does not exclude elements not listed.
Hereinafter, the present invention will be described while showing embodiments. It should be understood that throughout this specification, expressions in the singular also include the concept of the plural unless specifically stated otherwise. Thus, articles in the singular (eg, “a,” “an,” “the,” etc. in the English language) should be understood to include their plural concepts as well, unless specifically stated otherwise.
In addition, it should be understood that the terms used in this specification have the meanings commonly used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification (including definitions) will control.
　「ハロゲン」とは、フッ素原子、塩素原子、臭素原子、およびヨウ素原子を包含する。特にフッ素原子および塩素原子が好ましい。 "Halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Fluorine and chlorine atoms are particularly preferred.
　「アルキル」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の炭化水素基を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ｎ－へプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デシル等が挙げられる。
　「アルキル」の好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチルが挙げられる。さらに好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチルが挙げられる。 "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.
Preferred embodiments of "alkyl" 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.
　「アルケニル」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。例えば、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル等が挙げられる。
　「アルケニル」の好ましい態様として、ビニル、アリル、プロペニル、イソプロペニル、ブテニルが挙げられる。さらに好ましい態様として、エテニル、ｎ－プロペニル、等が挙げられる。 The term “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 chain or branched hydrocarbon groups. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl. etc.
Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl and butenyl. More preferred embodiments include ethenyl, n-propenyl, and the like.
　「アルキニル」とは、任意の位置に１以上の三重結合を有する、炭素数２～１０、好ましくは炭素数２～８、さらに好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。さらに任意の位置に二重結合を有していてもよい。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等を包含する。
　「アルキニル」の好ましい態様として、エチニル、プロピニル、ブチニル、ペンチニルが挙げられる。さらに好ましい態様として、エチニル、プロピニル等が挙げられる。 The term "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.
　「芳香族炭素環式基」とは、単環または２環以上の、環状芳香族炭化水素基を意味する。例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。
「芳香族炭素環式基」の好ましい態様として、フェニルが挙げられる。 An “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.
　「芳香族炭素環」とは、上記「芳香族炭素環式基」から導かれる環を意味する。 "Aromatic carbocyclic ring" means a ring derived from the above "aromatic carbocyclic group".
　「非芳香族炭素環式基」とは、単環または２環以上の、環状飽和炭化水素基または環状非芳香族不飽和炭化水素基を意味する。２環以上の「非芳香族炭素環式基」は、単環または２環以上の非芳香族炭素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
　さらに、「非芳香族炭素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000011
　単環の非芳香族炭素環式基としては、炭素数３～１６が好ましく、より好ましくは炭素数３～１２、さらに好ましくは炭素数４～８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
　２環以上の非芳香族炭素環式基としては、炭素数８～２０が好ましく、より好ましくは炭素数８～１６である。例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 A "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".
Furthermore, the "non-aromatic carbocyclic group" also includes a group that forms a bridge or a spiro ring as shown below.
Figure JPOXMLDOC01-appb-C000011
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.
　「非芳香族炭素環」とは、上記「非芳香族炭素環式基」から導かれる環を意味する。 "Non-aromatic carbocyclic ring" means a ring derived from the above "non-aromatic carbocyclic group".
　上記式（Ｉ）において、ｎが１である場合、「Ｒ２ｂおよびＲ４ａが、結合する炭素原子と一緒になって形成する、置換もしくは非置換の非芳香族炭素環」とは、例えば以下の環が挙げられる。
Figure JPOXMLDOC01-appb-C000012
（式中、各記号は上記と同義） In the above formula (I), when n is 1, the "substituted or unsubstituted non-aromatic carbocyclic ring formed by R 2b and R 4a together with the carbon atoms to which they are attached" includes, for example, the following ring.
Figure JPOXMLDOC01-appb-C000012
(In the formula, each symbol has the same meaning as above)
　上記式（Ｉ）において、ｎが１である場合、「Ｒ４ａおよびＲ４ｂが、結合する炭素原子と一緒になって形成する、置換もしくは非置換の非芳香族炭素環」とは、例えば以下の環が挙げられる。
Figure JPOXMLDOC01-appb-C000013
（式中、各記号は上記と同義） In the above formula (I), when n is 1, "a substituted or unsubstituted non-aromatic carbocyclic ring formed by R 4a and R 4b together with the carbon atoms to which they are attached" means, for example, the following ring.
Figure JPOXMLDOC01-appb-C000013
(In the formula, each symbol has the same meaning as above)
　「芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、芳香族環式基を意味する。
　２環以上の芳香族複素環式基は、単環または２環以上の芳香族複素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含し、該結合手はいずれの環に有していても良い。
　単環の芳香族複素環式基としては、５～８員が好ましく、より好ましくは５員または６員である。５員芳香族複素環式基としては、例えば、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリル、フリル、チエニル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル等が挙げられる。６員芳香族複素環式基としては、例えば、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル等が挙げられる。
　２環の芳香族複素環式基としては、８～１０員が好ましく、より好ましくは９員または１０員である。例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンズイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等が挙げられる。９員芳香族複素環式基としては、インドリル、イソインドリル、インダゾリル、インドリジニル、プリニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンズイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾトリアゾリル、ベンゾフラニル、イミダゾピリジル、トリアゾロピリジル、オキサゾロピリジル、チアゾロピリジル等が挙げられる。１０員芳香族複素環式基としては、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プテリジニル、ピラジノピリダジニル等が挙げられる。
　３環以上の芳香族複素環式基としては、１３～１５員が好ましい。例えば、カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチイニル、フェノキサジニル、ジベンゾフリル等が挙げられる。 “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. Examples of 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. For example, 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.
　「芳香族複素環」とは、上記「芳香族複素環式基」から導かれる環を意味する。 "Aromatic heterocyclic ring" means a ring derived from the above "aromatic heterocyclic group".
　「非芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、非芳香族環式基を意味する。２環以上の非芳香族複素環式基は、単環または２環以上の非芳香族複素環式基に、上記「芳香族炭素環式基」、「非芳香族炭素環式基」、および／または「芳香族複素環式基」におけるそれぞれの環が縮合したもの、さらに、単環または２環以上の非芳香族炭素環式基に、上記「芳香族複素環式基」における環が縮合したものも包含し、該結合手はいずれの環に有していても良い。
　さらに、「非芳香族複素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000014
　単環の非芳香族複素環式基としては、３～８員が好ましく、より好ましくは５員または６員である。
　３員非芳香族複素環式基としては、例えば、チイラニル、オキシラニル、アジリジニルが挙げられる。４員非芳香族複素環式基としては、例えば、オキセタニル、アゼチジニルが挙げられる。５員非芳香族複素環式基としては、例えば、オキサチオラニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、テトラヒドロフリル、ジヒドロチアゾリル、テトラヒドロイソチアゾリル、ジオキソラニル、ジオキソリル、チオラニル等が挙げられる。６員非芳香族複素環式基としては、例えば、ジオキサニル、チアニル、ピペリジル、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロピラニル、ジヒドロオキサジニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキサジニル、チイニル、チアジニル等が挙げられる。７員非芳香族複素環式基としては、例えば、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、オキセパニルが挙げられる。
　２環以上の非芳香族複素環式基としては、８～２０員が好ましく、より好ましくは８～１３員、さらに好ましくは８～１０員である。例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。 "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. means 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.
Furthermore, the “non-aromatic heterocyclic group” also includes a group that forms a bridge or a spiro ring as shown below.
Figure JPOXMLDOC01-appb-C000014
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.
　「非芳香族複素環」とは、上記「非芳香族複素環式基」から導かれる環を意味する。 "Non-aromatic heterocyclic ring" means a ring derived from the above "non-aromatic heterocyclic group".
　上記式（Ｉ）において、ｎが１である場合、「Ｒ２ｂおよびＲ４ａが、結合する炭素原子と一緒になって形成する、置換もしくは非置換の非芳香族複素環」とは、例えば以下の環が挙げられる。
Figure JPOXMLDOC01-appb-C000015
（式中、Ｒｘは水素原子、置換もしくは非置換のアルキル等、その他の記号は前記と同義） In the above formula (I), when n is 1, the "substituted or unsubstituted non-aromatic heterocyclic ring formed by R 2b and R 4a together with the carbon atoms to which they are attached" includes, for example, the following ring.
Figure JPOXMLDOC01-appb-C000015
(Wherein, R x is a hydrogen atom, substituted or unsubstituted alkyl, etc., and other symbols are as defined above)
　上記式（Ｉ）において、ｎが１である場合、「Ｒ４ａおよびＲ４ｂが、結合する炭素原子と一緒になって形成する、置換もしくは非置換の非芳香族複素環」とは、例えば以下の環が挙げられる。
Figure JPOXMLDOC01-appb-C000016
（式中、Ｒｘは置換もしくは非置換のアルキル等、その他の記号は前記と同義） In the above formula (I), when n is 1, "a substituted or unsubstituted non-aromatic heterocyclic ring formed by R 4a and R 4b together with the carbon atom to which they are attached" means, for example, the following ring.
Figure JPOXMLDOC01-appb-C000016
(Wherein, R x is substituted or unsubstituted alkyl, etc., and other symbols are as defined above)
　「トリアルキルシリル」とは、上記「アルキル」３個がケイ素原子に結合している基を意味する。３個のアルキル基は同一でも異なっていてもよい。例えば、トリメチルシリル、トリエチルシリル、ｔｅｒｔ－ブチルジメチルシリル等が挙げられる。 "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.
　本明細書中、「置換基群αで置換されていてもよい」とは、「置換基群αから選択される1以上の基で置換されていてもよい」ことを意味する。置換基群β、γおよびγ’についても同様である。 In the present specification, "optionally substituted with substituent group α" means "optionally substituted with one or more groups selected from substituent group α". The same applies to the substituent groups β, γ and γ'.
　「置換アルキル」、「置換アルケニル」、「置換アルキニル」、「置換アルキルオキシ」、「置換アルケニルオキシ」、「置換アルキニルオキシ」、「置換アルキルカルボニルオキシ」、「置換アルケニルカルボニルオキシ」、「置換アルキニルカルボニルオキシ」、「置換アルキルカルボニル」、「置換アルケニルカルボニル」、「置換アルキニルカルボニル」、「置換アルキルオキシカルボニル」、「置換アルケニルオキシカルボニル」、「置換アルキニルオキシカルボニル」、「置換アルキルスルファニル」、「置換アルケニルスルファニル」、「置換アルキニルスルファニル」、「置換アルキルスルフィニル」、「置換アルケニルスルフィニル」、「置換アルキニルスルフィニル」、「置換アルキルスルホニル」、「置換アルケニルスルホニル」、「置換アルキニルスルホニル」等の置換基としては、次の置換基群Ａが挙げられる。任意の位置の炭素原子が次の置換基群Ａから選択される１以上の基と結合していてもよい。
　置換基群Ａ：ハロゲン、ヒドロキシ、カルボキシ、ホルミル、ホルミルオキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、ペンタフルオロチオ、トリアルキルシリル、
置換基群αで置換されていてもよいアルキルオキシ、置換基群αで置換されていてもよいアルケニルオキシ、置換基群αで置換されていてもよいアルキニルオキシ、置換基群αで置換されていてもよいアルキルカルボニルオキシ、置換基群αで置換されていてもよいアルケニルカルボニルオキシ、置換基群αで置換されていてもよいアルキニルカルボニルオキシ、置換基群αで置換されていてもよいアルキルカルボニル、置換基群αで置換されていてもよいアルケニルカルボニル、置換基群αで置換されていてもよいアルキニルカルボニル、置換基群αで置換されていてもよいアルキルオキシカルボニル、置換基群αで置換されていてもよいアルケニルオキシカルボニル、置換基群αで置換されていてもよいアルキニルオキシカルボニル、置換基群αで置換されていてもよいアルキルスルファニル、置換基群αで置換されていてもよいアルケニルスルファニル、置換基群αで置換されていてもよいアルキニルスルファニル、置換基群αで置換されていてもよいアルキルスルフィニル、置換基群αで置換されていてもよいアルケニルスルフィニル、置換基群αで置換されていてもよいアルキニルスルフィニル、置換基群αで置換されていてもよいアルキルスルホニル、置換基群αで置換されていてもよいアルケニルスルホニル、置換基群αで置換されていてもよいアルキニルスルホニル、
置換基群βで置換されていてもよいアミノ、置換基群βで置換されていてもよいイミノ、置換基群βで置換されていてもよいカルバモイル、置換基群βで置換されていてもよいスルファモイル、
置換基群γで置換されていてもよい芳香族炭素環式基、置換基群γ’で置換されていてもよい非芳香族炭素環式基、置換基群γで置換されていてもよい芳香族複素環式基、置換基群γ’で置換されていてもよい非芳香族複素環式基、置換基群γで置換されていてもよい芳香族炭素環オキシ、置換基群γ’で置換されていてもよい非芳香族炭素環オキシ、置換基群γで置換されていてもよい芳香族複素環オキシ、置換基群γ’で置換されていてもよい非芳香族複素環オキシ、置換基群γで置換されていてもよい芳香族炭素環カルボニルオキシ、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニルオキシ、置換基群γで置換されていてもよい芳香族複素環カルボニルオキシ、置換基群γ’で置換されていてもよい非芳香族複素環カルボニルオキシ、置換基群γで置換されていてもよい芳香族炭素環カルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニル、置換基群γで置換されていてもよい芳香族複素環カルボニル、置換基群γ’で置換されていてもよい非芳香族複素環カルボニル、置換基群γで置換されていてもよい芳香族炭素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環オキシカルボニル、置換基群γで置換されていてもよい芳香族複素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環オキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシ、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシ、置換基群γで置換されていてもよい芳香族複素環アルキルオキシ、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシ、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシカルボニル、置換基群γで置換されていてもよい芳香族複素環アルキルオキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環スルファニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルファニル、置換基群γで置換されていてもよい芳香族複素環スルファニル、置換基群γ’で置換されていてもよい非芳香族複素環スルファニル、置換基群γで置換されていてもよい芳香族炭素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルフィニル、置換基群γで置換されていてもよい芳香族複素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族複素環スルフィニル、置換基群γで置換されていてもよい芳香族炭素環スルホニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルホニル、置換基群γで置換されていてもよい芳香族複素環スルホニルおよび置換基群γ’で置換されていてもよい非芳香族複素環スルホニル。 "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkyloxy", "substituted alkenyloxy", "substituted alkynyloxy", "substituted alkylcarbonyloxy", "substituted alkenylcarbonyloxy", "substituted alkynyl"carbonyloxy","substitutedalkylcarbonyl","substitutedalkenylcarbonyl","substitutedalkynylcarbonyl","substitutedalkyloxycarbonyl","substitutedalkenyloxycarbonyl","substitutedalkynyloxycarbonyl","substitutedalkylsulfanyl"," Substituents such as "substituted alkenylsulfanyl", "substituted alkynylsulfanyl", "substituted alkylsulfinyl", "substituted alkenylsulfinyl", "substituted alkynylsulfinyl", "substituted alkylsulfonyl", "substituted alkenylsulfonyl", "substituted alkynylsulfonyl" Examples include the following Substituent Group A. 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 α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, substituted with substituent group α alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α , alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, substituted with substituent group α alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α sulfanyl, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, substituted with substituent group α alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,
amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, optionally substituted with substituent group β sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic oxy optionally substituted with substituent group γ, aromatic heterocyclic oxy optionally substituted with substituent group γ', non-aromatic heterocyclic oxy optionally substituted with substituent group γ', substituent aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocyclic optionally substituted with substituent group γ ring carbonyloxy, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', substituent group γ aromatic carbocyclic oxycarbonyl optionally substituted with, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxy which may be substituted with substituent group γ carbonyl, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', substituent aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, substituent group γ' non-aromatic carbocyclic sulfanyl optionally substituted with, aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ , non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', non-substituted optionally substituted with substituent group γ' aromatic heterocyclic sulfinyl, aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', substituted with substituent group γ aromatic heterocyclic sulfonyl which may be optionally substituted and non-aromatic heterocyclic sulfonyl which may be substituted with substituent group γ';
置換基群α：ハロゲン、ヒドロキシ、カルボキシ、アルキルオキシ、ハロアルキルオキシ、アルケニルオキシ、アルキニルオキシ、スルファニル、およびシアノ。 Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
置換基群β：ハロゲン、ヒドロキシ、カルボキシ、シアノ、置換基群αで置換されていてもよいアルキル、置換基群αで置換されていてもよいアルケニル、置換基群αで置換されていてもよいアルキニル、置換基群αで置換されていてもよいアルキルカルボニル、置換基群αで置換されていてもよいアルケニルカルボニル、置換基群αで置換されていてもよいアルキニルカルボニル、置換基群αで置換されていてもよいアルキルスルファニル、置換基群αで置換されていてもよいアルケニルスルファニル、置換基群αで置換されていてもよいアルキニルスルファニル、置換基群αで置換されていてもよいアルキルスルフィニル、置換基群αで置換されていてもよいアルケニルスルフィニル、置換基群αで置換されていてもよいアルキニルスルフィニル、置換基群αで置換されていてもよいアルキルスルホニル、置換基群αで置換されていてもよいアルケニルスルホニル、置換基群αで置換されていてもよいアルキニルスルホニル、
置換基群γで置換されていてもよい芳香族炭素環式基、置換基群γ’で置換されていてもよい非芳香族炭素環式基、置換基群γで置換されていてもよい芳香族複素環式基、置換基群γ’で置換されていてもよい非芳香族複素環式基、置換基群γで置換されていてもよい芳香族炭素環アルキル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキル、置換基群γで置換されていてもよい芳香族複素環アルキル、置換基群γ’で置換されていてもよい非芳香族複素環アルキル、置換基群γで置換されていてもよい芳香族炭素環カルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニル、置換基群γで置換されていてもよい芳香族複素環カルボニル、置換基群γ’で置換されていてもよい非芳香族複素環カルボニル、置換基群γで置換されていてもよい芳香族炭素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環オキシカルボニル、置換基群γで置換されていてもよい芳香族複素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環オキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環スルファニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルファニル、置換基群γで置換されていてもよい芳香族複素環スルファニル、置換基群γ’で置換されていてもよい非芳香族複素環スルファニル、置換基群γで置換されていてもよい芳香族炭素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルフィニル、置換基群γで置換されていてもよい芳香族複素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族複素環スルフィニル、置換基群γで置換されていてもよい芳香族炭素環スルホニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルホニル、置換基群γで置換されていてもよい芳香族複素環スルホニルおよび置換基群γ’で置換されていてもよい非芳香族複素環スルホニル。 Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, optionally substituted with substituent group α alkynyl, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, substituted with substituent group α alkenylsulfonyl which may be substituted, alkynylsulfonyl which may be substituted with substituent group α,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic alkyl optionally substituted with substituent group γ, aromatic heterocyclic alkyl optionally substituted with substituent group γ', non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', substituent aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ , non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', substituent group γ aromatic carbocyclic sulfanyl optionally substituted with, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, substituted non-aromatic heterocyclic sulfanyl optionally substituted with group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' carbocyclic sulfinyl, aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', optionally substituted with substituent group γ good aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and substituted with substituent group γ' non-aromatic heterocyclic sulfonyl which may be
置換基群γ：置換基群α、アルキル、ハロアルキル、ヒドロキシアルキル、アルケニル、アルキニル、アルキルカルボニル、ハロアルキルカルボニル、アルケニルカルボニルおよびアルキニルカルボニル。 Substituent Group γ: Substituent Group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.
置換基群γ’：置換基群γおよびオキソ。 Substituent group γ': Substituent group γ and oxo.
　「置換芳香族炭素環式基」、「置換芳香族複素環式基」、「置換芳香族炭素環オキシ」、「置換芳香族複素環オキシ」、「置換芳香族炭素環カルボニルオキシ」、「置換芳香族複素環カルボニルオキシ」、「置換芳香族炭素環カルボニル」、「置換芳香族複素環カルボニル」、「置換芳香族炭素環オキシカルボニル」、「置換芳香族複素環オキシカルボニル」、「置換芳香族炭素環スルファニル」、「置換芳香族複素環スルファニル」、「置換芳香族炭素環スルフィニル」、「置換芳香族複素環スルフィニル」、「置換芳香族炭素環スルホニル」および「置換芳香族複素環スルホニル」等の「芳香族炭素環」および「芳香族複素環」の環上の置換基としては、次の置換基群Ｂが挙げられる。環上の任意の位置の原子が次の置換基群Ｂから選択される１以上の基と結合していてもよい。
　置換基群Ｂ：ハロゲン、ヒドロキシ、カルボキシ、ホルミル、ホルミルオキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、ペンタフルオロチオ、トリアルキルシリル、
置換基群αで置換されていてもよいアルキル、置換基群αで置換されていてもよいアルケニル、置換基群αで置換されていてもよいアルキニル、置換基群αで置換されていてもよいアルキルオキシ、置換基群αで置換されていてもよいアルケニルオキシ、置換基群αで置換されていてもよいアルキニルオキシ、置換基群αで置換されていてもよいアルキルカルボニルオキシ、置換基群αで置換されていてもよいアルケニルカルボニルオキシ、置換基群αで置換されていてもよいアルキニルカルボニルオキシ、置換基群αで置換されていてもよいアルキルカルボニル、置換基群αで置換されていてもよいアルケニルカルボニル、置換基群αで置換されていてもよいアルキニルカルボニル、置換基群αで置換されていてもよいアルキルオキシカルボニル、置換基群αで置換されていてもよいアルケニルオキシカルボニル、置換基群αで置換されていてもよいアルキニルオキシカルボニル、置換基群αで置換されていてもよいアルキルスルファニル、置換基群αで置換されていてもよいアルケニルスルファニル、置換基群αで置換されていてもよいアルキニルスルファニル、置換基群αで置換されていてもよいアルキルスルフィニル、置換基群αで置換されていてもよいアルケニルスルフィニル、置換基群αで置換されていてもよいアルキニルスルフィニル、置換基群αで置換されていてもよいアルキルスルホニル、置換基群αで置換されていてもよいアルケニルスルホニル、置換基群αで置換されていてもよいアルキニルスルホニル、
置換基群βで置換されていてもよいアミノ、置換基群βで置換されていてもよいイミノ、置換基群βで置換されていてもよいカルバモイル、置換基群βで置換されていてもよいスルファモイル、
置換基群γで置換されていてもよい芳香族炭素環式基、置換基群γ’で置換されていてもよい非芳香族炭素環式基、置換基群γで置換されていてもよい芳香族複素環式基、置換基群γ’で置換されていてもよい非芳香族複素環式基、置換基群γで置換されていてもよい芳香族炭素環オキシ、置換基群γ’で置換されていてもよい非芳香族炭素環オキシ、置換基群γで置換されていてもよい芳香族複素環オキシ、置換基群γ’で置換されていてもよい非芳香族複素環オキシ、置換基群γで置換されていてもよい芳香族炭素環カルボニルオキシ、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニルオキシ、置換基群γで置換されていてもよい芳香族複素環カルボニルオキシ、置換基群γ’で置換されていてもよい非芳香族複素環カルボニルオキシ、置換基群γで置換されていてもよい芳香族炭素環カルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニル、置換基群γで置換されていてもよい芳香族複素環カルボニル、置換基群γ’で置換されていてもよい非芳香族複素環カルボニル、置換基群γで置換されていてもよい芳香族炭素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環オキシカルボニル、置換基群γで置換されていてもよい芳香族複素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環オキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環アルキル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキル、置換基群γで置換されていてもよい芳香族複素環アルキル、置換基群γ’で置換されていてもよい非芳香族複素環アルキル、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシ、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシ、置換基群γで置換されていてもよい芳香族複素環アルキルオキシ、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシ、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシカルボニル、置換基群γで置換されていてもよい芳香族複素環アルキルオキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシアルキル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシアルキル、置換基群γで置換されていてもよい芳香族複素環アルキルオキシアルキル、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシアルキル、置換基群γで置換されていてもよい芳香族炭素環スルファニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルファニル、置換基群γで置換されていてもよい芳香族複素環スルファニル、置換基群γ’で置換されていてもよい非芳香族複素環スルファニル、置換基群γで置換されていてもよい芳香族炭素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルフィニル、置換基群γで置換されていてもよい芳香族複素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族複素環スルフィニル、置換基群γで置換されていてもよい芳香族炭素環スルホニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルホニル、置換基群γで置換されていてもよい芳香族複素環スルホニルおよび置換基群γ’で置換されていてもよい非芳香族複素環スルホニル。 "substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic carbocyclic oxy", "substituted aromatic heterocyclic oxy", "substituted aromatic carbocyclic carbonyloxy", "substituted Aromatic heterocycle carbonyloxy", "substituted aromatic carbocycle carbonyl", "substituted aromatic heterocycle carbonyl", "substituted aromatic carbocycle oxycarbonyl", "substituted aromatic heterocycle oxycarbonyl", "substituted aromatic carbocyclic sulfanyl", "substituted aromatic heterocyclic sulfanyl", "substituted aromatic carbocyclic sulfinyl", "substituted aromatic heterocyclic sulfinyl", "substituted aromatic carbocyclic sulfonyl" and "substituted aromatic heterocyclic sulfonyl", etc. Examples of substituents on the ring of the “aromatic carbocyclic ring” and “aromatic heterocyclic ring” include the following substituent group B. Any atom 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 α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, optionally substituted with substituent group α alkyloxy, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, substituent group α alkenylcarbonyloxy optionally substituted with, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, even if substituted with substituent group α alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, substituent alkynyloxycarbonyl optionally substituted with group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, substituted with substituent group α alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, substituent group alkylsulfonyl optionally substituted with α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,
amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, optionally substituted with substituent group β sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic oxy optionally substituted with substituent group γ, aromatic heterocyclic oxy optionally substituted with substituent group γ', non-aromatic heterocyclic oxy optionally substituted with substituent group γ', substituent aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocyclic optionally substituted with substituent group γ ring carbonyloxy, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', substituent group γ aromatic carbocyclic oxycarbonyl optionally substituted with, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxy which may be substituted with substituent group γ carbonyl, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' non-aromatic carbocyclic alkyl optionally substituted with substituent group γ, aromatic heterocyclic alkyl optionally substituted with substituent group γ', non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', substituted with substituent group γ optionally substituted aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ′, aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' good non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted by substituent group γ, substituted non-aromatic carbocyclic alkyloxyalkyl optionally substituted with group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' non-aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', substituent group γ aromatic heterocyclic sulfanyl optionally substituted with, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, substituted non-aromatic carbocyclic sulfinyl optionally substituted with group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' heterocyclic sulfinyl, aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', optionally substituted with substituent group γ aromatic heterocyclic sulfonyl and non-aromatic heterocyclic sulfonyl optionally substituted with a substituent group γ';
　「置換非芳香族炭素環式基」、「置換非芳香族複素環式基」、「置換非芳香族炭素環オキシ」、「置換非芳香族複素環オキシ」、「置換非芳香族炭素環カルボニルオキシ」、「置換非芳香族複素環カルボニルオキシ」、「置換非芳香族炭素環カルボニル」、「置換非芳香族複素環カルボニル」、「置換非芳香族炭素環オキシカルボニル」、「置換非芳香族複素環オキシカルボニル」、「置換非芳香族炭素環スルファニル」、「置換非芳香族複素環スルファニル」、「置換非芳香族炭素環スルフィニル」、「置換非芳香族複素環スルフィニル」、「置換非芳香族炭素環スルホニル」、「置換非芳香族複素環スルホニル」、「Ｒ２ｂおよびＲ４ａが、結合する炭素原子と一緒になって形成する置換もしくは非置換の非芳香族炭素環」、「Ｒ４ａおよびＲ４ｂが、結合する炭素原子と一緒になって形成する置換もしくは非置換の非芳香族炭素環」、「Ｒ２ｂおよびＲ４ａが、結合する炭素原子と一緒になって形成する置換もしくは非置換の非芳香族複素環」および「Ｒ４ａおよびＲ４ｂが、結合する炭素原子と一緒になって形成する置換もしくは非置換の非芳香族複素環」の「非芳香族炭素環」および「非芳香族複素環」の環上の置換基としては、次の置換基群Ｃが挙げられる。環上の任意の位置の原子が次の置換基群Ｃから選択される１以上の基と結合していてもよい。
　置換基群Ｃ：置換基群Ｂおよびオキソ。 "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocyclic oxy", "substituted non-aromatic heterocyclic oxy", "substituted non-aromatic carbocyclic carbonyl oxy", "substituted non-aromatic heterocyclic carbonyloxy", "substituted non-aromatic carbocyclic carbonyl", "substituted non-aromatic heterocyclic carbonyl", "substituted non-aromatic carbocyclic oxycarbonyl", "substituted non-aromatic heterocycle oxycarbonyl”, “substituted non-aromatic carbocycle sulfanyl”, “substituted non-aromatic heterocycle sulfanyl”, “substituted non-aromatic carbocycle sulfinyl”, “substituted non-aromatic heterocycle sulfinyl”, “substituted non-aromatic carbocyclic sulfonyl”, “substituted non-aromatic heterocyclic sulfonyl”, “substituted or unsubstituted non-aromatic carbocyclic ring formed by R 2b and R 4a together with the carbon atoms to which they are attached”, “R 4a and the substituted or unsubstituted non-aromatic carbocyclic ring formed by R 4b together with the bonding carbon atom”, “the substituted or unsubstituted aromatic carbocyclic ring formed by R 2b and R 4a together with the "Non-aromatic carbocyclic ring" and "Non-aromatic heterocyclic ring formed by R 4a and R 4b together with the carbon atoms to which they are attached" Substituents on the ring of "aromatic heterocycle" 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.
　「非芳香族炭素環」および「非芳香族複素環」が「オキソ」で置換されている場合、以下のように炭素原子上の２個の水素原子が置換されている環を意味する。
Figure JPOXMLDOC01-appb-C000017
 When "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.
Figure JPOXMLDOC01-appb-C000017
　「置換アミノ」、「置換イミノ」、「置換カルバモイル」および「置換スルファモイル」の置換基としては、次の置換基群Ｄが挙げられる。置換基群Ｄから選択される１または２の基で置換されていてもよい。
　置換基群Ｄ：ハロゲン、ヒドロキシ、カルボキシ、シアノ、置換基群αで置換されていてもよいアルキル、置換基群αで置換されていてもよいアルケニル、置換基群αで置換されていてもよいアルキニル、置換基群αで置換されていてもよいアルキルカルボニル、置換基群αで置換されていてもよいアルケニルカルボニル、置換基群αで置換されていてもよいアルキニルカルボニル、置換基群αで置換されていてもよいアルキルスルファニル、置換基群αで置換されていてもよいアルケニルスルファニル、置換基群αで置換されていてもよいアルキニルスルファニル、置換基群αで置換されていてもよいアルキルスルフィニル、置換基群αで置換されていてもよいアルケニルスルフィニル、置換基群αで置換されていてもよいアルキニルスルフィニル、置換基群αで置換されていてもよいアルキルスルホニル、置換基群αで置換されていてもよいアルケニルスルホニル、置換基群αで置換されていてもよいアルキニルスルホニル、
置換基群βで置換されていてもよいアミノ、置換基群βで置換されていてもよいイミノ、置換基群βで置換されていてもよいカルバモイル、置換基群βで置換されていてもよいスルファモイル、
置換基群γで置換されていてもよい芳香族炭素環式基、置換基群γ’で置換されていてもよい非芳香族炭素環式基、置換基群γで置換されていてもよい芳香族複素環式基、置換基群γ’で置換されていてもよい非芳香族複素環式基、置換基群γで置換されていてもよい芳香族炭素環アルキル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキル、置換基群γで置換されていてもよい芳香族複素環アルキル、置換基群γ’で置換されていてもよい非芳香族複素環アルキル、置換基群γで置換されていてもよい芳香族炭素環カルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニル、置換基群γで置換されていてもよい芳香族複素環カルボニル、置換基群γ’で置換されていてもよい非芳香族複素環カルボニル、置換基群γで置換されていてもよい芳香族炭素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環オキシカルボニル、置換基群γで置換されていてもよい芳香族複素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環オキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環スルファニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルファニル、置換基群γで置換されていてもよい芳香族複素環スルファニル、置換基群γ’で置換されていてもよい非芳香族複素環スルファニル、置換基群γで置換されていてもよい芳香族炭素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルフィニル、置換基群γで置換されていてもよい芳香族複素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族複素環スルフィニル、置換基群γで置換されていてもよい芳香族炭素環スルホニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルホニル、置換基群γで置換されていてもよい芳香族複素環スルホニルおよび置換基群γ’で置換されていてもよい非芳香族複素環スルホニル。 Substituents of “substituted amino”, “substituted imino”, “substituted carbamoyl” and “substituted sulfamoyl” include Substituent Group D below. It may be substituted with one or two groups selected from Substituent Group D.
Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, optionally substituted with substituent group α alkynyl, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, substituted with substituent group α alkenylsulfonyl which may be substituted, alkynylsulfonyl which may be substituted with substituent group α,
amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, optionally substituted with substituent group β sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic alkyl optionally substituted with substituent group γ, aromatic heterocyclic alkyl optionally substituted with substituent group γ', non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', substituent aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ , non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', substituent group γ aromatic carbocyclic sulfanyl optionally substituted with, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, substituted non-aromatic heterocyclic sulfanyl optionally substituted with group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' carbocyclic sulfinyl, aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', optionally substituted with substituent group γ good aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and substituted with substituent group γ' non-aromatic heterocyclic sulfonyl which may be
　Ｒ１における「置換アルキル」の置換基としては、例えば、
置換もしくは非置換の芳香族複素環式基；
置換もしくは非置換の非芳香族複素環式基；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ１における「置換アルキル」の置換基としては、例えば、
置換芳香族複素環式基（置換基：アルキルオキシ、アルキル）もしくは非置換芳香族複素環式基；
置換非芳香族複素環式基（置換基：オキソ）もしくは非置換非芳香族複素環式基；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of "substituted alkyl" for R 1 include:
substituted or unsubstituted aromatic heterocyclic group;
substituted or unsubstituted non-aromatic heterocyclic groups;
are mentioned. It may be substituted with one or more groups selected from these.
Examples of substituents of "substituted alkyl" for R 1 include:
substituted aromatic heterocyclic group (substituent: alkyloxy, alkyl) or unsubstituted aromatic heterocyclic group;
substituted non-aromatic heterocyclic group (substituent: oxo) or unsubstituted non-aromatic heterocyclic group;
are mentioned. It may be substituted with one or more groups selected from these.
　Ｒ１における「置換もしくは非置換の芳香族複素環式基」の置換基としては、例えば、
置換もしくは非置換のアルキル；
ハロゲン；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ１における「置換もしくは非置換の芳香族複素環式基」の置換基としては、例えば、
非置換アルキル；ハロゲン；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 1 include:
substituted or unsubstituted alkyl;
halogen;
are mentioned. It may be substituted with one or more groups selected from these.
Examples of substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 1 include:
unsubstituted alkyl; halogen;
are mentioned. It may be substituted with one or more groups selected from these.
　Ｒ３における「置換もしくは非置換の芳香族複素環式基」の置換基としては、例えば、
置換もしくは非置換のアルキル；
置換もしくは非置換のアミノ；
ハロゲン；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ３における「置換もしくは非置換の芳香族複素環式基」の置換基としては、例えば、
置換アルキル（置換基：ハロゲン、非芳香族炭素環式基）もしくは非置換アルキル；
置換アミノ（置換基：アルキル）もしくは非置換アミノ；
ハロゲン；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 3 include:
substituted or unsubstituted alkyl;
substituted or unsubstituted amino;
halogen;
is mentioned. It may be substituted with one or more groups selected from these.
Examples of substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 3 include:
substituted alkyl (substituent: halogen, non-aromatic carbocyclic group) or unsubstituted alkyl;
substituted amino (substituent: alkyl) or unsubstituted amino;
halogen;
is mentioned. It may be substituted with one or more groups selected from these.
　Ｒ３における「置換もしくは非置換の非芳香族複素環式基」の置換基としては、例えば、
ハロゲン；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" for R 3 include:
halogen;
is mentioned. It may be substituted with one or more groups selected from these.
　Ｒ３における「置換もしくは非置換の芳香族炭素環式基」の置換基としては、例えば、
置換もしくは非置換のアルキルオキシ；
ハロゲン；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ３における「置換もしくは非置換の芳香族炭素環式基」の置換基としては、例えば、
非置換アルキルオキシ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of the “substituted or unsubstituted aromatic carbocyclic group” for R 3 include:
substituted or unsubstituted alkyloxy;
halogen;
is mentioned. It may be substituted with one or more groups selected from these.
Examples of substituents of the “substituted or unsubstituted aromatic carbocyclic group” for R 3 include:
unsubstituted alkyloxy;
is mentioned. It may be substituted with one or more groups selected from these.
　Ｒ２ａにおける「置換もしくは非置換の芳香族炭素環式基」の置換基としては、例えば、
ハロゲン；
シアノ；
置換もしくは非置換のアルキル；
置換もしくは非置換のアルキルオキシ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ２ａにおける「置換もしくは非置換の芳香族炭素環式基」の置換基としては、例えば、
ハロゲン；
シアノ；
置換アルキル（置換基：アルキルで置換された芳香族複素環式基、ハロゲンで置換された芳香族炭素環式基、ハロゲンで置換された芳香族炭素環オキシ）もしくは非置換アルキル；
置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 2a include:
halogen;
Cyano;
substituted or unsubstituted alkyl;
substituted or unsubstituted alkyloxy;
are mentioned. It may be substituted with one or more groups selected from these.
Examples of substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 2a include:
halogen;
Cyano;
substituted alkyl (substituent: alkyl-substituted aromatic heterocyclic group, halogen-substituted aromatic carbocyclic group, halogen-substituted aromatic carbocyclic oxy) or unsubstituted alkyl;
substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy;
are mentioned. It may be substituted with one or more groups selected from these.
　Ｒ２ａにおける「置換もしくは非置換の芳香族炭素環式基」の置換基としては、例えば、
ハロゲン；
シアノ；
置換アルキル（置換基：アルキルで置換された芳香族複素環式基、ハロゲンで置換された芳香族炭素環式基、ヒドロキシアルキルで置換された芳香族炭素環式基、ハロゲンで置換された芳香族炭素環オキシ、ハロゲン）もしくは非置換アルキル；
置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 2a include:
halogen;
Cyano;
Substituted alkyl (substituent: alkyl-substituted aromatic heterocyclic group, halogen-substituted aromatic carbocyclic group, hydroxyalkyl-substituted aromatic carbocyclic group, halogen-substituted aromatic carbocyclic oxy, halogen) or unsubstituted alkyl;
substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy;
are mentioned. It may be substituted with one or more groups selected from these.
　Ｒ２ａにおける「置換もしくは非置換のアルキル」の置換基としては、例えば、
ハロゲン；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of the “substituted or unsubstituted alkyl” for R 2a include:
halogen;
are mentioned. It may be substituted with one or more groups selected from these.
　Ｒ４ａにおける「置換もしくは非置換の芳香族炭素環式基」の置換基としては、例えば、
ハロゲン；
置換もしくは非置換の芳香族炭素環オキシ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ４ａにおける「置換もしくは非置換の芳香族炭素環式基」の置換基としては、例えば、
ハロゲン；
非置換芳香族炭素環オキシ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 4a include:
halogen;
substituted or unsubstituted aromatic carbocyclic oxy;
is mentioned. It may be substituted with one or more groups selected from these.
Examples of substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 4a include:
halogen;
unsubstituted aromatic carbocyclic oxy;
is mentioned. It may be substituted with one or more groups selected from these.
　Ｒ４ａにおける「置換もしくは非置換のアルキル」の置換基としては、例えば、
置換もしくは非置換の芳香族炭素環式基；
置換もしくは非置換のアミノ；
ハロゲン；
置換もしくは非置換の非芳香族炭素環式基；
置換もしくは非置換のアルキルオキシ；
置換もしくは非置換の芳香族複素環式基；
シアノ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ４ａにおける「置換もしくは非置換のアルキル」の置換基としては、例えば、
置換芳香族炭素環式基（置換基：シアノ、ハロゲン）もしくは非置換芳香族炭素環式基；
置換アミノ（置換基：アルキル）もしくは非置換アミノ；
ハロゲン；
非置換非芳香族炭素環式基；
置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシ；
非置換芳香族複素環式基；
シアノ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of "substituted or unsubstituted alkyl" for R 4a include:
substituted or unsubstituted aromatic carbocyclic groups;
substituted or unsubstituted amino;
halogen;
substituted or unsubstituted non-aromatic carbocyclic groups;
substituted or unsubstituted alkyloxy;
substituted or unsubstituted aromatic heterocyclic group;
Cyano;
is mentioned. It may be substituted with one or more groups selected from these.
Examples of substituents of "substituted or unsubstituted alkyl" for R 4a include:
substituted aromatic carbocyclic group (substituent: cyano, halogen) or unsubstituted aromatic carbocyclic group;
substituted amino (substituent: alkyl) or unsubstituted amino;
halogen;
unsubstituted non-aromatic carbocyclic group;
substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy;
an unsubstituted aromatic heterocyclic group;
Cyano;
is mentioned. It may be substituted with one or more groups selected from these.
　Ｒ４ａにおける「置換もしくは非置換のアルキル」の置換基としては、例えば、
置換もしくは非置換の芳香族炭素環式基；
置換もしくは非置換のアミノ；
ハロゲン；
置換もしくは非置換の非芳香族炭素環式基；
置換もしくは非置換のアルキルオキシ；
置換もしくは非置換の芳香族複素環式基；
シアノ；
ヒドロキシ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ４ａにおける「置換もしくは非置換のアルキル」の置換基としては、例えば、
置換芳香族炭素環式基（置換基：シアノ、ハロゲン）もしくは非置換芳香族炭素環式基；
置換アミノ（置換基：アルキル）もしくは非置換アミノ；
ハロゲン；
非置換非芳香族炭素環式基；
置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシ；
非置換芳香族複素環式基；
シアノ；
ヒドロキシ；
が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of substituents of "substituted or unsubstituted alkyl" for R 4a include:
substituted or unsubstituted aromatic carbocyclic groups;
substituted or unsubstituted amino;
halogen;
substituted or unsubstituted non-aromatic carbocyclic groups;
substituted or unsubstituted alkyloxy;
substituted or unsubstituted aromatic heterocyclic group;
Cyano;
hydroxy;
is mentioned. It may be substituted with one or more groups selected from these.
Examples of substituents of "substituted or unsubstituted alkyl" for R 4a include:
substituted aromatic carbocyclic group (substituent: cyano, halogen) or unsubstituted aromatic carbocyclic group;
substituted amino (substituent: alkyl) or unsubstituted amino;
halogen;
unsubstituted non-aromatic carbocyclic group;
substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy;
an unsubstituted aromatic heterocyclic group;
Cyano;
hydroxy;
is mentioned. It may be substituted with one or more groups selected from these.
　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000018
で示される化合物における実施形態として、例えば、式（Ｉ’）：
Figure JPOXMLDOC01-appb-C000019
（式中、Ｒ１、Ｒ２ａ、Ｒ３およびＲ４ａは、上記（１）と同義）で示される化合物が挙げられる。Ｒ１、Ｒ２ａ、Ｒ３およびＲ４ａの好ましい態様を以下に示す。式（Ｉ’）で示される化合物としては、以下に示される具体例のすべての組み合わせの態様が例示される。 Formula (I):
Figure JPOXMLDOC01-appb-C000018
For example, as an embodiment in a compound represented by formula (I'):
Figure JPOXMLDOC01-appb-C000019
(wherein R 1 , R 2a , R 3 and R 4a are the same as defined in (1) above). Preferred embodiments of R 1 , R 2a , R 3 and R 4a are shown below. As the compound represented by formula (I′), all combinations of specific examples shown below are exemplified.
　Ｒ１は、置換アルキル、置換アルケニル、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換のアミノまたは置換もしくは非置換のカルバモイルが挙げられる（以下、Ａ－１とする）。
　Ｒ１は、置換アルキル、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基が挙げられる（以下、Ａ－２とする）。
　Ｒ１は、置換アルキルが挙げられる（以下、Ａ－３とする）。
　Ｒ１は、置換もしくは非置換の芳香族複素環式基が挙げられる（以下、Ａ－４とする）。
　Ｒ１は、置換もしくは非置換の非芳香族複素環式基が挙げられる（以下、Ａ－５とする）。
　Ｒ１は、置換基群ａ（置換基群ａ：置換もしくは非置換の芳香族複素環式基；および、置換もしくは非置換の非芳香族複素環式基）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキル、または、置換基群ｂ（置換基群ｂ：置換もしくは非置換のアルキル；および、ハロゲン）から選択される１以上の置換基で置換された芳香族複素環式基もしくは非置換芳香族複素環式基が挙げられる（以下、Ａ－６とする）。
　Ｒ１は、置換基群ａ’（置換基群ａ’：置換芳香族複素環式基（置換基：アルキルオキシおよびアルキル）もしくは非置換芳香族複素環式基；および、置換非芳香族複素環式基（置換基：オキソ）もしくは非置換非芳香族複素環式基）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキル、または、置換基群ｂ’（置換基群ｂ’：非置換アルキルおよびハロゲン）から選択される１以上の置換基で置換された芳香族複素環式基もしくは非置換芳香族複素環式基が挙げられる（以下、Ａ－７とする）。
　Ｒ１は、置換基群ａ（置換基群ａ：置換もしくは非置換の芳香族複素環式基；および、置換もしくは非置換の非芳香族複素環式基）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキルが挙げられる（以下、Ａ－８とする）。
　Ｒ１は、置換基群ｂ（置換基群ｂ：置換もしくは非置換のアルキル；および、ハロゲン）から選択される１以上の置換基で置換された芳香族複素環式基もしくは非置換芳香族複素環式基が挙げられる（以下、Ａ－９とする）。
　Ｒ１は、置換基群ａ’（置換基群ａ’：置換芳香族複素環式基（置換基：アルキルオキシ、およびアルキル）もしくは非置換芳香族複素環式基；および、置換非芳香族複素環式基（置換基：オキソ）もしくは非置換非芳香族複素環式基）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキルが挙げられる（以下、Ａ－１０とする）。
　Ｒ１は、置換基群ｂ’（置換基群ｂ’：非置換アルキルおよびハロゲン）から選択される１以上の置換基で置換された芳香族複素環式基もしくは非置換芳香族複素環式基が挙げられる（以下、Ａ－１１とする）。
　Ｒ１は、ハロゲンで置換された芳香族複素環式基が挙げられる（以下、Ａ－１２とする）。
　Ｒ１は、ハロゲンで置換された６員芳香族複素環式基が挙げられる（以下、Ａ－１３とする）。
　Ｒ１は、置換芳香族複素環式基（置換基：アルキル）で置換されたアルキルが挙げられる（以下、Ａ－１４とする）。
　Ｒ１は、置換５員芳香族複素環式基（置換基：アルキル）で置換されたアルキルが挙げられる（以下、Ａ－１５とする）。
　Ｒ１は、ハロゲンで置換された６員芳香族複素環式基、または、置換５員芳香族複素環式基（置換基：アルキル）で置換されたアルキルが挙げられる（以下、Ａ－１６とする）。 R 1 is substituted alkyl, substituted alkenyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Examples include substituted non-aromatic carbocyclic groups, substituted or unsubstituted amino and substituted or unsubstituted carbamoyl (hereinafter referred to as A-1).
R 1 includes a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-2).
R 1 includes substituted alkyl (hereinafter referred to as A-3).
R 1 includes a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-4).
R 1 includes a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-5).
R 1 is one or more substituents selected from substituent group a (substituent group a: substituted or unsubstituted aromatic heterocyclic group; and substituted or unsubstituted non-aromatic heterocyclic group) Alkyl or unsubstituted alkyl substituted with, or an aromatic heterocyclic ring substituted with one or more substituents selected from substituent group b (substituent group b: substituted or unsubstituted alkyl; and halogen) and an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-6).
R 1 is a substituent group a' (substituent group a': substituted aromatic heterocyclic group (substituents: alkyloxy and alkyl) or unsubstituted aromatic heterocyclic group; and substituted non-aromatic heterocyclic ring Alkyl or unsubstituted alkyl substituted with one or more substituents selected from the formula group (substituent: oxo) or unsubstituted non-aromatic heterocyclic group), or substituent group b' (substituent group b ': unsubstituted alkyl and halogen) or an aromatic heterocyclic group substituted with one or more substituents (hereinafter referred to as A-7).
R 1 is one or more substituents selected from substituent group a (substituent group a: substituted or unsubstituted aromatic heterocyclic group; and substituted or unsubstituted non-aromatic heterocyclic group) (hereinafter referred to as A-8).
R 1 is an aromatic heterocyclic group or an unsubstituted aromatic heterocyclic group substituted with one or more substituents selected from substituent group b (substituent group b: substituted or unsubstituted alkyl; and halogen) A cyclic group can be mentioned (hereinafter referred to as A-9).
R 1 is a substituent group a' (substituent group a': substituted aromatic heterocyclic group (substituents: alkyloxy and alkyl) or unsubstituted aromatic heterocyclic group; and substituted non-aromatic heterocyclic group Alkyl or unsubstituted alkyl substituted with one or more substituents selected from a cyclic group (substituent: oxo) or unsubstituted unaromatic heterocyclic group) (hereinafter referred to as A-10) .
R 1 is an aromatic heterocyclic group or an unsubstituted aromatic heterocyclic group substituted with one or more substituents selected from substituent group b' (substituent group b': unsubstituted alkyl and halogen) (hereinafter referred to as A-11).
R 1 includes a halogen-substituted aromatic heterocyclic group (hereinafter referred to as A-12).
R 1 includes a 6-membered aromatic heterocyclic group substituted with halogen (hereinafter referred to as A-13).
R 1 includes alkyl substituted with a substituted aromatic heterocyclic group (substituent: alkyl) (hereinafter referred to as A-14).
R 1 includes alkyl substituted with a substituted 5-membered aromatic heterocyclic group (substituent: alkyl) (hereinafter referred to as A-15).
R 1 includes a 6-membered aromatic heterocyclic group substituted with halogen, or an alkyl substituted with a substituted 5-membered aromatic heterocyclic group (substituent: alkyl) (hereinafter referred to as A-16 and do).
　Ｒ２ａは、水素原子、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルが挙げられる（以下、Ｂ－１とする）。
　Ｒ２ａは、置換もしくは非置換の芳香族炭素環式基が挙げられる（以下、Ｂ－２とする）。
　Ｒ２ａは、置換基群ｃ（置換基群ｃ：ハロゲン；シアノ；置換もしくは非置換のアルキル；および、置換もしくは非置換のアルキルオキシ）から選択される１以上の置換基で置換された芳香族炭素環式基または非置換芳香族炭素環式基が挙げられる（以下、Ｂ－３とする）。
　Ｒ２ａは、置換基群ｃ’（置換基群ｃ’：ハロゲン；シアノ；置換アルキル（置換基：アルキルで置換された芳香族複素環式基、ハロゲンで置換された芳香族炭素環式基、ハロゲンで置換された芳香族炭素環オキシ）もしくは非置換アルキル；および、置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシ）から選択される１以上の置換基で置換された芳香族炭素環式基または非置換芳香族炭素環式基が挙げられる（以下、Ｂ－４とする）。
　Ｒ２ａは、ハロゲンで置換された芳香族炭素環式基が挙げられる（以下、Ｂ－５とする）。
　Ｒ２ａは、２以上のハロゲンで置換された芳香族炭素環式基が挙げられる（以下、Ｂ－６とする）。
　Ｒ２ａは、２以上のハロゲン；および、置換アルキル（置換基：アルキルで置換された芳香族複素環式基、ハロゲンで置換された芳香族炭素環式基、およびハロゲンで置換された芳香族炭素環オキシ）もしくは非置換アルキル；で置換された芳香族炭素環式基が挙げられる（以下、Ｂ－７とする）。
　Ｒ２ａは、３以上のハロゲンで置換された芳香族炭素環式基が挙げられる（以下、Ｂ－８とする）。
　Ｒ２ａは、ハロゲンおよびシアノで置換された芳香族炭素環式基が挙げられる（以下、Ｂ－９とする）。 R 2a is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted unsubstituted Examples thereof include aromatic heterocyclic groups, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl (hereinafter referred to as B-1).
R 2a includes a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as B-2).
R 2a is an aromatic substituted with one or more substituents selected from substituent group c (substituent group c: halogen; cyano; substituted or unsubstituted alkyl; and substituted or unsubstituted alkyloxy) A carbocyclic group or an unsubstituted aromatic carbocyclic group can be mentioned (hereinafter referred to as B-3).
R 2a is a substituent group c' (substituent group c': halogen; cyano; substituted alkyl (substituent: alkyl-substituted aromatic heterocyclic group, halogen-substituted aromatic carbocyclic group, one or more selected from halogen-substituted aromatic carbocyclic oxy) or unsubstituted alkyl; and substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy) Examples include an aromatic carbocyclic group substituted with a substituent or an unsubstituted aromatic carbocyclic group (hereinafter referred to as B-4).
R 2a includes a halogen-substituted aromatic carbocyclic group (hereinafter referred to as B-5).
R 2a includes an aromatic carbocyclic group substituted with 2 or more halogens (hereinafter referred to as B-6).
R 2a is 2 or more halogen; and substituted alkyl (substituents: alkyl-substituted aromatic heterocyclic group, halogen-substituted aromatic carbocyclic group, and halogen-substituted aromatic carbon ring oxy) or unsubstituted alkyl; (hereinafter referred to as B-7).
R 2a includes an aromatic carbocyclic group substituted with 3 or more halogens (hereinafter referred to as B-8).
R 2a includes halogen- and cyano-substituted aromatic carbocyclic groups (hereinafter referred to as B-9).
　Ｒ３は、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族炭素環式基が挙げられる（以下、Ｃ－１とする）。
　Ｒ３は、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基が挙げられる（以下、Ｃ－２とする）。
　Ｒ３は、置換基群ｄ（置換基群ｄ：置換もしくは非置換のアルキル；置換もしくは非置換のアミノ；および、ハロゲン）から選択される１以上の置換基で置換された芳香族複素環式基または非置換芳香族複素環式基が挙げられる（以下、Ｃ－３とする）。
　Ｒ３は、置換基群ｄ’（置換基群ｄ’：置換アルキル（置換基：ハロゲン、および非芳香族炭素環式基）もしくは非置換アルキル；置換アミノ（置換基：アルキル）もしくは非置換アミノ；および、ハロゲン）から選択される１以上の置換基で置換された芳香族複素環式基または非置換芳香族複素環式基が挙げられる（以下、Ｃ－４とする）。
　Ｒ３は、アルキルおよびハロゲンで置換された芳香族複素環式基または非置換芳香族複素環式基が挙げられる（以下、Ｃ－５とする）。
　Ｒ３は、アルキルおよびハロゲンで置換された芳香族複素環式基が挙げられる（以下、Ｃ－６とする）。
　Ｒ３は、アルキルおよびハロゲンで置換された芳香族複素環式基または非置換芳香族複素環式基が挙げられる（以下、Ｃ－７とする）。
　Ｒ３は、アルキルおよびハロゲンで置換された芳香族複素環式基が挙げられる（以下、Ｃ－８とする）。
　Ｒ３は、アルキルおよびハロゲンで置換された９員芳香族複素環式基または非置換９員芳香族複素環式基が挙げられる（以下、Ｃ－９とする）。
　Ｒ３は、アルキルおよびハロゲンで置換された９員芳香族複素環式基が挙げられる（以下、Ｃ－１０とする）。
　Ｒ３は、アルキルおよびハロゲンで置換されたインダゾリルが挙げられる（以下、Ｃ－１１とする）。
　Ｒ３は、式：
Figure JPOXMLDOC01-appb-C000020
（式中、Ｒ３ａは、水素原子またはハロゲンであり；
Ｒ３ｂは、置換もしくは非置換のアルキルである）で示される基が挙げられる（以下、Ｃ－１２とする）。
　Ｒ３は、式：
Figure JPOXMLDOC01-appb-C000021
（式中、Ｒ３ａは、ハロゲンであり；
Ｒ３ｂは、置換アルキル（置換基：ハロゲンまたは非芳香族炭素環式基）もしくは非置換アルキルである）で示される基が挙げられる（以下、Ｃ－１３とする）。
　Ｒ３は、式：
Figure JPOXMLDOC01-appb-C000022
（式中、Ｒ３ａは、ハロゲンであり；
Ｒ３ｂは、ハロゲンで置換されたアルキルもしくは非置換アルキルである）で示される基が挙げられる（以下、Ｃ－１４とする）。 R 3 is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic carbon A cyclic group can be mentioned (hereinafter referred to as C-1).
R 3 includes a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as C-2).
R 3 is an aromatic heterocyclic substituted with one or more substituents selected from substituent group d (substituent group d: substituted or unsubstituted alkyl; substituted or unsubstituted amino; and halogen) group or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-3).
R 3 is substituent group d' (substituent group d': substituted alkyl (substituent: halogen and non-aromatic carbocyclic group) or unsubstituted alkyl; substituted amino (substituent: alkyl) or unsubstituted amino and halogen), or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-4).
R 3 includes an aromatic heterocyclic group substituted with alkyl and halogen or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-5).
R 3 includes an aromatic heterocyclic group substituted with alkyl and halogen (hereinafter referred to as C-6).
R 3 includes an aromatic heterocyclic group substituted with alkyl and halogen or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-7).
R 3 includes an aromatic heterocyclic group substituted with alkyl and halogen (hereinafter referred to as C-8).
R 3 includes a 9-membered aromatic heterocyclic group substituted with alkyl and halogen or an unsubstituted 9-membered aromatic heterocyclic group (hereinafter referred to as C-9).
R 3 includes a 9-membered aromatic heterocyclic group substituted with alkyl and halogen (hereinafter referred to as C-10).
R 3 includes indazolyl substituted with alkyl and halogen (hereinafter referred to as C-11).
R3 has the formula:
Figure JPOXMLDOC01-appb-C000020
(wherein R 3a is a hydrogen atom or halogen;
R 3b is a substituted or unsubstituted alkyl) (hereinafter referred to as C-12).
R3 has the formula:
Figure JPOXMLDOC01-appb-C000021
(wherein R 3a is halogen;
R 3b includes groups represented by substituted alkyl (substituent: halogen or non-aromatic carbocyclic group) or unsubstituted alkyl (hereinafter referred to as C-13).
R3 has the formula:
Figure JPOXMLDOC01-appb-C000022
(wherein R 3a is halogen;
R 3b is alkyl or unsubstituted alkyl substituted with halogen) (hereinafter referred to as C-14).
　Ｒ４ａは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基が挙げられる（以下、Ｄ－１とする）。
　Ｒ４ａは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族炭素環式基が挙げられる（以下、Ｄ－２とする）。
　Ｒ４ａは、水素原子、置換基群ｅ（置換基群ｅ：ハロゲン；および、置換もしくは非置換の芳香族炭素環オキシ）から選択される１以上の置換基で置換された芳香族炭素環式基もしくは非置換芳香族炭素環式基、または、置換基群ｆ（置換基群ｆ：置換もしくは非置換の芳香族炭素環式基；置換もしくは非置換のアミノ；ハロゲン；置換もしくは非置換の非芳香族炭素環式基；置換もしくは非置換のアルキルオキシ；置換もしくは非置換の芳香族複素環式基；および、シアノ）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキルが挙げられる（以下、Ｄ－３とする）。
　Ｒ４ａは、水素原子、置換基群ｅ’（置換基群ｅ’：ハロゲンおよび非置換芳香族炭素環オキシ）から選択される１以上の置換基で置換された芳香族炭素環式基もしくは非置換芳香族炭素環式基、または、置換基群ｆ’（置換基群ｆ’：置換芳香族炭素環式基（置換基：シアノ、ハロゲン）もしくは非置換芳香族炭素環式基；置換アミノ（置換基：アルキル）もしくは非置換アミノ；ハロゲン；非置換非芳香族炭素環式基；置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシ；非置換芳香族複素環式基；および、シアノ）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキルが挙げられる（以下、Ｄ－４とする）。
　Ｒ４ａは、水素原子、または、置換基群ｅ（置換基群ｅ：ハロゲン；および、置換もしくは非置換の芳香族炭素環オキシ）から選択される１以上の置換基で置換された芳香族炭素環式基もしくは非置換芳香族炭素環式基が挙げられる（以下、Ｄ－５とする）。
　Ｒ４ａは、水素原子、または、置換基群ｅ’（置換基群ｅ’：ハロゲンおよび非置換芳香族炭素環オキシ）から選択される１以上の置換基で置換された芳香族炭素環式基もしくは非置換芳香族炭素環式基が挙げられる（以下、Ｄ－６とする）。
　Ｒ４ａは、水素原子、または、置換基群ｆ（置換基群ｆ：置換もしくは非置換の芳香族炭素環式基；置換もしくは非置換のアミノ；ハロゲン；置換もしくは非置換の非芳香族炭素環式基；置換もしくは非置換のアルキルオキシ；置換もしくは非置換の芳香族複素環式基；および、シアノ）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキルが挙げられる（以下、Ｄ－７とする）。
　Ｒ４ａは、水素原子、または、置換基群ｆ’（置換基群ｆ’：置換芳香族炭素環式基（置換基：シアノ、およびハロゲン）もしくは非置換芳香族炭素環式基；置換アミノ（置換基：アルキル）もしくは非置換アミノ；ハロゲン；非置換非芳香族炭素環式基；置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシ；非置換芳香族複素環式基；および、シアノ）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキルが挙げられる（以下、Ｄ－８とする）。
　Ｒ４ａは、水素原子が挙げられる（以下、Ｄ－９とする）。
　Ｒ４ａは、置換基群ｅ（置換基群ｅ：ハロゲン；および、置換もしくは非置換の芳香族炭素環オキシ）から選択される１以上の置換基で置換された芳香族炭素環式基もしくは非置換芳香族炭素環式基が挙げられる（以下、Ｄ－１０とする）。
　Ｒ４ａは、置換基群ｆ（置換基群ｆ：置換もしくは非置換の芳香族炭素環式基；置換もしくは非置換のアミノ；ハロゲン；置換もしくは非置換の非芳香族炭素環式基；置換もしくは非置換のアルキルオキシ；置換もしくは非置換の芳香族複素環式基；および、シアノ）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキルが挙げられる（以下、Ｄ－１１とする）。
　Ｒ４ａは、置換基群ｅ’（置換基群ｅ’：ハロゲンおよび非置換芳香族炭素環オキシ）から選択される１以上の置換基で置換された芳香族炭素環式基もしくは非置換芳香族炭素環式基が挙げられる（以下、Ｄ－１２とする）。
　Ｒ４ａは、置換基群ｆ’（置換基群ｆ’：置換芳香族炭素環式基（置換基：シアノ、ハロゲン）もしくは非置換芳香族炭素環式基；置換アミノ（置換基：アルキル）もしくは非置換アミノ；ハロゲン；非置換非芳香族炭素環式基；置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシ；非置換芳香族複素環式基；および、シアノ）から選択される１以上の置換基で置換されたアルキルもしくは非置換アルキルが挙げられる（以下、Ｄ－１３とする）。
　Ｒ４ａは、非置換アルキルが挙げられる。（以下、Ｄ－１４とする）。
　Ｒ４ａは、置換芳香族炭素環式基（置換基：シアノ、ハロゲン）もしくは非置換芳香族炭素環式基で置換されたアルキルが挙げられる（以下、Ｄ－１５とする）。
　Ｒ４ａは、置換アミノ（置換基：アルキル）もしくは非置換アミノで置換されたアルキルが挙げられる（以下、Ｄ－１６とする）。
　Ｒ４ａは、ハロゲンで置換されたアルキルが挙げられる（以下、Ｄ－１７とする）。
　Ｒ４ａは、非置換非芳香族炭素環式基で置換されたアルキルが挙げられる（以下、Ｄ－１８とする）。
　Ｒ４ａは、置換アルキルオキシ（置換基：ハロゲンで置換された芳香族炭素環式基）もしくは非置換アルキルオキシで置換されたアルキルが挙げられる（以下、Ｄ－１９とする）。
　Ｒ４ａは、非置換アルキルオキシで置換されたアルキルが挙げられる（以下、Ｄ－２０とする）。
　Ｒ４ａは、非置換芳香族複素環式基で置換されたアルキルが挙げられる（以下、Ｄ－２１とする）。
　Ｒ４ａは、シアノで置換されたアルキルが挙げられる（以下、Ｄ－２２とする）。 R 4a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Examples include an unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as D-1).
R 4a includes a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as D-2) .
R 4a is a hydrogen atom, an aromatic carbocyclic ring substituted with one or more substituents selected from substituent group e (substituent group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy) group or unsubstituted aromatic carbocyclic group, or substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted unsubstituted substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano). (hereinafter referred to as D-3).
R 4a is a hydrogen atom, an aromatic carbocyclic group substituted with one or more substituents selected from substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy) or non- Substituted aromatic carbocyclic group, or substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituent: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino ( halogen; unsubstituted aromatic carbocyclic group; substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy; unsubstituted aromatic and cyano) or alkyl substituted with one or more substituents (hereinafter referred to as D-4).
R 4a is a hydrogen atom or an aromatic carbon substituted with one or more substituents selected from substituent group e (substituent group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy) A cyclic group or an unsubstituted aromatic carbocyclic group can be mentioned (hereinafter referred to as D-5).
R 4a is a hydrogen atom or an aromatic carbocyclic group substituted with one or more substituents selected from substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy) Alternatively, an unsubstituted aromatic carbocyclic group can be mentioned (hereinafter referred to as D-6).
R 4a is a hydrogen atom or a substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic ring substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano). , D-7).
R 4a is a hydrogen atom, or substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituents: cyano and halogen) or unsubstituted aromatic carbocyclic group; substituted amino ( halogen; unsubstituted aromatic carbocyclic group; substituted alkyloxy (substituent: halogen-substituted aromatic carbocyclic group) or unsubstituted alkyloxy; unsubstituted aromatic and cyano) or alkyl substituted with one or more substituents (hereinafter referred to as D-8).
R 4a includes a hydrogen atom (hereinafter referred to as D-9).
R 4a is an aromatic carbocyclic group substituted with one or more substituents selected from substituent group e (substituent group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy) or non- and substituted aromatic carbocyclic groups (hereinafter referred to as D-10).
R 4a is a substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic group; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano). do).
R 4a is an aromatic carbocyclic group or an unsubstituted aromatic group substituted with one or more substituents selected from substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy) carbocyclic groups (hereinafter referred to as D-12);
R 4a is a substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituent: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino (substituent: alkyl) or unsubstituted amino; halogen; unsubstituted unaromatic carbocyclic group; substituted alkyloxy (substituent: aromatic carbocyclic group substituted with halogen) or unsubstituted alkyloxy; unsubstituted aromatic heterocyclic group; and cyano) substituted with one or more substituents or unsubstituted alkyl (hereinafter referred to as D-13).
R 4a includes unsubstituted alkyl. (hereinafter referred to as D-14).
R 4a includes alkyl substituted with a substituted aromatic carbocyclic group (substituent: cyano, halogen) or an unsubstituted aromatic carbocyclic group (hereinafter referred to as D-15).
R 4a includes substituted amino (substituent: alkyl) or alkyl substituted with unsubstituted amino (hereinafter referred to as D-16).
R 4a includes halogen-substituted alkyl (hereinafter referred to as D-17).
R 4a includes alkyl substituted with an unsubstituted non-aromatic carbocyclic group (hereinafter referred to as D-18).
R 4a includes substituted alkyloxy (substituent: aromatic carbocyclic group substituted with halogen) or alkyl substituted with unsubstituted alkyloxy (hereinafter referred to as D-19).
R 4a includes alkyl substituted with unsubstituted alkyloxy (hereinafter referred to as D-20).
R 4a includes alkyl substituted with an unsubstituted aromatic heterocyclic group (hereinafter referred to as D-21).
R 4a includes cyano-substituted alkyl (hereinafter referred to as D-22).
　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000023
で示される化合物における実施形態として、例えば、式（Ｉ’’）：
Figure JPOXMLDOC01-appb-C000024
（式中、Ｒ１、Ｒ２ａ、Ｒ３およびＲ４ａは、上記（１）と同義）で示される化合物が挙げられる。Ｒ１、Ｒ２ａ、Ｒ３およびＲ４ａの好ましい態様を以下に示す。式（Ｉ’’）で示される化合物としては、以下に示される具体例のすべての組み合わせの態様が例示される。 Formula (I):
Figure JPOXMLDOC01-appb-C000023
For example, as an embodiment in a compound represented by formula (I''):
Figure JPOXMLDOC01-appb-C000024
(wherein R 1 , R 2a , R 3 and R 4a are the same as defined in (1) above). Preferred embodiments of R 1 , R 2a , R 3 and R 4a are shown below. As the compound represented by formula (I''), all combinations of specific examples shown below are exemplified.
　Ｒ１は、上記（Ａ－１）、（Ａ－２）、（Ａ－３）、（Ａ－４）、（Ａ－５）、（Ａ－６）、（Ａ－７）、（Ａ－８）、（Ａ－９）、（Ａ－１０）、（Ａ－１１）、（Ａ－１２）または（Ａ－１３）が挙げられる。 R 1 is the above (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A- 8), (A-9), (A-10), (A-11), (A-12) or (A-13).
　Ｒ２ａは、上記（Ｂ－１）、（Ｂ－２）、（Ｂ－３）、（Ｂ－４）、（Ｂ－５）、（Ｂ－６）、（Ｂ－７）、（Ｂ－８）または（Ｂ－９）が挙げられる。 R 2a is the above (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B- 8) or (B-9).
　Ｒ３は、上記（Ｃ－１）、（Ｃ－２）、（Ｃ－３）、（Ｃ－４）、（Ｃ－５）、（Ｃ－６）、（Ｃ－７）、（Ｃ－８）、（Ｃ－９）、（Ｃ－１０）、（Ｃ－１１）、（Ｃ－１２）、（Ｃ－１３）または（Ｃ－１４）が挙げられる。 R 3 is the above (C-1), (C-2), (C-3), (C-4), (C-5), (C-6), (C-7), (C- 8), (C-9), (C-10), (C-11), (C-12), (C-13) or (C-14).
　Ｒ４ａは、上記（Ｄ－１）、（Ｄ－２）、（Ｄ－３）、（Ｄ－４）、（Ｄ－５）、（Ｄ－６）、（Ｄ－７）、（Ｄ－８）、（Ｄ－９）、（Ｄ－１０）、（Ｄ－１１）、（Ｄ－１２）、（Ｄ－１３）、（Ｄ－１４）、（Ｄ－１５）、（Ｄ－１６）、（Ｄ－１７）、（Ｄ－１８）、（Ｄ－１９）、（Ｄ－２０）、（Ｄ－２１）または（Ｄ－２２）が挙げられる。 R 4a is the above (D-1), (D-2), (D-3), (D-4), (D-5), (D-6), (D-7), (D- 8), (D-9), (D-10), (D-11), (D-12), (D-13), (D-14), (D-15), (D-16) , (D-17), (D-18), (D-19), (D-20), (D-21) or (D-22).
　式（Ｉ’）および式（Ｉ’’）で示される化合物における実施形態として、以下の組み合わせが挙げられる。
（ａ１）
Ｒ１は、（Ａ－３）または（Ａ－４）であり；
Ｒ２ａは、（Ｂ－５）であり；
Ｒ３は、（Ｃ－１４）であり；
Ｒ４ａは、（Ｄ－９）、（Ｄ－１４）または（Ｄ－２０）である。
（ａ２）
Ｒ１は、（Ａ－１０）または（Ａ－１１）であり；
Ｒ２ａは、（Ｂ－５）であり；
Ｒ３は、（Ｃ－１４）であり；
Ｒ４ａは、（Ｄ－９）、（Ｄ－１４）または（Ｄ－２０）である。
（ｂ１）
Ｒ１は、（Ａ－３）または（Ａ－４）であり；
Ｒ２ａは、（Ｂ－５）であり；
Ｒ３は、（Ｃ－１０）であり；
Ｒ４ａは、（Ｄ－９）、（Ｄ－１４）または（Ｄ－２０）である。
（ｂ２）
Ｒ１は、（Ａ－１０）または（Ａ－１１）であり；
Ｒ２ａは、（Ｂ－５）であり；
Ｒ３は、（Ｃ－１０）であり；
Ｒ４ａは、（Ｄ－９）、（Ｄ－１４）または（Ｄ－２０）である。 Embodiments of compounds represented by formula (I′) and formula (I″) include the following combinations.
(a1)
R 1 is (A-3) or (A-4);
R 2a is (B-5);
R 3 is (C-14);
R 4a is (D-9), (D-14) or (D-20).
(a2)
R 1 is (A-10) or (A-11);
R 2a is (B-5);
R 3 is (C-14);
R 4a is (D-9), (D-14) or (D-20).
(b1)
R 1 is (A-3) or (A-4);
R 2a is (B-5);
R 3 is (C-10);
R 4a is (D-9), (D-14) or (D-20).
(b2)
R 1 is (A-10) or (A-11);
R 2a is (B-5);
R 3 is (C-10);
R 4a is (D-9), (D-14) or (D-20).
　式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物は、特定の異性体に限定するものではなく、全ての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体等）、ラセミ体またはそれらの混合物を含む。例えば、式（Ｉ）においてＹが＝Ｎ－であり、Ｘが－ＮＲ５－であり、Ｒ５が水素原子である化合物は、以下のような互変異性体を包含する。
Figure JPOXMLDOC01-appb-C000025
　式（Ｉ’）および式（Ｉ’’）についても同様である。
Figure JPOXMLDOC01-appb-C000026
　例えば、式（Ｉ）においてＹが＝ＣＲ６－であり、Ｒ６が水素原子であり、ＸがＮＨである化合物は、以下のような互変異性体を包含する。
Figure JPOXMLDOC01-appb-C000027
 The compounds of formula (I), formula (I′) and formula (I″) are not limited to any particular isomer, but all possible isomers (e.g. keto-enol isomers, imine - enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof. For example, a compound of formula (I) in which Y is =N-, X is -NR 5 -, and R 5 is a hydrogen atom includes the following tautomers.
Figure JPOXMLDOC01-appb-C000025
The same applies to formula (I') and formula (I'').
Figure JPOXMLDOC01-appb-C000026
For example, compounds of formula (I) in which Y is =CR 6 —, R 6 is a hydrogen atom, and X is NH include the following tautomers.
Figure JPOXMLDOC01-appb-C000027
　式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物の一つ以上の水素、炭素および／または他の原子は、それぞれ水素、炭素および／または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、123Ｉおよび３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、該「放射性標識体」は、代謝薬物動態研究、結合アッセイにおける研究および／または診断のツールとして有用である。 One or more hydrogen, carbon and/or other atoms of the compounds of Formula (I), Formula (I') and Formula (I'') are isotopes of hydrogen, carbon and/or other atoms, respectively can be replaced with Examples of such 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), Formula (I') and 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), formula (I') and 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.
　式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示されるトリチウム標識化合物は、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下または非存在下で、式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。トリチウム標識化合物を調製するための他の適切な方法は、“Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）”を参照することができる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。 Radiolabeled compounds of formula (I), formula (I') and formula (I'') can be prepared by methods well known in the art. For example, the tritium-labeled compounds represented by formula (I), formula (I') and formula (I'') can be converted to formula (I), formula (I') and formula (I') by a catalytic dehalogenation reaction using tritium. It can be prepared by introducing tritium into a specific compound represented by formula (I''). This method suitably comprises compounds of formula (I), formula (I′) and formula (I″) in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base. It involves reacting the halogen-substituted precursor with tritium gas. Other suitable methods for preparing tritiated compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds can be prepared by using starting materials with a 14 C carbon.
　式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物の製薬上許容される塩としては、例えば、式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物と、アルカリ金属（例えば、リチウム、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム、バリウム等）、マグネシウム、遷移金属（例えば、亜鉛、鉄等）、アンモニア、有機塩基（例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、メグルミン、エチレンジアミン、ピリジン、ピコリン、キノリン等）およびアミノ酸との塩、または無機酸（例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等）、および有機酸（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、コハク酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸、トリフルオロ酢酸等）との塩が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。 Pharmaceutically acceptable salts of the compounds represented by formula (I), formula (I') and formula (I'') include, for example, formula (I), formula (I') and formula (I'') with a compound represented by an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metal (e.g., zinc, iron, etc.), ammonia, an organic base ( (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, odorants). Hydrochloric acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by a commonly used method.
　本発明の式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）、共結晶および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物、共結晶および結晶多形も包含する。「溶媒和物」は、式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物またはその製薬上許容される塩を、再結晶することで結晶多形を形成する場合がある。「共結晶」は、式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物または塩とカウンター分子が同一結晶格子内に存在することを意味し、任意の数のカウンター分子を含んでいても良い。 The compounds represented by formula (I), formula (I′) and formula (I″) of the present invention or pharmaceutically acceptable salts thereof can be converted into solvates (e.g., hydrates, etc.), co-crystals and/or or may form crystalline polymorphs, and the invention also includes such various solvates, co-crystals and crystalline polymorphs. A "solvate" is a compound of Formula (I), Formula (I') and Formula (I'') coordinated with any number of solvent molecules (e.g., water molecules, etc.) good too. When the compound represented by formula (I), formula (I') and formula (I'') or a pharmaceutically acceptable salt thereof absorbs water by being left in the atmosphere, and adsorbed water adheres. and may form hydrates. In addition, the compounds represented by formula (I), formula (I') and formula (I'') or their pharmaceutically acceptable salts may be recrystallized to form polymorphs. "Co-crystal" means that a compound or salt of formula (I), formula (I') and formula (I'') and a counter molecule are present in the same crystal lattice, and any number of counter It may contain molecules.
　本発明の式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物に変換される化合物、胃酸等により加水分解されて式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えば“Ｄｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ，　１９８５”に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compounds of Formula (I), Formula (I′) and Formula (I″) of the present invention, or pharmaceutically acceptable salts thereof, may form prodrugs, and the present invention provides such various Also includes prodrugs of 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. Prodrugs are compounds that undergo enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo and are converted into compounds represented by formula (I), formula (I') and formula (I''). , gastric acid, etc. to convert to compounds represented by formula (I), formula (I') and formula (I''). 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.
　式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物またはその製薬上許容される塩がヒドロキシル基を有する場合は、例えば、ヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロライド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えば、ＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔｅｒｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、ｐ－ＣＨ３Ｏ－ＰｈＳＯ３－、ＰｈＳＯ３－、ｐ－ＣＨ３ＰｈＳＯ３－が挙げられる。 When the compound represented by formula (I), formula (I') and formula (I'') or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and a suitable acyl halide, Prodrugs such as acyloxy derivatives and sulfonyloxy derivatives prepared by reacting with suitable acid anhydrides, suitable sulfonyl chlorides, suitable sulfonyl anhydrides and mixed anhydrides or by using condensing agents is exemplified. For example, CH 3 COO-, C 2 H 5 COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH(NH 2 ) COO—, CH 2 N(CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p -CH 3 O-PhSO 3 -, PhSO 3 -, p-CH 3 PhSO 3 -.
　本発明に係る化合物は、コロナウイルス３ＣＬプロテアーゼ阻害活性を有するため、コロナウイルス３ＣＬプロテアーゼが関与する疾患の治療および／または予防剤として有用である。本発明において「治療剤および／または予防剤」という場合、症状改善剤も包含する。コロナウイルス３ＣＬプロテアーゼが関与する疾患としては、ウイルス感染症が挙げられ、好ましくはコロナウイルス感染症が挙げられる。
　一つの態様として、コロナウイルスとしては、ヒトに感染するコロナウイルスが挙げられる。ヒトに感染するコロナウイルスとしては、ＨＣｏＶ－２２９Ｅ、ＨＣｏＶ－ＮＬ６３、ＨＣｏＶ－ＨＫＵ１、ＨＣｏＶ－ＯＣ４３、ＳＡＲＳ－ＣｏＶ、ＭＥＲＳ－ＣｏＶ、および／またはＳＡＲＳ－ＣｏＶ－２が挙げられる。
　一つの態様として、コロナウイルスとしては、アルファコロナウイルスおよび／またはベータコロナウイルス、より好ましくはベータコロナウイルスが挙げられる。
　一つの態様として、アルファコロナウイルスとしては、ＨＣｏＶ－２２９ＥおよびＨＣｏＶ－ＮＬ６３が挙げられる。特に好ましくは、ＨＣｏＶ－２２９Ｅが挙げられる。
　一つの態様として、ベータコロナウイルスとしては、ＨＣｏＶ－ＨＫＵ１、ＨＣｏＶ－ＯＣ４３、ＳＡＲＳ－ＣｏＶ、ＭＥＲＳ－ＣｏＶ、および／またはＳＡＲＳ－ＣｏＶ－２が挙げられる。好ましくはＨＣｏＶ－ＯＣ４３またはＳＡＲＳ－ＣｏＶ－２、特に好ましくはＳＡＲＳ－ＣｏＶ－２が挙げられる。
　一つの態様として、ベータコロナウイルスとしては、ベータコロナウイルスＡ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ａ）、ベータコロナウイルスＢ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ｂ）、およびベータコロナウイルスＣ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ｃ）が挙げられる。より好ましくは、ベータコロナウイルスＡ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ａ）、およびベータコロナウイルスＢ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ｂ）、特に好ましくはベータコロナウイルスＢ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ｂ）が挙げられる。
　ベータコロナウイルスＡ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ａ）としては、例えばＨＣｏＶ－ＨＫＵ１およびＨＣｏＶ－ＯＣ４３、好ましくは、ＨＣｏＶ－ＯＣ４３が挙げられる。ベータコロナウイルスＢ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ｂ）としては、例えばＳＡＲＳ－ＣｏＶおよびＳＡＲＳ－ＣｏＶ－２、好ましくはＳＡＲＳ－ＣｏＶ－２が挙げられる。ベータコロナウイルスＣ系統（β－ｃｏｒｏｎａｖｉｒｕｓ　ｌｉｎｅａｇｅ　Ｃ）としては、好ましくはＭＥＲＳ－ＣｏＶが挙げられる。
　一つの態様として、コロナウイルスとしては、ＨＣｏＶ－２２９Ｅ、ＨＣｏＶ－ＯＣ４３、および／またはＳＡＲＳ－ＣｏＶ－２、特に好ましくはＳＡＲＳ－ＣｏＶ－２が挙げられる。
　コロナウイルス感染症としては、ＨＣｏＶ－２２９Ｅ、ＨＣｏＶ－ＮＬ６３、ＨＣｏＶ－ＯＣ４３、ＨＣｏＶ－ＨＫＵ１、ＳＡＲＳ－ＣｏＶ、ＭＥＲＳ－ＣｏＶ、および／またはＳＡＲＳ－ＣｏＶ－２による感染症が挙げられる。好ましくは、ＨＣｏＶ－２２９Ｅ、ＨＣｏＶ－ＯＣ４３、および／またはＳＡＲＳ－ＣｏＶ－２による感染症、特に好ましくは、ＳＡＲＳ－ＣｏＶ－２による感染症が挙げられる。
　コロナウイルス感染症としては、特に好ましくは、新型コロナウイルス感染症（ＣＯＶＩＤ－１９）が挙げられる。 Since the compound according to the present invention has coronavirus 3CL protease inhibitory activity, it is useful as a therapeutic and/or prophylactic agent for diseases associated with coronavirus 3CL protease. In the present invention, the term "therapeutic agent and/or prophylactic agent" also includes symptom improving agents. Diseases involving coronavirus 3CL protease include viral infections, preferably coronavirus infections.
In one embodiment, 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.
In one embodiment, coronaviruses include alphacoronaviruses and/or betacoronaviruses, more preferably betacoronaviruses.
In one aspect, alphacoronaviruses include HCoV-229E and HCoV-NL63. Particularly preferred is HCoV-229E.
In one aspect, 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.
In one embodiment, the betacoronavirus includes betacoronavirus A strain (β-coronavirus lineage A), betacoronavirus B strain (β-coronavirus lineage B), and betacoronavirus C strain (β-coronavirus lineage C). are mentioned. More preferred are β-coronavirus lineage A and β-coronavirus lineage B, particularly preferably β-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 C preferably includes MERS-CoV.
In one embodiment, coronaviruses include HCoV-229E, HCoV-OC43 and/or SARS-CoV-2, particularly preferably SARS-CoV-2.
Coronavirus infections include infections by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. Preferred are 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.
（本発明の化合物の製造法）
　本発明に係る式（Ｉ）、式（Ｉ’）および式（Ｉ’’）で示される化合物は、例えば、下記に示す一般的合成法によって製造することができる。抽出、精製等は、通常の有機化学の実験で行う処理を行えばよい。
　本発明の化合物は、当該分野において公知の手法を参考にしながら製造することができる。例えば、ＷＯ２０１８／０７４３９０およびＷＯ２０１２／０２０７４９を参考にして製造することができる。 (Method for producing the compound of the present invention)
The compounds represented by formula (I), formula (I') and 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 experiments.
The compounds of the present invention can be produced with reference to methods known in the art. For example, it can be manufactured with reference to WO2018/074390 and WO2012/020749.
（Ａ法）Ｚが－ＮＲ１－であり、Ｗが＝Ｎ－である場合
Figure JPOXMLDOC01-appb-C000028
（式中、各記号は前期と同義である。）
（第１工程）
　ＷＯ２０１２／０２０７４９記載の合成法に従い、化合物（Ａ－１）と化合物（Ａ－２）を反応させることにより、化合物（Ａ－３）を製造することができる。
（第２工程）
　ＷＯ２０１８／０７４３９０記載の合成法に従い、化合物（Ａ－３）を塩基、窒化塩化りん三量体存在下、化合物（Ａ－４）と反応させることにより化合物（Ａ－５）を製造することができる。
（第３工程）
　ＷＯ２０１８／０７４３９０記載の合成法に従い、化合物（Ａ－５）を塩基存在下、トリメチルアミン塩酸塩、メタンスルホニルクロリドと適当な溶媒中で反応させることにより化合物（Ｉ－Ａ）を製造することができる。
　得られた所望の化合物（Ｉ－Ａ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製、およびキラルカラムを用いたＳＦＣ分取（液化炭酸－メタノール（またはエタノール等））により光学分割することができる。または、キラルな化合物（Ａ－４）を用いて、キラルな化合物（Ｉ－Ａ）を製造することができる。 (Method A) When Z is -NR 1 - and W is =N-
Figure JPOXMLDOC01-appb-C000028
(In the formula, each symbol has the same meaning as the previous term.)
(First step)
Compound (A-3) can be produced by reacting compound (A-1) with compound (A-2) according to the synthesis method described in WO2012/020749.
(Second step)
Compound (A-5) can be produced by reacting compound (A-3) with compound (A-4) in the presence of a base and a phosphorus oxychloride trimer according to the synthesis method described in WO2018/074390. .
(Third step)
Compound (IA) can be produced by reacting compound (A-5) with trimethylamine hydrochloride and methanesulfonyl chloride in a suitable solvent in the presence of a base according to the synthesis method described in WO2018/074390.
The obtained desired compound (IA) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.), if necessary, and SFC fractionation using a chiral column (liquefied carbonic acid-methanol (or ethanol, etc.) ) can be optically resolved. Alternatively, chiral compound (IA) can be produced using chiral compound (A-4).
（Ｂ法）Ｚが－ＣＲ１’＝であり、Ｒ１’が置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換もしくは非置換の非芳香族炭素環式基である場合
Figure JPOXMLDOC01-appb-C000029
（式中、Ｈａｌはハロゲンであり、ＲＡおよびＲＢは、それぞれ独立して水素原子、Ｃ１－Ｃ３アルキルであるか、または一緒になって置換もしくは非置換の非芳香族環を形成し、その他の記号は前記と同義である。）
（第１工程）
　ＷＯ２０１８／０７４３９０記載の合成法に従い、化合物（Ｂ－１）にハロゲン化試薬を適当な溶媒中で反応させることにより、化合物（Ｂ－２）を製造することができる。
（第２工程）
　ＷＯ２０１８／０７４３９０記載の合成法に従い、化合物（Ｂ－２）を金属触媒および塩基存在下、ボロン酸またはボロン酸エステル（Ｂ－３）と適当な溶媒中で反応させることにより、化合物（Ｉ－Ｂ）を製造することができる。
　得られた所望の化合物（Ｉ－Ｂ）は、要すれば常法（例、カラムクロマトグラフィー、再結晶など）により精製、およびキラルカラムを用いたＳＦＣ分取（液化炭酸－メタノール（またはエタノール等））により光学分割することができる。 (Method B) Z is —CR 1′ = and R 1′ is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic When it is a heterocyclic group or a substituted or unsubstituted non-aromatic carbocyclic group
Figure JPOXMLDOC01-appb-C000029
(wherein Hal is halogen, R A and R B are each independently a hydrogen atom, C1-C3 alkyl, or together form a substituted or unsubstituted non-aromatic ring, Other symbols have the same meanings as above.)
(First step)
Compound (B-2) can be produced by reacting compound (B-1) with a halogenating reagent in a suitable solvent according to the synthesis method described in WO2018/074390.
(Second step)
According to the synthesis method described in WO2018/074390, the compound (B-2) is reacted with a boronic acid or boronate ester (B-3) in the presence of a metal catalyst and a base in an appropriate solvent to give compound (IB ) can be manufactured.
The obtained desired compound (IB) can be purified by a conventional method (eg, column chromatography, recrystallization, etc.), if necessary, and subjected to SFC fractionation using a chiral column (liquefied carbonic acid-methanol (or ethanol, etc.) ) can be optically resolved.
　本発明に係る化合物は、コロナウイルス３ＣＬプロテアーゼ阻害活性を有するため、ウイルス感染症の治療および／または予防剤として有用である。
　さらに本発明化合物は、医薬としての有用性を備えており、好ましくは、下記のいずれか、または複数の優れた特徴を有している。
ａ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ２Ｃ１９、ＣＹＰ２Ｄ６、ＣＹＰ３Ａ４等）に対する阻害作用が弱い。
ｂ）高いバイオアベイラビリティー、適度なクリアランス等良好な薬物動態を示す。
ｃ）代謝安定性が高い。
ｄ）ＣＹＰ酵素（例えば、ＣＹＰ３Ａ４）に対し、不可逆的阻害作用を示さない。
ｅ）変異原性を有さない。
ｆ）心血管系のリスクが低い。
ｇ）高い溶解性を示す。
ｈ）タンパク質非結合率（ｆｕ値）が高い。
ｉ）高いコロナウイルス３ＣＬプロテアーゼ選択性を有している。
ｊ）高いコロナウイルス増殖阻害活性を有している。例えば、ヒト血清（ＨＳ）またはヒト血清アルブミン（ＨＳＡ）添加下において、高いコロナウイルス増殖阻害活性を有している。
ｋ）３ＣＬプロテアーゼ阻害剤耐性ウイルスに対して、高い増殖阻害活性を有する。
　コロナウイルス増殖阻害剤としては、例えば後述のＣＰＥ抑制効果確認試験（ＳＡＲＳ－ＣｏＶ－２）において、例えばＥＣ５０が１０μＭ以下、好ましくは１μＭ以下、より好ましくは１００ｎＭ以下である態様が挙げられる。 Since the compounds according to the present invention have coronavirus 3CL protease inhibitory activity, they are useful as therapeutic and/or prophylactic agents for viral infections.
Furthermore, 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.).
b) shows good pharmacokinetics such as high bioavailability and moderate clearance;
c) high metabolic stability;
d) It does not exhibit irreversible inhibitory effects on CYP enzymes (eg CYP3A4).
e) not mutagenic;
f) low cardiovascular risk;
g) exhibit high solubility;
h) High protein non-binding rate (fu value).
i) have high coronavirus 3CL protease selectivity;
j) It has high coronavirus growth inhibitory activity. For example, it has high coronavirus growth inhibitory activity under the addition of human serum (HS) or human serum albumin (HSA).
k) It has high growth inhibitory activity against 3CL protease inhibitor-resistant viruses.
Examples of coronavirus growth inhibitors include embodiments in which EC 50 is 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less in the CPE suppression effect confirmation test (SARS-CoV-2) described later.
　本発明の医薬組成物は、経口的、非経口的のいずれの方法でも投与することができる。非経口投与の方法としては、経皮、皮下、静脈内、動脈内、筋肉内、腹腔内、経粘膜、吸入、経鼻、点眼、点耳、膣内投与等が挙げられる。 The pharmaceutical composition of the present invention can be administered orally or parenterally. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear and intravaginal administration.
　経口投与の場合は常法に従って、内用固形製剤（例えば、錠剤、散剤、顆粒剤、カプセル剤、丸剤、フィルム剤等）、内用液剤（例えば、懸濁剤、乳剤、エリキシル剤、シロップ剤、リモナーデ剤、酒精剤、芳香水剤、エキス剤、煎剤、チンキ剤等）等の通常用いられるいずれの剤型に調製して投与すればよい。錠剤は、糖衣錠、フィルムコーティング錠、腸溶性コーティング錠、徐放錠、トローチ錠、舌下錠、バッカル錠、チュアブル錠または口腔内崩壊錠であってもよく、散剤および顆粒剤はドライシロップであってもよく、カプセル剤は、ソフトカプセル剤、マイクロカプセル剤または徐放性カプセル剤であってもよい。 For oral administration, internal solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.), internal liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, etc.) It may be prepared and administered in any commonly used dosage form such as a drug, limonade, alcohol, aromatic water, extract, decoction, tincture, and the like. 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. Alternatively, the capsules may be soft capsules, microcapsules or sustained release capsules.
　非経口投与の場合は、注射剤、点滴剤、外用剤（例えば、点眼剤、点鼻剤、点耳剤、エアゾール剤、吸入剤、ローション剤、注入剤、塗布剤、含嗽剤、浣腸剤、軟膏剤、硬膏剤、ゼリー剤、クリーム剤、貼付剤、パップ剤、外用散剤、坐剤等）等の通常用いられるいずれの剤型でも好適に投与することができる。注射剤は、Ｏ／Ｗ、Ｗ／Ｏ、Ｏ／Ｗ／Ｏ、Ｗ／Ｏ／Ｗ型等のエマルジョンであってもよい。 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.
　本発明化合物の有効量にその剤型に適した賦形剤、結合剤、崩壊剤、滑沢剤等の各種医薬用添加剤を必要に応じて混合し、医薬組成物とすることができる。さらに、該医薬組成物は、本発明化合物の有効量、剤型および／または各種医薬用添加剤を適宜変更することにより、小児用、高齢者用、重症患者用または手術用の医薬組成物とすることもできる。例えば、小児用医薬組成物は、新生児（出生後４週未満）、乳児（出生後４週～１歳未満）幼児（１歳以上７歳未満）、小児（７歳以上１５歳未満）若しくは１５歳～１８歳の患者に投与されうる。例えば、高齢者用医薬組成物は、６５歳以上の患者に投与されうる。 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.
　本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、経口投与する場合、通常０．０５～２００ｍｇ／ｋｇ／日であり、好ましくは０．１～１００ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～２００ｍｇ／ｋｇ／日であり、好ましくは０．０１～１００ｍｇ／ｋｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。 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 200 mg / kg/day, preferably within the range of 0.1 to 100 mg/kg/day. In the case of parenteral administration, it is generally 0.005 to 200 mg/kg/day, preferably 0.01 to 100 mg/kg/day, although it varies greatly depending on the route of administration. It may be administered once to several times a day.
　本発明化合物は、該化合物の作用の増強または該化合物の投与量の低減等を目的として、例えば、他の新型コロナウイルス感染症（ＣＯＶＩＤ－１９）の治療薬（該治療薬としては、承認を受けた薬剤、および開発中または今後開発される薬剤を含む）（以下、併用薬剤と称する）と組み合わせて用いてもよい。この際、本発明化合物と併用薬剤の投与時期は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。さらに、本発明化合物と併用薬剤とは、それぞれの活性成分を含む２種類以上の製剤として投与されてもよいし、それらの活性成分を含む単一の製剤として投与されてもよい。 For the purpose of enhancing the action of the compound or reducing the dosage of the compound, 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). In this case, 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. Furthermore, 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.
　併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物と併用薬剤の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明化合物１重量部に対し、併用薬剤を０．０１～１００重量部用いればよい。 The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. In addition, 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.
　以下に実施例および参考例、ならびに試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。 The present invention will be described in more detail below with examples, reference examples, and test examples, but the present invention is not limited by these.
　また、本明細書中で用いる略語は以下の意味を表す。
ＣＤＩ：カルボニルジイミダゾール
ＤＢＵ：１，８－ジアザビシクロ［５．４．０］－７－ウンデセン
ＤＩＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＦＢＳ：ウシ胎児血清
ＨＣＣＰ：ヘキサクロロシクロトリホスファゼン
ＭＥＭ：イーグル最小必須培地
ＳＦＣ：超臨界流体クロマトグラフィー
ｍＭ：ｍｍｏｌ／Ｌ
μＭ：μｍｏｌ／Ｌ
ｎＭ：ｎｍｏｌ／Ｌ Abbreviations used in this specification have the following meanings.
CDI: carbonyldiimidazole DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DIEA: N,N-diisopropylethylamine FBS: fetal bovine serum HCCP: hexachlorocyclotriphosphazene MEM: Eagle's minimum essential medium SFC: Supercritical fluid chromatography mM: mmol/L
μM: μmol/L
nM: nmol/L
（化合物の同定方法）
　各実施例で得られたＮＭＲ分析は４００ＭＨｚで行い、ＤＭＳＯ－ｄ６、ＣＤＣｌ３を用いて測定した。また、ＮＭＲデータを示す場合は、測定した全てのピークを記載していない場合が存在する。
　明細書中にＲＴとあるのは、ＬＣ／ＭＳ：液体クロマトグラフィー／質量分析でのリテンションタイムを表し、以下の条件で測定した。
（測定条件１）
カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（登録商標）ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）　（Ｗａｔｅｒｓ）
流速：０．８ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジエント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行った後、０．５分間、１００％溶媒［Ｂ］を維持した。
（測定条件２）
カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ　（２．２μｍ、ｉ．ｄ．３．０ｘ５０ｍｍ）　（Ｓｈｉｍａｄｚｕ）
流速：１．６ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジエント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。
　なお、明細書中、ＭＳ（ｍ／ｚ）との記載は、質量分析で観測された値を示す。 (Compound identification method)
NMR analyzes obtained in each example were performed at 400 MHz and measured using DMSO-d 6 , CDCl 3 . Moreover, when NMR data are shown, there are cases where not all measured peaks are described.
RT in the specification represents retention time in LC/MS: liquid chromatography/mass spectrometry, and was measured under the following conditions.
(Measurement condition 1)
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1×50 mm) (Waters)
Flow rate: 0.8 mL/min UV detection wavelength: 254 nm
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: After performing a linear gradient of 5%-100% solvent [B] in 3.5 minutes , 100% solvent [B] was maintained for 0.5 min.
(Measurement condition 2)
Column: Shim-pack XR-ODS (2.2 μm, id 3.0×50 mm) (Shimadzu)
Flow rate: 1.6 mL/min UV detection wavelength: 254 nm
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid. 100% solvent [B] was maintained for minutes.
In the specification, the description of MS (m/z) indicates the value observed by mass spectrometry.
（化合物の分取方法）
（ＳＦＣ分取）
カラム：ＩＡ　（２０ｘ２５０ｍｍ）（日本分光）
流速：２０ｍＬ／分
ＵＶ検出波長：２２０ｎｍ
移動相：［Ａ］は二酸化炭素、［Ｂ］はエタノール
［Ａ］：［Ｂ］＝　３０：７０
グラジエント：なし (Compound isolation method)
(SFC preparative)
Column: IA (20x250mm) (JASCO Corporation)
Flow rate: 20 mL/min UV detection wavelength: 220 nm
Mobile phase: [A] is carbon dioxide, [B] is ethanol [A]: [B] = 30: 70
Gradient: none
（単結晶構造解析の測定と解析方法）
　単結晶構造解析の測定条件および解析方法を以下に示す。
（装置）
リガク社製　ＸｔａＬＡＢ Ｐ２００ ＭＭ００７
（測定条件）
測定温度：２５℃
使用波長：ＣｕＫα線（λ＝１．５４１８Å）
ソフト：CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
（データ処理）
ソフト：CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
データはローレンツ及び偏光補正、吸収補正を行った。
（結晶構造解析）
　直接法プログラムＳｈｅｌＸＴ（Ｓｈｅｌｄｒｉｃｋ, Ｇ.Ｍ.，２０１５）を用いて位相決定を行い、精密化はＳｈｅｌＸＬ（Ｓｈｅｌｄｒｉｃｋ, Ｇ.Ｍ.，２０１５）を用いて、ｆｕｌｌ－ｍａｔｒｉｘ最小二乗法を実施した。非水素原子の温度因子はすべて異方性で精密化を行った。水素原子はＳｈｅｌＸＬのデフォルトパラメータを用いて計算により導入し、ｒｉｄｉｎｇ　ａｔｏｍとして取り扱った。全ての水素原子は、等方性パラメーターで精密化を行った。
　図１および図２の作図にはＰＬＡＴＯＮ（Ｓｐｅｋ，１９９１）／ＯＲＴＥＰ（Ｊｏｈｎｓｏｎ，１９７６）を使用した。 (Measurement and analysis method for single crystal structure analysis)
The measurement conditions and analysis method for single crystal structure analysis are shown below.
(Device)
Rigaku XtaLAB P200 MM007
(Measurement condition)
Measurement temperature: 25°C
Wavelength used: CuKα rays (λ = 1.5418 Å)
Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
(Data processing)
Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)
The data were Lorentz-, polarization-, and absorption-corrected.
(Crystal structure analysis)
Phase determination was performed using the direct method program ShelXT (Sheldrick, G.M., 2015), and refinement was performed using ShelXL (Sheldrick, G.M., 2015) using the full-matrix least-squares method. All temperature factors of non-hydrogen atoms were anisotropically refined. Hydrogen atoms were introduced by calculation using the default parameters of ShelXL and treated as riding atoms. All hydrogen atoms were refined with isotropic parameters.
PLATON (Spek, 1991)/ORTEP (Johnson, 1976) was used to draw Figures 1 and 2 .
（参考例１）化合物２の合成
Figure JPOXMLDOC01-appb-C000030
工程１　化合物１の合成
　３－クロロ－５－フルオロベンズアルデヒド（３．００ｇ、１８．９ｍｍｏｌ）、ニトロメタン（３０．７ｍＬ、５６８ｍｍｏｌ）およびトリエチルアミン（１３．１ｍＬ、９５．０ｍｍｏｌ）を混合し、室温で２４時間攪拌した。反応溶液に酢酸エチルおよび２ｍｏｌ／Ｌ塩化水素水溶液を加え、有機層を飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水で洗浄し、硫酸ナトリウムで乾燥した。硫酸ナトリウムを濾別し、ろ液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、化合物１（３．８０ｇ、１７．３ｍｍｏｌ、収率９２％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝２２０、ＲＴ＝１．７２ｍｉｎ、ＬＣ／ＭＳ測定条件１ (Reference Example 1) Synthesis of Compound 2
Figure JPOXMLDOC01-appb-C000030
Step 1 Synthesis of compound 1 Mix 3-chloro-5-fluorobenzaldehyde (3.00 g, 18.9 mmol), nitromethane (30.7 mL, 568 mmol) and triethylamine (13.1 mL, 95.0 mmol) and give 24% at room temperature. Stirred for hours. Ethyl acetate and 2 mol/L aqueous hydrogen chloride solution were added to the reaction solution, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain compound 1 (3.80 g, 17.3 mmol, yield 92%).
LC/MS (ESI): m/z=220, RT=1.72min, LC/MS measurement condition 1
工程２　化合物２の合成
　化合物１（１００ｍｇ、０．４５５ｍｍｏｌ）にメタノール（５ｍＬ）を加え、０℃に冷却した。反応溶液に、塩化ニッケル（ＩＩ）六水和物（１０８ｍｇ、０．４５５ｍｍｏｌ）および水素化ホウ素ナトリウム（８６．０ｍｇ、２．２８ｍｍｏｌ）を加え、０℃で５分間攪拌した。反応完了後、反応溶液に水を加えた。生じた不溶物を濾別し、ろ液を酢酸エチルで洗浄した。溶媒を濃縮し、酢酸エチルとクロロホルムで洗浄後、アミノカラムクロマトグラフィー（ヘキサン／酢酸エチルおよびクロロホルム／メタノール）で精製し、化合物２（６０．０ｍｇ、０．３１６ｍｍｏｌ、収率７０％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝１９０、ＲＴ＝０．８１ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 2 Synthesis of compound 2 Methanol (5 mL) was added to compound 1 (100 mg, 0.455 mmol) and cooled to 0°C. Nickel (II) chloride hexahydrate (108 mg, 0.455 mmol) and sodium borohydride (86.0 mg, 2.28 mmol) were added to the reaction solution and stirred at 0° C. for 5 minutes. After completion of the reaction, water was added to the reaction solution. The resulting insoluble matter was filtered off, and the filtrate was washed with ethyl acetate. The solvent was concentrated, washed with ethyl acetate and chloroform, and purified by amino column chromatography (hexane/ethyl acetate and chloroform/methanol) to obtain compound 2 (60.0 mg, 0.316 mmol, yield 70%). .
LC/MS (ESI): m/z=190, RT=0.81min, LC/MS measurement condition 1
（参考例２）化合物６の合成
Figure JPOXMLDOC01-appb-C000031
工程１　化合物３の合成
　窒素雰囲気下、亜鉛（１．３０ｇ、１９．９ｍｍｏｌ）、ＴＨＦ（１０ｍＬ）および１，２－ジブロモエタン（０．０１７０ｍＬ、０．１９９ｍｍｏｌ）を混合し、３０分間加熱還流した。反応溶液を室温まで冷却し、３－フルオロベンジルブロミド（０．９７７ｍＬ、７．９７ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応溶液に、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム（０．１０２ｇ、０．１９９ｍｍｏｌ）および２－ブロモ－４，５－ジフルオロ安息香酸メチル（１．００ｇ、３．９８ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応溶液に１ｍｏｌ／Ｌ塩化水素水溶液を加え、水層を酢酸エチルで抽出した。有機層を水および飽和塩化ナトリウム水で洗浄後、硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、化合物３（１．１８ｇ、４．２１ｍｍｏｌ、収率１００％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝２８１、ＲＴ＝２．７６ｍｉｎ、ＬＣ／ＭＳ測定条件１ (Reference Example 2) Synthesis of Compound 6
Figure JPOXMLDOC01-appb-C000031
Step 1 Synthesis of Compound 3 Under nitrogen atmosphere, zinc (1.30 g, 19.9 mmol), THF (10 mL) and 1,2-dibromoethane (0.0170 mL, 0.199 mmol) were mixed and heated under reflux for 30 minutes. . The reaction solution was cooled to room temperature, 3-fluorobenzyl bromide (0.977 mL, 7.97 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Bis(tri-tert-butylphosphine)palladium (0.102 g, 0.199 mmol) and methyl 2-bromo-4,5-difluorobenzoate (1.00 g, 3.98 mmol) were added to the reaction solution and Stirred for 30 minutes. A 1 mol/L aqueous solution of hydrogen chloride was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain compound 3 (1.18 g, 4.21 mmol, yield 100%).
LC/MS (ESI): m/z=281, RT=2.76min, LC/MS measurement condition 1
工程２　化合物４の合成
　化合物３（３００ｍｇ、１．０７０ｍｍｏｌ）、ＴＨＦ（３ｍＬ）、メタノール（３ｍＬ）および１ｍｏｌ／Ｌの水酸化ナトリウム水溶液（３２１１μＬ、３．２１ｍｍｏｌ）を混合し、室温で１．５時間攪拌した。反応溶液を濃縮し、得られた残渣に１ｍｏｌ／Ｌの塩化水素水溶液を加え、ジクロロメタンで抽出した。溶媒を減圧留去し、化合物４（２８２ｍｇ、１．０６ｍｍｏｌ、収率９９％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝２６７、ＲＴ＝２．２９ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 2 Synthesis of Compound 4 Compound 3 (300 mg, 1.070 mmol), THF (3 mL), methanol (3 mL) and 1 mol/L aqueous sodium hydroxide solution (3211 μL, 3.21 mmol) were mixed and Stirred for hours. The reaction solution was concentrated, a 1 mol/L hydrogen chloride aqueous solution was added to the resulting residue, and the mixture was extracted with dichloromethane. The solvent was distilled off under reduced pressure to obtain compound 4 (282 mg, 1.06 mmol, yield 99%).
LC/MS (ESI): m/z=267, RT=2.29min, LC/MS measurement condition 1
工程３　化合物５の合成
　化合物４（２８２ｍｇ、１．０６ｍｍｏｌ）、１，１’－カルボニルジイミダゾール（２０６ｍｇ、１．２７ｍｍｏｌ）およびＴＨＦ（２．８ｍＬ）を混合し、１時間加熱還流し、室温まで冷却した（反応溶液Ａとする）。
　別の反応容器中で、カリウムｔｅｒｔ－ブトキシド（１７９ｍｇ、１．５９ｍｍｏｌ）およびＴＨＦ（２．８ｍＬ）を混合し、ニトロメタン（３４４μＬ、６．３６ｍｍｏｌ）をゆっくり添加した。反応溶液を室温で１時間攪拌し、上記の反応溶液Ａを室温でゆっくり添加した。反応溶液を室温で１時間攪拌後、５０℃で１．５時間攪拌した。反応溶液に１ｍｏｌ／Ｌ塩化水素水溶液を加え、水層を酢酸エチルで抽出した。有機層を水および飽和塩化ナトリウム水で洗浄し、硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、化合物５（３１５ｍｇ、１．０２ｍｍｏｌ、収率９６％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝３１０、ＲＴ＝２．５６ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 3 Synthesis of Compound 5 Compound 4 (282 mg, 1.06 mmol), 1,1′-carbonyldiimidazole (206 mg, 1.27 mmol) and THF (2.8 mL) were mixed and heated to reflux for 1 hour, and cooled to room temperature. It was cooled (reaction solution A).
In a separate reaction vessel potassium tert-butoxide (179 mg, 1.59 mmol) and THF (2.8 mL) were mixed and nitromethane (344 μL, 6.36 mmol) was slowly added. The reaction solution was stirred at room temperature for 1 hour, and the above reaction solution A was added slowly at room temperature. The reaction solution was stirred at room temperature for 1 hour and then at 50° C. for 1.5 hours. A 1 mol/L aqueous solution of hydrogen chloride was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (hexane/ethyl acetate) to give compound 5 (315 mg, 1.02 mmol, yield 96%).
LC/MS (ESI): m/z=310, RT=2.56min, LC/MS measurement condition 1
工程４　化合物６の合成
　化合物５（１００ｍｇ、０．３２３ｍｍｏｌ）、メタノール（２ｍＬ）およびパラジウム－炭素（６８．８ｍｇ、０．０３２ｍｍｏｌ）を混合し、水素雰囲気下（１気圧）、室温で１．５時間攪拌した。不要物をセライトろ過し、メタノールで洗浄した。溶液に水素化ホウ素ナトリウム（３６．７ｍｇ、０．９７０ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応溶液に水およびクロロホルムを加え、有機層を分離して濃縮した。残渣をアミノカラムクロマトグラフィー（ヘキサン／酢酸エチル、クロロホルム／メタノール）で精製し、化合物６（５３．５ｍｇ、０．１９０ｍｍｏｌ、収率５９％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝２８０、ＲＴ＝１．７５ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 4 Synthesis of compound 6 Compound 5 (100 mg, 0.323 mmol), methanol (2 mL) and palladium-carbon (68.8 mg, 0.032 mmol) were mixed and under hydrogen atmosphere (1 atm), 1.5 Stirred for hours. Unnecessary substances were filtered through celite and washed with methanol. Sodium borohydride (36.7 mg, 0.970 mmol) was added to the solution and stirred at room temperature for 30 minutes. Water and chloroform were added to the reaction solution, and the organic layer was separated and concentrated. The residue was purified by amino column chromatography (hexane/ethyl acetate, chloroform/methanol) to obtain compound 6 (53.5 mg, 0.190 mmol, yield 59%).
LC/MS (ESI): m/z=280, RT=1.75min, LC/MS measurement condition 1
（参考例３）化合物１０の合成
Figure JPOXMLDOC01-appb-C000032
工程１　化合物８の合成
　２－ブロモ－１，４－ジクロロベンゼン（７．７６ｇ、３４．４ｍｍｏｌ）およびＴＨＦ（２４ｍＬ）を混合し、氷－アセトン浴中で冷却した。反応溶液にイソプロピルマグネシウムクロリド　塩化リチウム錯体（１．３Ｍ　ＴＨＦ溶液、２６．４ｍＬ、３４．４ｍｍｏｌ）を－６０℃以下で滴下し、－７８℃で５分間攪拌した。反応溶液を氷浴下、０℃で３０分間攪拌した。化合物７（３．００ｇ、１３．７５ｍｍｏｌ）およびＴＨＦ（２１ｍＬ）を混合し、反応溶液に０℃で加えた。反応溶液を０℃で１０分間攪拌し、室温で２０時間攪拌した。氷浴下、反応溶液に１０％クエン酸水溶液（３０ｍＬ）を加え、水層を酢酸エチルで抽出した。有機層を水および飽和塩化ナトリウム水で洗浄し、硫酸ナトリウムで乾燥し、ろ過した。ろ液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、化合物８（２．２８ｇ、７．５０ｍｍｏｌ、収率５５％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝３０４、ＲＴ＝２．２０ｍｉｎ、ＬＣ／ＭＳ測定条件１ (Reference Example 3) Synthesis of compound 10
Figure JPOXMLDOC01-appb-C000032
Step 1 Synthesis of Compound 8 2-Bromo-1,4-dichlorobenzene (7.76 g, 34.4 mmol) and THF (24 mL) were mixed and cooled in an ice-acetone bath. Isopropylmagnesium chloride lithium chloride complex (1.3M THF solution, 26.4 mL, 34.4 mmol) was added dropwise to the reaction solution at -60°C or lower, and the mixture was stirred at -78°C for 5 minutes. The reaction solution was stirred at 0° C. for 30 minutes in an ice bath. Compound 7 (3.00 g, 13.75 mmol) and THF (21 mL) were mixed and added to the reaction solution at 0°C. The reaction solution was stirred at 0° C. for 10 minutes and at room temperature for 20 hours. A 10% aqueous citric acid solution (30 mL) was added to the reaction solution in an ice bath, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain compound 8 (2.28 g, 7.50 mmol, yield 55%).
LC/MS (ESI): m/z = 304, RT = 2.20 min, LC/MS measurement condition 1
工程２　化合物９の合成
　窒素雰囲気下、化合物８（４．０８ｇ、１３．４１ｍｍｏｌ）、ＴＨＦ（２０ｍＬ）およびメタノール（２０ｍＬ）を混合した。氷浴下、反応溶液に水素化ホウ素ナトリウム（１．０２ｇ、２６．８ｍｍｏｌ）を少しずつ加えた。反応溶液を０℃で２時間攪拌し、アセトン（５ｍＬ）を加えた。反応溶液を０℃で１０分間攪拌し、飽和炭酸水素ナトリウム水溶液（２０ｍＬ）を加え、室温で水（２０ｍＬ）を加えた。水層を酢酸エチルで抽出し、有機層を水および飽和塩化ナトリウム水で洗浄した。有機層を硫酸ナトリウムで乾燥し、ろ過して濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、化合物９（３．８４ｇ、１２．５ｍｍｏｌ、収率９４％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝３０６、ＲＴ＝２．０２ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 2 Synthesis of Compound 9 Compound 8 (4.08 g, 13.41 mmol), THF (20 mL) and methanol (20 mL) were mixed under a nitrogen atmosphere. Under an ice bath, sodium borohydride (1.02 g, 26.8 mmol) was added little by little to the reaction solution. The reaction solution was stirred at 0° C. for 2 hours and acetone (5 mL) was added. The reaction solution was stirred at 0° C. for 10 minutes, saturated aqueous sodium hydrogencarbonate solution (20 mL) was added, and water (20 mL) was added at room temperature. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain compound 9 (3.84 g, 12.5 mmol, yield 94%).
LC/MS (ESI): m/z = 306, RT = 2.02 min, LC/MS measurement condition 1
工程３　化合物１０の合成
　化合物９（３．８４ｇ、１２．５４ｍｍｏｌ）をジクロロメタン（３１ｍＬ）に溶解した。反応溶液に４ｍｏｌ／Ｌ塩酸・１，４－ジオキサン溶液（１５．７ｍＬ、６２．７ｍｍｏｌ）を室温で加え、反応溶液を室温で３時間攪拌した。反応溶液を濃縮し、イソプロピルエーテルを加え、残渣をろ過して乾燥し、化合物１０（２．９４ｇ、１２．１２ｍｍｏｌ、収率９７％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝２０６、ＲＴ＝０．７６ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 3 Synthesis of Compound 10 Compound 9 (3.84 g, 12.54 mmol) was dissolved in dichloromethane (31 mL). A 4 mol/L hydrochloric acid/1,4-dioxane solution (15.7 mL, 62.7 mmol) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated, isopropyl ether was added, the residue was filtered and dried to obtain compound 10 (2.94 g, 12.12 mmol, yield 97%).
LC/MS (ESI): m/z=206, RT=0.76min, LC/MS measurement condition 1
（参考例４）化合物１９の合成
Figure JPOXMLDOC01-appb-C000033
工程１　化合物１７の合成
　１－ブロモ－５－クロロ－２，４－ジフルオロベンゼン（２７．３ｇ、１０４ｍｍｏｌ）およびＴＨＦ（５５ｍＬ）を混合し、氷－塩化ナトリウム浴中で冷却した。反応溶液にイソプロピルマグネシウムクロリド（２ｍｏｌ／Ｌ　ＴＨＦ溶液、１６１ｍＬ、３２３ｍｍｏｌ）を１０℃以下で滴下し、－１０℃で４５分間攪拌した。化合物１６（２７．３ｇ、１０４ｍｍｏｌ）およびＴＨＦ（２７３ｍＬ）を混合し、反応溶液に滴下した。反応溶液を室温で３時間攪拌し、室温で終夜静置した。氷浴下、反応溶液に１０％クエン酸水溶液（４００ｍＬ）を加え、水層を酢酸エチルで抽出した。有機層を水および飽和塩化ナトリウム水で洗浄し、硫酸マグネシウムで乾燥し、ろ過した。ろ液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、化合物１７（３６．６ｇ、１０５ｍｍｏｌ、収率１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３）δ：１．４６（９Ｈ，ｓ），３．２５（３Ｈ，ｓ），３．６９－３．７６（２Ｈ，ｍ），５．１８（１Ｈ，ｔ，Ｊ＝４．０Ｈｚ），５．６３（１Ｈ，ｄ，Ｊ　＝７．７Ｈｚ），７．０１（１Ｈ，ｄｄ，Ｊ＝１０．２，８．４Ｈｚ），７．９８（１Ｈ，ｔ，Ｊ＝７．７Ｈｚ）． (Reference Example 4) Synthesis of compound 19
Figure JPOXMLDOC01-appb-C000033
Step 1 Synthesis of Compound 17 1-Bromo-5-chloro-2,4-difluorobenzene (27.3 g, 104 mmol) and THF (55 mL) were mixed and cooled in an ice-sodium chloride bath. Isopropylmagnesium chloride (2 mol/L THF solution, 161 mL, 323 mmol) was added dropwise to the reaction solution at 10°C or lower, and the mixture was stirred at -10°C for 45 minutes. Compound 16 (27.3 g, 104 mmol) and THF (273 mL) were mixed and added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 3 hours and allowed to stand at room temperature overnight. A 10% aqueous citric acid solution (400 mL) was added to the reaction solution in an ice bath, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain compound 17 (36.6 g, 105 mmol, yield 100%).
1 H NMR (CDCl 3 ) δ: 1.46 (9H, s), 3.25 (3H, s), 3.69-3.76 (2H, m), 5.18 (1H, t, J = 4.0 Hz), 5.63 (1H, d, J = 7.7 Hz), 7.01 (1H, dd, J = 10.2, 8.4 Hz), 7.98 (1H, t, J = 7 .7 Hz).
工程２　化合物１８の合成
　窒素雰囲気下、化合物１７（３７．５ｇ、１０７ｍｍｏｌ）およびＴＨＦ（３７５ｍＬ）を混合し、ドライアイス－アセトン浴中で冷却した。氷浴下、反応溶液に水素化ジイソブチルアルミニウム（１．０２ｍｏｌ／Ｌ　ヘキサン溶液、２１０ｍＬ、２１４ｍｍｏｌ）を－１０℃以下で滴下し、－１０℃で１５分間攪拌した。氷浴下、反応溶液に飽和ロッシェル塩水溶液（６５０ｍＬ）、酢酸エチルを加え、室温で１時間攪拌し、水層を酢酸エチルで抽出した。有機層を水および飽和塩化ナトリウム水で洗浄し、硫酸マグネシウムで乾燥し、ろ過した。ろ液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、化合物１８（３３．８ｇ、９６ｍｍｏｌ、収率９０％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３）δ：１．４３（９Ｈ，ｓ），３．３４（３Ｈ，ｓ），３．４９（２Ｈ，ｄ，Ｊ＝２．４Ｈｚ），４．０１　（１Ｈ，ｄ，Ｊ　＝２．５Ｈｚ），４．２０（１Ｈ，ｄ，Ｊ＝７．０Ｈｚ），５．０８（１Ｈ，ｄｄ，Ｊ＝７．２，４．７Ｈｚ），５．２２（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．８９（１Ｈ，ｔ，Ｊ＝９．２Ｈｚ），７．５４（１Ｈ，ｔ，　Ｊ＝７．８Ｈｚ）． Step 2 Synthesis of Compound 18 Compound 17 (37.5 g, 107 mmol) and THF (375 mL) were mixed under a nitrogen atmosphere and cooled in a dry ice-acetone bath. Under an ice bath, diisobutylaluminum hydride (1.02 mol/L hexane solution, 210 mL, 214 mmol) was added dropwise to the reaction solution at -10°C or lower, and the mixture was stirred at -10°C for 15 minutes. A saturated aqueous Rochelle salt solution (650 mL) and ethyl acetate were added to the reaction solution in an ice bath, the mixture was stirred at room temperature for 1 hour, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain compound 18 (33.8 g, 96 mmol, yield 90%).
1 H NMR (CDCl 3 ) δ: 1.43 (9H, s), 3.34 (3H, s), 3.49 (2H, d, J = 2.4 Hz), 4.01 (1H, d, J = 2.5 Hz), 4.20 (1H, d, J = 7.0 Hz), 5.08 (1H, dd, J = 7.2, 4.7 Hz), 5.22 (1H, d, J = 6.1 Hz), 6.89 (1 H, t, J = 9.2 Hz), 7.54 (1 H, t, J = 7.8 Hz).
工程３　化合物１９の合成
　化合物１８（３３．８ｇ、９６ｍｍｏｌ）と塩酸（４ｍｏｌ／Ｌ　メタノール溶液、１３５ｍＬ、５４０ｍｍｏｌ）を混合し、反応溶液を室温で３０分攪拌した。ヘキサン（２７０ｍＬ）を加え、室温で１０分間攪拌後、残渣をろ過して乾燥し、化合物１９（２４．０ｇ、８３ｍｍｏｌ、収率８７％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝２５１［Ｍ＋Ｈ］＋、ＲＴ＝１．１２ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 3 Synthesis of Compound 19 Compound 18 (33.8 g, 96 mmol) and hydrochloric acid (4 mol/L methanol solution, 135 mL, 540 mmol) were mixed, and the reaction solution was stirred at room temperature for 30 minutes. Hexane (270 mL) was added, and after stirring at room temperature for 10 minutes, the residue was filtered and dried to give compound 19 (24.0 g, 83 mmol, yield 87%).
LC/MS (ESI): m/z=251 [M+H] + , RT=1.12 min, LC/MS measurement condition 1
　化合物（Ｉ－００７６）および化合物（Ｉ－００６４）の合成
Figure JPOXMLDOC01-appb-C000034
工程１　化合物１１の合成
　窒素雰囲気下、５－クロロピリジン－３－アミン（１８．９ｇ、１４７ｍｍｏｌ）をアセトニトリル（２０８ｍＬ）に溶解した。クロロギ酸フェニル（１９．５ｍＬ、１５５ｍｍｏｌ）をアセトニトリル（１９ｍＬ）に溶解し、氷浴下で反応溶液に滴下した。反応溶液を室温で３時間攪拌し、氷浴で冷却した。沈殿物をろ過および乾燥し、化合物１１（３８．１ｇ、１３４ｍｍｏｌ、収率９１％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝２４９、ＲＴ＝１．９８ｍｉｎ、ＬＣ／ＭＳ測定条件１ Synthesis of compound (I-0076) and compound (I-0064)
Figure JPOXMLDOC01-appb-C000034
Step 1 Synthesis of Compound 11 Under a nitrogen atmosphere, 5-chloropyridin-3-amine (18.9 g, 147 mmol) was dissolved in acetonitrile (208 mL). Phenyl chloroformate (19.5 mL, 155 mmol) was dissolved in acetonitrile (19 mL) and added dropwise to the reaction solution under an ice bath. The reaction solution was stirred at room temperature for 3 hours and cooled in an ice bath. The precipitate was filtered and dried to give compound 11 (38.1 g, 134 mmol, 91% yield).
LC/MS (ESI): m/z = 249, RT = 1.98 min, LC/MS measurement condition 1
工程２　化合物１２の合成
　化合物１１（３０．７ｇ、１０８ｍｍｏｌ）、ジメチルアセトアミド（３０７ｍＬ）および１Ｈ－ピラゾール－１－カルボキシアミジン塩酸塩（１５．８ｇ、１０８ｍｍｏｌ）を室温で混合した。反応溶液にＤＢＵ（４０．６ｍＬ、２６９ｍｍｏｌ）を滴下し、８０℃で４５分間攪拌した。反応溶液を氷浴で冷却し、ＣＤＩ（３４．９ｇ、２１５ｍｍｏｌ）およびＤＢＵ（３２．５ｍＬ、２１５ｍｍｏｌ）を加えた。反応溶液を氷浴下で３時間攪拌し、氷水（３００ｍＬ）に注いだ。反応溶液に６ｍｏｌ／Ｌ塩化水素水溶液を滴下し、反応溶液に水（６００ｍＬ）およびジイソプロピルエーテル（２００ｍＬ）を加え、沈殿物をろ過した。残渣を水およびジイソプロピルエーテルで洗浄、乾燥し、化合物１２（２６．０ｇ、８９．０ｍｍｏｌ、収率８３％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝２９１、ＲＴ＝１．１３ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 2 Synthesis of Compound 12 Compound 11 (30.7 g, 108 mmol), dimethylacetamide (307 mL) and 1H-pyrazole-1-carboxamidine hydrochloride (15.8 g, 108 mmol) were mixed at room temperature. DBU (40.6 mL, 269 mmol) was added dropwise to the reaction solution and stirred at 80° C. for 45 minutes. The reaction solution was cooled in an ice bath and CDI (34.9 g, 215 mmol) and DBU (32.5 mL, 215 mmol) were added. The reaction solution was stirred under an ice bath for 3 hours and poured into ice water (300 mL). A 6 mol/L aqueous hydrogen chloride solution was added dropwise to the reaction solution, water (600 mL) and diisopropyl ether (200 mL) were added to the reaction solution, and the precipitate was filtered. The residue was washed with water and diisopropyl ether and dried to obtain compound 12 (26.0 g, 89.0 mmol, yield 83%).
LC/MS (ESI): m/z=291, RT=1.13 min, LC/MS measurement condition 1
工程３　化合物１３の合成
　化合物１２（６．７１ｇ、２０．５ｍｍｏｌ）、ｔｅｒｔ－アミルアルコール（３４ｍＬ）、２，２－ジメチル酪酸（３１．５ｍＬ、２５２ｍｍｏｌ）、トリエチルアミン（５．６９ｍＬ、４１．０ｍｍｏｌ）および６－クロロ－２－メチル－２Ｈ－インダゾール－５－アミン（３．９１ｇ、２１．５ｍｍｏｌ）を混合し、反応溶液を１２０℃で６時間攪拌した。反応溶液を室温に冷却し、酢酸エチルを加えた。沈殿物をろ過し、残渣を酢酸エチルで洗浄、乾燥し、化合物１３（６．００ｇ、１４．８ｍｍｏｌ、収率７２％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝４０４、ＲＴ＝１．３１ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 3 Synthesis of compound 13 Compound 12 (6.71 g, 20.5 mmol), tert-amyl alcohol (34 mL), 2,2-dimethylbutyric acid (31.5 mL, 252 mmol), triethylamine (5.69 mL, 41.0 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (3.91 g, 21.5 mmol) were mixed and the reaction solution was stirred at 120° C. for 6 hours. The reaction solution was cooled to room temperature and ethyl acetate was added. The precipitate was filtered, the residue was washed with ethyl acetate and dried to obtain compound 13 (6.00 g, 14.8 mmol, yield 72%).
LC/MS (ESI): m/z = 404, RT = 1.31 min, LC/MS measurement condition 1
工程４　化合物１４の合成
　化合物１３（０．４５ｇ、１．１１ｍｍｏｌ）およびアセトニトリル（１４ｍＬ）を混合した。反応溶液にＨＣＣＰ（０．４６４ｇ、１．３４ｍｍｏｌ）およびＤＩＥＡ（０．２５３ｍＬ、１．４５ｍｍｏｌ）を加え、室温で攪拌した。反応溶液に化合物１０（０．３５１ｇ、１．４５ｍｍｏｌ）およびＤＩＥＡ（０．５８２ｍＬ、３．３３ｍｍｏｌ）を加えた。反応溶液を飽和炭酸水素ナトリウム水溶液（２０ｍＬ）に注ぎ、２０分間攪拌し、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水で洗浄後、無水硫酸マグネシウムで乾燥、ろ過し、溶媒を減圧留去した。残渣をアミノカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、化合物１４（０．５４５ｇ、０．９２３ｍｍｏｌ、収率８３％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝５９０、ＲＴ＝１．７８ｍｉｎ、ＬＣ／ＭＳ測定条件１ Step 4 Synthesis of Compound 14 Compound 13 (0.45 g, 1.11 mmol) and acetonitrile (14 mL) were mixed. HCCP (0.464 g, 1.34 mmol) and DIEA (0.253 mL, 1.45 mmol) were added to the reaction solution and stirred at room temperature. Compound 10 (0.351 g, 1.45 mmol) and DIEA (0.582 mL, 3.33 mmol) were added to the reaction solution. The reaction solution was poured into saturated aqueous sodium hydrogencarbonate solution (20 mL), stirred for 20 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by amino column chromatography (chloroform/methanol) to give compound 14 (0.545 g, 0.923 mmol, yield 83%).
LC/MS (ESI): m/z = 590, RT = 1.78 min, LC/MS measurement condition 1
工程５　化合物１５（化合物Ｉ－００７６および化合物Ｉ－００６４のラセミ混合物）の合成
　氷冷下、ＤＭＦ（３ｍＬ）にメタンスルホニルクロリド（０．４３２ｍＬ、５．５４ｍｍｏｌ）およびＮ、Ｎ、Ｎ’、Ｎ’－テトラメチル－１、３－プロパンジアミン（０．７２１ｍＬ、５．５４）を加え、０℃で５分間攪拌した。続いて、氷冷下化合物１４（０．５４５ｇ、０．９２３ｍｍｏｌ）のＤＭＦ（３ｍＬ）溶液を加え、０℃で５分間攪拌後、室温で１時間攪拌した。別途調整したメタンスルホニルクロリド（０．４３２ｍＬ、５．５４ｍｍｏｌ）およびＮ、Ｎ、Ｎ’、Ｎ’－テトラメチル－１、３－プロパンジアミン（０．７２１ｍＬ、５．５４）のＤＭＦ（２ｍＬ）溶液を加え、室温で２時間１５分攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加え、５分間攪拌し、水を加えて、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水で洗浄後、無水硫酸マグネシウムで乾燥、ろ過し、溶媒を減圧留去した。残渣をアミノカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、化合物１５（０．１１７ｇ、０．２０４ｍｍｏｌ、収率２２％）を得た。
ＬＣ／ＭＳ（ＥＳＩ）：ｍ／ｚ＝５７５、ＲＴ＝２．０４ｍｉｎ、ＬＣ／ＭＳ測定条件１
１Ｈ－ＮＭＲ（ＣＤＣｌ3）δ：３．６８－３．７７（ｍ，１Ｈ），４．２０（ｓ，３Ｈ），　４．５４－４．６０（ｍ，１Ｈ），５．８６－５．９４（ｍ，１Ｈ），７．０４－７．５２（ｍ，４Ｈ），７．７８（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），７．８４（ｓ，１Ｈ），７．６７－７．９４（ｍ，１Ｈ），８．６０－８．６８（ｍ，２Ｈ）． Step 5 Synthesis of compound 15 (racemic mixture of compound I-0076 and compound I-0064) Methanesulfonyl chloride (0.432 mL, 5.54 mmol) and N, N, N', N '-Tetramethyl-1,3-propanediamine (0.721 mL, 5.54) was added and stirred at 0° C. for 5 minutes. Subsequently, a solution of compound 14 (0.545 g, 0.923 mmol) in DMF (3 mL) was added under ice-cooling, and the mixture was stirred at 0° C. for 5 minutes and then at room temperature for 1 hour. Separately prepared solution of methanesulfonyl chloride (0.432 mL, 5.54 mmol) and N,N,N',N'-tetramethyl-1,3-propanediamine (0.721 mL, 5.54) in DMF (2 mL) was added and stirred at room temperature for 2 hours and 15 minutes. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added to the reaction solution, the mixture was stirred for 5 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by amino column chromatography (chloroform/methanol) to give compound 15 (0.117 g, 0.204 mmol, yield 22%).
LC/MS (ESI): m/z=575, RT=2.04min, LC/MS measurement condition 1
1H-NMR (CDCl 3 ) δ: 3.68-3.77 (m, 1H), 4.20 (s, 3H), 4.54-4.60 (m, 1H), 5.86-5. 94 (m, 1H), 7.04-7.52 (m, 4H), 7.78 (d, J=9.0Hz, 1H), 7.84 (s, 1H), 7.67-7. 94 (m, 1H), 8.60-8.68 (m, 2H).
工程６　化合物（Ｉ－００７６）および化合物（Ｉ－００６４）の分離精製
　工程５で得られた化合物１５を上記ＳＦＣ分取の方法により精製し、化合物（Ｉ－００７６、４２．１ｍｇ、０．０７３ｍｍｏｌ）および化合物（Ｉ－００６４、４５．２ｍｇ、０．０７９ｍｍｏｌ）を得た。
化合物（Ｉ－００７６）：保持時間　１１．８分
化合物（Ｉ－００６４）：保持時間　４．９分 Step 6 Separation and purification of compound (I-0076) and compound (I-0064) Compound 15 obtained in Step 5 was purified by the above SFC preparative method, compound (I-0076, 42.1 mg, 0.073 mmol ) and compound (I-0064, 45.2 mg, 0.079 mmol).
Compound (I-0076): Retention time 11.8 minutes Compound (I-0064): Retention time 4.9 minutes
　上記一般的合成法および実施例に記載の方法に準じて、以下の化合物を合成した。構造および物性（ＬＣ／ＭＳデータ）を以下の表に示す。
　なお、構造式中、「くさび形」および「破線」は立体配置を示す。 The following compounds were synthesized according to the above general synthetic method and the methods described in the examples. Structures and physical properties (LC/MS data) are shown in the table below.
In the structural formulas, "wedge" and "broken line" indicate the configuration.
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000138
　ここで、Ｒ２ａおよびＲ２ｂにおける立体配置を決定するために、代表化合物として化合物（Ｉ－０１４３）の単結晶構造解析を行った。
　上記に記載した、本発明の化合物の製造法、参考例１～４および実施例１と同様にして、化合物（Ｉ－０１４３）を合成した。
　化合物をエタノールに溶解し、貧溶媒として水を用いて蒸気拡散法にて結晶を作成した。 Here, in order to determine the configuration of R 2a and R 2b , single crystal structure analysis of compound (I-0143) was performed as a representative compound.
Compound (I-0143) was synthesized in the same manner as in Reference Examples 1 to 4 and Example 1, the method for producing the compound of the present invention described above.
The compound was dissolved in ethanol and crystals were formed by the vapor diffusion method using water as a poor solvent.
　化合物（Ｉ－０１４３）の単結晶構造解析の結果を以下に示す。
　Ｒ１　（Ｉ＞２．００ｓ（Ｉ））は０．０４７０であり、最終の差フーリエから電子密度の欠如も誤置もないことを確認した。
　結晶学的データを表１０５に示す。
Figure JPOXMLDOC01-appb-T000139
 The results of single crystal structure analysis of compound (I-0143) are shown below.
R1 (I>2.00 s(I)) was 0.0470, confirming neither missing nor misplaced electron densities from the final difference Fourier.
Crystallographic data are shown in Table 105.
Figure JPOXMLDOC01-appb-T000139
　また、非水素原子の原子座標を表１０６～表１０７に示す。ここで、Ｕ（ｅｑ）とは、等価等方性温度因子を意味する。
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000141
 Tables 106 and 107 show atomic coordinates of non-hydrogen atoms. Here, U(eq) means an equivalent isotropic temperature factor.
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000141
　次に、水素原子の原子座標を表１０８に示す。ここで、Ｕ（ｅｑ）とは、等価等方性温度因子を意味する。また、表１０８の水素原子の番号は、結合している非水素原子の番号に関連して付けた。
Figure JPOXMLDOC01-appb-T000142
 Next, Table 108 shows atomic coordinates of hydrogen atoms. Here, U(eq) means an equivalent isotropic temperature factor. Also, the numbers of the hydrogen atoms in Table 108 are associated with the numbers of the non-hydrogen atoms to which they are attached.
Figure JPOXMLDOC01-appb-T000142
　さらに、原子間角度（単位：度）を表１０９～表１１０に示す。
Figure JPOXMLDOC01-appb-T000143
 Further, Tables 109 to 110 show interatomic angles (unit: degree).
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000144
　化合物（Ｉ－０１４３）の分子構造図を図１に示す。
　なお、表１０６～表１０７および表１０９～表１１０における非水素原子の番号は、それぞれ図１に記載された番号に対応している。 FIG. 1 shows the molecular structure diagram of the compound (I-0143).
The numbers of non-hydrogen atoms in Tables 106 to 107 and Tables 109 to 110 respectively correspond to the numbers shown in FIG.
　図１に示される通り、化合物（Ｉ－０１４３）は、Ｒ２ａに相当する基がＳ配置であることが示唆された。
　また、化合物（Ｉ－０１４３）および化合物（Ｉ－０１４３）の光学異性体である化合物（Ｉ－０１４０）の下記試験例２の結果は、以下の通りであった。
　化合物（Ｉ－０１４３）：０．００１１μＭ
　化合物（Ｉ－０１４０）：２．２μＭ
　Ｒ２ａに相当する基がＳ配置である化合物（Ｉ－０１４３）がより高活性値を示していた。
　ここで、本明細書中において、Ｒ２ａおよびＲ２ｂにおける立体配置が異なる光学異性体が存在する場合、試験例２の活性値がより高活性を示した化合物のＲ２ａに相当する基をＳ配置と同定し、もう一方の光学異性体をＲ配置と同定し、表１～表１０４に示した。 As shown in FIG. 1, it was suggested that the group corresponding to R 2a in compound (I-0143) was in the S configuration.
The results of Test Example 2 below for compound (I-0143) and compound (I-0140), which is an optical isomer of compound (I-0143), were as follows.
Compound (I-0143): 0.0011 μM
Compound (I-0140): 2.2 μM
A compound (I-0143) in which the group corresponding to R 2a is in the S configuration exhibited a higher activity value.
Here, in the present specification, when there are optical isomers with different steric configurations in R 2a and R 2b , the group corresponding to R 2a of the compound showing higher activity value in Test Example 2 is S configuration and the other optical isomer was identified as the R configuration and shown in Tables 1-104.
　次に、Ｒ２ａおよびＲ２ｂ、ならびに、Ｒ４ａおよびＲ４ｂにおける立体配置を決定するために、代表化合物として化合物（Ｉ－０２５２）の単結晶構造解析を行った。
　上記に記載した、本発明の化合物の製造法、参考例１～４および実施例１と同様にして、化合物（Ｉ－０２５２）を合成した。
　化合物を酢酸メチルに溶解し、貧溶媒としてヘキサンを用いて蒸気拡散法にて結晶を作成した。 Next, in order to determine the configuration of R 2a and R 2b and R 4a and R 4b , single crystal structure analysis of compound (I-0252) was performed as a representative compound.
Compound (I-0252) was synthesized in the same manner as in Reference Examples 1 to 4 and Example 1, the method for producing the compound of the present invention described above.
The compound was dissolved in methyl acetate and crystals were formed by the vapor diffusion method using hexane as a poor solvent.
　化合物（Ｉ－０２５２）の単結晶構造解析の結果を以下に示す。
　Ｒ１　（Ｉ＞２．００ｓ（Ｉ））は０．０４４４であり、最終の差フーリエから電子密度の欠如も誤置もないことを確認した。
　結晶学的データを表１１１に示す。
Figure JPOXMLDOC01-appb-T000145
 The results of single crystal structure analysis of compound (I-0252) are shown below.
R1 (I>2.00 s(I)) was 0.0444, confirming neither missing nor misplaced electron densities from the final difference Fourier.
Crystallographic data are shown in Table 111.
Figure JPOXMLDOC01-appb-T000145
　また、非水素原子の原子座標を表１１２～表１１３に示す。ここで、Ｕ（ｅｑ）とは、等価等方性温度因子を意味する。
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
 Tables 112 and 113 show atomic coordinates of non-hydrogen atoms. Here, U(eq) means an equivalent isotropic temperature factor.
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
　次に、水素原子の原子座標を表１１４に示す。ここで、Ｕ（ｅｑ）とは、等価等方性温度因子を意味する。また、表１１４の水素原子の番号は、結合している非水素原子の番号に関連して付けた。
Figure JPOXMLDOC01-appb-T000148
 Next, Table 114 shows atomic coordinates of hydrogen atoms. Here, U(eq) means an equivalent isotropic temperature factor. Also, the numbers of the hydrogen atoms in Table 114 are associated with the numbers of the non-hydrogen atoms to which they are attached.
Figure JPOXMLDOC01-appb-T000148
　さらに、原子間角度（単位：度）を表１１５～表１１６に示す。
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
 Further, Tables 115 and 116 show interatomic angles (unit: degrees).
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
　化合物（Ｉ－０２５２）の分子構造図を図２に示す。
　なお、表１１２～表１１３および表１１５～表１１６における非水素原子の番号は、それぞれ図１に記載された番号に対応している。 FIG. 2 shows the molecular structure diagram of the compound (I-0252).
The numbers of non-hydrogen atoms in Tables 112 to 113 and Tables 115 to 116 respectively correspond to the numbers shown in FIG.
　図２に示される通り、化合物（Ｉ－０２５２）は、Ｒ２ａに相当する基がＳ配置であることが示唆された。
　ここで、本明細書中において、Ｒ２ａおよびＲ２ｂ、ならびに、Ｒ４ａおよびＲ４ｂにおける立体配置が異なる異性体が存在する場合、試験例２の活性値がより高活性を示した化合物のＲ２ａに相当する基をＳ配置と同定し、もう一方の異性体をＲ配置として同定し、表１～表１０４に示した。 As shown in FIG. 2, it was suggested that the group corresponding to R 2a in compound (I-0252) was in the S configuration.
Here, in the present specification, when there are isomers with different steric configurations in R 2a and R 2b and R 4a and R 4b , the activity value of Test Example 2 shows higher activity. The group corresponding to 2a was identified as the S configuration and the other isomer was identified as the R configuration and shown in Tables 1-104.
　以下に、本発明化合物の生物試験例を記載する。
　本発明に係る式（Ｉ）で示される化合物は、コロナウイルス３ＣＬプロテアーゼ阻害作用を有し、コロナウイルス３ＣＬプロテアーゼを阻害するものであればよい。
　具体的には、以下に記載する評価方法において、ＩＣ５０は５０μＭ以下が好ましく、より好ましくは、１μＭ以下、さらにより好ましくは１００ｎＭ以下である。 Biological test examples of the compound of the present invention are described below.
The compound represented by the formula (I) according to the present invention has a coronavirus 3CL protease inhibitory action and may inhibit coronavirus 3CL protease.
Specifically, in the evaluation method described below, the IC50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.
試験例１：ｈｕｍａｎ　ＴＭＰＲＳＳ２発現Ｖｅｒｏ　Ｅ６細胞（Ｖｅｒｏ　Ｅ６／ＴＭＰＲＳＳ２細胞）を用いたＣｙｔｏｐａｔｈｉｃ　ｅｆｆｅｃｔ（ＣＰＥ）抑制効果確認試験
＜操作手順＞
・被験試料の希釈、分注
　予め被験試料をＤＭＳＯで適度な濃度に希釈し、２～５倍段階希釈系列を作製後、３８４ウェルプレートに分注する。
・細胞およびＳＡＲＳ－ＣｏＶ－２の希釈、分注
　ＶｅｒｏＥ６／ＴＭＰＲＳＳ２細胞（ＪＣＲＢ１８１９、５×１０３ｃｅｌｌｓ／ｗｅｌｌ）とＳＡＲＳ－ＣｏＶ－２（１００－３００ＴＣＩＤ５０／ｗｅｌｌ）を培地（ＭＥＭ、２％ＦＢＳ、ペニシリン－ストレプトマイシン）で混合し、被験試料が入ったウェルに分注した後、ＣＯ２インキュベーターで３日間培養する。
・ＣｅｌｌＴｉｔｅｒ－Ｇｌｏ（登録商標）２．０の分注および発光シグナルの測定
　３日間培養したプレートを室温に戻した後、ＣｅｌｌＴｉｔｅｒ－Ｇｌｏ（登録商標）２．０を各ウェルに分注し、プレートミキサーで混和する。一定時間置いた後、プレートリーダーで発光シグナル（Ｌｕｍ）を測定する。 Test Example 1: Cytopathic effect (CPE) suppression effect confirmation test using human TMPRSS2-expressing Vero E6 cells (Vero E6/TMPRSS2 cells) <Operating procedure>
・Dilution and dispensing of test sample Dilute the test sample with DMSO in advance to an appropriate concentration, prepare a 2- to 5-fold serial dilution series, and then dispense into a 384-well plate.
・Dilution and dispensing of cells and SARS-CoV-2 VeroE6/TMPRSS2 cells (JCRB1819, 5×10 3 cells/well) and SARS-CoV-2 (100-300 TCID 50 /well) in medium (MEM, 2% FBS) , penicillin-streptomycin), dispensed into wells containing test samples, and cultured in a CO 2 incubator for 3 days.
Dispense of CellTiter-Glo (registered trademark) 2.0 and measurement of luminescence signal After returning the plate cultured for 3 days to room temperature, CellTiter-Glo (registered trademark) 2.0 is dispensed into each well, and the plate Mix with a mixer. After a certain period of time, the luminescence signal (Lum) is measured with a plate reader.
＜各測定項目値の算出＞
・５０％　ＳＡＲＳ－ＣｏＶ－２感染細胞死阻害濃度（ＥＣ５０）算出
　ｘを化合物濃度の対数値、ｙを％Ｅｆｆｉｃａｃｙとしたとき、以下のＬｏｇｉｓｔｉｃ回帰式で阻害曲線を近似し、ｙ＝５０（％）を代入したときのｘの値をＥＣ５０として算出する。

y = min + (max - min)/{1 + (X50/x) ^Hill}

%Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100%
cell control： the average of Lum of cell control wells
virus control： the average of Lum of virus control wells

min：y軸下限値、max：y軸上限値、X50：変曲点のx座標、Hill：minとmaxの中間点でのカーブの傾き <Calculation of each measurement item value>
・ 50% SARS-CoV-2 infected cell death inhibitory concentration (EC 50 ) calculation When x is the logarithmic value of the compound concentration and y is % Efficacy, the inhibition curve is approximated by the following Logistic regression equation, y = 50 ( %) is substituted and the value of x is calculated as EC50 .

y = min + (max - min)/{1 + (X50/x)^Hill}

%Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100%
cell control: the average of Lum of cell control wells
virus control: the average of Lum of virus control wells

min: lower limit of y-axis, max: upper limit of y-axis, X50: x coordinate of inflection point, Hill: slope of curve at midpoint between min and max
　本発明化合物を本質的に上記のとおり試験した。結果を以下に示す。
　なお、ＥＣ５０値は、１μＭ未満を「Ａ」、１μＭ以上１０μＭ未満を「Ｂ」とする。
（結果）
化合物Ｉ－０００７：０．０６μＭ
化合物Ｉ－００２６：０．０５μＭ
化合物Ｉ－００２９：２．５μＭ
化合物Ｉ－００３１：１．１μＭ
化合物Ｉ－００４４：０．２５μＭ
化合物Ｉ－００４５：０．１３μＭ
化合物Ｉ－００７６：０．０２５μＭ
化合物Ｉ－０１２９：０．１２μＭ
化合物Ｉ－０１４９：１．３μＭ
化合物Ｉ－０１５９：０．６８μＭ
化合物Ｉ－０２０２：６．７μＭ
化合物Ｉ－０２０５：０．０５２μＭ
化合物Ｉ－０２２２：０．７６μＭ
化合物Ｉ－０３１５：１．９μＭ
化合物Ｉ－０３３７：０．４７μＭ The compounds of the invention were tested essentially as described above. The results are shown below.
For the EC50 value, less than 1 µM is "A", and 1 µM or more and less than 10 µM is "B".
(result)
Compound I-0007: 0.06 μM
Compound I-0026: 0.05 μM
Compound I-0029: 2.5 μM
Compound I-0031: 1.1 μM
Compound I-0044: 0.25 μM
Compound I-0045: 0.13 μM
Compound I-0076: 0.025 μM
Compound I-0129: 0.12 μM
Compound I-0149: 1.3 μM
Compound I-0159: 0.68 μM
Compound I-0202: 6.7 μM
Compound I-0205: 0.052 μM
Compound I-0222: 0.76 μM
Compound I-0315: 1.9 μM
Compound I-0337: 0.47 μM
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000153
試験例２：ＳＡＲＳ－ＣｏＶ－２　３ＣＬプロテアーゼに対する阻害活性試験
＜材料＞
・市販のＲｅｃｏｍｂｉｎａｎｔ　ＳＡＲＳ－ＣｏＶ－２　３ＣＬ　Ｐｒｏｔｅａｓｅ
・市販の基質ペプチド
　Ｄａｂｃｙｌ－Ｌｙｓ－Ｔｈｒ－Ｓｅｒ－Ａｌａ－Ｖａｌ－Ｌｅｕ－Ｇｌｎ－Ｓｅｒ－Ｇｌｙ－Ｐｈｅ－Ａｒｇ－Ｌｙｓ－Ｍｅｔ－Ｇｌｕ（Ｅｄａｎｓ）－ＮＨ２（配列番号：１）
・Ｉｎｔｅｒｎａｌ　Ｓｔａｎｄａｒｄペプチド
　Ｄａｂｃｙｌ－Ｌｙｓ－Ｔｈｒ－Ｓｅｒ－Ａｌａ－Ｖａｌ－Ｌｅｕ（１３Ｃ６，１５Ｎ）－Ｇｌｎ（配列番号：２）
　Ｄａｂｃｙｌ－Ｌｙｓ－Ｔｈｒ－Ｓｅｒ－Ａｌａ－Ｖａｌ－Ｌｅｕ（１３Ｃ６，１５Ｎ）－Ｇｌｎは、文献（Atherton, E.; Sheppard, R. C.、“In Solid Phase Peptide Synthesis, A Practical Approach”、IRL Press at Oxford University Pres、1989.およびBioorg. Med. Chem.、５巻、９号、１９９７年、１８８３－１８９１頁、等）を参考に合成できる。以下に一例を示す。
　Ｒｉｎｋアミド樹脂を用いて、Ｆｍｏｃ固相合成によって、Ｈ－Ｌｙｓ－Ｔｈｒ－Ｓｅｒ－Ａｌａ－Ｖａｌ－Ｌｅｕ（１３Ｃ６，１５Ｎ）－Ｇｌｕ（ｒｅｓｉｎ）－ＯαＯｔＢｕ（Ｌｙｓ側鎖はＢｏｃ保護、Ｔｈｒ側鎖はｔｅｒｔ－ブチル基で保護、Ｓｅｒ側鎖はｔｅｒｔ－ブチル基で保護、ＧｌｕのＣ末端ＯＨはｔｅｒｔ－ブチル基で保護されており、Ｇｌｕ側鎖のカルボン酸を樹脂に縮合）を合成する。Ｎ末端Ｄａｂｃｙｌ基の修飾は４－ジメチルアミノアゾベンゼン－４’－カルボン酸（Ｄａｂｃｙｌ－ＯＨ）をＥＤＣ／ＨＯＢＴを用いて樹脂上で縮合する。最終脱保護、および樹脂からの切り出しはＴＦＡ／ＥＤＴ＝９５：５で処理することで行う。その後、逆相ＨＰＬＣによって精製する。
・ＲａｐｉｄＦｉｒｅ　Ｃａｒｔｒｉｄｇｅ　Ｃ４　ｔｙｐｅＡ
＜操作手順＞
・アッセイバッファーの調製
　本試験では、２０ｍＭ　Ｔｒｉｓ－ＨＣｌ、１００ｍＭ　塩化ナトリウム、１ｍＭ　ＥＤＴＡ、１０ｍＭ　ＤＴＴ、０．０１％　ＢＳＡからなるアッセイバッファーを使用する。ＩＣ５０値が１０ｎＭ以下の化合物については、２０ｍＭ　Ｔｒｉｓ－ＨＣｌ、１ｍＭ　ＥＤＴＡ、１０ｍＭ　ＤＴＴ、０．０１％　ＢＳＡからなるアッセイバッファーを使用する。
・被験試料の希釈、分注
　予め被験試料をＤＭＳＯで適度な濃度に希釈し、２～５倍段階希釈系列を作製後、３８４ウェルプレートに分注する。
・酵素と基質の添加、酵素反応
　準備した化合物プレートに、８μＭの基質、及び６または０．６ｎＭの酵素溶液を添加し、室温で３～５時間インキュベーションを行う。その後、反応停止液（０．０６７μＭ　Ｉｎｔｅｒｎａｌ　Ｓｔａｎｄａｒｄ、０．１％　ギ酸、１０または２５％　アセトニトリル）を加え酵素反応を停止させる。
・反応産物の測定
　反応完了したプレートはＲａｐｉｄＦｉｒｅ　Ｓｙｓｔｅｍ　３６０及び質量分析器（Ａｇｉｌｅｎｔ、６５５０　ｉＦｕｎｎｅｌ　Ｑ－ＴＯＦ）、またはＲａｐｉｄ　Ｆｉｒｅ　Ｓｙｓｔｅｍ　３６５及び質量分析器（Ａｇｉｌｅｎｔ、　６４９５Ｃ　Ｔｒｉｐｌｅ　Ｑｕａｄｒｕｐｏｌｅ）を用いて測定する。測定時の移動相としてＡ溶液（７５％　イソプロパノール、１５％　アセトニトリル、５ｍＭ　ギ酸アンモニウム）とＢ溶液（０．０１％　トリフルオロ酢酸、０．０９％　ギ酸）を用いる。
　質量分析器によって検出された反応産物は、ＲａｐｉｄＦｉｒｅ　Ｉｎｔｅｇｒａｔｏｒまたは同等の解析が可能なプログラムを用いて算出しＰｒｏｄｕｃｔ　ａｒｅａ値とする。また、同時に検出されたＩｎｔｅｒｎａｌ　Ｓｔａｎｄａｒｄも算出しＩｎｔｅｒｎａｌ　Ｓｔａｎｄａｒｄ　ａｒｅａ値とする。
＜各測定項目値の算出＞
・Ｐ／ＩＳの算出
前項目で得られたａｒｅａ値を下記の式によって計算し、Ｐ／ＩＳを算出する。
Ｐ／ＩＳ＝　Ｐｒｏｄｕｃｔ　ａｒｅａ値／　Ｉｎｔｅｒｎａｌ　Ｓｔａｎｄａｒｄ　ａｒｅａ値
・５０％　ＳＡＲＳ－ＣｏＶ－２　３ＣＬプロテアーゼ阻害濃度（ＩＣ５０）算出
　ｘを化合物濃度の対数値、ｙを％Ｉｎｈｉｂｉｔｉｏｎとしたとき、以下のＬｏｇｉｓｔｉｃ回帰式で阻害曲線を近似し、ｙ＝５０（％）を代入したときのｘの値をＩＣ５０として算出する。

y = min + (max - min)/{1 + (X50/x) ^Hill}

%Inhibition = {1-(Sample - Control(-)) / Control(+)-Control(-))} * 100

Control(-)：the average of P/IS of enzyme inhibited condition wells 
Control(+)：the average of P/IS of DMSO control wells
min：y軸下限値、max：y軸上限値、X50：変曲点のx座標、Hill：minとmaxの中間点でのカーブの傾き Test Example 2: SARS-CoV-2 3CL protease inhibitory activity test <Material>
・Commercially available Recombinant SARS-CoV-2 3CL Protease
- Commercially available substrate peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1)
- Internal Standard peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln (SEQ ID NO: 2)
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln is described in the literature (Atherton, E.; Sheppard, R.C., "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University). Pres, 1989. and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below.
H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu (Lys side chain is Boc protected, Thr side chain is protected with a tert-butyl group, the Ser side chain is protected with a tert-butyl group, the C-terminal OH of Glu is protected with a tert-butyl group, and the carboxylic acid of the Glu side chain is condensed with the resin). Modification of the N-terminal Dabcyl group involves condensation of 4-dimethylaminoazobenzene-4′-carboxylic acid (Dabcyl-OH) on the resin using EDC/HOBT. Final deprotection and cleavage from the resin are performed by treatment with TFA/EDT=95:5. It is then purified by reverse phase HPLC.
・Rapid Fire Cartridge C4 type A
<Operation procedure>
-Preparation of assay buffer In this test, an assay buffer consisting of 20 mM Tris-HCl, 100 mM sodium chloride, 1 mM EDTA, 10 mM DTT and 0.01% BSA is used. For compounds with IC 50 values of 10 nM or less, an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, 0.01% BSA is used.
・Dilution and dispensing of test sample Dilute the test sample with DMSO in advance to an appropriate concentration, prepare a 2- to 5-fold serial dilution series, and then dispense into a 384-well plate.
Addition of Enzyme and Substrate, Enzyme Reaction Add 8 μM substrate and 6 or 0.6 nM enzyme solution to the prepared compound plate and incubate at room temperature for 3 to 5 hours. Thereafter, a reaction stop solution (0.067 μM Internal Standard, 0.1% formic acid, 10 or 25% acetonitrile) is added to stop the enzymatic reaction.
Measurement of Reaction Products Reaction completed plates are measured using a Rapid Fire System 360 and mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a Rapid Fire System 365 and mass spectrometer (Agilent, 6495C Triple Quadrupole). A solution (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and B solution (0.01% trifluoroacetic acid, 0.09% formic acid) are used as mobile phases for measurement.
The reaction product detected by the mass spectrometer is calculated using RapidFire Integrator or a program capable of equivalent analysis and taken as a product area value. In addition, the internal standard detected at the same time is also calculated and used as the internal standard area value.
<Calculation of each measurement item value>
・P/IS is calculated by calculating the area value obtained in the item before calculating P/IS using the following formula.
P / IS = Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC 50 ) calculation When x is the logarithmic value of the compound concentration and y is % Inhibition, the following Logistic regression formula The inhibition curve is approximated with , and the value of x when y=50 (%) is substituted is calculated as IC50 .

y = min + (max - min)/{1 + (X50/x)^Hill}

%Inhibition = {1-(Sample-Control(-)) / Control(+)-Control(-))} * 100

Control(-): the average of P/IS of enzyme inhibited condition wells
Control(+): the average of P/IS of DMSO control wells
min: lower limit of y-axis, max: upper limit of y-axis, X50: x coordinate of inflection point, Hill: slope of curve at midpoint between min and max
　本発明化合物を本質的に上記のとおり試験した。結果を以下に示す。
　なお、ＩＣ５０値は、０．１μＭ未満を「Ａ」、０．１μＭ以上１μＭ未満を「Ｂ」、１μＭ以上１０μＭ未満を「Ｃ」とする。
（結果）
化合物Ｉ－０００３：０．０１４μＭ
化合物Ｉ－０００７：０．００１５μＭ
化合物Ｉ－００２６：０．００８３μＭ
化合物Ｉ－００２９：０．００２２μＭ
化合物Ｉ－００３１：０．００８１μＭ
化合物Ｉ－００４４：０．００８５μＭ
化合物Ｉ－００４５：０．００７７μＭ
化合物Ｉ－００５２：１μＭ
化合物Ｉ－００５５：０．８９μＭ
化合物Ｉ－００７６：０．０００９９μＭ
化合物Ｉ－０１０４：９．３μＭ
化合物Ｉ－０１０７：０．４μＭ
化合物Ｉ－０１１５：１．８μＭ
化合物Ｉ－０１２９：０．００４９μＭ
化合物Ｉ－０１４９：０．０８４μＭ
化合物Ｉ－０１５９：０．０３６μＭ
化合物Ｉ－０１６８：０．００３９μＭ
化合物Ｉ－０２０２：０．３３μＭ
化合物Ｉ－０２０５：０．００３４μＭ
化合物Ｉ－０２２２：０．０３２μＭ
化合物Ｉ－０３１５：０．２μＭ
化合物Ｉ－０３３７：０．０５μＭ The compounds of the invention were tested essentially as described above. The results are shown below.
The IC 50 value is "A" when less than 0.1 μM, "B" when 0.1 μM or more and less than 1 μM, and "C" when 1 μM or more and less than 10 μM.
(result)
Compound I-0003: 0.014 μM
Compound I-0007: 0.0015 μM
Compound I-0026: 0.0083 μM
Compound I-0029: 0.0022 μM
Compound I-0031: 0.0081 μM
Compound I-0044: 0.0085 μM
Compound I-0045: 0.0077 μM
Compound I-0052: 1 μM
Compound I-0055: 0.89 μM
Compound I-0076: 0.00099 μM
Compound I-0104: 9.3 μM
Compound I-0107: 0.4 μM
Compound I-0115: 1.8 μM
Compound I-0129: 0.0049 μM
Compound I-0149: 0.084 μM
Compound I-0159: 0.036 μM
Compound I-0168: 0.0039 μM
Compound I-0202: 0.33 μM
Compound I-0205: 0.0034 μM
Compound I-0222: 0.032 μM
Compound I-0315: 0.2 μM
Compound I-0337: 0.05 μM
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000157
［参考例５］
　国際公開第２０１８／０７４３９０号（特許文献１）の化合物Ｉ－００８９およびＩ－０１８９を、本質的に試験例２の通り試験した。結果を以下の表に示す。 [Reference Example 5]
Compounds I-0089 and I-0189 of WO2018/074390 were tested essentially as in Test Example 2. Results are shown in the table below.
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000158
　国際公開第２０１８／０７４３９０号（特許文献１）の化合物Ｉ－００８９およびＩ－０１８９は、９．９μＭまでの濃度で、ＳＡＲＳ－ＣｏＶ－２　３ＣＬプロテアーゼに対する阻害活性を示さなかった。 Compounds I-0089 and I-0189 of International Publication No. 2018/074390 (Patent Document 1) did not exhibit inhibitory activity against SARS-CoV-23CL protease at concentrations up to 9.9 μM.
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
　本発明の化合物は、任意の従来の経路により、特に、経腸、例えば、経口で、例えば、錠剤またはカプセル剤の形態で、または非経口で、例えば注射液剤または懸濁剤の形態で、局所で、例えば、ローション剤、ゲル剤、軟膏剤またはクリーム剤の形態で、または経鼻形態または座剤形態で医薬組成物として投与することができる。少なくとも１種の薬学的に許容される担体または希釈剤と一緒にして、遊離形態または薬学的に許容される塩の形態の本発明の化合物を含む医薬組成物は、従来の方法で、混合、造粒またはコーティング法によって製造することができる。例えば、経口用組成物としては、賦形剤、崩壊剤、結合剤、滑沢剤等および有効成分等を含有する錠剤、顆粒剤、カプセル剤とすることができる。また、注射用組成物としては、溶液剤または懸濁剤とすることができ、滅菌されていてもよく、また、保存剤、安定化剤、緩衝化剤等を含有してもよい。 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. For example, 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. For example, 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.
　本発明に係る化合物は、コロナウイルス３ＣＬプロテアーゼに対する阻害作用を有し、コロナウイルス３ＣＬプロテアーゼが関与する疾患または状態の治療剤および／または予防剤として有用であると考えられる。 The compound according to the present invention has an inhibitory effect on coronavirus 3CL protease, and is believed to be useful as a therapeutic and/or prophylactic agent for diseases or conditions involving coronavirus 3CL protease.

Claims (21)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、
    　破線は、結合の存在または不存在を示し；
    　Ｘは、－ＮＲ５－、－ＣＲ５Ｒ５’－、－Ｏ－または－Ｓ－であり；
    　Ｙは、＝Ｎ－または＝ＣＲ６－であり；
    　Ｚは、－ＮＲ１－または－ＣＲ１’＝であり；
    　Ｗは、＝Ｎ－、－Ｏ－、－ＣＲ７Ｒ７’－または－ＮＲ８－であり；
    　Ｒ１は、置換アルキル、置換アルケニル、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換のアミノまたは置換もしくは非置換のカルバモイルであり；
    　Ｒ１’は、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換のアミノまたは置換もしくは非置換のカルバモイルであり；
    　Ｒ３は、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族炭素環式基であり；
    　Ｒ２ａは、水素原子、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり；
    　Ｒ２ｂは、水素原子または置換もしくは非置換のアルキルであり；
    　ｎは、１または２であり；
    　Ｒ４ａは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基であり；
    　Ｒ４ｂは、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
    　ｎが１である場合は、Ｒ２ｂおよびＲ４ａは結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく；
    　ｎが１である場合は、Ｒ４ａおよびＲ４ｂは結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく；
    　Ｒ５およびＲ５’は、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
    　Ｒ６は、水素原子または置換もしくは非置換のアルキルであり；
    　Ｒ７およびＲ７’は、それぞれ独立して、水素原子または置換もしくは非置換のアルキルであり；
    　Ｒ８は、水素原子または置換もしくは非置換のアルキルである）で示される化合物（ただし、以下の化合物：
    Figure JPOXMLDOC01-appb-C000002
    を除く）、またはその製薬上許容される塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (In the formula,
    dashed lines indicate the presence or absence of a bond;
    X is -NR 5 -, -CR 5 R 5' -, -O- or -S-;
    Y is =N- or =CR 6 -;
    Z is —NR 1 — or —CR 1′ =;
    W is =N-, -O-, -CR 7 R 7' - or -NR 8 -;
    R 1 is substituted alkyl, substituted alkenyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted a substituted non-aromatic carbocyclic group, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl;
    R 1′ is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl;
    R 3 is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic carbon is a cyclic group;
    R 2a is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted unsubstituted an aromatic heterocyclic group, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
    R 2b is a hydrogen atom or substituted or unsubstituted alkyl;
    n is 1 or 2;
    Each R 4a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic ring is a formula group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;
    each R 4b is independently a hydrogen atom or a substituted or unsubstituted alkyl;
    When n is 1, R 2b and R 4a together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. often;
    When n is 1, R 4a and R 4b together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. often;
    R 5 and R 5′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl;
    R 6 is a hydrogen atom or substituted or unsubstituted alkyl;
    R 7 and R 7′ are each independently a hydrogen atom or a substituted or unsubstituted alkyl;
    R 8 is a hydrogen atom or substituted or unsubstituted alkyl) (provided that the following compounds:
    Figure JPOXMLDOC01-appb-C000002
    ), or a pharmaceutically acceptable salt thereof.
  2. 　Ｙが＝Ｎ－である、請求項１記載の化合物またはその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is =N-.
  3. 　Ｘが－ＮＨ－である、請求項１または２記載の化合物またはその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X is -NH-.
  4. 　Ｚが－ＮＲ１－である、請求項１～３のいずれかに記載の化合物またはその製薬上許容される塩。 4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Z is -NR 1 -.
  5. 　Ｗが＝Ｎ－である、請求項１～４のいずれかに記載の化合物またはその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein W is =N-.
  6. 　Ｒ１が置換アルキル、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基である、請求項１～５のいずれかに記載の化合物またはその製薬上許容される塩。 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable compound thereof, wherein R 1 is a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group Salt to be served.
  7. 　Ｒ１が置換もしくは非置換の芳香族複素環式基である、請求項１～６のいずれかに記載の化合物またはその製薬上許容される塩。 7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 1 is a substituted or unsubstituted aromatic heterocyclic group.
  8. 　Ｒ３が置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基である、請求項１～７のいずれかに記載の化合物またはその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 3 is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group .
  9. 　Ｒ２ａが置換もしくは非置換の芳香族炭素環式基である、請求項１～８のいずれかに記載の化合物またはその製薬上許容される塩。 9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 2a is a substituted or unsubstituted aromatic carbocyclic group.
  10. 　Ｒ２ｂが水素原子である、請求項１～９のいずれかに記載の化合物またはその製薬上許容される塩。 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R2b is a hydrogen atom.
  11. 　Ｒ４ａがそれぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族炭素環式基である、請求項１～１０のいずれかに記載の化合物またはその製薬上許容される塩。 Claims 1 to 10, wherein each R 4a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic carbocyclic group A compound according to any one of or a pharmaceutically acceptable salt thereof.
  12. 　Ｒ４ｂが水素原子である、請求項１～１１のいずれかに記載の化合物またはその製薬上許容される塩。 12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R4b is a hydrogen atom.
  13. 　ｎが１である、請求項１～１２のいずれかに記載の化合物またはその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein n is 1.
  14. 　化合物Ｉ－０００７、Ｉ－００７６、Ｉ－００９７、Ｉ－０１４２、Ｉ－０１４３、Ｉ－０３２６およびＩ－０３３２からなる群から選択される、請求項１記載の化合物またはその製薬上許容される塩。 The compound of Claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds I-0007, I-0076, I-0097, I-0142, I-0143, I-0326 and I-0332 .
  15. 　請求項１～１４のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。 A pharmaceutical composition containing the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.
  16. 　請求項１～１４のいずれかに記載の化合物またはその製薬上許容される塩を含有する、コロナウイルス３ＣＬプロテアーゼ阻害剤。 A coronavirus 3CL protease inhibitor containing the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.
  17. 　請求項１～１４のいずれかに記載の化合物またはその製薬上許容される塩を含有する、コロナウイルス増殖阻害剤。 A coronavirus growth inhibitor containing the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.
  18. 　コロナウイルスが、アルファコロナウイルスおよび／またはベータコロナウイルスである、請求項１７記載のコロナウイルス増殖阻害剤。 The coronavirus growth inhibitor according to claim 17, wherein the coronavirus is an alphacoronavirus and/or a betacoronavirus.
  19. 　コロナウイルスが、ＳＡＲＳ－ＣｏＶ－２である、請求項１７記載のコロナウイルス増殖阻害剤。 The coronavirus growth inhibitor according to claim 17, wherein the coronavirus is SARS-CoV-2.
  20. 　請求項１～１４のいずれかに記載の化合物、またはその製薬上許容される塩を投与することを特徴とする、コロナウイルス３ＣＬプロテアーゼの関与する疾患の治療および／または予防方法。 A method for treating and/or preventing diseases associated with coronavirus 3CL protease, which comprises administering the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.
  21. 　コロナウイルス３ＣＬプロテアーゼの関与する疾患の治療および／または予防に使用するための、請求項１～１４のいずれかに記載の化合物またはその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, for use in treating and/or preventing diseases involving coronavirus 3CL protease.
PCT/JP2022/032906 2021-09-03 2022-09-01 Bicyclic nitrogen-containing heterocyclic derivative having virus growth inhibitory activity and pharmaceutical composition containing same WO2023033098A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021143644 2021-09-03
JP2021-143644 2021-09-03

Publications (1)

Publication Number Publication Date
WO2023033098A1 true WO2023033098A1 (en) 2023-03-09

Family

ID=85412305

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/032906 WO2023033098A1 (en) 2021-09-03 2022-09-01 Bicyclic nitrogen-containing heterocyclic derivative having virus growth inhibitory activity and pharmaceutical composition containing same

Country Status (1)

Country Link
WO (1) WO2023033098A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115109041A (en) * 2022-06-07 2022-09-27 杭州科巢生物科技有限公司 Synthetic method and intermediate of 3CL protein inhibitor Encetavir
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018074390A1 (en) * 2016-10-17 2018-04-26 塩野義製薬株式会社 Bicyclic nitrogenated heterocyclic derivative and pharmaceutical composition containing same
JP2019182865A (en) * 2018-04-16 2019-10-24 塩野義製薬株式会社 Pharmaceutical composition containing bicyclic nitrogen-containing heterocyclic derivative
JP2019182806A (en) * 2018-04-16 2019-10-24 塩野義製薬株式会社 Bicyclic heterocyclic derivative and pharmaceutical composition containing the same
WO2022138987A1 (en) * 2021-04-14 2022-06-30 塩野義製薬株式会社 Triazine derivative having virus propagation inhibitory effect, and pharmaceutical composition containing same
JP2022108241A (en) * 2021-01-12 2022-07-25 ウエストレイク・ファーマシューティカル・（ハンヂョウ）・カンパニー・リミテッド Protease inhibitors, and preparation and uses thereof
JP2022537595A (en) * 2020-06-29 2022-08-26 ブイティーブイ・セラピューティクス・エルエルシー Quinoline derivatives, pharmaceutically acceptable salts and methods of use thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018074390A1 (en) * 2016-10-17 2018-04-26 塩野義製薬株式会社 Bicyclic nitrogenated heterocyclic derivative and pharmaceutical composition containing same
JP2019182865A (en) * 2018-04-16 2019-10-24 塩野義製薬株式会社 Pharmaceutical composition containing bicyclic nitrogen-containing heterocyclic derivative
JP2019182806A (en) * 2018-04-16 2019-10-24 塩野義製薬株式会社 Bicyclic heterocyclic derivative and pharmaceutical composition containing the same
JP2022537595A (en) * 2020-06-29 2022-08-26 ブイティーブイ・セラピューティクス・エルエルシー Quinoline derivatives, pharmaceutically acceptable salts and methods of use thereof
JP2022108241A (en) * 2021-01-12 2022-07-25 ウエストレイク・ファーマシューティカル・（ハンヂョウ）・カンパニー・リミテッド Protease inhibitors, and preparation and uses thereof
WO2022138987A1 (en) * 2021-04-14 2022-06-30 塩野義製薬株式会社 Triazine derivative having virus propagation inhibitory effect, and pharmaceutical composition containing same
JP7105430B1 (en) * 2021-04-14 2022-07-25 塩野義製薬株式会社 TRIAZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AKAJI KENICHI, KONNO HIROYUKI: "Design and Evaluation of Anti-SARS-Coronavirus Agents Based on Molecular Interactions with the Viral Protease", MOLECULES, vol. 25, no. 17, pages 3920, XP055826867, DOI: 10.3390/molecules25173920 *
LIU YUZHI; LIANG CHENGYUAN; XIN LIANG; REN XIAODONG; TIAN LEI; JU XINGKE; LI HAN; WANG YONGBO; ZHAO QIANQIAN; LIU HONG; CAO WENQIA: "The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 206, 6 August 2020 (2020-08-06), AMSTERDAM, NL , XP086299093, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2020.112711 *
OLUBIYI OLUJIDE O., OLAGUNJU MARYAM, KEUTMANN MONIKA, LOSCHWITZ JENNIFER, STRODEL BIRGIT: "High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2", MOLECULES, vol. 25, no. 14, pages 3193, XP055944494, DOI: 10.3390/molecules25143193 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
CN115109041A (en) * 2022-06-07 2022-09-27 杭州科巢生物科技有限公司 Synthetic method and intermediate of 3CL protein inhibitor Encetavir
CN115109041B (en) * 2022-06-07 2024-03-19 杭州科巢生物科技有限公司 Synthesis method and intermediate of 3CL protein inhibitor Entecavir

Similar Documents

Publication Publication Date Title
JP7105430B1 (en) TRIAZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2023033098A1 (en) Bicyclic nitrogen-containing heterocyclic derivative having virus growth inhibitory activity and pharmaceutical composition containing same
CN107531693B (en) 5 or 8-substituted imidazo [1, 5-a ] pyridines as indoleamine, tryptophan dioxygenase inhibitors
TW202214604A (en) Nitrile-containing antiviral compounds
CN109952300B (en) 5-or 8-substituted imidazo [1,5-a ] pyridines
WO2023054292A1 (en) Pharmaceutical composition containing triazine derivative
JP7253866B1 (en) Orally Administered Formulations Containing Triazine Derivatives
KR20210025061A (en) Ligand for cerebloon (CRBN)
TW200916459A (en) Antiviral compounds
CA2692460A1 (en) Hiv reverse transcriptase inhibitors
WO2023042879A1 (en) Bicyclic heterocyclic derivative having viral growth inhibitory activity and pharmaceutical composition containing same
WO2009005693A1 (en) Novel hiv reverse transcriptase inhibitors
JP7261529B1 (en) Method for producing triazine derivative having virus growth inhibitory action
JP2023537402A (en) Functionalized peptides as antiviral agents
WO2023022216A1 (en) Nucleoside derivatives and prodrugs thereof having viral growth inhibitory action
CN116782904A (en) Pharmaceutical composition containing triazine derivative
WO2023095860A1 (en) Covid-19 treatment medicine characterized by combining 3cl protease inhibitor and covid-19 treatment drug
JP7236065B1 (en) Pharmaceutical composition containing triazine derivative
WO2023048151A1 (en) Cyclic peptide having virus proliferation inhibition activity
JP2005538184A (en) 8-Hydroxy-1-oxo-tetrahydropyrrolopyrazine compounds useful as HIV integrase inhibitors
JP7454729B2 (en) Pharmaceutical composition containing an amide derivative with antiviral activity
JP7358657B2 (en) Amide derivatives with antiviral activity
WO2023195530A1 (en) Uracil derivative having viral growth inhibitory activity and pharmaceutical composition containing same
RU2806042C1 (en) Triazine derivatives having inhibitory activity against virus replication, and pharmaceutical composition containing them
CN117999257A (en) Bicyclic heterocyclic derivatives having virus proliferation inhibitory activity and pharmaceutical compositions containing the same

Legal Events

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

Ref document number: 22864680

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE