WO2023033098A1 - Dérivé hétérocyclique contenant de l'azote bicyclique ayant une activité inhibitrice de la croissance virale et composition pharmaceutique le contenant - Google Patents

Dérivé hétérocyclique contenant de l'azote bicyclique ayant une activité inhibitrice de la croissance virale et composition pharmaceutique le contenant Download PDF

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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
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substituted
unsubstituted
group
compound
aromatic heterocyclic
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PCT/JP2022/032906
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Japanese (ja)
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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
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塩野義製薬株式会社
国立大学法人北海道大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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.

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Abstract

La présente invention concerne un composé ayant une activité inhibitrice contre la protéase du coronavirus 3CL ou un sel pharmaceutiquement acceptable de celui-ci et une composition pharmaceutique le contenant. L'invention concerne également un composé représenté par la formule (I) (dans la formule ; X représente -NH-, etc ; Y représente =N-, etc ; Z représente -NR1-, etc. ; W représente =N-, etc ; R1 représente un groupe alkyle substitué, un groupe hétérocyclique aromatique substitué ou non substitué, etc. ; R2a représente un groupe cyclique de carbone aromatique substitué ou non substitué, etc. ; R2b représente un atome d'hydrogène, etc. ; n représente 1, etc ; R4a représente un atome d'hydrogène, un alkyle substitué ou non substitué, etc ; et R4b représente un atome d'hydrogène, etc.), ou un sel pharmaceutiquement acceptable de celui-ci.
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US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
CN115109041A (zh) * 2022-06-07 2022-09-27 杭州科巢生物科技有限公司 一种3cl蛋白抑制剂恩赛特韦的合成方法及其中间体
CN115109041B (zh) * 2022-06-07 2024-03-19 杭州科巢生物科技有限公司 一种3cl蛋白抑制剂恩赛特韦的合成方法及其中间体
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