WO2023095860A1 - ３ｃｌプロテアーゼ阻害剤及びｃｏｖｉｄ－１９治療用薬剤を組み合わせることを特徴とするｃｏｖｉｄ－１９治療用医薬 - Google Patents

３ｃｌプロテアーゼ阻害剤及びｃｏｖｉｄ－１９治療用薬剤を組み合わせることを特徴とするｃｏｖｉｄ－１９治療用医薬 Download PDF

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WO2023095860A1
WO2023095860A1 PCT/JP2022/043490 JP2022043490W WO2023095860A1 WO 2023095860 A1 WO2023095860 A1 WO 2023095860A1 JP 2022043490 W JP2022043490 W JP 2022043490W WO 2023095860 A1 WO2023095860 A1 WO 2023095860A1
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compound
group
substituted
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aromatic heterocyclic
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French (fr)
Japanese (ja)
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龍一 矢野
敦子 山本
治謙 登
輝久 加藤
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Shionogi and Co Ltd
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Priority to US18/711,747 priority patent/US20250025459A1/en
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/102—Coronaviridae (F)
    • C07K16/104—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the present invention relates to medicaments featuring specific combinations of novel coronavirus infection (COVID-19) therapeutic and/or prophylactic agents.
  • COVID-19 novel coronavirus infection
  • the coronavirus which belongs to the subfamily Orthocoronavirus subfamily, Coronaviridae, order of the Nidoviridae, has a genome size of about 30 kilobases, and is the largest single-stranded + stranded RNA virus among known RNA viruses.
  • Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, and there are two types of coronaviruses that infect humans: Alphacoronavirus (HCoV-229E, HCoV-229E, HCoV -NL63) and five members of the genus Betacoronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2).
  • HCoV-229E HCoV-NL63, HCoV-HKU1, HCoV-OC43
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome coronavirus
  • SARS-CoV novel coronavirus
  • Non-Patent Document 1 The novel coronavirus disease (COVID-19) that broke out in Wuhan, China in December 2019 spread rapidly throughout the international community, and was declared a pandemic by the WHO on March 11, 2020. As of September 21, 2022, the confirmed number of infected people reached 610 million or more, and the number of deaths reached 6.5 million or more (Non-Patent Document 1). Droplet infection, contact infection and aerosol infection have been reported as the main infection routes of SARS-CoV-2. (Non-Patent Document 2). The incubation period is about 2 to 14 days, and cold-like symptoms such as fever (87.9%), dry cough (67.7%), malaise (38.1%), and phlegm (33.4%) are typical. (Non-Patent Document 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, etc. occurs. Multiple organ failure such as renal failure and liver failure has also been reported.
  • Compounds and antibodies that act on various mechanisms that are effective against SARS-CoV-2 are being studied as potential therapeutic agents against COVID-19.
  • Examples include anti-SARS-CoV-2 monoclonal antibodies, RNA-dependent RNA polymerase inhibitors, 3CL protease inhibitors, TMPRSS2 inhibitors, and the like.
  • coronaviruses When coronaviruses infect cells, they synthesize various proteins required for self-replication. Among them are two polyproteins, the replication complexes that make up 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: Additionally, in July 2021, ClinicalTrials.com announced that a Phase 2/3 trial of PF-07321332 in combination with ritonavir will begin in COVID-19 patients with high-risk factors. gov (NCT04960202).
  • Ritonavir acts as a pharmacokinetic enhancer by inhibiting drug metabolism by CYP3A.
  • Pfizer's website showed that PAXLOVIDTM (PF-07321332; ritonavir) reduced the risk of hospitalization or death by 89% compared to placebo in high-risk adults. was reported (Non-Patent Document 14).
  • Non-Patent Documents 5 to 8 Compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 5 to 8, but in any of the documents, the compound represented by (A) in the pharmaceutical of the present invention, the compound having 3CL protease inhibitory activity, and others A method of treating COVID-19 in combination with other COVID-19 therapeutic agents is neither described nor suggested.
  • Patent Documents 1 to 4 disclose triazine derivatives having P2X3 and/or P2X2 /3 receptor antagonism. is neither mentioned nor suggested.
  • Non-Patent Documents 9 to 11 disclose triazine derivatives having antitumor effects, but none of these documents describes or suggests coronavirus 3CL protease inhibitory activity or antiviral effects.
  • An object of the present invention is to provide a compound having coronavirus 3CL protease inhibitory activity and a compound that is useful for the treatment and / or prevention of novel coronavirus infections, etc., with high efficacy against COVID-19 by using different drugs in combination. It is to provide medicine.
  • the present invention provides a medicament useful for the treatment and/or prevention of COVID-19, which causes less emergence of low-susceptibility viruses and less side effects.
  • the present invention relates to the following.
  • R 2 is a 6-membered aromatic carbocyclic group substituted with 1, 2 or 3 substituents selected from Substituent Group G;
  • (A) has the formula: The medicament according to any one of the above items (1) to (4), which is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (A) is represented by formula (IB): The medicament according to any one of the above items (1) to (5), which is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is an anti-SARS-CoV-2 monoclonal antibody, RNA-dependent RNA polymerase inhibitor, or 3CL protease inhibitor (excluding compounds represented by formula (I) or pharmaceutically acceptable salts thereof) ) and a TMPRSS2 inhibitor, the pharmaceutical according to any one of the above items (1) to (6).
  • (B) is (i) or (ii): (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, AT-527, PF-07321332, PF-00835231, GC376 or camostat, or a pharmaceutically acceptable salt thereof;
  • the medicament according to any one of the above items (1) to (7), which is at least one antibody selected from or a compound or a pharmaceutically acceptable salt thereof.
  • (B) is (i) or (ii): (i) casilibimab or imdevimab, (ii) molnupiravir, remdesivir, PF-07321332 or camostat, or a pharmaceutically acceptable salt thereof;
  • the medicament according to any one of the above items (1) to (8) which is at least one antibody selected from or a compound or a pharmaceutically acceptable salt thereof.
  • (11) The medicament according to any one of the above items (1) to (10), wherein (A) and (B) are administered in combination.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive pressure ventilation, etc.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive pressure ventilation, etc.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive pressure ventilation, etc.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive pressure ventilation, etc.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive pressure ventilation, etc.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive pressure ventilation, etc.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive pressure ventilation, etc.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive pressure ventilation, etc.
  • Action enhancer e.g., tracheostomy, gastrostomy, positive
  • the compound represented by (A) in the medicament of the present invention has inhibitory activity against coronavirus 3CL protease, and the medicament of the present invention is a therapeutic and/or prophylactic agent for COVID-19, and a COVID-19 severe It is useful as an action-enhancing agent for antioxidation inhibitors.
  • FIG. 1 shows a powder X-ray diffraction pattern of fumaric acid co-crystal Form I of the compound represented by formula (IB).
  • the horizontal axis represents 2 ⁇ (°), and the vertical axis represents intensity (Count).
  • FIG. 2 shows a structural diagram in the asymmetric unit of fumaric acid co-crystal Form I of the compound of formula (IB).
  • the "COVID-19 aggravation inhibitor" of (B) in combination with (A) includes, for example, an anti-SARS-CoV-2 agent, an immunomodulator or an immunosuppressant.
  • the "COVID-19 aggravation inhibitor” used in (B) is a compound or antibody different from the compound represented by formula (I) or a pharmaceutically acceptable salt thereof used in (A).
  • the "COVID-19 aggravation inhibitor” used in (B) may be one or two or more drugs, and is not limited to one drug.
  • COVID-19 aggravation suppressor is not limited to those on the market or under development, but those on the market or under development include casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab, bebuterobimab, molnupiravir, remdesivir, AT- 527, PF-07321332, PF-00835231, Camostat and the like.
  • casilibimab particularly preferred are casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab, bebuterobimab, molnupiravir, remdesivir, PF-07321332, and camostat. Furthermore, casilibimab and imdevimab are preferred.
  • "COVID-19 aggravation agents" include, for example, mixtures of two neutralizing antibody drugs known as antibody cocktail therapy, including casilibimab and imdevimab, tixagevimab and silgavimab.
  • Anti-SARS-CoV-2 agents include, for example, anti-SARS-CoV-2 monoclonal antibodies, anti-SARS-CoV-2 polyclonal antibodies, RNA-dependent RNA polymerase inhibitors, 3CL protease inhibitors (wherein the above formula (I) or a pharmaceutically acceptable salt thereof), TMPRSS2 inhibitors, and the like.
  • anti-SARS-CoV-2 monoclonal antibodies include, for example, casilibimab (REGN10933), imdevimab (REGN10987), bamuranivimab (LY-CoV555), etesevimab (LY-CoV016), sotrovimab (VIR-7831, GSK4182136), AZD7442 ( Tixagevimab: AZD8895 and Silgavimab: AZD1061), Regdanvimab (CT-P59), TY-027, BRII-196, BRII-198, Bebuterobimab (LY-CoV1404), STI-2020, BI-767551 (DZIF-10c), VIR- 7832, STI-1499, etc., but not limited to these.
  • anti-SARS-CoV-2 monoclonal antibody examples include casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab, bebuterobimab and the like.
  • Anti-SARS-CoV-2 polyclonal antibodies include, but are not limited to, Sab-185 and the like.
  • RNA-dependent RNA polymerase inhibitor may be any agent that has an RNA-dependent RNA polymerase inhibitory action and corresponds to the above anti-SARS-CoV-2 agent.
  • prodrugs thereof may be used.
  • RNA-dependent RNA polymerase inhibitors include, for example, EIDD-1931 (NHC), molnupiravir (MK-4482, EIDD-2081) which is a prodrug of EIDD-1931, remdesivir, favipiravir, AT-511, AT- 511 prodrugs AT-527, Enisamium, Ribavirin, etc., but not limited to.
  • Preferable examples of "RNA-dependent RNA polymerase inhibitors” include molnupiravir, remdesivir and the like.
  • the “3CL protease inhibitor” is any agent that has a 3CL protease inhibitory effect and corresponds to the above anti-SARS-CoV-2 agent (provided that the compound represented by the above formula (I) or a pharmaceutically acceptable excluding salt that is used). Alternatively, prodrugs thereof may be used.
  • Examples of "3CL protease inhibitors” include, but are not limited to, PF-07321332, PF-00835231, lopinavir, darunavir, GC376, EDP-235, PBI-0451, and the like.
  • “3CL protease inhibitor” preferably includes PF-07321332 and the like.
  • TMPRSS2 inhibitor may be any agent that has a TMPRSS2 inhibitory effect and corresponds to the above anti-SARS-CoV-2 agent. Also, prodrugs thereof may be used. Examples of “TMPRSS2 inhibitors” include, but are not limited to, camostat and the like.
  • anti-SARS-CoV-2 agents include, for example, interferon beta-1a, peginterferon alfa-2b, peginterferon lambda, 2-deoxy-D-glucose, iota-carrageenan, nitazoxanide, niclosamide, ensovibep (MP0420), Pyronaridine- Artesunate and the like, but are not limited thereto.
  • Immunomodulators or immunosuppressants include, for example, steroids, Janus kinase (JAK) inhibitors, anti-IL-6 receptor monoclonal antibodies, anti-human IL-1 ⁇ monoclonal antibodies, IL-1 inhibitors, anti-human TNF ⁇ monoclonals Antibody, anti-CD73 monoclonal antibody, anti-CCR5 receptor monoclonal antibody, anti-LIGHT monoclonal antibody, anti-GM-CSF monoclonal antibody, anti-GM-CSF receptor monoclonal antibody, DP1 inhibitor, H2 receptor antagonist, androgen receptor antagonist GM-CSF preparations, calpain inhibitors, gelsolin stimulants, anti-human plasma kallikrein monoclonal antibodies, anti-C5 monoclonal antibodies, anti-rheumatic agents and the like.
  • JAK Janus kinase
  • anti-IL-6 receptor monoclonal antibodies include, for example, steroids, Janus kinase (JAK) inhibitors, anti-IL-6 receptor monoclo
  • (B) is the following (i) or (ii): (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, AT-527, PF-07321332, PF-00835231, GC376 or camostat, or a pharmaceutically acceptable salt thereof; "At least one antibody selected from, or a compound or a pharmaceutically acceptable salt thereof” is an embodiment in which (B) is at least one antibody selected from (i), (B) is ( ii) is at least one compound selected from or a pharmaceutically acceptable salt thereof, and (B) is at least one antibody selected from (i) and at least one compound selected from (ii) or a pharmaceutically acceptable salt thereof.
  • (B) includes casilibimab, imdevimab and sotrovimab. In one embodiment, (B) includes casilibimab and imdevimab. In one embodiment, (B) includes imdevimab and sotrovimab. In one embodiment, (B) includes casilibimab and sotrovimab. In one embodiment, (B) includes casilibimab. In one embodiment, (B) includes imdevimab. In one embodiment, (B) includes sotrovimab. In one embodiment, (B) includes tixagevimab, silgavimab and bebuterobimab. In one embodiment, (B) includes bebuterobimab. In one embodiment, (B) includes tixagevimab and silgavimab. In one embodiment, (B) includes tixagevimab. In one embodiment, (B) includes silgavimab.
  • 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, and still more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. straight or branched chain hydrocarbon groups.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl. More preferred embodiments include ethenyl, n-propenyl, and the like.
  • alkynyl refers to a group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. It includes straight chain or branched hydrocarbon groups. Furthermore, it may have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Preferred embodiments of "alkynyl” include ethynyl, propynyl, butynyl and pentynyl. More preferred embodiments include ethynyl, propynyl and the like.
  • Aromatic carbocyclic group means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthryl, phenanthryl and the like. A preferred embodiment of the "aromatic carbocyclic group” is phenyl.
  • a "6-membered aromatic carbocyclic group” means a monocyclic cyclic aromatic hydrocarbon group. Examples include phenyl.
  • 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 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.
  • “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 You may have it in any ring.
  • 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. is 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.
  • the “5- to 6-membered aromatic heterocyclic group” means a 5- or 6-membered aromatic heterocyclic group among the above “aromatic heterocyclic groups”.
  • the “9- to 10-membered aromatic heterocyclic group” means a 9- or 10-membered aromatic heterocyclic group among the above “aromatic heterocyclic groups”.
  • 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 a ring in which each ring in the "aromatic heterocyclic group” is condensed, and a 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.
  • Examples of 5-membered non-aromatic heterocyclic groups include 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.
  • substituent group ⁇ means “optionally substituted with one or more groups selected from substituent group ⁇ ". The same applies to the substituent groups ⁇ , ⁇ and ⁇ '.
  • Substituent group ⁇ halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
  • Substituent group ⁇ halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkynyl, alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylsulfanyl optionally substituted with substituent group ⁇ , alkenylsulfanyl optionally substituted with substituent group ⁇ , alkynylsulfanyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally substituted with substituent group ⁇ , alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇ , alken
  • Substituent Group ⁇ Substituent Group ⁇ , alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.
  • Substituent group ⁇ ' Substituent group ⁇ and oxo.
  • substituents on the ring of the "aromatic carbocyclic ring” and “aromatic heterocyclic ring” of the "substituted aromatic carbocyclic group” and “substituted aromatic heterocyclic group” include the following substituent group B. be done. 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
  • substituents on the ring of the "non-aromatic carbocyclic ring” and “non-aromatic heterocyclic ring” of the "substituted non-aromatic carbocyclic group” and “substituted non-aromatic heterocyclic group” include the following substituents: Group C is mentioned. An atom at any position on the ring may be bonded to one or more groups selected from Substituent Group C below. Substituent Group C: Substituent Group B and oxo.
  • non-aromatic carbocycle and “non-aromatic heterocycle” are substituted with “oxo” they mean rings in which two hydrogen atoms on the carbon atoms are substituted as follows.
  • substituents of the "substituted or unsubstituted aromatic heterocyclic group" or “substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group” for R 1 include: halogen; substituted or unsubstituted alkyl; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic heterocyclic group” or “substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group” for R 1 include: halogen; substituted alkyl (hydroxy as substituent); unsubstituted alkyl; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted 6-membered aromatic carbocyclic group" for R 2 include: halogen; cyano; substituted or unsubstituted alkyl; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted 6-membered aromatic carbocyclic group" for R 2 include: halogen; cyano; substituted alkyl (halogen as substituent); unsubstituted alkyl; are mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic heterocyclic group" or “substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group” for R 3 include: halogen; substituted or unsubstituted alkyl; substituted or unsubstituted non-aromatic heterocyclic groups; is mentioned. It may be substituted with one or more groups selected from these.
  • substituents of the "substituted or unsubstituted aromatic heterocyclic group” or “substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group” for R 3 include: halogen; substituted alkyl (as substituents, halogen, hydroxy, alkylcarbonylamino, non-aromatic heterocyclic group); unsubstituted alkyl; substituted non-aromatic heterocyclic group (as a substituent, alkylcarbonyl); unsubstituted non-aromatic heterocyclic group; are mentioned. It may be substituted with one or more groups selected from these.
  • R 1 , R 2 , R 3 and m in the compound represented by are shown below.
  • Y, -X-, R 5a , R 5b , n, R 4a and R 4b are as defined in item (1) above.
  • R 1 includes a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-1).
  • R 1 includes a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group (hereinafter referred to as A-2).
  • R 1 includes an aromatic heterocyclic group or an unsubstituted aromatic heterocyclic group substituted with halogen, substituted alkyl (substituent: hydroxy) or unsubstituted alkyl (hereinafter referred to as A-3).
  • R 1 includes a 5- to 6-membered aromatic heterocyclic group or an unsubstituted 5- to 6-membered aromatic heterocyclic group substituted with halogen, substituted alkyl (substituent: hydroxy) or unsubstituted alkyl (hereinafter , A-4).
  • R 1 includes an aromatic heterocyclic group substituted with unsubstituted alkyl or halogen, or an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-5).
  • R 1 includes a 5- to 6-membered aromatic heterocyclic group substituted with unsubstituted alkyl or halogen, or an unsubstituted 5- to 6-membered aromatic heterocyclic group (hereinafter referred to as A-6).
  • R 1 includes unsubstituted alkyl or halogen-substituted aromatic heterocyclic group (hereinafter referred to as A-7).
  • R 1 includes unsubstituted alkyl or halogen-substituted 5- to 6-membered aromatic heterocyclic group (hereinafter referred to as A-8).
  • R 1 includes an aromatic heterocyclic group substituted with unsubstituted alkyl or an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-9).
  • R 1 includes a 5- to 6-membered aromatic heterocyclic group substituted with unsubstituted alkyl or an unsubstituted 5- to 6-membered aromatic heterocyclic group (hereinafter referred to as A-10).
  • R 1 includes an aromatic heterocyclic group substituted with unsubstituted alkyl (hereinafter referred to as A-11).
  • R 1 includes a 5- to 6-membered aromatic heterocyclic group substituted with unsubstituted alkyl (hereinafter referred to as A-12).
  • R 2 includes a substituted or unsubstituted 6-membered aromatic carbocyclic group (hereinafter referred to as B-1).
  • R 2 includes a 6-membered aromatic carbocyclic group substituted with halogen, cyano, substituted alkyl (substituent: halogen) or unsubstituted alkyl (hereinafter referred to as B-2).
  • R 2 includes a 6-membered aromatic carbocyclic group substituted with halogen, cyano, or unsubstituted alkyl (hereinafter referred to as B-3).
  • R 2 includes a 6-membered aromatic carbocyclic group substituted with 2 to 4 substituents selected from Substituent Group G (Substituent Group G: halogen, cyano and unsubstituted alkyl) (hereinafter , B-4).
  • R 2 includes a 6-membered aromatic carbocyclic group substituted with 2 to 3 substituents selected from Substituent Group G (Substituent Group G: halogen, cyano and unsubstituted alkyl) (hereinafter , B-5).
  • R 2 includes a 6-membered aromatic carbocyclic group substituted with 3 to 4 substituents selected from Substituent Group G (Substituent Group G: halogen, cyano and unsubstituted alkyl) (hereinafter , B-6).
  • R 2 includes a 6-membered aromatic carbocyclic group substituted with 3 halogens (hereinafter referred to as B-7).
  • R 3 includes a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as C-1).
  • C-2 includes a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group (hereinafter referred to as C-2).
  • C-3 includes an aromatic heterocyclic group substituted with halogen or substituted or unsubstituted alkyl (hereinafter referred to as C-3).
  • C-4 includes a 9- to 10-membered aromatic heterocyclic group substituted with halogen or substituted or unsubstituted alkyl (hereinafter referred to as C-4).
  • C-5 includes an aromatic heterocyclic group substituted with halogen or unsubstituted alkyl
  • R 3 includes a 9- to 10-membered aromatic heterocyclic group substituted with halogen or unsubstituted alkyl (hereinafter referred to as C-6).
  • R 3 includes indazolyl substituted with halogen or unsubstituted alkyl (hereinafter referred to as C-7).
  • R 3 includes indazolyl substituted with halogen and unsubstituted alkyl (hereinafter referred to as C-8).
  • n is 0 or 1 (hereinafter referred to as D-1). Examples of m include 0 (hereinafter referred to as D-2). m includes 1 (hereinafter referred to as D-3).
  • the compounds of formula (I) are not limited to any particular isomer, but include all possible isomers (e.g. keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers , rotamers, etc.), racemates or mixtures thereof.
  • compounds of formula (I) include the following tautomers.
  • compound (I-003) includes the following tautomers and mixtures thereof.
  • compound (I-005) includes the following tautomers and mixtures thereof.
  • One or more hydrogen, carbon and/or other atoms of the compounds of Formula (I) may be substituted with isotopes of hydrogen, carbon and/or other atoms, respectively.
  • isotopes include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O , 31 P, 32 P, 35 S, 18 F, 123 I and Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included, as is 36 Cl.
  • the compounds of formula (I) also include such isotopically substituted compounds.
  • the isotopically substituted compounds are also useful as pharmaceuticals and include all radiolabeled compounds of formula (I).
  • crystal of the compound represented by formula (I) may be a deuterium conversion product.
  • Crystals of the compound represented by formula (I) may be labeled with isotopes (eg, 3 H, 14 C, 35 S, 125 I, etc.).
  • Radiolabeled compounds of formula (I) can be prepared by methods well known in the art.
  • a tritium-labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) through a catalytic dehalogenation reaction using tritium.
  • This method comprises reacting a suitably halogenated precursor of a compound of formula (I) with tritium gas in the presence or absence of a base, in the presence of a suitable catalyst such as Pd/C.
  • a suitable catalyst such as Pd/C.
  • 14 C-labeled compounds can be prepared by using starting materials with a 14 C carbon.
  • Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, the compound represented by formula (I) and an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid) , trifluoroacetic acid, citric acid, lactic acid, tarta
  • a complex of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be used in the medicament of the present invention.
  • Compounds of formula (I) or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates, etc.), co-crystals and/or clathrates, and are herein They are described as "complexes”.
  • solvate as used herein may be coordinated with any number of solvent molecules (eg, water molecules, etc.) with respect to the compound represented by formula (I), for example.
  • solvent molecules eg, water molecules, etc.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb water, attach adsorbed water, or form a hydrate.
  • Solvent molecules include, for example, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane , 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene , xylene, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl
  • co-crystal means a regular arrangement of counter-molecules within the same crystal lattice, and may contain any number of counter-molecules.
  • a co-crystal refers to an intermolecular interaction between a compound and a counter molecule through non-covalent and non-ionic chemical interactions such as hydrogen bonding and van der Waals forces.
  • a co-crystal of the compound of formula (IB) may consist of the compound of formula (IB) and a counter molecule, and may contain any number of counter molecules.
  • it consists of the compound represented by formula (IB) and fumaric acid, and may contain any number of fumaric acids.
  • the compound of formula (IB) and fumaric acid are co-crystals in a 1:1 molar ratio.
  • Co-crystals are distinguished from salts in that the compounds remain essentially uncharged or neutral.
  • Co-crystals are distinguished from hydrates or solvates in that the counter molecule is not water or a solvent.
  • crystal means a solid in which constituent atoms, ions, molecules, etc. are arranged regularly in three dimensions, and is distinguished from amorphous solids that do not have such a regular internal structure. be.
  • a crystal of the compound according to the present invention may be a single crystal, a twin crystal, a polycrystal, or the like.
  • crystals may have “crystal polymorphs” that have the same composition but different arrangements in the crystal, and these are collectively referred to as “crystal forms”.
  • Crystalline morphology and crystallinity can be measured by a number of techniques including, for example, powder X-ray diffraction measurements, Raman spectroscopy, infrared spectroscopy, moisture adsorption-desorption measurements, differential scanning calorimetry, dissolution properties. can.
  • a compound of formula (I), a pharmaceutically acceptable salt thereof, or a complex thereof may also be recrystallized to form a "polymorph".
  • a pharmaceutically acceptable salt thereof or a complex thereof may also be recrystallized to form a "polymorph".
  • crystal polymorphs can be used, and two or more thereof can be used. Even mixtures can be used.
  • X-ray powder diffraction X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Crystalline forms of the compound of Formula (IB) are distinguishable by their X-ray powder diffraction patterns and characteristic diffraction peaks.
  • the crystalline form of the compound of Formula (IB) can be distinguished from other crystalline forms by the presence of characteristic diffraction peaks.
  • a characteristic diffraction peak is a peak selected from an observed diffraction pattern.
  • the characteristic diffraction peaks are preferably selected from about 10, more preferably about 5, even more preferably about 3 in the diffraction pattern.
  • the peak that is confirmed in the crystal and not confirmed in other crystals is a characteristic peak that is preferable for identifying the crystal.
  • One or even two such characteristic peaks can characterize the crystal.
  • the diffraction angle (2 ⁇ ) in powder X-ray diffraction can have an error within the range of ⁇ 0.2°, so the value of the diffraction angle in powder X-ray diffraction is within the range of about ⁇ 0.2°.
  • the compound according to the present invention includes not only crystals in which the diffraction angles of the peaks in X-ray powder diffraction completely match, but also crystals in which the diffraction angles of the peaks match with an error of about ⁇ 0.2°.
  • Single crystal structure analysis It is one of the methods for identifying a crystal, and it is possible to obtain crystallographic parameters of the crystal, as well as atomic coordinates (values indicating spatial positional relationships among atoms) and a three-dimensional structural model. See Toshio Sakurai, "A Guide to X-ray Structural Analysis,” published by Shokabo (1983), Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968). Single crystal structure analysis is useful for identifying the crystal structures of the complexes, salts, optical isomers, tautomers, and geometric isomers of the present invention.
  • (A method) (Wherein, Alk is C1-C3 alkyl, Lg 1 is a leaving group, R 6 is a hydrogen atom, and other symbols are as defined above.)
  • (First step) Compound (A-1) or its hydrochloride or bromate, etc., in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethylimidazolidinone, dimethylsulfoxide, THF, etc.
  • a base such as DBU, triethylamine, N,N-diisopropylethylamine, pyridine (preferably DBU), at -20 ° C. to 50 ° C., preferably from -10 ° C.
  • reaction mixture is treated with a carbonylating agent such as 1,1′-carbonyldiimidazole, phosgene, triphosgene, etc., and a base such as DBU, triethylamine, N,N-diisopropylethylamine, pyridine (preferably DBU);
  • a carbonylating agent such as 1,1′-carbonyldiimidazole, phosgene, triphosgene, etc.
  • a base such as DBU, triethylamine, N,N-diisopropylethylamine, pyridine (preferably DBU);
  • Compound (A-3) can be produced by reacting at 20°C to 50°C, preferably from -10°C to under ice cooling.
  • Preferred halogens are chlorine, iodine and bromine, and preferred —OSO 2 (C t F 2t+1 ) groups are —OTf groups (trifluoromethanesulfonate).
  • the optically active isocyanate (A-2) the compound represented by the optically active compound (IA) can be produced.
  • Compound (D) when Y is N and m is 0 (Wherein, Alk is C1-C3 alkyl, Pro is C1-C4 alkyl or tert-butoxycarbonyl, Lg 2 is a leaving group, R 6 is a hydrogen atom, and other symbols are as defined above. be.)
  • Compound (D-2) can be produced from compound (D-1) in the same manner as in the second step of Method A above.
  • Compound (D-3) can be produced by treating compound (D-2) with a strong acid such as TFA at -20°C to room temperature, preferably at room temperature, in the presence or absence of an organic solvent. can.
  • Compound (D-4) can be produced from compound (D-3) in the same manner as in the third step of Method A above.
  • Compound (ID) can be produced by Goldberg amination reaction using compound (D-4) and compound (D-5). Examples of the leaving group include those described in Method A, Step 1 above.
  • the catalyst for example, commercially available copper catalysts such as copper iodide, copper cyanide and copper bromide can be used.
  • copper iodide such as copper iodide, copper cyanide and copper bromide
  • a ligand 1,2-dimethylethylenediamine, trans-N,N'-dimethylcyclohexane-1,2-diamine and the like can be used. Potassium carbonate, potassium phosphate and the like can be used as the base.
  • NMP, dioxane, DMSO, etc. can be used as a solvent.
  • the reaction temperature may range from room temperature to a temperature at which the solvent is refluxed, preferably under reflux with
  • the compound represented by (A) in the pharmaceutical of the present invention has coronavirus 3CL protease inhibitory activity, it is useful as a therapeutic and/or prophylactic agent for viral infections. Furthermore, the compound represented by (A) in the medicament of the present invention is useful as a medicament, 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.).
  • CYP enzymes eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • b) show good pharmacokinetics such as high bioavailability and moderate clearance; c) high metabolic stability; d) Does not exhibit irreversible inhibitory action on CYP enzymes (eg, CYP3A4) within the concentration range of the measurement conditions described herein. 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).
  • HS human serum
  • HSA human serum albumin
  • the salt, crystal, complex, or co-crystal of the compound represented by (A) in the medicament of the present invention is useful as a medicament, and is preferably one or more of the following excellent It has characteristics.
  • bb) It exhibits good pharmacokinetics, such as high bioavailability, moderate clearance, high AUC, and high peak blood concentration.
  • gg) exhibit high solubility, high chemical stability and low hygroscopicity;
  • (B) in the medicament of the present invention can be a commercially available product. ), etc., by methods known in the art.
  • the present invention provides (A) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (B) COVID-19 aggravation inhibitors (excluding compounds represented by formula (I) or pharmaceutically acceptable salts thereof); To provide a pharmaceutical characterized by combining
  • the present invention provides a pharmaceutical for suppressing aggravation of COVID-19, which is a combination of (A) and (B).
  • the "medicine characterized by combination” means a drug containing each compound, a mode in which each compound is used as a combination drug, a mode in which the compounds are used as a kit, a mode in which they are administered simultaneously, and a mode in which they are administered at intervals.
  • a mode in which a drug is used in combination with another drug is also included, and is sometimes abbreviated as “combination”, but these are synonymous.
  • the compound represented by formula (I) of (A) or a pharmaceutically acceptable salt thereof can be used in combination with (B) to enhance its action.
  • the present invention provides a COVID-19 aggravation inhibitory action enhancer of (B) containing (A). In one aspect, the present invention provides a COVID-19 aggravation inhibitory action enhancer of (A), which contains (B).
  • a preferred embodiment is a medicine characterized by combining the following (A) and (B).
  • (A) is a compound represented by (a-1), (a-2), (a-3), (a-4) or a pharmaceutically acceptable salt thereof, or the formula: is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is from an anti-SARS-CoV-2 monoclonal antibody, an RNA-dependent RNA polymerase inhibitor, a 3CL protease inhibitor (excluding the compound of (A) or a pharmaceutically acceptable salt thereof) and a TMPRSS2 inhibitor At least one selected from the group consisting of
  • a preferred embodiment is a medicine characterized by combining the following (A) and (B).
  • (A) is a compound represented by (a-1), (a-2), (a-3), (a-4) or a pharmaceutically acceptable salt thereof, or the formula: is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is (i) or (ii) of the following: (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, AT-527, PF-07321332, PF-00835231, GC376 or camostat, or a pharmaceutically acceptable salt thereof; at least one antibody or compound or pharmaceutically acceptable salt thereof selected from
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-4) above or a pharmaceutically acceptable salt thereof.
  • (B) is from an anti-SARS-CoV-2 monoclonal antibody, an RNA-dependent RNA polymerase inhibitor, a 3CL protease inhibitor (excluding the compound of (A) or a pharmaceutically acceptable salt thereof) and a TMPRSS2 inhibitor At least one selected from the group consisting of
  • Another embodiment is a medicine characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-4) above or a pharmaceutically acceptable salt thereof.
  • (B) is an anti-SARS-CoV-2 monoclonal antibody.
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-4) above or a pharmaceutically acceptable salt thereof.
  • (B) is (i) or (ii): (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, AT-527, PF-07321332, PF-00835231, GC376 or camostat, or a pharmaceutically acceptable salt thereof; at least one antibody or compound or pharmaceutically acceptable salt thereof selected from
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-3) above or a pharmaceutically acceptable salt thereof.
  • (B) is from an anti-SARS-CoV-2 monoclonal antibody, an RNA-dependent RNA polymerase inhibitor, a 3CL protease inhibitor (excluding the compound of (A) or a pharmaceutically acceptable salt thereof) and a TMPRSS2 inhibitor At least one selected from the group consisting of
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-3) above or a pharmaceutically acceptable salt thereof.
  • (B) is an anti-SARS-CoV-2 monoclonal antibody.
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-3) above or a pharmaceutically acceptable salt thereof.
  • (B) is (i) or (ii): (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, PF-07321332, GC376 or camostat, or a pharmaceutically acceptable salt thereof; at least one antibody or compound or pharmaceutically acceptable salt thereof selected from
  • A is a compound represented by (a-2) above or a pharmaceutically acceptable salt thereof.
  • B is from an anti-SARS-CoV-2 monoclonal antibody, an RNA-dependent RNA polymerase inhibitor, a 3CL protease inhibitor (excluding the compound of (A) or a pharmaceutically acceptable salt thereof) and a TMPRSS2 inhibitor At least one selected from the group consisting of
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-2) above or a pharmaceutically acceptable salt thereof.
  • (B) is an anti-SARS-CoV-2 monoclonal antibody.
  • A is a compound represented by (a-2) above or a pharmaceutically acceptable salt thereof.
  • B is (i) or (ii) of the following: (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, PF-07321332, GC376 or camostat, or a pharmaceutically acceptable salt thereof; at least one antibody or compound or pharmaceutically acceptable salt thereof selected from
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-1) above or a pharmaceutically acceptable salt thereof.
  • (B) is from an anti-SARS-CoV-2 monoclonal antibody, an RNA-dependent RNA polymerase inhibitor, a 3CL protease inhibitor (excluding the compound of (A) or a pharmaceutically acceptable salt thereof) and a TMPRSS2 inhibitor At least one selected from the group consisting of
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-1) above or a pharmaceutically acceptable salt thereof.
  • (B) is an anti-SARS-CoV-2 monoclonal antibody.
  • Another embodiment is a medicine characterized by combining the following (A) and (B).
  • (A) is the compound represented by (a-1) above or a pharmaceutically acceptable salt thereof.
  • (B) is (i) or (ii) of the following: (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, PF-07321332, GC376 or camostat, or a pharmaceutically acceptable salt thereof; at least one antibody or compound or pharmaceutically acceptable salt thereof selected from
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) has the formula: is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is from an anti-SARS-CoV-2 monoclonal antibody, an RNA-dependent RNA polymerase inhibitor, a 3CL protease inhibitor (excluding the compound of (A) or a pharmaceutically acceptable salt thereof) and a TMPRSS2 inhibitor At least one selected from the group consisting of
  • Another embodiment is a medicine characterized by combining the following (A) and (B).
  • (A) has the formula: is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is an anti-SARS-CoV-2 monoclonal antibody.
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) has the formula: is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is (i) or (ii): (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, PF-07321332, GC376 or camostat, or a pharmaceutically acceptable salt thereof; at least one antibody or compound or pharmaceutically acceptable salt thereof selected from
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) has the formula (IB): is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is from an anti-SARS-CoV-2 monoclonal antibody, an RNA-dependent RNA polymerase inhibitor, a 3CL protease inhibitor (excluding the compound of (A) or a pharmaceutically acceptable salt thereof) and a TMPRSS2 inhibitor At least one selected from the group consisting of
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) has the formula (IB): is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is an anti-SARS-CoV-2 monoclonal antibody.
  • Another embodiment is a medicament characterized by combining the following (A) and (B).
  • (A) has the formula (IB): is a compound represented by or a pharmaceutically acceptable salt thereof.
  • (B) is (i) or (ii): (i) casilibimab, imdevimab, sotrovimab, tixagevimab, silgavimab or bebuterobimab, (ii) molnupiravir, remdesivir, PF-07321332, GC376 or camostat, or a pharmaceutically acceptable salt thereof; at least one antibody or compound or pharmaceutically acceptable salt thereof selected from
  • the medicament of the present invention can be administered either 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 medicament of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, if necessary.
  • the pharmaceutical composition can be prepared for children, the elderly, critically ill patients, or for surgery by appropriately changing the effective amount of the compound in the medicine of the present invention, dosage form and/or various pharmaceutical additives.
  • It can also be a pharmaceutical composition.
  • 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), infants (1 to less than 7 years of age), children (7 to less than 15 years of age), or 15 Patients between the ages of 18 and 18 can be administered.
  • geriatric pharmaceutical compositions may be administered to patients 65 years of age or older.
  • the dosage of the pharmaceutical composition containing the compound represented by (A) in the medicament of the present invention is It is desirable to set it after considering the age, body weight, type and degree of disease, route of administration, etc., but when administered orally, it is usually 0.05 to 200 mg / kg / day, preferably 0.1 to 200 mg / kg / day. within the range of 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 dosage of the pharmaceutical of the present invention can be appropriately selected based on clinically used dosages.
  • the compounding ratio of the compound represented by (A) and the concomitant drug (B) 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, 0.001 to 1000 parts by weight of the concomitant drug of (B) may be used per 1 part by weight of the compound of (A).
  • the medicament or action-enhancing agent of the present invention is used for the treatment and/or prevention of coronavirus infections, particularly infections caused by SARS-CoV-2.
  • the SARS-CoV-2 that causes the target infection of the medicament or action-enhancing agent of the present invention is a low-susceptibility virus.
  • Low susceptibility includes narrowly defined resistant viruses (ie, viruses for which antiviral drugs do not respond), as well as viruses with susceptibility that respond only at concentrations higher than originally expected.
  • Low susceptibility is usually determined relative to a reference strain in any measurement system for antiviral agents, and can be measured, for example, using a plaque reduction assay.
  • the medicament or action enhancer of the present invention is used for immunocompromised patients.
  • a patient with weakened immunity is determined as follows. That is, force measurement can be performed by collecting a small amount of blood and examining 3 to 10 items such as types, ratios, and functions of lymphocytes.
  • immunity can be determined by the number of white blood cells, and when the white blood cell count is below the numerical range of a normal person, it can be determined that immunity is low. The following are normal values, and below these values can be regarded as a decrease in immunity.
  • the medicament of the present invention or the action enhancer (A) is characterized by reducing the appearance frequency of the low-susceptibility virus (A).
  • the medicament or action enhancer of the present invention is used by adults aged 50 and over. In one preferred embodiment, the medicament or action enhancer of the present invention is used by adults aged 65 and over. In one preferred embodiment, the medicament or action enhancer of the present invention is used by adults aged 75 and over.
  • the medicament or action-enhancing agent of the present invention is also used for SARS-CoV-2 unvaccinated patients. This is because SARS-CoV-2 unvaccinated patients are assumed to be one of the so-called high-risk groups.
  • the invention also provides (i) 50 years of age or older; (ii) obesity (e.g., BMI>30 kg/ m2 or greater), (iii) cardiovascular disease (including, for example, hypertension); (iv) asthma or chronic lung disease; (v) type 1 or type 2 diabetes, (vi) chronic renal failure (including, for example, dialysis patients); (vii) chronic liver disease, and (viii) immunosuppressive conditions (e.g., malignant tumor therapy, bone marrow or organ transplantation, immunodeficiency, uncontrolled HIV, AIDS, sickle cell anemia, thalassemia, long-term use of immunosuppressants, etc.) ) (ix) chronic obstructive pulmonary disease (COPD), (x) Dyslipidemia (xi) Smoking (xii) Immunodeficiency after solid organ transplantation (xiii) Pregnancy (xiv) Patients with neurodevelopmental disorders or complex medical conditions (e.g., cerebral palsy, congenital), e
  • the medicament or action-enhancing agent of the present invention is also used in patients with pneumonia caused by SARS-CoV-2.
  • the medicament or action-enhancing agent of the present invention also (i) patients with ECMO (extracorporeal membrane oxygenator); (ii) ventilated patients; (iii) patients in the ICU; (iv) Patients with at least one of oxygen saturation (SpO 2 ) below 93% (room air) or patients requiring oxygen inhalation.
  • ECMO extracorporeal membrane oxygenator
  • the medicament or action-enhancing agent of the present invention also (i) oxygen saturation ( SpO2 ) less than 94% (room air, sea level); (ii) PaO2 / FiO2 is less than 300 mmHg; (iii) respiratory rate of 30 or more/min; and (iv) pulmonary infiltration of 50% or more.
  • doctors should provide guidelines for treatment and / or prevention such as specifying the target patient or subject of the present invention as a treatment subject, dosage and administration, precautions, etc.
  • These official documents are not limited to paper media and are provided via the Internet.
  • various other sources of information can be used to provide preventive or therapeutic guidance to doctors and the like. Therefore, it is understood that the present invention encompasses embodiments that are used based on information other than package inserts and labels.
  • the invention includes administering to a subject in need of an effective amount of (A) and (B) having one or more of the characteristics described herein. -19 prevention and/or treatment, or enhancement of COVID-19 aggravation suppression effect.
  • the invention also provides a combination of (A) and (B) having one or more of the characteristics described herein for the prevention and/or treatment of COVID-19, or , provides use in the manufacture of a medicament for reducing the severity of COVID-19.
  • Boc tert-butoxycarbonyl
  • CDI carbonyldiimidazole
  • DBU 1,8-diazabicyclo[5.4.0]-7-undecene
  • DIEA N,N-diisopropylethylamine
  • DMA N,N-dimethylacetamide
  • DMF N,N -dimethylformamide
  • DMSO dimethylsulfoxide
  • DTT dithiothreitol
  • EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • EDT 1,2-ethanedithiol
  • EDTA ethylenediaminetetraacetic acid
  • FBS fetal bovine serum
  • HOBT 1- Hydroxybenzotriazole
  • LHMDS lithium bis(trimethylsilyl)amide
  • MEM Eagle's minimum essential medium
  • NMP N-methylpyrrolidone
  • Pd(OAc) 2 palladium acetate
  • Step 2 Synthesis of compound 15
  • the crude product of compound 14 (8.3 g), DMF (85 mL) and methyl iodide (4.84 mL, 77 mmol) were mixed, and the reaction solution was stirred at 50°C for 40 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and washed with water. A 2 mol/L sodium hydroxide aqueous solution was added to the aqueous layer, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate.
  • Step 5 Synthesis of compound (I-003) 6-chloro-2-methyl-2H-indazol-5-amine (55.3 mg, 0.304 mmol), compound 17 (100 mg, 0.254 mmol) and THF (1 mL) Mixed. The reaction solution was cooled in an ice bath and LHMDS (0.761 mL, 0.761 mmol) was added. The reaction solution was stirred in an ice bath for 40 minutes and saturated aqueous ammonium chloride solution was added. The organic layer was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain compound (I-003) (80 mg, 0.145 mmol, yield 57.4%).
  • Step 2 Synthesis of Compound 19
  • Compound 18 (1.51 g, 4.04 mmol) and TFA (3.02 mL) were mixed. The reaction solution was stirred at room temperature for 4 hours and allowed to stand overnight. TFA was distilled off under reduced pressure, and toluene was added to the residue for azeotropic distillation. Isopropyl ether was added to the residue to suspend it, followed by filtration to obtain compound 19 (1.22 g, 3.84 mmol, yield 95%).
  • Step 3 Synthesis of compound 20 Compound 19 (200 mg, 0.63 mmol), DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol) and 3-(chloromethyl)-1-methyl-1H-1,2, 4-triazole hydrochloride (159 mg, 0.946 mmol) was mixed. The reaction solution was stirred at 60° C. for 2 hours and saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated.
  • the residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate and chloroform and collected by filtration. Mix the residue, DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol) and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (159 mg, 0.946 mmol) bottom.
  • the reaction solution was stirred at 60° C. for 6 hours and saturated aqueous ammonium chloride solution was added.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine.
  • the organic layer was dried over magnesium sulfate, filtered and concentrated.
  • Step 4 Synthesis of compound (I-005) Compound 20 (115 mg, 0.279 mmol), THF (2.30 mL) and 6-chloro-2-methyl-2H-indazol-5-amine (60.8 mg, 0.335 mmol) ) were mixed. LHMDS (558 ⁇ L, 0.558 mmol) was added dropwise to the reaction solution at 0°C. The reaction solution was stirred at 0° C. for 2.5 hours and at room temperature for 40 minutes, and saturated aqueous ammonium chloride solution was added. After extraction with chloroform, the organic layer was concentrated.
  • Volume means the unit cell volume and Z means the number of molecules in the unit cell.
  • the compound represented by (A) in the medicament of the present invention has coronavirus 3CL protease inhibitory activity 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).
  • ⁇ 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.
  • 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 compound designated (A) in the medicament of the invention was 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.
  • Compound I-003 0.014 ⁇ M
  • Compound I-005 0.010 ⁇ M
  • Compound I-006 0.0058 ⁇ M
  • Compound I-010 0.0054 ⁇ M
  • Compound I-012 0.0091 ⁇ M
  • Compound I-017 0.0034 ⁇ M
  • Compound I-023 0.0063 ⁇ M
  • Compound I-035 0.0098 ⁇ M
  • Test Example 3 Combination effect confirmation test ⁇ Operating procedure> - Dilution and dispensing of test samples Each test sample is diluted with DMSO and medium (MEM, 2% FBS, penicillin-streptomycin) to an appropriate concentration, and a serial dilution series is prepared in a 96-well plate. ⁇ Dilution and dispensing of cells and SARS-CoV-2 VeroE6/TMPRSS2 cells (JCRB1819, 1.5 ⁇ 10 4 cells/well) and SARS-CoV-2 (1000TCID 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.
  • MEM 2% FBS
  • penicillin-streptomycin penicillin-streptomycin
  • CI Combination Index
  • CI Combination Index
  • EC 50 SARS-CoV-2-infected cell death inhibitory concentration Tested as 100% inhibition for cells not infected with virus, and 0% inhibition for cells cultured under conditions that do not contain the test sample after virus infection EC 50 is calculated using XL fit 5.3.1.3 after calculating SARS-CoV-2 infected cell death inhibition rate of samples.
  • A EC50 of test substance A single agent
  • D B EC50 of test substance B alone
  • D A/A+B concentration of test substance A when SARS-CoV-2 infected cell death is inhibited by 50% when test substances A and B are used together
  • D B/A+B SARS-CoV-2 infection when test substances A and B are used together
  • the CI value when test substances A and B are used together at a ratio corresponding to the ratio of the EC50 values of single agents is calculated.
  • Table 17 shows the CI values when the compound (I-005) (free form) and the COVID-19 aggravation inhibitor were used in combination at a ratio corresponding to the ratio of the EC 50 values for each single agent.
  • Table 18 shows the CI values when the compound (I-003) (free form) and the COVID-19 aggravation inhibitor were used in combination at a ratio corresponding to the ratio of the EC 50 values for each single agent.
  • the formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.
  • the compounds in the medicaments or action-enhancing agents of the invention can be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. injectable solutions or suspensions. It can be administered as a pharmaceutical composition in the form of a cloud, topically, for example, in the form of a lotion, gel, ointment or cream, or in nasal or suppository form.
  • the medicaments or action enhancers of the present invention in free form or in pharmaceutically acceptable salt form, together with at least one pharmaceutically acceptable carrier or diluent are admixed, formulated in a conventional manner. It can be manufactured by granulation or coating methods.
  • 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 medicament or action enhancer according to the present invention is used to treat symptoms and/or diseases induced by infection with SARS-CoV-2, and symptoms and/or effects induced by infection with SARS-CoV-2. Or it is considered to be useful as a preventive agent for diseases.

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JP2023177240A (ja) * 2022-06-01 2023-12-13 シャンシー・パンロン・ファーマシューティカル・カンパニー・リミテッド ３－トリアゾリルメチル－１，３，５－トリアジン－２，４－ジオン化合物、およびその調製方法と応用
WO2024009120A1 (en) * 2022-07-08 2024-01-11 Ascletis Bioscience Co., Ltd. Triazine derivatives and methods of use thereof
US12091420B2 (en) 2022-08-05 2024-09-17 Gilead Sciences, Inc. SARS-COV2 main protease inhibitors

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