WO2023180189A1 - Composés antiviraux ciblant les mpro - Google Patents

Composés antiviraux ciblant les mpro Download PDF

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WO2023180189A1
WO2023180189A1 PCT/EP2023/056837 EP2023056837W WO2023180189A1 WO 2023180189 A1 WO2023180189 A1 WO 2023180189A1 EP 2023056837 W EP2023056837 W EP 2023056837W WO 2023180189 A1 WO2023180189 A1 WO 2023180189A1
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alkyl
optionally substituted
compound
fluoro
independently selected
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PCT/EP2023/056837
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English (en)
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Simon Richards
Marco Derudas
Nanna AHLSTEN
Konstantinos PAPACHRISTOS
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Exscientia Ai Limited
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Priority claimed from GBGB2204118.0A external-priority patent/GB202204118D0/en
Priority claimed from GBGB2204199.0A external-priority patent/GB202204199D0/en
Application filed by Exscientia Ai Limited filed Critical Exscientia Ai Limited
Publication of WO2023180189A1 publication Critical patent/WO2023180189A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to compounds for the treatment of viral infections.
  • aspects of the invention relate to compounds, compositions, uses and methods for the treatment of one or more coronavirus infection; particularly SARS-CoV-2 (COVID-19).
  • coronavirus infection particularly SARS-CoV-2 (COVID-19).
  • BACKGROUND Coronaviruses are enveloped, positive-strand RNA viruses that infect a wide range of animal hosts, and cause illnesses such as the common cold, severe acute respiratory syndrome (SARS) and the recently identified Middle East respiratory syndrome (MERS).
  • SARS-CoV-2 Middle East respiratory syndrome
  • the COVID-19 genome encodes a number of structural and non-structural proteins, including: 3-chymotrypsin-like protease, papain-like protease, helicase, and RNA-dependent RNA polymerase (non-structural); and spike glycoprotein and a variety of accessory proteins (structural).
  • structural and non-structural proteins including: 3-chymotrypsin-like protease, papain-like protease, helicase, and RNA-dependent RNA polymerase (non-structural); and spike glycoprotein and a variety of accessory proteins (structural).
  • the non-structural proteins and the spike glycoprotein are considered to be essential for the life cycle of the virus and, therefore, represent potential targets for drug development.
  • the 3-chymotrypsin-like protease (CL pro ), also known as M Pro or Nsp5, cleaves viral proteins by hydrolysing the bond following the amino acid glutamine in order to provide a further twelve structural proteins (notated Nsp4 to Nsp16), which include the RNA-dependent RNA polymerase (RdRp, Nsp12) and helicase (Nsp13) which are essential for the virus’ replication machinery. Therefore, if M pro is effectively inhibited it could be expected that the infectious cycle of the virus cannot be continued (Wu, F., Zhao, S., Yu, B. et al. A new coronavirus associated with human respiratory disease in China.
  • the present disclosure is directed to compounds and compositions for use in methods, and in corresponding methods, for the treatment of viral infections; particular for the treatment, prevention and/or alleviation of coronavirus infections in a subject.
  • the compounds and compositions of the disclosure may be suitable for the treatment, prevention and/or alleviation of SARS-CoV-2 (COVID-19) infections.
  • the compounds and compositions of the disclosure may have utility in the treatment, prevention and/or alleviation of coronavirus infections caused by one or more strain of coronavirus.
  • the compound is not a compound selected from one or more (e.g. all) of: CPD0077063, CPD0084200, CPD0084205, CPD0084207, CPD0084208, CPD0084209, CPD0084210, CPD0084211, CPD0084212, CPD0084215, CPD0084216, CPD0084217, CPD0084221, CPD0084228, CPD0084231, CPD0084235, CPD0084242, CPD0084248, CPD0084249, CPD0084250, CPD0084252, CPD0084253, CPD0084254, CPD0084301, CPD0084531, CPD0084769, CPD0186407, CPD0186408, CPD0186409, CPD0186410, CPD0186412, CPD0186526, CPD0186529, CPD0186530, CPD0187053, CPD0187106
  • R 1 does not comprise a lactam (monocyclic) ring.
  • any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof of the compounds disclosed herein.
  • a method of treatment comprising administration of a therapeutically effective amount of a compound of any aspect or embodiment of the disclosure, or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof of the compound, or a composition comprising the compound, to a patient in need thereof.
  • the patient has a viral infection.
  • a method of treating a viral infection comprising administering one or more compound according to any aspect or embodiment of the disclosure, or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or a composition comprising the compound to a subject in need thereof.
  • the viral infection is coronavirus.
  • the coronavirus is selected form the group consisting: SARS, MERS, 229E, OC43, HKU1, NL63 and SARS- CoV-2 (COVID-19) or combinations or two, three, four or more thereof.
  • R 1 is selected from the following monocyclic or bicyclic cycloalkyl, aryl, heteroaryl structures: pyridine, ⁇ -lactam, ⁇ -lactam, cyclohexyl, cyclopentyl, ⁇ -lactone, cyclobutyl optionally fused to phenyl, pyrazole, thiazole, triazole, pyridine, cyclopentandiene; and wherein said R 1 is optionally substituted with C 1 -C 3 alkyl which optionally carries one to four heteroatoms independently selected from N, O and S.
  • R 1 is selected from any one of the following structures:
  • R 1 is isoquinoline, quinoline, CH2- ⁇ -lactam, CH2- ⁇ -lactam or CH2-pyridine.
  • R 3 is selected from any one of the following structures:
  • R 3 may have the following structure: wherein R 7 is aryl or heteroaryl; and R 8 is independently from R 7 selected from the group consisting of: C 1-6 alkyl or C 3-6 cycloalkyl optionally comprising one or more heteroatoms, such as N, O and S; particularly N or O; more particularly N.
  • R 3 is selected from one of the following structures:
  • R 6 and R 2 together with the nitrogen and carbon respectively to which they attach form one of the following structures:
  • R 6 and R 2 together with the nitrogen and carbon to which they are attached may form one of the following structures:
  • R 1’ is nitrile.
  • the therapeutic uses of the invention may be in a method comprising administering the compound orally, topically, by inhalation, by intranasal administration, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.
  • the use is in a method comprising administering a compound of formula (I).
  • the methods and/or therapeutic uses of the invention may comprise administering the compound according to formula (I) with one or more additional therapeutic agent.
  • the one or more additional therapeutic agent is selected from at least one additional antiviral agent.
  • the at least one additional antiviral agent may be selected from an inhibitor of viral RNA-dependent RNA polymerase, an inhibitor of virus-encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor-induced conformational changes in virus spike glycoprotein that are associated with virus entry, or combinations thereof.
  • administering may comprise administering the compound according to formula (I) simultaneously, sequentially or separately from the one or more additional therapeutic agent.
  • a method of treating or preventing a viral infection in a subject in need thereof comprising administering to the subject an effective amount of the compound of the following formula or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: wherein the compound is defined according to any aspect and embodiment herein.
  • the viral infection is coronavirus, typically SARS- CoV-2 (COVID-19).
  • the compound is an inhibitor of the virus-encoded protease M pro .
  • the method comprises administering the compound orally, topically, by inhalation, by intranasal administration, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.
  • the method may comprises administering a compound of formula (I).
  • the method may comprise administering the compound according to Formula (I) with one or more additional therapeutic agent.
  • the compound according to Formula (I) and the one or more additional therapeutic agent are administered simultaneously, sequentially or separately.
  • the one or more additional therapeutic agent is selected from at least one additional antiviral agent.
  • the one additional antiviral agent is selected from an inhibitor of viral RNA- dependent RNA polymerase, an inhibitor of virus-encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor-induced conformational changes in virus spike glycoprotein that are associated with virus entry, or combinations thereof.
  • a pharmaceutical composition comprising: an effective amount of the compound of the following formula or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: (I), wherein R 1 is monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, typically R 1 may be a five or six membered cycloalkyl or heteroaryl, optionally having one or more substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via an alkyl linker such as -CH 2 - or -CH 2 (CH 2 )-; R 1’ is nitrile (CN); R 1a is absent, hydrogen, deuterium or C 1-6 alkyl (suitably R 1a may be hydrogen or methyl); R 2 is hydrogen or R 2 and R 6 taken together with the nitrogen and
  • R 1 is isoquinoline, quinoline, CH 2 - ⁇ -lactam, CH 2 - ⁇ -lactam or CH 2 -pyridine.
  • R 3 is selected from any one of the following structures:
  • R 3 may have the following structure: wherein R 7 is aryl or heteroaryl; and R 8 is independently from R 7 selected from the group consisting of: C 1-6 alkyl or C 3-6 cycloalkyl optionally comprising one or more heteroatoms, such as N, O and S; particularly N or O; more particularly N.
  • R 3 is selected from one of the following structures:
  • R 6 and R 2 together with the nitrogen and carbon respectively to which they attach, form one of the following structures:
  • R 6 and R 2 together with the nitrogen and carbon to which they are attached may form one of the following structures:
  • R 1’ is nitrile.
  • the compound of formula (I) has the following structures: wherein R 1 is selected from the group consisting of monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, as described above.
  • the pharmaceutically acceptable carrier may be selected from one or more diluent, adjuvant, excipient or vehicle; e.g. an adjuvant may be alum (aluminium hydroxide).
  • the pharmaceutical composition is for use in the treatment or prevention of a viral infection.
  • the viral infection is coronavirus and especially the viral infection is SARS-CoV-2 (COVID-19).
  • the viral infection may be selected from any coronavirus, such as SARS, MERS, SARS-CoV-2 (COVID-19) or combinations thereof.
  • the pharmaceutical composition is for use in a method comprising administering a pharmaceutical composition comprising a compound of formula (I).
  • the use of the pharmaceutical composition may be in a method comprising administering the pharmaceutical composition comprising a compound according to formula (I) in combination with one or more additional therapeutic agent.
  • the administering of the pharmaceutical composition comprising a compound according to formula (I) may be performed simultaneously, sequentially or separately from the one or more additional therapeutic agent.
  • the one or more additional therapeutic agent is selected from at least one additional antiviral agent.
  • the at least one additional antiviral agent may especially be selected from an inhibitor of viral RNA-dependent RNA polymerase, an inhibitor of virus-encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor-induced conformational changes in virus spike glycoprotein that are associated with virus entry, or combinations thereof.
  • the pharmaceutical composition is adapted for administration by a route selected from oral, topical, inhalation, intranasal, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.
  • a method for inhibiting or preventing coronavirus infection such as infection of COVID-19, the method comprising administering a compound according to formula (I) to a subject and/or a cell capable of being infected with or already infected with coronavirus.
  • a compound according to formula (I) provided for use in inhibiting or preventing coronavirus infection coronavirus, wherein the use is in a method comprising administering the compound to a subject and/or a cell capable of being infected with or already infected with coronavirus.
  • Figure 1 is a schematic representation showing COVID-19 viral entry and replication in the cell.
  • Figure 1 is a schematic representation showing COVID-19 viral entry and replication in the cell.
  • DETAILED DESCRIPTION Described herein are compounds and compositions (e.g. organic molecules, research tools, pharmaceutical formulations and therapeutics); uses for the compounds and compositions of the invention (in vitro and in vivo); as well as corresponding methods, whether diagnostic, therapeutic or for research applications. The chemical synthesis and biological testing of the compounds of the invention are also described.
  • the compounds, compositions, uses and methods have utility in research towards and/or the treatment of diseases in animals, such as humans.
  • the diseases are in particular viral infections, such as caused by coronavirus, and more specifically COVID-19.
  • the compounds may also or alternatively be useful as lead molecules for the selection, screening and development of further derivatives that may have one or more improved beneficial drug property, as desired.
  • Such further selection and screening may be carried out using the proprietary computational evolutionary algorithm described e.g. in the Applicant’s earlier published patent application WO 2011/061548, which is hereby incorporated by reference in its entirety.
  • the compounds of the invention are advantageously amide derivatives.
  • the invention also encompasses salts, solvates, tautomers, enantiomers and functional derivatives of the compounds of the invention.
  • the compounds are described for use in the treatment of viral infections such as coronavirus and more specifically COVID-19.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g. in organic, physical or theoretical chemistry; biochemistry and molecular biology).
  • the practice of the present invention employs conventional techniques in chemistry and chemical methods, biochemistry, molecular biology, pharmaceutical formulation, and delivery and treatment regimens for patients, which are within the capabilities of a person of ordinary skill in the art.
  • compositions and pharmaceutical formulations comprising the compounds of the invention.
  • Such a compound or molecule as disclosed herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted.
  • Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • tautomer refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer. It will be appreciated that certain compounds provided herein may contain one or more centres of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
  • Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (I) or (II), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non- radioactive atoms has been replaced by one of its radioactive enriched isotopes.
  • Radiolabelled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.
  • the term ‘deuterium’ as used herein refers to an isotope of hydrogen that has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen.
  • Deuterium herein is represented by the symbol ‘D’.
  • the term ‘deuterated’ by itself or used to modify a compound or group as used herein refers to the presence of at least one deuterium atom attached to carbon.
  • the term ‘deuterated compound’ refers to a compound which contains one or more carbon-bound deuterium(s). In a deuterated compound of the present disclosure, when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%.
  • the term ‘undeuterated’ or ‘non-deuterated’ as used herein refers to the ratio of deuterium atoms of which is not more than the natural isotopic deuterium content, which is about 0.015%; in other words, all hydrogen are present at their natural isotopic percentages. Unless otherwise stated, when a position is designated specifically as ‘H’ or ‘hydrogen’, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • Prodrugs and solvates of the compounds of the invention are also encompassed within the scope of the invention.
  • the term 'prodrug' means a compound (e.g. a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, solvate or ester of the compound.
  • compositions and medicaments of the invention therefore may comprise prodrugs of the compounds of the invention.
  • the compounds of the disclosure are themselves prodrugs which may be metabolised in vivo to give the therapeutically effective compound.
  • a sulfoxide prodrug may be metabolized in vivo to the therapeutically active sulfone (see Basarab G.S. et al., (2008), Bioorg Med Chem Lett, 18(16),4716-4722; Gibhard L. et al., (2008), Antimicrobial Agents and Chemotherapy, 62(12),00261-18).
  • the terms 'individual', 'subject', or 'patient' are used interchangeably to indicate an animal that may be suffering from a medical (pathological) condition and may be responsive to a molecule, pharmaceutical drug, medical treatment or therapeutic treatment regimen of the disclosure.
  • the animal is suitably a mammal, such as a human, cow, sheep, pig, dog, cat, bat, mouse or rat.
  • the subject may be a human.
  • terms ‘treat’ or ‘treatment’ refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • ‘Treatment’ can also mean prolonging survival as compared to expected survival if not receiving treatment
  • the term ‘preventing’ as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.
  • the term ‘alkyl’ refers to a monovalent, optionally substituted, saturated aliphatic hydrocarbon radical. Any number of carbon atoms may be present, but typically the number of carbon atoms in the alkyl group may be from 1 to about 20, from 1 to about 12, from 1 to about 6 or from 1 to about 4.
  • a C1-12 alkyl refers to any alkyl group containing 1 to 12 carbon atoms in the chain.
  • An alkyl group may be a straight chain (i.e. linear), branched chain, or cyclic.
  • “Lower alkyl’ refers to an alkyl of 1 to 6 carbon atoms in the chain, and may have from 1 to 4 carbon atoms, or 1 to 2 carbon atoms.
  • lower alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl (C5H11), sec-butyl, tert-butyl, sec-amyl, tert-pentyl, 2-ethylbutyl, 2,3-dimethylbutyl, and the like.
  • Higher alkyl refers to alkyls of 7 carbons and above, including n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n- tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, and the like, along with branched variations thereof.
  • a linear carbon chain of say 4 to 6 carbons would refer to the chain length not including any carbons residing on a branch, whereas in a branched chain it would refer to the total number.
  • Optional substituents for alkyl and other groups are described below.
  • substituted means that one or more hydrogen atoms (attached to a carbon or heteroatom) is replaced with a selection from the indicated group of substituents, provided that the designated atom's normal valency under the existing circumstances is not exceeded.
  • the group may be optionally substituted with particular substituents at positions that do not significantly interfere with the preparation of compounds falling within the scope of this invention and on the understanding that the substitution(s) does not significantly adversely affect the biological activity or structural stability of the compound. Combinations of substituents are permissible only if such combinations result in stable compounds.
  • stable compound or ‘stable structure’, it is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and/or formulation into an efficacious therapeutic agent.
  • optionally substituted it is meant that the group concerned is either unsubstituted, or at least one hydrogen atom is replaced with one of the specified substituent groups, radicals or moieties. Any radical / group / moiety described herein that may be substituted (or optionally substituted) may be substituted with one or more (e.g. one, two, three, four or five) substituents, which are independently selected from the designated group of substituents. Thus, substituents may be selected from the group: halogen (or ‘halo’, e.g.
  • substituents are on an aryl or other cyclic ring system
  • two adjacent atoms may be substituted with a methylenedioxy or ethylenedioxy group.
  • the substituents are selected from: halogen, hydroxy, amino, thiol, cyano, (C 1 - C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, heteroaryl, (C 1 -C 6 )alkylthio, oxo, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, nitro, phosphate, azido, (C 1 - C 6 )alkoxycarbonyl, carboxy, (
  • the substituents are selected from one or more of: fluoro, chloro, bromo, hydroxy, (C 1 -C 6 )alkyl, (C 1 - C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 5 -C 6 )aryl, a 5- or 6-membered heteroaryl, (C 4 -C 6 )cycloalkyl, a 4- to 6- membered heterocycloalkyl, cyano, (C 1 -C 6 )alkylthio, amino, -NH(alkyl), -NH((C 1 -C 6 )cycloalkyl), -N((C 1 - C 6 )alkyl)2, -OC(O)-(C 1 -C 6 )alkyl, -OC(O)-(C 5 -C 6 )aryl, -OC(O)-(C 1 -C 6 )cycloalkyl, carboxy
  • the substituents are selected from one or more of: fluoro, chloro, bromo, hydroxy, amino, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy, wherein alkyl and alkoxy are optionally substituted by one or more chloro.
  • Particularly preferred substituents are: chloro, methyl, ethyl, methoxy and ethoxy.
  • cyano refers to a –CN radical.
  • hydroxyl refers to an –OH radical.
  • amino refers to an —NH 2 group.
  • halo refers to a monovalent halogen radical chosen from chloro, bromo, iodo, and fluoro.
  • a ‘halogenated’ compound is one substituted with one or more halo substituent. Particular halo groups are F, Cl and Br; and most particularly are F or Cl. In some preferred embodiments the halo group is F.
  • C 1 -C 6 haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • a C1-C3 haloalkyl group is linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms substituted with at least one halogen atom.
  • C 1 -C 3 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g.
  • the term ‘geminal’ refers to substituent atoms or groups attached to the same atom in a molecule.
  • the term ‘vicinal’ refers to substituent atoms or groups attached to adjacent atoms in a molecule.
  • the stereochemical relationship between the substituent atoms or groups can be cis, trans, undefined, or unresolved.
  • the term ‘independently’ in reference to the substitution of a parent moiety with one or more substituents, means that the parent moiety may be substituted with any of the listed substituents, either individually or in combination, and any number of chemically possible substituents may be used. In any of the embodiments, where a group is substituted, it may contain up to 5, up to 4, up to 3, or 1 and 2 substituents.
  • useful substituents include: phenyl or pyridine, independently substituted with one or more lower alkyl, lower alkoxy or halo substituents, such as: chlorophenyl, dichlorophenyl, trichlorophenyl, tolyl, xylyl, 2-chloro-3-methylphenyl, 2,3-dichloro- 4- methylphenyl, etc.
  • "Alkylene” or "alkylenyl” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group as defined above.
  • alkylene include methylene, ethylene and propylene.
  • alkenyl refers to a monovalent, optionally substituted, unsaturated aliphatic hydrocarbon radical.
  • the number of carbon atoms in the alkenyl group may be indicated, such as from 2 to about 20.
  • a C2- 12 alkenyl or C 2-12 alkenyl refers to an alkenyl group containing 2 to 12 carbon atoms in the structure.
  • Alkenyl groups may be straight (i.e. linear), branched chain, or cyclic.
  • ‘Lower alkenyl’ refers to an alkenyl of 1 to 6 carbon atoms, and may have from 1 to 4 carbon atoms, or 1 to 2 carbon atoms.
  • lower alkenyl radicals include ethenyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, isopropenyl, isobutenyl, and the like.
  • Higher alkenyl refers to alkenyls of seven carbons and above, such as 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-dodecenyl, 1-tetradecenyl, 1- hexadecenyl, 1-octadecenyl, 1-eicosenyl, and the like, along with branched variations thereof.
  • Optional substituents include are described elsewhere.
  • Alkenylene means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above.
  • alkenyl and ‘lower alkynyl’ is defined similarly to the term ‘alkenyl’, except that it includes at least one carbon-carbon triple bond.
  • alkoxy refers to a monovalent radical of the formula RO-, where R is any alkyl, alkenyl or alkynyl as defined herein. Alkoxy groups may be optionally substituted by any of the optional substituents described herein.
  • ‘Lower alkoxy’ has the formula RO-, where the R group is a lower alkyl, alkenyl or alkynyl.
  • Representative alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, n- pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, isopentyloxy, amyloxy, sec-butoxy, tert-butoxy, tert- pentyloxy, and the like.
  • Preferred alkoxy groups are methoxy and ethoxy.
  • aryl refers to a substituted or unsubstituted aromatic carbocyclic radical containing from 5 to about 15 carbon atoms; and preferably 5 or 6 carbon atoms.
  • An aryl group may have only one individual carbon ring, or may comprise one or more fused rings in which at least one ring is aromatic in nature.
  • a ‘phenyl’ is a radical formed by removal of a hydrogen atom from a benzene ring, and may be substituted or unsubstituted.
  • a ‘phenoxy’ group therefore, is a radical of the formula RO-, wherein R is a phenyl radical.
  • Benzyl is a radical of the formula R-CH 2 -, wherein R is phenyl
  • ‘benzyloxy’ is a radical of the formula RO-, wherein R is benzyl.
  • aryl radicals include, phenyl, naphthyl, benzyl, biphenyl, furanyl, pyridinyl, indanyl, anthraquinolyl, tetrahydronaphthyl, a benzoic acid radical, a furan-2-carboxylic acid radical, and the like.
  • a ‘heteroaryl’ group is herein defined as a substituted or unsubstituted ‘aryl’ group in which one or more carbon atoms in the ring structure has been replaced with a heteroatom, such as nitrogen, oxygen or sulphur.
  • the heteroaryl group contains one or two heteroatoms selected from N, O and S. Particularly suitable heteroatoms are N and O; and a preferred heteroatom is N.
  • a heteroaryl group may have only one ring, or may comprise one or more fused rings in which at least one ring contains at least one heteroatom.
  • heteroaryl groups include: furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine and cinnoline.
  • Heteroaryl groups include as described herein comprise but are not limited to thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalziny
  • a heterocyclic group may have only one individual ring, or may comprise one or more fused rings in which at least one ring contains a heteroatom. It may be fully saturated or partially saturated, and may be substituted or unsubstituted as in the case or aryl and heteroaryl groups.
  • Representative examples of unsaturated 5- membered heterocycles with only one heteroatom include 2- or 3-pyrrolyl, 2- or 3-furanyl, and 2- or 3- thiophenyl.
  • Corresponding partially saturated or fully saturated radicals include 3-pyrrolin-2-yl, 2- or 3- pyrrolindinyl, 2- or 3-tetrahydrofuranyl, and 2- or 3-tetrahydrothiophenyl.
  • Representative unsaturated 5-membered heterocyclic radicals having two heteroatoms include imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and the like. The corresponding fully saturated and partially saturated radicals are also included.
  • Representative examples of unsaturated 6-membered heterocycles with only one heteroatom include 2-, 3-, or 4-pyridinyl, 2H-pyranyl, and 4H-pryanyl.
  • Corresponding partially saturated or fully saturated radicals include 2-, 3-, or 4-piperidinyl, 2-, 3-, or 4-tetrahydropyranyl and the like.
  • Representative unsaturated 6-membered heterocyclic radicals having two heteroatoms include 3- or 4- pyridazinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, morpholino, and the like.
  • the corresponding fully saturated and partially saturated radicals are also included, e.g.2-piperazine.
  • the heterocyclic radical is bonded through an available carbon atom or heteroatom in the heterocyclic ring directly to the entity or through a linker such as an alkylene such as methylene or ethylene.
  • the disclosure encompasses fused ring systems, for example, ‘bicyclic’ or ‘tricyclic’ ring systems.
  • a fused ring system may include more than one fused aromatic ring, more than one fused non-aromatic / aliphatic ring, or one or more aromatic ring fused to one or more non-aromatic / aliphatic ring, such as a fusion of an aryl group with a cycloalkyl (or cycloalkenyl) group.
  • fused ring system termed a bicyclic (or tricyclic) aryl is attached to the associated molecule via an aryl group, whereas a bicyclic (or tricyclic) cycloalkyl / cycloalkoxyl is attached to the associated molecule via the cycloalkyl / cycloalkoxyl group.
  • a bicyclic (or tricyclic) heteroaryl or heterocycloalkyl / heterocycloalkenyl need not contain heteroatoms in each of the fused ring systems.
  • a bicyclic of tricyclic heteroaryl group may have one or more heteroatoms in any ring of the fused ring system, and not necessarily in the aryl ring that is the point of attachment to the associated molecule.
  • a bicyclic of tricyclic heterocycloalkyl or heterocycloalkenyl group may have one or more heteroatoms in any ring of the fused ring system, and not necessarily in the heterocycloalkyl or heterocycloalkenyl ring that is the point of attachment to the associated molecule.
  • pharmaceutically acceptable indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the subject being treated therewith.
  • room temperature is intended to mean a temperature of from about 18 to 28°C, typically between about 18 and 25°C, and more typically between about 18 and 22°C. As used herein, the phrase ‘room temperature’ may be shortened to ‘rt’ or ‘RT’.
  • Coronavirus as a drug target Figure 1 is a schematic drawing showing viral entry and replication in a host mammalian cell, providing an overview of potential therapeutic targets for novel drug discovery. Figure 1 shows the spike protein of a coronavirus in complex with Angiotensin-converting enzyme 2 (ACE2), which is believed to be a vital interaction for viral entry into the host cell.
  • ACE2 Angiotensin-converting enzyme 2
  • the host ribosome translates the viral genome and forms a long polyprotein which contains its own proteases, such as M pro (C 3 L Pro ) and Papain-like protease (PL pro ), which each exhibit different substrate specificity.
  • proteases cleave the polyprotein into multiple non-structural protein molecules including RNA- dependent RNA polymerase (RdRp, RNA Pol) which is directly involved in the replication and transcription of viral RNA and, therefore, the correct synthesis of this protein is crucial for viral replication.
  • RdRp, RNA Pol RNA- dependent RNA polymerase
  • an antiviral compound according to the invention having the structural Formula (I) including any diastereomers and enantiomers, or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof:
  • the compound of the Formula (I) is described for use in the treatment of infections caused by viruses.
  • the virus is suitably coronavirus such as SARS, MERS, 229E, OC43, HKU1, NL63 and SARS-CoV-2 (COVID-19) or combinations or two, three, four or more thereof.
  • the compounds and compositions of the disclosure are suitable for treatment of a viral infection caused by COVID-19, and are particularly useful due to their broad spectrum activity (e.g.
  • the compound of Formula (I) is not a compound selected from: CPD0077063, CPD0084200, CPD0084205, CPD0084207, CPD0084208, CPD0084209, CPD0084210, CPD0084211, CPD0084212, CPD0084215, CPD0084216, CPD0084217, CPD0084221, CPD0084228, CPD0084231, CPD0084235, CPD0084242, CPD0084248, CPD0084249, CPD0084250, CPD0084252, CPD0084253, CPD0084254, CPD0084301, CPD0084531, CPD0084769, CPD0186407, CPD0186408, CPD0186409, CPD0186410, CPD0186412, CPD0186526, CPD0186529, CPD0186530, CPD0187053, CPD0187106, CPD0187107, CPD
  • R 1 may be monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via a C 1 -C 3 alkylene linker, wherein the alkylene linker may optionally be substituted with one to three R 9 .
  • R 1 may be selected from the following monocyclic or bicyclic cycloalkyl, aryl, heteroaryl structures: pyridine, cyclohexyl, cyclopentyl, ⁇ -lactone, cyclobutyl optionally fused to phenyl, pyrazole, thiazole, triazole, pyridine, cyclopentandiene; and wherein R 1 is optionally substituted with C 1 -C 3 alkyl which optionally carries one to four heteroatoms independently selected from N, O and S.
  • R 1 may be selected from a five or six membered cycloalkyl or heteroaryl group, which is optionally substituted with one or two R 9 .
  • R 1 is not a monocyclic lactam, wherein the lactam is directly connected to the remaining compound (I) or connected to the remaining compound via a C 1 -C 3 alkylene linker. In various embodiments, R 1 is not . In embodiments, R 1 may be a bicyclic group selected from bicyclic cycloalkyl, bicyclic heterocycloalkyl, bicyclic aryl or bicyclic heteroaryl, and combinations thereof, any of which bicyclic group is optionally substituted with one or two R 9 .
  • R 1 may be a bicyclic group selected from bicyclic cycloalkyl, bicyclic heterocycloalkyl, bicyclic aryl or bicyclic heteroaryl, and combinations thereof.
  • R 1 may be selected from any one of the following structures:
  • R 1 may be selected from any one of the following structures:
  • R 1 may be selected from any one of the following structures:
  • R 1 may be selected from any one of the following structures: In some embodiments, R 1 may be selected from pyrrolidin-2-one, isoquinoline, quinoline, CH 2 -pyridine, CH 2 -benzo[b][1,4]oxazin-3(4H)-one, phthalazine, 4H-pyrido[1,2-a]pyrimidin-4-one and naphthyridine (e.g.1,6; 2,6; and 3,6-naphthyridine), which may be optionally substituted with one or two R 9 .
  • R 1 may be selected from pyrrolidin-2-one, isoquinoline, quinoline, CH 2 -pyridine, CH 2 -benzo[b][1,4]oxazin-3(4H)-one, phthalazine, 4H-pyrido[1,2-a]pyrimidin-4-one and naphthyridine (e.g.1,6; 2,6; and 3,6-naphthy
  • R 1 may be selected from quinoline, CH2-pyridine, CH2-benzo[b][1,4]oxazin-3(4H)-one, phthalazine, 4H-pyrido[1,2-a]pyrimidin-4-one and naphthyridine (e.g.1,6; 2,6; and 3,6-naphthyridine), which may be optionally substituted with one or two R 9 .
  • R 1 may be selected from CH 2 -pyridine, CH 2 -benzo[b][1,4]oxazin-3(4H)-one, phthalazine, 4H-pyrido[1,2-a]pyrimidin-4-one and naphthyridine (e.g.1,6; 2,6; and 3,6-naphthyridine), which may be optionally substituted with one or two R 9 .
  • R 9 may be selected from the group consisting of deuterium, oxo, F, Cl, hydroxy, cyano, amino, C 1 -C 2 alkyl, and C 1 -C 2 alkyoxy.
  • R 9 may be selected from the group consisting of deuterium, oxo, F, Cl, hydroxy, cyano, amino, methyl, and methoxy. Beneficially, R 9 may be selected from the group consisting of F, oxo, methyl, and methoxy.
  • R 9 may be fluoro; R 9 may be oxo; R 9 may be methyl; or R 9 may be methoxy.
  • R 1a may be hydrogen, deuterium or methyl. In embodiments R 1a may particularly be hydrogen.
  • R 2 may be selected from the group consisting of hydrogen; straight or branched C 1 -C 6 alkyl; straight or branched C 1 -C 6 alkoxy; (C 1 -C 6 alkoxy)-C 1 -C 6 alkyl or (C 1 -C 6 alkyl)-C 1 -C 6 alkoxy, where each alkyl or alkoxy group may be optionally substituted with one to three fluoro, hydroxy, oxo or C 1 -C 3 alkoxy.
  • R 2 may be selected from the group consisting of hydrogen; straight or branched C 1 - C 3 alkyl; straight or branched C 1 -C 3 alkoxy; (C 1 -C 3 alkoxy)-C 1 -C 3 alkyl or (C 1 -C 3 alkyl)-C 1 -C 3 alkoxy, wherein each alkyl or alkoxy group may be optionally substituted with one to three fluoro, hydroxy or oxo.
  • R 2 may be selected from the group consisting of hydrogen; C 1 -C 2 alkyl; or C 1 -C 2 alkoxy; wherein each alkyl or alkoxy group may be optionally substituted with one to three fluoro, hydroxy or oxo.
  • R 2 may be selected from the group consisting of hydrogen; methyl, ethyl, methoxy or ethoxy. In various embodiments, R 2 may be hydrogen.
  • R 6 may be selected from the group consisting of straight or brached C 2 -C 5 alkyl which is optionally substituted with a cyano or with one to three fluoro, or (C 3 -C 6 cycloalkyl)-C 1 -C 3 alkyl which is optionally substituted with one or two substituents selected from trifluoromethyl and C 1 -C 3 alkyl, wherein the C 1 - C 3 alkyl is optionally substituted with one to five fluoro.
  • R 6 is C 3 -C 5 alkyl or (C 3 -C 5 cycloalkyl)-C 1 -C 2 alkyl, optionally substituted with one to three fluoro; particularly, wherein R 6 is selected from n-butyl, sec-butyl, iso-butyl, tert-butyl alkyl or cyclopropyl-CH2-, optionally substituted with one to three fluoro.
  • R 2 and R 6 taken together with the nitrogen and carbon atoms to which they are attached may form a pyrrolidine or piperidine ring, which is optionally substituted with one to three R 2a .
  • R 2 and R 6 taken together with the nitrogen and carbon atoms to which they are attached may form a pyrrolidine or piperidine ring, which is optionally substituted with one or two R 2a .
  • R 2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C 1 -C 6 alkyl optionally substituted with one to three fluoro, and C 1 -C 6 alkoxy optionally substituted with one to three fluoro.
  • R 2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C 1 -C 2 alkyl optionally substituted with one to three fluoro, and C 1 -C 2 alkoxy optionally substituted with one to three fluoro.
  • R 2a at each occurrence is independently selected from fluoro and methyl which is optionally substituted with one to three fluoro; preferably, R 2a is methyl.
  • two R 2a groups when attached to adjacent carbon atoms and taken together with the carbon atoms to which they are attached may form a C 3 -C 6 cycloalkyl which is optionally substituted with one to four R 2b , such that R 2 and R 6 form a fused bicyclic ring.
  • two R 2a groups when attached to adjacent carbon atoms and taken together with the carbon atoms to which they are attached may form a C 3 -C 4 cycloalkyl which is optionally substituted with one to three R 2b , such that R 2 and R 6 form a fused bicyclic ring.
  • two R 2a groups when attached to adjacent carbon atoms and taken together with the carbon atoms to which they are attached form a C 5 -C 6 cycloalkyl which is optionally substituted with one to three R 2b , such that R 2 and R 6 form a fused bicyclic ring.
  • two R 2a groups when attached to the same carbon atom and taken together with the carbon atom to which they are attached may form a C 3 -C 6 cycloalkyl which is optionally substituted with one to four R 2b , such that R 2 and R 6 form a spiro bicyclic ring.
  • two R 2a groups when attached to the same carbon atom and taken together with the carbon atom to which they are attached may form a C 3 -C 4 cycloalkyl which is optionally substituted with one to three R 2b , such that R 2 and R 6 form a spiro bicyclic ring.
  • two R 2a groups when attached to the same carbon atom and taken together with the carbon atom to which they are attached may form a C 5 -C 6 cycloalkyl which is optionally substituted with one to three R 2b , such that R 2 and R 6 form a spiro bicyclic ring.
  • R 2b at each occurrence may be optionally independently selected from fluoro, hydroxy, C 1 -C 2 alkyl optionally independently substituted with one to three fluoro or hydroxy, and C 1 -C 2 alkoxy optionally independently substituted with one to three fluoro or hydroxy.
  • R 2b at each occurrence may be optionally independently selected from fluoro and methyl which is optionally substituted with one to three fluoro or hydroxy.
  • R 2b at each occurrence is methyl.
  • both R 2b may be attached to the same carbon atom.
  • two R 2a may be attached to adjacent carbon atoms of a pyrrolidine or piperidine ring and are joined together to form a cyclopropyl ring; and wherein two R 2b substituents may be attached to the same carbon atom of the cyclopropyl ring, and wherein both R 2b substituents may be methyl.
  • R 2 and R 6 taken together form the following structure: .
  • two R 2b groups when attached to the same carbon and taken together with the carbon to which they are attached may form a C 3 -C 6 cycloalkyl which is optionally substituted with one to three R 9 .
  • two R 2b groups when attached to the same carbon and taken together with the carbon to which they are attached may form a C 3 -C 4 cycloalkyl which is optionally substituted with one or two R 9 .
  • R 9 may be selected from the group consisting of fluoro, hydroxy, C 1 -C 3 alkyl optionally independently substituted with one to three fluoro or hydroxy, and C 1 -C 3 alkoxy optionally independently substituted with one to three fluoro or hydroxy.
  • R 9 may be selected from the group consisting of fluoro, hydroxy, C 1 -C 2 alkyl optionally independently substituted with one to three fluoro, and C 1 -C 2 alkoxy optionally independently substituted with one to three fluoro.
  • R 9 may be fluoro.
  • R 9 may be hydroxy.
  • R 9 may be methyl.
  • R 9 may be ethyl.
  • R 6 and R 2 together with the nitrogen and carbon respectively to which they attach may form one of the following structures:
  • R 6 and R 2 together with the nitrogen and carbon respectively to which they attach may form one of the following structures:
  • R 6 and R 2 together with the nitrogen and carbon respectively to which they attach may form one of the following structures:
  • R 3 may be selected from the group consisting of straight or branched C 1 -C 8 alkyl, straight or branched C 1 -C 8 alkoxy, and straight or branched (C 1 -C 6 alkoxy)-C 1 -C 6 alkyl, wherein R 3 is optionally substituted with one to five R 4 .
  • R 3 may be selected from the group consisting of straight or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, and straight or branched (C 1 -C 4 alkoxy)-C 1 -C 4 alkyl, wherein R 3 is optionally substituted with one to four R 4 .
  • R 3 may be selected from the group consisting of straight or branched C 1 -C 5 alkyl, straight or branched C 1 -C 5 alkoxy, and straight or branched (C 1 -C 3 alkoxy)-C 1 -C 3 alkyl, wherein R 3 is optionally substituted with one to three R 4 .
  • R 3 may be selected from the group consisting of ethyl, straight or branched propyl (propyl, isopropyl), straight or branched butyl (n-butyl, sec-butyl, iso-butyl, tert-butyl), and straight or branched chain pentyl (n-pentyl, isopentyl, sec-isopentyl, tert-pentyl, neopentyl), wherein R 3 is optionally substituted with one to three R 4 .
  • R 3 may be selected from the group consisting of propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, sec-isopentyl, tert-pentyl and neopentyl, wherein R 3 is optionally substituted with one to three R 4 .
  • R 3 may be selected from the group consisting of isopropyl, sec-butyl, iso-butyl, tert-butyl, isopentyl, sec-isopentyl, tert-pentyl and neopentyl optionally substituted with one to three R 4 .
  • R 3 may be selected from isobutyl and neopentyl optionally substituted with one to three fluoro, hydroxyl or methoxyl.
  • R 3 may be selected from the group consisting of C 3 -C 12 cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C 3 -C 12 cycloalkyl)-C 1 - C 6 alkyl, C 3 -C 12 cycloalkoxy, (C 3 -C 12 cycloalkoxy)-C 1 -C 6 alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C 1 -C 6 alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C 6 -C 10 aryl optionally fused with
  • R 3 may be selected from the group consisting of C 3 -C 10 cycloalkyl, C5-C 10 aryl, 5- to 10- membered heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C 3 - C 10 cycloalkyl)-C 1 -C 6 alkyl, C 3 -C 10 cycloalkoxy, (C 3 -C 10 cycloalkoxy)-C 1 -C 6 alkyl, 4- to 10-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to three heteroatoms independently selected from N, O and S(O)n; (4- to 10-membered heterocycloalkyl)-C 1 -C 6 alkyl wherein said heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; C 6 -
  • R 3 may be selected from the group consisting of C 3 -C 10 cycloalkyl, C 5 -C 10 aryl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, any of which is optionally fused with a 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S, and wherein each R 3 group is optionally substituted with one to three R 4 .
  • R 3 may be selected from the group consisting of (C 3 -C 10 cycloalkyl)-C 1 -C 6 alkyl, (4- to 10-membered heterocycloalkyl)-C 1 -C 4 alkyl wherein said heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S; C 6 -C 10 aryl optionally fused with a C4- C 6 cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C 6 -C 10 aryl)-C 1 -C 6 alkyl; 5- to 10-membered heteroaryl comprising one to four heteroatoms independently selected from N, O and S, which is optionally fused with a C 5 -C 6 cycloalkyl; (5- to 10-membered heteroaryl)-C 1 -C 6 alkyl wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; (C 6 - C 6
  • R 3 may be selected from the group consisting of (C 5 -C 6 cycloalkyl)-C 2 - C 5 alkyl, 5- to 6-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to three heteroatoms independently selected from N, O and S; (5- to 6-membered heterocycloalkyl)-C 2 -C 5 alkyl wherein said heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S; C 6 -C 10 aryl optionally fused with a C 5 -C 6 cycloalkyl or a 5- to 6-membered heterocycloalkyl; (C 6 - C 10 aryl)-C 2 -C 5 alkyl; 5- to 6-membered heteroaryl comprising one to three heteroatoms independently selected from N, O and S, which is optionally fused with a C
  • R 3 may be selected from (C 3 -C 10 cycloalkyl)-C 1 -C 6 alkyl, and wherein each R 3 group is optionally substituted with one to three R 4 .
  • R 3 may be selected from (C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl, and wherein each R 3 group is optionally substituted with one to three R 4 .
  • R 3 may be selected from (C 3 -C 5 cycloalkyl)-C 1 -C 3 alkyl, and wherein each R 3 group is optionally substituted with one to three R 4 .
  • R 3 is selected from (C 3 -C 4 cycloalkyl)-C 1 -C 3 alkyl, and wherein each R 3 group is optionally substituted with one to three R 4 .
  • R 3 may be selected from the group consisting of straight or branched C 1 -C 5 alkyl (e.g.
  • ethyl isopropyl, sec-butyl, iso-butyl, tert-butyl, isopentyl, sec-isopentyl, tert-pentyl, neopentyl), (C 3 -C 6 cycloalkyl)-C 2 -C 5 alkyl; (4- to 6-membered heterocycloalkyl)- C 1 -C 5 alkyl wherein said heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S; (C5-C 10 aryl)-C 1 -C 5 alkyl; 4- to 6-membered heteroaryl)-C 1 -C 5 alkyl wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; and wherein each R 3 group is optionally substituted with one or two R 4 .
  • R 3 may be selected from the group consisting of straight or branched C 1 -C 5 alkyl and (C 3 - C 6 cycloalkyl)-C 2 -C 5 alkyl; and wherein each R 3 group is optionally substituted with one or two R 4 .
  • R 4 at each occurrence may be independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl or amino.
  • R 4 at each occurrence may be independently selected from the group consisting of (C 1 -C 6 alkyl)amino optionally substituted with one to five fluoro or with one to three R 9 , di(C 1 - C 6 alkyl)amino optionally substituted with one to ten fluoro or with one to three R 9 , C 1 -C 6 alkyl optionally substituted with one to five fluoro or with one to three R 9 , (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S and wherein the heteroaryl is optionally substituted with one to three R 9 ; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and wherein the heterocycloalkyl is optionally substituted with one to three R 9 ; C 1 -C 6 alkyl
  • R 4 at each occurrence may be independently selected from the group consisting of (C 1 - C 4 alkyl)amino optionally substituted with one to three fluoro or with one to three R 9 , di(C 1 - C 4 alkyl)amino optionally substituted with one to five fluoro or with one to three R 9 , C 1 -C 4 alkyl optionally substituted with one to three fluoro or with one to three R 9 , (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S and wherein the heteroaryl is optionally substituted with one to three R 9 ; (5- to 6-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S and wherein the heterocycloalkyl is optionally substituted with one to three R 9 ; C 1 -C 4 alkoxy optionally substitute
  • R 4 at each occurrence may be independently selected from C 1 -C 4 alkyl-C(O)NH- optionally substituted with one to three fluoro or one to three R 9 . More particularly, R 4 at each occurrence may be independently selected from C 1 -C 3 alkyl-C(O)NH- optionally substituted with one to three fluoro or one to three R 9 .
  • Each R 3 may have 0, 1, 2 or 3 R 4 ; for example, there may be 0, 1 or 2 R 4 groups.
  • R 4 may be selected from CH 3 -C(O)NH-, CH 2 F-C(O)NH-, CHF 2 -C(O)NH- and CF 3 -C(O)NH-.
  • R 4 at each occurrence may be independently selected from the group consisting of C 3 -C 6 cycloalkyl optionally substituted with one to three fluoro or C 1 -C 3 alkyl or R 5 ; C 3 -C 6 cycloalkyl- C(O)NH- optionally substituted with one to five fluoro or R 5 ; 4- to 7-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or R 5 and wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; 5- to 6-membered heteroaryl)- C(O)NH- optionally substituted with one to five fluoro or R 5 and wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; C 1 -C 6 alkyl-OC(O)NH- optionally substituted with one to five fluoro or R 5 ; C 1 -C 6 alkyl-OC
  • R 4 may be a 4- to 7-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or R 5 and wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n.
  • R 4 may be a 4- to 6-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or one to three R 5 and wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S.
  • R 4 may be a 4- to 5-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or one or two R 5 and wherein the heterocycloalkyl moiety comprises one or two heteroatoms independently selected from N and O.
  • R 4 may be a 4- to 5-membered heterocycloalkyl-C(O)NH- optionally substituted with one to three fluoro or one or two R 5 and wherein the heterocycloalkyl moiety comprises one or two heteroatoms independently selected from N and O.
  • R 4 may be a 5-membered heterocycloalkyl-C(O)NH- optionally substituted with one to three fluoro or one R 5 and wherein the heterocycloalkyl moiety comprises one or two heteroatoms independently selected from N and O.
  • R 4 is tetrahydrofuran, which is optionally substituted with one to three fluoro or one R 5 .
  • R 5 may be selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, phenyl, phenoxy, C 3 -C 6 cycloalkyl, C 3 - C 6 cycloalkoxy, 4- to 6- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R 5 is optionally independently substituted with one to three R 9 ; and n at each occurrence is independently selected from 0, 1 and 2.
  • R 5 may be selected from C 1 -C 2 alkyl, C 1 -C 2 alkoxy, phenyl, phenoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, 4- to 6- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N and O, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N and O; wherein each R 5 is optionally independently substituted with one to three R 9 .
  • R 3 may in various embodiments be selected from any one of the following structures:
  • R 3 may be selected from any one of the following structures:
  • R 3 may be selected from any one of the following structures:
  • R 3 may be selected from any one of the following structures: In some particular embodiments, R 3 may have the following structure: wherein R 7 is aryl or heteroaryl; and R 8 is independently from R 7 selected from the group consisting of: C 1-6 alkyl or C 3-6 cycloalkyl optionally comprising one or more heteroatoms, such as N, O and S; particularly N or O; more particularly N.
  • R 3 may be selected from any one of the following structures: wherein R 7 may be selected from the group consisting of: methyl, trifluoromethyl, CH 3 (CF 2 H)-, tertiary- butyl; and R 8 may be independently from R 7 selected from the group consisting of: H, tertiary butyl and isopropyl.
  • R 3 may be selected from one of the following structures:
  • compounds of the disclosure may have one of the following structures of Formula (II) or (III): wherein R 1 may be as defined according to any of the aspects and embodiments disclosed herein.
  • R 1 may be selected from the group consisting of monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, as described herein.
  • the compounds of the present disclosure may be selected from any one of the compounds shown in Tables 1A, 1B and 1C.
  • the compound of the present disclosure may be selected from a compound listed in Table 2.
  • the compound of the present disclosure may be selected from a compound listed in Table 3.
  • Table 1A Exemplary compounds of the present disclosure
  • Table 1B Exemplary compounds of the present disclosure
  • Table 1C Exemplary compounds of the present disclosure Dosage Forms, Medicaments and Pharmaceuticals
  • the compounds, molecules or agents of the invention may be used to treat (e.g. cure, alleviate or prevent) one or more diseases, infections or disorders.
  • the compounds and molecules may be manufactured into medicaments or may be incorporated or formulated into pharmaceutical compositions.
  • the molecules, compounds and compositions of the invention may be administered by any convenient route, for example, methods of administration include intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intravaginal, transdermal, rectally, by inhalation, or topically to the skin.
  • Delivery systems are also known to include, for example, encapsulation in liposomes, microgels, microparticles, microcapsules, capsules, etc. Any other suitable delivery system known in the art is also envisioned in use of the present invention.
  • Administration can be systemic or local. The mode of administration may be left to the discretion of the practitioner. The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic properties of the particular active agent; the chosen mode and route of administration; the age, health and weight of the recipient; the nature of the disease or disorder to be treated; the extent of the symptoms; any simultaneous or concurrent treatments; the frequency of treatment; and the effect desired. In general, a daily dosage of active agent of between about 0.001 and about 1,000 mg/kg of body weight can be expected.
  • the dosage may suitably be within the range of about 0.01 to about 100 mg/kg, between about 0.1 to about 25 mg/kg, or between about 0.1 and 10 mg/kg.
  • the required dosage of the active agent of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • Dosage forms of the pharmaceutical compositions of the invention suitable for administration may contain from about 1 mg to about 2,000 mg of the active ingredient per unit.
  • the daily dosage of compounds may be at least about 10 mg and at most about 1,500 mg per human dose; such as between about 25 and 1,250 mg or suitably between about 50 and 1,000 mg.
  • each of the compounds of the general Formula (I) may be present in vivo in a concentration of at least about 10 nM.
  • the compound of the disclosure may be present in vivo in a concentration of at least 10 nm and at most about 10 ⁇ M, for example, between about 10 nM and about 10 ⁇ M, between about 25 nM and about 500 nM or between about 10 nm and about 100 nM.
  • concentration may be measured in blood or other bodily fluid (e.g. whole blood or serum) as an unbound compound.
  • the 'effective amount' or 'therapeutically effective amount' is meant to describe an amount of compound or a composition of the invention that is effective in curing, inhibiting, alleviating, reducing or preventing the adverse effects of the viral infection to be treated (especially COVID-19 infection), or the amount necessary to achieve a physiological or biochemically-detectable effect.
  • the compound or agent is able to produce the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • an effective amount of the compound or composition of the invention may have the effect of reducing, inhibiting or preventing viral replication, especially COVID-19 viral replication in a cell, such as a human cell.
  • Particularly preferred cells are those that express the ACE2 receptor; including cells of the nasal passages, respiratory tract, lungs and/or intestine.
  • a compound of the invention When administered to a subject, a compound of the invention is suitably administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • One or more additional pharmaceutical acceptable carrier such as diluents, adjuvants, excipients or vehicles
  • Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin. Pharmaceutical formulations and compositions of the invention are formulated to conform to regulatory standards and according to the chosen route of administration.
  • Acceptable pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilising, thickening, lubricating and colouring agents may be used.
  • the pharmaceutically acceptable vehicles are generally sterile. Water is a suitable vehicle when the compound of the invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or buffering agents.
  • the medicaments and pharmaceutical compositions of the invention can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, powders, gels, capsules (for example, capsules containing liquids or powders), modified-release formulations (such as slow or sustained-release formulations), suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • suitable pharmaceutical vehicles are described in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, see for example pages 1447- 1676.
  • compositions or medicaments of the invention are formulated in accordance with routine procedures as a pharmaceutical composition adapted for oral administration (more suitably for humans).
  • Compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • the pharmaceutically acceptable vehicle is a capsule, tablet or pill.
  • Orally administered compositions may contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavouring agents such as peppermint, oil of wintergreen, or cherry; colouring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • the compositions When the composition is in the form of a tablet or pill, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, so as to provide a sustained release of active agent over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions.
  • fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • a time delay material such as glycerol monostearate or glycerol stearate may also be used.
  • Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunem, or the ileum), or the large intestine.
  • One skilled in the art is able to prepare formulations that will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the peptide (or derivative) or by release of the peptide (or derivative) beyond the stomach environment, such as in the intestine.
  • a coating impermeable to at least pH 5.0 would be essential.
  • examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac, which may be used as mixed films.
  • CAT cellulose acetate trimellitate
  • HPMCP 50 hydroxypropylmethylcellulose phthalate
  • HPMCP 55 HPMCP 55
  • PVAP polyvinyl acetate phthalate
  • Eudragit L30D Trivial acetate phthalate
  • CAP cellulose acetate phthalate
  • Eudragit S Eudragit S
  • Shellac Shellac
  • Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride.
  • Potential nonionic detergents that could be included in the formulation as surfactants include: lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 20, 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions may also include a solubilising agent. Another suitable route of administration for the therapeutic compositions of the invention is via pulmonary or nasal delivery. Additives may be included to enhance cellular uptake of the therapeutic agent of the invention, such as the fatty acids oleic acid, linoleic acid and linolenic acid.
  • the therapeutic agents of the invention may also be formulated into compositions for topical application to the skin of a subject.
  • the agents may be formulated separately or in a single dosage form, depending on the prescribed most suitable administration regime for each of the agents concerned.
  • the pharmaceutical compositions of the invention may be used in a treatment regime involving simultaneous, separate or sequential administration with the other one or more therapeutic agent.
  • the other therapeutic agent(s) may comprise a compound of the invention or a therapeutic agent known in the art).
  • the molecules and pharmaceutical compositions of the invention may be formulated and suitable for administration to the central nervous system (CNS) and/or for crossing the blood-brain barrier (BBB).
  • CNS central nervous system
  • BBB blood-brain barrier
  • Tetrahydrofuran was purchased from Nan Ya Plastics Corporation.
  • Dichloromethane was purchased from Jiangsu Lee & Man Chemical.
  • N,N-Dimethylformamide was purchased from Xilong Scientific.
  • Methanol was purchased from Chron Chemicals.
  • Ethanol was purchased from Sinopharm Chemical Reagent.1,4-Dioxane (TP) was purchased from Infinity Scientific.
  • Moisture content of tetrahydrofuran, dichloromethane and N,N-dimethylformamide were lower than 100 ppm, and were used without further treatment.
  • Methanol, ethanol and 1,4-dioxane were pre-dried over 4 ⁇ molecular sieves before use.
  • N,N-dimethylformamide (purity>99.9%, ACS/HPLC certified) purchased from Anhui Zesheng Technology was used as reagent. Solvent extra dry over molecular sieves including N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and dimethylacetamide were purchased from Acros Organics.
  • Agilent (Degasser: 1200; Pump: 1260; Hip-ALS: 1200; TCC: 1200; DAD: 1100) Series LC-MS system with DAD-ELSD and Agilent LC-MS G6110A, mass-spectrometer.
  • Agilent (Degasser: 1200; Pump: 1260; Hip-ALS: 1100; TCC: 1260; DAD: 1100) Series LC-MS system with DAD and Agilent LC-MS G1956A, mass-spectrometer.
  • Agilent (Degasser: 1200; Pump: 1200; Hip-ALS: 1100; TCC: 1200; DAD: 1200) Series LC-MS system with DAD and Agilent LC-MS G1956A, mass-spectrometer.
  • Shimadzu LC-MS Shimadzu LC-20AD Series LC-MS system with SPD-M20A and Shimadzu LC-MS LCMS-2020, mass- spectrometer.
  • HPLC instruments were from Shimadzu.
  • Flow rate 3mL/min; Detector: PDA. Column Temp: 35 °C; Back Pressure: 100 Bar.
  • Microwave irradiator Instrument Biotage Initiator+.
  • Microwave power 0-400 W. pressure range :0-30 bar.
  • Method B 0-60AB, Agilent Instrument: Agilent 1100 ⁇ G1956A SingleQuad; Column: Kinetex@ 5um EVO C1830*2.1 mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 0-60% B, 0.8-1.2 min 60% B; flow 1.5 ml/min; temperature: 50°C; PDA: 220 nm & 254 nm.
  • Method C 5-95AB, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml/min; temperature: 50°C; PDA: 220 nm & 254 nm.
  • Method D 5-95AB, Agilent Instrument: Agilent 1100 ⁇ G1956A SingleQuad; Column: Kinetex@ 5 ⁇ m EVO C1830*2.1 mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml/min; temperature: 50°C; PDA: 220 nm & 254 nm.
  • Method E 10-80CD, Agilent Instrument: Agilent 1200 ⁇ G6110A SingleQuad; Column: XBridge C182.1*50 mm, 5 ⁇ m; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 10-80% B, 1.2-1.6 min 80% B; flow 1.2 ml/min; temperature: 40°C; DAD: 220 nm & 254 nm.
  • Method F 0-60CD, Agilent Instrument: Agilent 1200 ⁇ G6110A SingleQuad; Column: XBridge C182.1*50 mm, 5 ⁇ m; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 0-60% B, 1.2-1.6 min 60% B; flow 1.0 ml/min; temperature: 40°C; DAD: 220 nm & 254 nm.
  • Method G 5-95CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 ⁇ m; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 5-95% B, 0.8- 1.2 min 95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method H 0-60CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 ⁇ m; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min, 0-60% B, 1.2- 1.6 min, 60% B; flow 1.0 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method I 5-95CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 5-95% B, 0.8- 1.2 min, 95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method J 0-60CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 ⁇ m; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 0-60% B, 0.8- 1.2 min, 60% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method K 5-95CD, Agilent Instrument: Agilent LCMS-2020 SingleQuad; Column: XBridge C182.1*50mm, 5 ⁇ m; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.7 min, 5-95% B, 0.7-1.0 min, 95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method L 5-95AB, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 ⁇ m; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-3.6 min, 5-95% B, 3.6-4.0 min, 95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method M 0-60CD, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 3.5 ⁇ m; eluent A: 0.025% NH3•H2O in water ⁇ v/v ⁇ , eluent B: acetonitrile; gradient: 0-0.8 min, 0-60% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method N 0-60AB, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 3.5 ⁇ m; eluent A: 0.0375% TFA in water (v/v), eluent B: 0.01875% TFA in Acetonitrile (v/v); gradient: 0-0.8 min, 0-60% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method O 5-95AB, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 3.5 ⁇ m; eluent A: 0.0375% TFA in water (v/v), eluent B: 0.01875% TFA in Acetonitrile (v/v); gradient: 0-0.8 min, 5-95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method P 5-95CD, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 3.5 ⁇ m; eluent A: 0.025% NH3•H2O in water (v/v), eluent B: Acetonitrile; gradient: 0-0.8 min, 5-95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • Method Q 5-95CD, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 5 ⁇ m; eluent A: 0.025% NH3•H2O in water ⁇ v/v ⁇ , eluent B: Acetonitrile; gradient: 0-3.0 min, 5-95% B, 3.0-3.5 min, 95% B 3.50-3.51 min, 95-5% B 3.51-4.00 min, 5% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm.
  • reaction mixture was diluted with water (20 ml), and then extracted with DCM (30 mL ⁇ 3). The combined organic layers were washed with water (20 mL ⁇ 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (100 mL ⁇ 5). The combined organic layers were washed with saturated sodium chloride solution (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Trimethylsilyl trifluoromethanesulfonate (1.25 g, 5.63 mmol, 1.02 mL, 2.50 eq) was then added to the solution above at 0°C. After stirring at 0°C for 1 h, borane (1.00 M in tetrahydrofuran, 2.25 mL, 1.00 eq) was added and stirred at 0°C for another 1 h.
  • the mixture was purified by reversed phase (Instrument: 80g Flash; Column: Welch Ultimate XB_C1820-40 ⁇ m; eluent A: water (0.01% FA), eluent B: acetonitrile; gradient: 0-15 min 0-62% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give benzyl 2-[[3-(trifluoromethyl) oxetan-3- yl]amino]acetate (200 mg, 0.691 mmol, 31% yield) as yellow oil.
  • the combined reaction mixture (EW30036-104 and EW30036-106) was diluted with water (60.0 mL) and extracted with ethyl acetate (60.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with water (50.0 mL), adjusted pH to 11 ⁇ 14 with sodium hydroxide and extracted with ethyl acetate (30.0 mL ⁇ 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carbonitrile (0.430 g, 2.25 mmol, 61% yield, 85% purity) as brown gum.
  • the obtained compound was purified by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30 mm, 10um); mobile phase: [IPA-ACN]; B%: 65%-65%, 6.6 min; 65min) to give Peak1 and Peak2.
  • Peak1 was further separated by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm,10um); mobile phase: [IPA-ACN]; B%: 45%-45%, 2.5 min; 50 min) and Peak2 was further separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10 ⁇ m); mobile phase: [0.1% NH 3 ⁇ H 2 O Metanol]; B%: 45%-45%, 4min; 50min) to give four isomers.
  • the mixture of the three unseparated diastereomers was further purified by SFC (column: REGIS(S,S)WHELK- O1(250mm*25mm,10 ⁇ m);mobile phase: [0.1% NH 3 ⁇ H 2 O in ethanol]; B%: 40%-40%,3.7;60min) to give peak 1 and a mixture of two unseparated diastereomers.
  • the mixture of two unseparated diastereomers was further purified by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: [0.1%N NH3 ⁇ H2O in methanol]; B%: 70%-70%, 9;50min) to give CPD0082408 (41.26 mg, 96.7 ⁇ mol, 19% yield, 99% purity) and CPD0082409 (11.14 mg, 26.2 ⁇ mol, 5% yield, 99% purity) as an off-white solids.
  • SFC column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: [0.1%N NH3 ⁇ H2O in methanol]; B%: 70%-70%, 9;50min
  • Peak 1 was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 ⁇ m; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 7min) and lyophilized to give CPD0082406 (8.91 mg, 20.7 ⁇ mol, 4% yield, 98% purity) as an off-white solid.
  • Peak 2 was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3 ⁇ m; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 7min) and lyophilized to give CPD0082407 (53.86 mg, 126 ⁇ mol, 25% yield, 99% purity) as an off-white solid.
  • reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (120 mL ⁇ 2). The combined organic layers were washed with brine (80.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with water (60.0 mL) and extracted with ethyl acetate (60.0 mL ⁇ 2). The combined organic layers were washed with brine (50.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic layers were washed with brine (50.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture (combined 3 batches) was poured into ammonium chloride aqueous solution (30.0 mL) and extracted with ethyl acetate (50.0 mL ⁇ 2). The combined organic layers were washed with brine (20.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue.
  • reaction mixture was poured into ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic layers were washed with brine (50.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue.
  • methyl 2-amino-3-(2-pyridyl)butanoate (3.00 g, 13.0 mmol, crude, 1.00 eq, HCl) was added at 25°C. After addition, the mixture was stirred at 25°C for 12 h. The reaction mixture was poured into ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic layers were washed with brine (50.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a reside.
  • a mixture of peak 1, peak 2 and peak 3 was further purified by SFC for twice (column: DAICEL CHIRALPAK AS (250mm*30mm,10um); mobile phase: [0.1%NH3 ⁇ H2O IPA]; B%: 35%-35%, 8min;140min) and SFC (column: REGIS(S,S)WHELK-O1 (250mm*25mm,10um); mobile phase: [0.1% NH 3 ⁇ H 2 O IPA]; B%: 55%-55%, 2.6; 60min) to give CPD0084193: (peak 1, 33.85 mg, 73.26 ⁇ mol, 9.39% yield, 99.9% purity), CPD0084194: (peak 2, 53.09 mg, 114.90 ⁇ mol, 14.73% yield, 99.9% purity), CPD0084195: (peak 3, 20.34 mg, 44.02 ⁇ mol, 5.64% yield, 99.9% purity) as a white solid.
  • reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (15.0 mL ⁇ 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to give a residue.
  • reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10.0 mL) and extracted with dichloromethane (10 mL ⁇ 3). The combined organic layers were washed by brine (15.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue.
  • reaction mixture was poured into water (60.0 mL) and extracted with ethyl acetate (60.0 mL ⁇ 2). The combined organic layers were washed with brine (60.0 mL ⁇ 2), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was poured into saturated ammonium chloride aqueous solution (10.0 mL) and extracted with ethyl acetate (30.0 mL ⁇ 2). The combined organic layers were washed with brine (20.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • hydrochloric acid solution (1M) was added to the mixture to adjust pH ⁇ 7 and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was added dropwise into saturated ammonium chloride aqueous solution (200 mL), diluted with water (200 mL) and extracted with ethyl acetate (200 mL ⁇ 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-1,3-benzothiazol-5- ylmethanol (3.00 g, 16.0 mmol, 84% yield, 90% purity) as a yellow oil.
  • the reaction mixture was quenched with sodium bicarbonate aqueous solution and sodium thiosulfate (150 mL) respectively at 25°C. After filtration, the filtrate was diluted with water (200 mL) and extracted with ethyl acetate (200 mL ⁇ 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-1,3-benzothiazole-5-carbaldehyde (2.60 g, 13.2 mmol, 75% yield, 85% purity) as yellow oil.
  • timethylsilyl cyanide (880 mg, 8.88 mmol, 1.11 mL, 1.2 eq) was added and the resulting mixture was stirred for 1 h.
  • the reaction mixture was added dropwise into saturated ammonium chloride aqueous solution (100 mL), diluted with water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced to give a residue.
  • Peak1 was further purified by SFC column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 ⁇ m); mobile phase: [Neu-IPA]; B%: 15%-15%, 6.0 min) twice to give CPD0084776 (6.66 mg, 12.3 ⁇ mol, 2% yield, 99.99% purity) as a white solid and impure CPD0084777.
  • CPD0084777 was purified by SFC column: REGIS(S,S) WHELK-O1(250mm*25mm,10um); mobile phase: [Neu-IPA]; B%: 30%-30%, 2.1 min twice to give CPD0084777 (17.7 mg, 32.9 ⁇ mol, 6.34% yield, 99.99% purity) as a white solid.
  • Peak2 was purified by SFC column: DAICEL CHIRALCEL OD (250mm*30mm, 10 um); mobile phase: [Neu- IPA]; B%: 20%-20%, 2.7 min for four times to give CPD0084778 (12 mg, 22.3 ⁇ mol, 4% yield, 99% purity) as a white solid and impure CPD0084779.
  • CPD0084779 was purified by SFC twice column: DAICEL CHIRALCEL OJ(250mm*30 mm,10 ⁇ m);mobile phase: [Neu-IPA]; B%: 0%-0%,6.0 min to give CPD0084779 (34.6 mg, 64.0 ⁇ mol, 12% yield, 99% purity) as a white solid.
  • CPD0084776 Preparation of CPD0084260, CPD0084780, CPD0084781, CPD0084906, and CPD0084907 Procedure for preparation of 5-oxo-7-trimethylsilyl-hept-6-ynoic acid
  • dichloromethane 500 mL
  • trimethyl(2-trimethylsilylethynyl)silane 49.3 g, 289 mmol, 65.5 mL, 1.10 eq
  • aluminum chloride (35.1 g, 263 mmol, 1.00 eq) at 0°C.
  • reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (30.0 mL ⁇ 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue.
  • the impure compound was further purified by SFC separation (column: DAICEL CHIRALPAK IC (250 mm*30 mm,10 ⁇ m); mobile phase: [Neu-IPA]; B%: 25%-25%, 2.8 min) to give (1R,2S,5S)-N-[(1R or S)-1-cyano-2-[(6R or S)-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-6-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6- dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (CPD0084906, 7.30 mg, 13.8 ⁇ mol, 7% yield, 99% purity) as a white solid and (1R,2S,5S)-N-[(1R or S)-1-cyano-2-[(6R
  • Methyl 2-amino-3-(2-oxo-1-piperidyl)propanoate (500 mg, 1.83 mmol, 1.00 eq, 2 hydrochloric acid) was then added to the mixture above. After stirring at 25°C for 16 h, the mixture was poured into water (40.0 mL) and extracted with ethyl acetate (40 mL ⁇ 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue.
  • reaction mixture was poured into ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (200 mL ⁇ 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • the filter cake was triturated with methyl tert-butyl ether and filtered.
  • the solid cake was dried under vacuum to give 8-(1,3-dioxolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (19.0 g, 94.4 mmol, 63% yield, 95% purity) as a yellow solid.
  • reaction mixture was concentrated and purified by reversed phase flash column (0.1% NH 3 ⁇ H 2 O, 50% - 60% ACN) to give tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2- oxo-1- (5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-ylmethyl) ethyl]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl] carbamate (510 mg, 0.865 mmol, 59% yield, 95% purity) as a white solid.
  • reaction mixture was quenched with saturated ammonium chloride solution (50.0 mL) at 0°C, diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL ⁇ 3). The combined organic layers were washed with brine (20.0 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to afford 5,6,7,8-tetrahydroisoquinolin-8-ol (3.6 g, 23.9 mmol, 96% yield, 99% purity) as brown oil.
  • reaction mixture was diluted with saturated ammonium chloride solution (50.0 mL) and extracted with ethyl acetate (50.0 mL ⁇ 3). The combined organic layers were washed with brine (30.0 mL ⁇ 5), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • 6-amino-5,7-dihydrocyclopenta[b]pyridine-6-carboxamide 110 mg, 362 ⁇ mol, 70% purity, 1.10 eq, hydrochloric acid
  • the reaction mixture was diluted with saturated ammonium chloride aqueous solution (20.0 mL) and extracted with ethyl acetate (20.0 mL ⁇ 2).
  • the combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was poured into ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (200 mL ⁇ 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • hydrochloric acid solution (1M) was added to the mixture to adjust pH ⁇ 7 and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL ⁇ 3). The combined organic layers were washed with brine (10.0 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched with saturated sodium bicarbonate solution (10.0 mL) and extracted with ethyl acetate (5.00 mL ⁇ 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.

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Abstract

L'invention concerne de nouveaux inhibiteurs de Mpro viraux selon la formule (I), leurs sels pharmaceutiquement acceptables, et des compositions pharmaceutiques de ceux-ci. L'invention concerne également des procédés d'utilisation de tels composés et compositions pour inhiber les Mpro et/ou pour traiter diverses infections virales; en particulier associées au coronavirus. Les composés et les compositions de l'invention peuvent être particulièrement utiles dans le traitement d'un large spectre de coronavirus.
PCT/EP2023/056837 2022-03-23 2023-03-16 Composés antiviraux ciblant les mpro WO2023180189A1 (fr)

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GBGB2204199.0A GB202204199D0 (en) 2022-03-24 2022-03-24 MPRO targeting antiviral compounds

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WO2024086111A1 (fr) * 2022-10-17 2024-04-25 Aligos Therapeutics, Inc. Composés antiviraux

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WO2011061548A2 (fr) 2009-11-20 2011-05-26 University Of Dundee Conception de molécules
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WO2021252644A1 (fr) * 2020-06-09 2021-12-16 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs procédés d'utilisation
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WO2011061548A2 (fr) 2009-11-20 2011-05-26 University Of Dundee Conception de molécules
WO2021252644A1 (fr) * 2020-06-09 2021-12-16 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs procédés d'utilisation
WO2021252491A1 (fr) * 2020-06-10 2021-12-16 Aligos Therapeutics, Inc. Composés antiviraux pour le traitement d'infections à coronavirus, picornavirus et norovirus
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* Cited by examiner, † Cited by third party
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WO2024086111A1 (fr) * 2022-10-17 2024-04-25 Aligos Therapeutics, Inc. Composés antiviraux

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