WO2024107778A1 - Nouveaux inhibiteurs de protéase pour le traitement d'infections à coronavirus - Google Patents

Nouveaux inhibiteurs de protéase pour le traitement d'infections à coronavirus Download PDF

Info

Publication number
WO2024107778A1
WO2024107778A1 PCT/US2023/079713 US2023079713W WO2024107778A1 WO 2024107778 A1 WO2024107778 A1 WO 2024107778A1 US 2023079713 W US2023079713 W US 2023079713W WO 2024107778 A1 WO2024107778 A1 WO 2024107778A1
Authority
WO
WIPO (PCT)
Prior art keywords
ealkyl
compound
mmol
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/US2023/079713
Other languages
English (en)
Inventor
Atsuko OCHIDA
Edcon Chang
Daniel Carney
Mallareddy Komandla
Terufumi Takagi
Atsutoshi OKABE
Jumpei AIDA
Leah Lynn Frye
Abba Elias LEFFLER
Eugene Richard Hickey
Original Assignee
Takeda Pharmaceutical Company Limited
Schrodinger, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Pharmaceutical Company Limited, Schrodinger, Inc. filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2024107778A1 publication Critical patent/WO2024107778A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to novel protease inhibitors useful for inhibiting coronavirus replication and methods for treating a subject infected by coronavirus including the SARS-CoV-2 virus.
  • Coronaviruses are a family of enveloped, single- stranded, positive-sense, RNA viruses that are known to cause disease in a wide variety of animals.
  • Zumla, A., et al. “Coronaviruses — drug discovery and therapeutic options,” Nature Reviews Drug Discovery 15(5):327-347 (2016). Seven coronaviruses are known to infect humans: SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-HKUl, HCoV-NL63 and HCoV-OC43.
  • SARS-CoV-2 is responsible for the CO VID-19 respiratory illness and the ensuing pandemic, which as of March 2022, has caused more than 6 million deaths worldwide (WHO COVID-19 dashboard https://covidl9.who.int/).
  • the SARS-CoV-2 genome contains 13-15 open reading frames that encode for a variety of structural and non- structural proteins (nsp’s).
  • nsp structural and non- structural proteins
  • ORF lab encodes for 2 overlapping polyproteins (ppi a, pplb) that are cleaved at sequence specific sites into 16 distinct nsp’s that are involved in viral replication, viral assembly, and host immune modulation. Shamsi, A. et al. (2016).
  • Cleavage of ppla and pplb into individual nsp’s is mediated by two viral proteases, the main protease (Mpro) and the papin-like protease (Pip).
  • Mpro main protease
  • Pip papin-like protease
  • the function of both of these proteases are necessary for coronavirus replication and pathogenesis. Shamsi, A. et al. (2016); Ullrich, S. and Nitsche, C. (2020).
  • the main protease cleaves peptides after a glutamine (Pl) that is adjacent to a hydrophobic residue such as leucine, phenylalanine, or valine (P2).
  • R 3 is H or -Ci-ealkyl
  • R 2 and R 3 together with the nitrogen atom and carbonyl group to which they are attached, form a heterocycloalkyl
  • R 4 is -Ci-ealkyl, -Co-ealkylene-cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein at each occurrence, each R 1 is optionally substituted with halo or C alkyl; wherein at each occurrence, -Ci-ealkyl, -Ci-ealkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, oxo, -CN, -NH2, -NH(Ci- ealkyl), -NH(Ci-ehaloalkyl), -N(Ci-ealkyl)2, -NHCO(Ci -ealkyl), -NHCO(Ci-ehaloalkyl), - NHSO(Ci-ealkyl), -NO2, -Ci-3al
  • Another aspect of the disclosure provides compounds selected from any of the compounds prepared in the examples, or a pharmaceutically acceptable salt thereof.
  • a further aspect of the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • An additional aspect of disclosure provides a method of treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of the disclosure.
  • Another aspect of the disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt or ester thereof, for use in treating a coronavirus infection in a human.
  • a further aspect of the disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt or ester thereof, for use in treating SARS-CoV-2 infection in a human.
  • Another aspect of the disclosure relates to a medical use of the compounds or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a coronavirus infection.
  • disease or “condition” refers to disturbances and/or anomalies that are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions.
  • compounds of the present disclosure are inhibitors of Mpro and can be used in treating or preventing diseases and conditions wherein inhibition of Mpro provides a benefit.
  • treatment As used herein, the terms “treatment,” “treat,” and “treating” are interchangeable and refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, including but not limited to therapeutic benefit.
  • treatment includes one or more of the following: (a) inhibiting the disorder (for example, decreasing one or more symptoms resulting from the disorder, and/or diminishing the extent of the disorder); (b) slowing or arresting the development of one or more symptoms associated with the disorder (for example, stabilizing the disorder and/or delaying the worsening or progression of the disorder); and/or (c) relieving the disorder (for example, causing the regression of clinical symptoms, ameliorating the disorder, delaying the progression of the disorder, and/or increasing quality of life).
  • inhibiting the disorder for example, decreasing one or more symptoms resulting from the disorder, and/or diminishing the extent of the disorder
  • slowing or arresting the development of one or more symptoms associated with the disorder for example, stabilizing the disorder and/or delaying the worsening or progression of the disorder
  • relieving the disorder for example, causing the regression of clinical symptoms, ameliorating the disorder, delaying the progression of the disorder, and/or increasing quality of life.
  • Therapeutic benefit includes eradication and/or amelioration of the underlying disorder being treated. It also includes the eradication and/or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • prevent refers to a method of preventing or delaying the onset of a disease or condition and/or its attendant symptoms or barring a subject from acquiring a disease. These terms may include “prophylactic treatment”, which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • administering or “administration” of the compound of formula (I), formula (II), formula A, formula B or formula B-l or a pharmaceutically acceptable salt thereof encompasses the delivery to a patient a compound or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, e.g., as described herein.
  • the term "therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disorder, is sufficient to effect such treatment of the disorder.
  • the effective amount will vary depending on the disorder, and its severity, and the age, weight, etc. of the subject to be treated.
  • the effective amount may be in one or more doses (for example, a single dose or multiple doses may be required to achieve the desired treatment endpoint).
  • An effective amount may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any co-administered compounds may optionally be lowered due to the combined action, additive or synergistic, of the compound.
  • patient or “subject” refers to human subject of any age groups and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys).
  • pharmaceutically acceptable or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • the term "pharmaceutically acceptable carrier” is used herein to refer to a material that is compatible with a recipient subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
  • the toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the active agent.
  • the term “orally” refers to administering a composition that is intended to be ingested. Examples of oral forms include, but are not limited to, tablets, pills, capsules, powders, granules, solutions or suspensions, and drops. Such forms may be swallowed whole or may be in chewable form.
  • halo refers to -Cl, -F, -Br, or -I.
  • alkyl refers to a straight- or branched-chain saturated hydrocarbon.
  • the chain may contain an indicated number of carbon atoms.
  • Ci-Cio or Cnio indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it; Ci-Ce or Ci-6 indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it.
  • an alkyl group contains from 1 to about 20 carbon atoms.
  • alkyl groups have 1 to about 10 carbon atoms.
  • alkyl groups (“lower alkyl”) have 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain.
  • Examples may include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, ec-butyl, zso-butyl, /e/7-butyl, pentyl, neopentyl, 2- methylbutyl,
  • alkylene includes an alkyl group that is substituted at two points.
  • An example is methylene (-CEE-), propylene (-CH2CH2CH2-), and the like.
  • substituted with 0, 1, 2, 3, or 4 substituents refers to that a group may be unsubstituted when the group is substituted with 0 substituent, or that the group is substituted with 1, 2, 3, or 4 substituents.
  • amino refers to -NH2.
  • aminoalkyl refers to an alkyl group where at least one hydrogen has been replaced with an amino (-NH2) group. In certain embodiments, the aminoalkyl group has one amino group. In certain embodiments, the aminoalkyl group has two amino groups, each on a different carbon atom.
  • amino protecting group refers to a protecting group that is suitable for preventing undesired reactions at an amino nitrogen.
  • Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, such as acetyl and trifluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), and l,l-di-(4'-methoxyphenyl)methyl; and the like.
  • acyl groups such as acetyl and trifluoroacetyl
  • alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc)
  • arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc
  • alkoxy refers to an alkyl group attached to a terminal oxygen atom, e.g., -O-alkyl.
  • Non-limiting exemplary alkoxy groups include methoxy (-OMe), ethoxy (-OEt), and /c/V-butoxy.
  • cycloalkyl refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C3-12 cycloalkyl, or the number of carbons designated, e.g., a
  • the cycloalkyl such as a cyclopropyl, a C4 cycloalkyl such as cyclobutyl, etc.
  • the cycloalkyl is bicyclic, i.e., it has two rings.
  • the cycloalkyl is monocyclic, i.e., it has one ring.
  • a cycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, oxo, -CN, -NH 2 , -NH(Ci- 6 alkyl), -NH(Ci- 6 haloalkyl), -N(Ci- 6 alkyl) 2 , -NHCO(Ci- 6 alkyl), - NHCO(Ci -ehaloalky 1), -NO2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci-ehydroxyalkyl, -Ci-ealkoxy, - SO 2 (Ci- 6 alkyl), and -SO 2 NH 2 .
  • cycloalkylene as used herein includes a cycloalkyl group that is substituted at two points.
  • aryl refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring systems having six to fourteen carbon atoms in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic.
  • monocyclic e.g., phenyl
  • bicyclic e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl
  • tricyclic e.g., fluorenyl tetrahydrofluorenyl, tetrahydr
  • the other ring(s) in the bicyclic or tricyclic ring system may be saturated, partially unsaturated, or fully unsaturated.
  • the bicyclic and tricyclic groups include benzofiised carbocyclic rings.
  • a benzofiised group includes a phenyl group fused with one or two 4 to 8 membered carbocyclic moieties.
  • An aryl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, oxo, -CN, -NH 2 , -NH(Ci- ealkyl), -NH(Ci-6haloalkyl), -N(Ci-6alkyl) 2 , -NHCO(Ci -ealkyl), -NHCO(Ci-ehaloalkyl), - N0 2 , -Ci-ealkyl, -Ci-ehaloalkyl, -Ci-ehydroxyalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), and - SO2NH2.
  • heteroaryl refers to monocyclic, bicyclic, or tricyclic ring systems containing five to fourteen ring atoms including carbon, zero, one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen.
  • the monocyclic ring system is aromatic and at least one of the rings in the bicyclic or tricyclic ring systems is aromatic.
  • the other ring(s) in the bicyclic or tricyclic ring system may be saturated, partially unsaturated, or fully unsaturated.
  • the heteroaryl has three heteroatoms.
  • the heteroaryl has two heteroatoms.
  • the heteroaryl has one heteroatom.
  • the heteroaryl has five to twelve ring atoms. In some embodiments, the heteroaryl has eight to twelve ring atoms. In some embodiments, the heteroaryl has eight or nine ring atoms. In some embodiments, the heteroaryl has nine ring atoms.
  • Non-limiting exemplary heteroaryl groups include thienyl (e.g., thien-2-yl and thien-3-yl), benzo [b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofiiryl, pyranyl, isobenzofiiranyl, benzooxazonyl, chromenyl, xanthenyl, 2/7-pyrrolyl, pyrrolyl (e.g., lH-pyrrol-2-yl and lH-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., lH-pyrazol-3-yl, lH-pyrazol-4-yl, and lH-pyrazol-5-yl), pyridyl (e.g., pyri
  • the heteroaryl group is indolyl. In some embodiments, the heteroaryl group is UT-indolyl. In some embodiments, the heteroaryl group is 5H-[l,3]dioxolo[4,5-f]indole.
  • the term heteroaryl also includes N-oxides. A nonlimiting exemplary N-oxide is pyridyl N-oxide.
  • a heteroaryl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, oxo, -CN, -NH 2 , -NH(Ci -ealkyl), -NH(Ci- ehaloalkyl), -N(Ci-ealkyl) 2 , -NHCO(Ci -ealkyl), -NHCO(Ci -ehaloalky 1), -NO2, -Ci-ealkyl, -Ci- ehaloalkyl, -Ci-ehydroxyalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), and -SO2NH2.
  • the term “heteroarylene” as used herein includes a heteroaryl group that is substituted at two points.
  • heterocycloalkyl refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic or bicyclic ring structure containing three to fourteen ring members, in which zero, one, two, or three of the ring atoms is a heteroatom. Each heteroatom is independently oxygen, sulfur, or nitrogen.
  • a bicyclic ring structure includes the fused, spiro, or bridged moiety.
  • the heterocycloalkyl has three heteroatoms.
  • the heterocycloalkyl has two heteroatoms.
  • the heterocycloalkyl has one heteroatom.
  • Non-limiting exemplary heterocycloalkyl groups include thiacyclohexanyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl and thietanyl, oxazinyl, oxetanyl, azetidinyl, thietanyl, dihydrofiiranyl, tetrahydrofiiranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydro-2H-pyran, dihydropyranyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydropyrimidine, pyrrolidinyl, dihydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl
  • a heterocycloalkyl group may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, -OH, oxo, -CN, -NH2, -NH(Ci- ealkyl), -NH(Ci-ehaloalkyl), -N(Ci-ealkyl)2, -NHCO(Ci -ealkyl), -NHCO(Ci-ehaloalkyl), - NO2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci-ehydroxyalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), and - SO2NH2.
  • haloalkyl refers to an alkyl group where at least one hydrogen has been replaced with a halo group. In certain embodiments, the haloalkyl group has one halo group. In certain embodiments, the haloalkyl group has two or three halo groups. In certain embodiments, the haloalkyl group is a perfluorinated alkyl group. Examples may include, but are not limited to, chloromethyl, trifluoromethyl, and the like.
  • hydroxyalkyl refers to an alkyl group where at least one hydrogen has been replaced with an alcohol (-OH) group.
  • the hydroxyalkyl group has one alcohol group.
  • the hydroxyalkyl group has two alcohol groups, each on a different carbon atom. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxy ethyl, and 1 -hydroxy ethyl.
  • the groups may be the same or different.
  • R a and R b are each independently alkyl, -F, -NH2, or -OH
  • a molecule with two R a groups and two R b groups could have all groups be an alkyl group (e.g., four different alkyl groups).
  • the first R a could be alkyl
  • the second R a could be -F
  • the first R b could be -OH
  • the second R b could be -NH2 (or any other substituents taken from the group).
  • both R a and the first R b could be -F
  • the second R b could be alkyl (z.e., some pairs of substituent groups may be the same, while other pairs may be different).
  • Compounds of the present disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • the present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
  • the individual enantiomers can be separated according to methods known in the art in view of the present disclosure.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure.
  • the present disclosure provides a compound of formula I:
  • R 3 is H or -Ci-ealkyl
  • R 2 and R 3 together with the nitrogen atom and carbonyl group to which they are attached, form a heterocycloalkyl
  • R 4 is -Ci-ealkyl, -Co-ealkylene-cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein at each occurrence, each R 1 is optionally substituted with halo or C alkyl; wherein at each occurrence, -Ci-ealkyl, -Ci-ealkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, oxo, -CN, -NH2, -NH(Ci- ealkyl), -NH(Ci -ehaloalkyl), -N(Ci-ealkyl)2, -NHCO(Ci -ealkyl), -NHCO(Ci -ehaloalkyl), - NHSO(Ci-ealkyl), -NO2, -Ci
  • R 1 is
  • R 1 is
  • R 1 is , optionally substituted with C alkyl (e.g., Me, Et, Pr, Bu).
  • C alkyl e.g., Me, Et, Pr, Bu
  • R 1 is
  • R 1 is
  • R 1 is
  • R 1 is
  • R 1 is
  • R 1 is
  • R 1 is
  • R 1 is
  • R 1 is
  • R 1 is
  • R 1 is
  • the compound of formula (I) is a compound of formula (II): wherein R 2 , R 3 , and R 4 are as defined herein.
  • R 2 is
  • cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, -OH, oxo, -CN, -NH2, -NH(Ci -ealkyl), -NH(Ci -ehaloalky 1), -N(Ci- ealkyl) 2 ,
  • R 2 is -Ci -ealkyl or -Ci -ealkoxy.
  • R 2 is -Me, -CHF2, -CF3.
  • R 2 is
  • R 2 is -Ci-ehaloalkyl.
  • R 2 is
  • R 2 is -Ci -eaminoalkyl or -Ci-ehydroxyalkyl.
  • R 2 is -Ci-ealkylene-NHCO-Ci-ealkyl or -Ci-ealkylene-
  • R 2 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R 2 is -Ci-6alkylene-NHSO2-Ci-ealkyl.
  • R 2 is selected from the group consisting of
  • R 2 is -Co-ealkylene-Cs-ecycloalkyl or -Cs-ecycloalkylene- phenyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, oxo, -CN, -NH2, -NH(Ci -ealkyl), -NH(Ci- ehaloalkyl), -N(Ci-ealkyl)2, -NHCO(Ci -ealkyl), -NHCO(Ci -ehaloalky 1), -NO2, -Ci-ealkyl, -Ci- ehaloalkyl, -Ci-ehydroxyalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), and -SO2NH2.
  • R 2 is -Cs-ecycloalkyl or -Cs-ecycloalkylene-phenyl, wherein the cycloalkyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -NH(Ci-ehaloalkyl), -NHCO(Ci-ehaloalkyl), and -Ci-ealkyl.
  • R 2 is -Cs-ecycloalkyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, -OH, -NH(Ci-ehaloalkyl), - NHCO(Ci -ehaloalky 1), and -Ci-ealkyl.
  • R 2 is C alkylene-Cs membered heterocycloalkyl optionally substituted with pyrrolidinyl.
  • R 2 is C alkylene-Ce membered heterocycloalkyl optionally substituted with piperidinyl, tetrahydropyranyl, or morpholinyl.
  • R 2 is Co-4alkylene(optionally substituted pyrrolidinyl).
  • R 2 is Ci-4alkylene(optionally substituted pyrrolidinyl).
  • R 2 is
  • R 2 is Co-4alkylene(optionally substituted piperidinyl. In some embodiments, R 2 is Co-4alkylene(optionally substituted tetrahydropyranyl). In some embodiments, R 2 is Co-4alkylene(optionally substituted morpholinyl). In some embodiments, R 2 is Ci-4alkylene(optionally substituted piperidinyl. In some embodiments, R 2 is Ci- 4alkylene (optionally substituted tetrahydropyranyl). In some embodiments, R 2 is Ci-
  • R 2 is ,
  • R 2 is -Cs-ecycloalkyl substituted with -OH, -NH(Ci- ehaloalkyl), or -NHCO(Ci -ehaloalky 1).
  • R 2 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R 2 is -Cs-ecycloalkylene-phenyl.
  • R 2 is
  • R 2 is 3-7 membered heterocycloalkyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo,
  • R 2 is 5-6 membered heterocycloalkyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, oxo, and - Ci -ealkyl.
  • R 2 is
  • R 2 is
  • R 2 is -Ci-6alkylene-C3-7 membered heterocycloalkyl.
  • R 2 is -Ci-ealkylene-Cs-e membered heterocycloalkyl.
  • R 2 is
  • R 2 is phenyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(Ci -ealkyl), - NH(Ci-ehaloalkyl), -N(Ci-ealkyl)2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci-ehydroxyalkyl, -Ci- ealkoxy, -SO2(Ci-ealkyl), and -SO2NH2.
  • R 2 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(Ci -ealkyl), - NH(Ci-ehaloalkyl), -N(Ci-ealkyl)2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci-ehydroxyalkyl, -Ci- ealkoxy, -SO2(Ci-ealkyl), and -SO2NH2.
  • R 2 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, -Ci-ealkyl, -Ci-ehaloalkyl, -SO2(Ci- ealkyl), and -SO2NH2.
  • R 2 is phenyl substituted with 2 substituents independently selected from the group consisting of -Ci -ehaloalky 1 and -SO2(Ci-ealkyl).
  • R 2 is
  • R 2 is -Co-ealkylene-(5-12 membered heteroaryl) or -(5-12 membered heteroarylene)-C3-ecycloalkyl, wherein the cycloalkyl and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(Ci-6alkyl), -NH(Ci -ehaloalky 1), -N(Ci- ealkyl)2, -NHCO(Ci -ealkyl), -NHCO(Ci-ehaloalkyl), -NO2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci- ehydroxyalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), and -SO2NH2.
  • R 2 is -Co-3alkylene-(5-lO membered heteroaryl) or -(5-10 membered heteroarylene)-C3-6cycloalkyl, wherein the cycloalkyl and heteroaryl are each independently substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, -NH2, -NH(Ci -ealkyl), -NH(Ci-ehaloalkyl), -N(Ci-ealkyl)2, -NHCO(Ci -ealkyl), -NHCO(Ci-ehaloalkyl), -Ci -ealkyl, -Ci-ehaloalkyl, -Ci-ehydroxyalkyl, - Ci-ealkoxy, -SO2(Ci-ealkyl), and -SO2NH2.
  • R 2 is -Co-3alkylene-(5-9 membered heteroaryl) or -(5-9 membered heteroarylene)-C3-ecycloalkyl, wherein the 5-9 membered heteroaryl contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the cycloalkyl and heteroaryl are each independently substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -CN, -NH2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci- ehydroxyalkyl, -Ci -ealkoxy, -SO 2 (Ci- 6 alkyl), and -SO2NH2.
  • R 2 is -Co-3alkylene-(5 membered heteroaryl) or -(5 membered heteroarylene)-C3-ecycloalkyl, wherein the 5 membered heteroaryl contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the cycloalkyl and heteroaryl are each independently substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -CN, -NH2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci- ehydroxyalkyl, -Ci -ealkoxy, -SO 2 (Ci- 6 alkyl), and -SO2NH2.
  • R 2 is 8-9 membered heteroaryl, wherein the 8-9 membered heteroaryl contains 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the 8-9 membered heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -CN, -NH2, -Ci -ealkyl, -Ci-ehaloalkyl, -Ci-ehydroxyalkyl, - Ci -ealkoxy, -SO 2 (Ci- 6 alkyl), and -SO2NH2.
  • R 2 is selected from any of the group in Table 1. Table 1
  • R 2 is selected from any of the following moieties in Table 2. Table 2
  • R 3 is H or Ci-ealkyl.
  • R 3 is H.
  • R 3 is -Me.
  • R 2 and R 3 together with the nitrogen atom and carbonyl group to which they are attached, form a 3-6 membered heterocycloalkyl substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, -OH, oxo, - CN, -NH 2 , -NH(Ci- 6 alkyl), -NH(Ci- 6 haloalkyl), -N(Ci- 6 alkyl) 2 , -NHCO(Ci- 6 alkyl), -NHCO(Ci-ehaloalkyl), -NO 2 , -Ci-ealkyl, -Ci-ehaloalkyl, -Ci-ehydroxyalkyl, -Ci-ealkoxy, - SO 2 (Ci- 6 alkyl), and -SO 2 NH 2 .
  • R 2 and R 3 together with the nitrogen atom and carbonyl group to which they are attached, form a 5-6 membered heterocycloalkyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, oxo, NH 2 , and - Ci -ealkyl.
  • R 2 and R 3 together with the nitrogen atom and carbonyl group to which they are attached, form
  • R 2 is selected from any of the groups in Table 2, and R 3 is H or -Me.
  • R 2 is selected from any of the groups in Table 1, and R 3 is H.
  • R 2 is selected from any of the groups in Table 2, and R 3 is H.
  • R 4 is -Ci-ealkyl, -Co-ealkylene-cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein at each occurrence, each R 1 is optionally substituted with halo or C alkyl (e.g., substituted with halo or C alkyl); wherein at each occurrence, -Ci-ealkyl, -Ci-ealkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, -OH, oxo, -CN, -NH2, -NH(Ci -ealkyl
  • R 4 is -Ci-ealkyl or phenyl, wherein phenyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, -OH, -CN, - NH2, -Ci-ealkyl, -Ci-ehaloalkyl, and -Ci-ealkoxy.
  • R 4 is -Ci-ealkyl.
  • R 4 is
  • R 4 is phenyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of F, Cl, and -Ci-ealkyl.
  • R 4 is selected from the group consisting of
  • R 4 is selected from the group consisting of
  • R 4 is selected from any of the groups in Table 3.
  • R 2 is selected from any of the groups in Table 2
  • R 3 is H or - Me
  • R 4 is selected from any of the groups in Table 3.
  • the compound of formula I or formula II is a compound of formula A
  • R 5 is halo, -OH, oxo, -CN, -NH2, -NH(Ci -ealkyl), -NH(Ci-ehaloalkyl), -N(Ci-ealkyl)2, -NHCO(Ci -ealkyl), -NHCO(Ci-ehaloalkyl), -NO2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci- ehydroxyalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), or -SO2NH2; and m is 0, 1, 2, 3, or 4.
  • the compound of formula I or formula II is a compound of formula A
  • R 5 is F, Cl, -OH, oxo, -CN, -NH2, -NH(Ci-ealkyl), -NH(Ci -ehaloalkyl), -N(Ci- ealkyl)2, -NHCO(Ci -ealkyl), -NHCO(Ci-ehaloalkyl), -NO2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci- ehydroxyalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), or -SO2NH2; and m is 0, 1, 2, 3, or 4.
  • R 2 is
  • R 3 is H or -Ci-ealkyl
  • R 2 and R 3 together with the nitrogen atom and carbonyl group to which they are attached, form a 5-6 membered heterocycloalkyl
  • R 5 is halo, -OH, -CN, -NH2, -Ci-ealkyl, -Ci -ehaloalkyl, or -Ci-ealkoxy; and m is 0, 1, 2, or 3, wherein at each occurrence, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, -OH, oxo, -CN, -NH2, -NH(Ci -ealkyl), -NH(Ci -ehaloalkyl), -N(Ci- ealkyl) 2 ,
  • the compound of formula I, formula II, or formula A is a compound of formula B
  • the compound of formula I, formula II, formula A, or formula B is a compound of formula B-l wherein R 2 , R 5 , and m are as defined herein.
  • R 5 is F, Cl, -CN, -Ci-ealkyl, -Ci -ehaloalkyl, or -Ci-ealkoxy; and m is 0, 1, or 2, wherein the cycloalkyl, heterocycloalkyl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of F, Cl, -OH, - CN, -NH2, -NH(Ci -ealkyl), -N(Ci-ealkyl)2, -NO2, -Ci-ealkyl, -Ci-ehaloalkyl, -Ci-ealkoxy, - SO 2 (Ci- 6 alkyl), or -CO(Ci- 6 alkyl).
  • R 2 is
  • R 5 is halo, or -Ci-ealkyl; and m is 0, 1, or 2, wherein the heteroaryl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(Ci-ealkyl), -N(Ci-ealkyl)2, -NO2, -Ci-ealkyl, - Ci -ehaloalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), and -CO(Ci -ealkyl).
  • R 2 is
  • R 5 is F, Cl, or -Ci-ealkyl; and m is 0, 1, or 2, wherein the heteroaryl is substituted with 0, 1, or 2 substituents selected from the group consisting of halo, -OH, -CN, -NH2, -NH(Ci-ealkyl), -N(Ci-ealkyl)2, -NO2, -Ci-ealkyl, - Ci -ehaloalkyl, -Ci-ealkoxy, -SO2(Ci-ealkyl), and -CO(Ci -ealkyl).
  • R 2 is
  • R 5 is F, Cl, or -Ci-ealkyl; and m is 0, 1, or 2, wherein the heteroaryl is substituted with 0, 1, or 2 substituents selected from the group consisting of F, Cl, -CN, -Ci-ealkyl, -Ci-ehaloalkyl, and -Ci-ealkoxy.
  • R 2 is selected from any of the groups in Table 2, R 5 is F, Cl, or -Ci-ealkyl, and m is 0, 1, or 2.
  • R 2 is selected from any of the groups in Table 2, R 5 is F, Cl, and m is 1 or 2.
  • R 2 is selected from any of the groups in Table 2, R 5 is F or Cl, and m is 2.
  • R 2 is -Ci-ealkylene-NHCO-Ci-ehaloalkyl
  • R 5 is halo; and m is 1 or 2.
  • R 2 is -Ci-ealkylene-NHCO-Ci-ehaloalkyl
  • R 5 is F or Cl; and m is 1 or 2.
  • R 5 is F or Cl; and m is 1 or 2.
  • R 5 is F or Cl; and m is 2.
  • R 5 is Cl; and m is 1.
  • R 2 is -Ci-4alkylene-(5 membered heterocycloalkyl);
  • R 5 is F, Cl; and m is 1 or 2.
  • R 5 is F or Cl; and m is 1 or 2.
  • R 5 is Cl; and m is 1.
  • the present disclosure provides a compound selected from any of the compounds 1-109 described in the examples, or a pharmaceutically acceptable salt thereof.
  • a compound, or a pharmaceutically acceptable salt thereof is selected from
  • a compound, or a pharmaceutically acceptable salt thereof is selected from
  • a pharmaceutical composition for treating a coronavirus infection in a human in need thereof comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the viral infection is caused by a coronavirus.
  • the viral infection is a coronavirus infection caused by SARS- CoV-2, SARS-CoV, MERS-CoV, 229E, NL63, OC43, or HKUl.
  • the coronavirus infection is caused by SARS-CoV-2.
  • the patient is suffering from COVID-19.
  • the coronavirus infection is caused by SARS-CoV.
  • the coronavirus infection is caused by MERS-CoV.
  • the treatment method inhibits Mpro.
  • the Mpro comprises one or more mutations.
  • the one or more mutations are located in and/or located near the active site of the MPro.
  • the one or more mutations are located at positions 10-100 (e.g, 10-20, 20-30, 30-50, 50-90, 90-100) of the Mpro (e.g, positions 15, 21, 89, 90). In some embodiments, the one or more mutations are located at positions 50-220 of the Mpro (e.g., 50-100, 100-220). In some embodiments, the one or more mutations are located at positions 50-100 of the Mpro.
  • the one or more mutations are located at position 15, 21, 89, and/or 90 of the Mpro.
  • the one or more mutations are located at position 132, 144, and/or 165 of the Mpro.
  • the one or more mutations are located at position 172, 192, and/or 205 of the Mpro.
  • the one or more mutations are located at positions 50, 166, and/or 167 of the Mpro.
  • the MPro mutants comprise one or more mutations, wherein the one or more mutations comprise L50F.
  • the one or more mutations comprise El 66 A.
  • the one or more mutations comprise L167F.
  • the one or more mutations comprise L50F, E166A, and/or L167F.
  • the one or more mutations comprise L50F, E166A, and L167F.
  • the one or more mutations of the MPro comprise S144M, S144F, S144A, S144G, S144Y, M165T, E166V, E166G, E166A, H172Q, H172F, Q192T, Q192S, Q192L, Q192A, Q192I, Q192P, Q192H, Q192V, Q192W, Q192C, and/or Q192F.
  • the one or more mutations of the Mpro comprise G15S, T21I, L89F, K90R, P132H, and/or L205V.
  • the one or more mutations of the MPro comprise G15S, T21I, L89F, K90R, P132H, S144M, S144F, S144A, S144G, S144Y, M165T, E166V, E166G, E166A, H172Q, H172F, Q192T, Q192S, Q192L, Q192A, Q192I, Q192P, Q192H, Q192V, Q192W, Q192C, and/or Q192F, and/or L205V.
  • the compound disclosed herein or a pharmaceutically acceptable salt thereof is administered orally.
  • the compound disclosed herein or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day.
  • the therapeutically effective amount is from 0.5 mg to 100 mg, 1 mg to 80 mg, or from 1 mg to 60 mg.
  • the compound disclosed herein is in a solid dosage form. [0185] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt or ester thereof, for use in treating a coronavirus infection in a human. [0186] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt or ester thereof, for use in treating SARS-CoV-2 infection in a human. [0187] In some embodiments, the compound disclosed herein is used for manufacture of a medicament for treating a coronavirus infection.
  • the present disclosure encompasses the preparation and use of salts of compounds of the present disclosure.
  • the pharmaceutical "pharmaceutically acceptable salt” refers to salts or zwitterionic forms of compounds of the present disclosure. Salts of compounds of the present disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with a suitable acid.
  • the pharmaceutically acceptable salts can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Non-limiting examples of salts of compounds of the present disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2- hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, pic
  • available amino groups present in the compounds of the present disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • any reference compounds of the present disclosure appearing herein is intended to include compounds of the present disclosure as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • the present disclosure encompasses the preparation and use of solvates of compounds of the present disclosure.
  • Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents.
  • the term "solvate” as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1 : 1 or about 1 :2, respectively.
  • This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • solvate encompasses both solution-phase and isolatable solvates.
  • Compounds of the present disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of compounds of the present disclosure.
  • a pharmaceutically acceptable solvent such as water, methanol, and ethanol
  • solvate is a hydrate.
  • a "hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
  • Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
  • a typical, non-limiting, process of preparing a solvate would involve dissolving a compound of the present disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration.
  • Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a crystal of the solvate.
  • Compounds of the present disclosure inhibit protease Mpro and are thus useful in the treatment or prevention of a variety of diseases and conditions.
  • compounds of the present disclosure are useful in methods of treating or preventing a disease or condition wherein inhibition of Mpro provides a benefit.
  • diseases and conditions include viral infections.
  • the viral infection is caused by a coronavirus.
  • the coronavirus infection is caused by a coronavirus including SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-HKUl, HCoV- NL63 and HCoV-OC43.
  • the coronavirus infection is caused by a coronavirus including SARS-CoV and MERS-CoV.
  • the coronavirus infection is caused by SARS-CoV-2.
  • the patient is suffering from COVID-19.
  • the patient is suffering from upper respiratory illness, severe interstitial pneumonia, and/or acute respiratory distress syndrome, aggravated by thrombosis in the pulmonary microcirculation. In certain embodiments, the patient is suffering from multi-organ failure.
  • the patient is suffering from fever, cough, tiredness, loss of taste or smell, shortness of breath or difficulty breathing, muscle aches, chills, sore throat, runny nose, headache, chest pain, and/or pink eye.
  • the coronavirus replication is inhibited.
  • the coronavirus polymerase is inhibited.
  • the coronavirus membrane fusion is inhibited.
  • the inhibition is in vitro or in vivo.
  • the present disclosure relates to a method of treating an individual suffering from a disease or condition wherein inhibition of Mpro provides a benefit comprising administering a therapeutically effective amount of a compound of the present disclosure to an individual in need thereof.
  • Compounds of the present disclosure are inhibitors of Mpro protein. Accordingly, diseases and conditions mediated by Mpro can be treated by employing these compounds.
  • the present disclosure is thus directed generally to a method for treating a condition or disorder responsive to Mpro inhibition in a subject, e.g., a human subject, suffering from, or at risk of suffering from, the condition or disorder, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure.
  • the present disclosure is directed to a method of inhibiting Mpro in a subject in need thereof, said method comprising administering to the subject an effective amount of at least one compound of the present disclosure.
  • the Mpro is SARS-CoV-2 Mpro.
  • the methods of the present disclosure can be accomplished by administering a compound of the present disclosure as the neat compound or as a pharmaceutical composition.
  • a human subject is treated with a compound of the present disclosure, or a pharmaceutical composition comprising a compound of the present disclosure, wherein the compound is administered in an amount sufficient to inhibit Mpro in the subject.
  • a compound of the present disclosure is administered in conjunction with a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of Mpro provides a benefit.
  • the second therapeutic agent is different from the compound of the present disclosure.
  • the second therapeutic agent can be an antiviral agent or an anti-inflamatory/host immune modulator.
  • the antiviral agent may include anti-SARS-CoV-2 monoclonal antibodies such as bamlanivimab/etesevimab, casirivimab/imdevimab, and Sotrovimab; RNA-polymerase inhibitors such as molnupiravir and remdesivir; papin-like protease inhibitors; and methyl transferase inhibitors.
  • the anti-inflamatory/host immune modulator may include steroidal such as dexamethasone; JAK inhibitors such as baricitinib and tofacitinib; and IL-6R blocking monoclonal antibodies such as tocilizumab and sarilumab.
  • steroidal such as dexamethasone
  • JAK inhibitors such as baricitinib and tofacitinib
  • IL-6R blocking monoclonal antibodies such as tocilizumab and sarilumab.
  • the second therapeutic agent is administered in an amount to provide its desired therapeutic effect.
  • the effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.
  • a compound of the present disclosure and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the compound of the present disclosure is administered before the second therapeutic agent or vice versa.
  • One or more doses of the compound of the present disclosure and/or one or more dose of the second therapeutic agent can be administered.
  • the compound of the present disclosure therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents.
  • a compound of the present disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration.
  • Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.
  • the compound or a pharmaceutically acceptable salt thereof is administered orally.
  • compositions include those wherein a compound of the present disclosure is administered in an effective amount to achieve its intended purpose.
  • the exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a compound of the present disclosure that is sufficient to maintain therapeutic effects.
  • Toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in animals.
  • MTD maximum tolerated dose
  • the dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index.
  • the dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective amount of a compound of the present disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and is ultimately determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the compound of the present disclosure that are sufficient to maintain the desired therapeutic effects.
  • the desired dose can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses sometimes are desired, or required.
  • a compound of the present disclosure can be administered at a frequency of four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose delivered per day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two-day rest, and another five daily doses (5/2/5); or, any dose regimen determined to be appropriate for the circumstance.
  • the compound or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day.
  • a compound of the present disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose.
  • a compound of the present disclosure can be administered, per dose, in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams, including all doses between 0.005 and 500 milligrams.
  • the therapeutically effective amount is from 0.5 mg to 100 mg, 1 mg to 80 mg, or from 1 mg to 60 mg.
  • the dosage of a composition containing a compound of the present disclosure, or a composition containing the same can be from about 1 pg/kg to about 200 mg/kg, about 1 pg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg.
  • the dosage of a composition can be at any dosage including, but not limited to, about 1 pg/kg.
  • the dosage of a composition may be at any dosage including, but not limited to, about 1 pg/kg, about
  • compounds of the present disclosure typically are administered in admixture with a pharmaceutical carrier to give a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice.
  • compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of compound of the present disclosure.
  • compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.
  • a therapeutically effective amount of the compound of the present disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
  • the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound of the present disclosure.
  • a liquid carrier such as water, petroleum, or oils of animal or plant origin
  • the liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols.
  • the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a compound of the present disclosure.
  • a therapeutically effective amount of a compound of the present disclosure is administered by intravenous, cutaneous, or subcutaneous injection
  • the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • the preparation of such parenterally acceptable solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
  • compositions for oral use can be obtained by adding the compound of the present disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
  • Compound of the present disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form.
  • suspensions of a compound of the present disclosure can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Compounds of the present disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases.
  • the compound of the present disclosure also can be formulated as a depot preparation.
  • Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compound of the present disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.
  • the compounds of the present disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents.
  • Compound of the present disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
  • the compound of the present disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • kits which comprise a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure.
  • the kit includes a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the present disclosure.
  • the kit further can include a device suitable for administering the composition according to the intended route of administration.
  • the compounds of the present disclosure can be prepared according to Scheme 1 and Scheme 2 below.
  • variables such as R 1 , R 2 , R 3 , and R 4 are the same as defined herein.
  • the expression “P” refers to H or an amino protecting group such as Boc or Cbz.
  • Step 1 can be performed in the presence of a suitable base, a coupling reagent, and a solvent.
  • the inorganic base may include bicarbonates, carbonates, phosphates, and acetates.
  • the organic base may include but is not limited to amines, e.g., tertiary amines such as DIEA.
  • the coupling reagent can be a suitable peptide coupling reagent including, without limitation, T3P, HO At, HOBt, HUT A, DCC, EDC, DIC, BOP, PyBOP, HATU, HBTU, TOTU, COMU, and TBTU.
  • the suitable solvent includes but is not limited to DCM, DMF, THF, DMSO, acetonitrile, ethers, ethyl acetate, 1,4-dioxane, and the like.
  • Step 2a and Step 2b in Steps 2a and 2b, the nitro group can be reduced to an amino group by catalytic hydrogenation using reagents such as Raney nickel or palladium-on- carbon, platinum(IV) oxide, or Urushibara nickel.
  • the nitro group can also be reduced to an amino group using iron in acidic media; sodium hydrosulfite; sodium sulfide (or hydrogen sulfide and base); tin(II) chloride; titanium(III) chloride; samarium; or hydroiodic acid.
  • the reduction is performed by using iron and NH4CI in ethanol and water, and the reaction is heated at a temperature at about 20 °C - 120 °C.
  • the reaction is heated at a temperature at about 50 °C - 120 °C. In some embodiments, the reaction is heated at a temperature at about 80 °C - 120 °C. In some embodiments, the reaction is heated at a temperature at about 50 °C - 100 °C. In some embodiments, the reaction is heated at a temperature at about 80 °C. In some embodiments, the reaction is heated at a temperature at about 100 °C.
  • Step 4a and Step 4b Steps 4a and 4b can be performed in the presence of a suitable base, a coupling reagent, and a solvent.
  • the inorganic base may include bicarbonates, carbonates, phosphates, and acetates.
  • the organic base may include but is not limited to amines, e.g., tertiary amines such as DIEA.
  • the coupling reagent can be a suitable peptide coupling reagent including, without limitation, T3P, HO At, HOBt, HUT A, DCC, EDC, DIC, BOP, PyBOP, HATU, HBTU, TOTU, COMU, and TBTU.
  • the suitable solvent includes but is not limited to DCM, DMF, THF, DMSO, acetonitrile, ethers, ethyl acetate, 1,4-dioxane, and the like.
  • Step 5 can be performed by deprotecting the amino group followed by a coupling reaction.
  • the deprotection reaction can be performed in the presence of a suitable acid and a solvent.
  • the acid may be an inorganic acid or an organic acid.
  • Non-limiting examples of the inorganic base may include hydrochloric acid, phosphoric acid, and sulfuric acid.
  • the organic acid may include but is not limited to TFA and p- toluenesulfonic acid.
  • the suitable solvent includes but is not limited to protic and aprotic solvents such as water, methanol, ethanol, DMF, DCM, EA, THF, DMSO, ether, ketone, 1,4- dioxane, and the like.
  • the suitable solvent may also be a combination of two or three solvents.
  • the deprotection can be performed by catalytic hydrogenation using reagent such as palladium-on-carbon.
  • the coupling reaction in Step 5 can be performed in the presence of a suitable base, a coupling reagent, and a solvent.
  • a suitable base may include bicarbonates, carbonates, phosphates, and acetates.
  • the organic base may include but is not limited to amines, e.g., tertiary amines such as DIEA.
  • the coupling reagent can be a suitable peptide coupling reagent including, without limitation, T3P, HO At, HOBt, HUT A, DCC, EDC, DIC, BOP, PyBOP, HATU, HBTU, TOTU, COMU, and TBTU.
  • the suitable solvent includes but is not limited to DCM, DMF, THF, DMSO, acetonitrile, ethers, ethyl acetate, 1,4-dioxane, and the like.
  • Step 1 (E)-N-methyl-N-(2-nitrovinyl)aniline
  • Step 3 (Z)-tert-butyl (2-nitrovinyl)carbamate r, Boc
  • Step 4 tert-butyl (2-nitroethyl)carbamate
  • Step 6 (3S,4S)-3-nitro-4-phenylpiperidine [0255] To a mixture of (3S,4S)-tert-butyl 3-nitro-4-phenyl-3,4-dihydropyridine-l(2H)- carboxylate (8.00 g, 26.29 mmol) in DCM (100 mL) was added EtsSiH (6.11 g, 52.57 mmol) and TFA (17.98 g, 157.72 mmol) at 0°C. And the mixture was stirred at 25°C for 5 hr. The mixture was concentrated to give a residue. The mixture was diluted with EEO (100 mL), extracted with PE (80 mL x3).
  • Step 7 imidazo[l,5-a]pyridin-8-yl((3S,4S)-3-nitro-4-phenylpiperidin-l-yl)methanone
  • Step 9 N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)acetamide
  • the crude product was purified by prep-HPLC (column: Xtimate Cl 8 100x30mmx l0
  • the product was further purified by prep-HPLC (column: Pheno menex Gemini-NX Cl 8 75x30mmx3pm; mobile phase: [water (lOrnM NH4HCO3)-ACN]; B%: 28%-58%, lOmin).
  • Compound 3 (2.5 mg, 4.2%) was obtained as a light yellow solid.
  • Step 1 (E)-N-methyl-N-(2-nitrovinyl)aniline
  • Step 4 tert-butyl (2-nitroethyl)carbamate
  • Step 5 (3S,4S)-tert-butyl 4-(3-chlorophenyl)-3-nitro-3,4-dihydropyridine-l(2H)- carboxylate
  • Step 7 ((3S,4S)-4-(3-chlorophenyl)-3-nitropiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 8 ((3S,4S)-3-amino-4-(3-chlorophenyl)piperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 9 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -yl)- 1 H-imidazole-2-carboxamide
  • ((3S,4S)-3-amino-4-(3-chlorophenyl)piperidin-l-yl)(imidazo[l,5- a]pyridin-8-yl)methanone 55 mg, 0.16 mmol
  • lH-imidazole-2-carboxylic acid 17.
  • PYBOP 121 mg, 0.23 mmol
  • DIEA 60 mg, 0.47 mmol
  • Example 7 Preparation of N-((3S,4S)-4-(4-chlorophenyl)-l-(imidazo[l,5-a]pyridine- 8-carbonyl)piperidin-3-yl)-lH-imidazole-5-carboxamide (Compound 7)
  • Step 1 (3S,4S)-tert-butyl 4-(4-chlorophenyl)-3-nitro-3,4-dihydropyridine-l(2H)- carboxylate
  • Step 3 ((3S,4S)-4-(4-chlorophenyl)-3-nitropiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 4 ((3S,4S)-3-amino-4-(4-chlorophenyl)piperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Example 10 2-ethyl-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)-lH-imidazole-5-carboxamide (Compound 10)
  • Step 1 (3S,4S)-tert-butyl 3-nitro-4-phenyl-3,4-dihydropyridine-l(2H)-carboxylate
  • Step 3 (3S,4S)-tert-butyl 3 -nitro-4-phenylpiperidine-l -carboxylate
  • Step 6 ((3S,4S)-3-amino-4-phenylpiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 7 2-ethyl-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin- 3 -yl)- 1 H-imidazole-5 -carboxamide
  • the crude product was purified by prep-HPLC (Phenomenex C18 75x30mmx3pm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 8%-38%, 1 Imin).
  • the product was purified by chiral SFC separation (DAICEL CHIRALPAK AS (250mmx30mm, 10pm); mobile phase: [0.1%NH 3 H2O ETOH]; B%: 35%-35%, min).
  • eak 1 compound 12 (2.8 mg, 4.6%) was obtained as a light yellow solid.
  • Peak 2 was further purified by prep-HPLC (Xtimate C18 100x30mmx l0pm; mobile phase: [water (FA)-ACN]; B%: 5%-35%, lOmin) to give compound 12 (48.4 mg, 80.6%) as a light yellow solid.
  • Example 13 (S)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin- 3 -y 1) - 3 , 3 -dimethyl-2-(methylsulfonamido)butanamide (Compound 13)
  • Stepl tert-butyl ((S)-l-(((3R,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3 -yl)amino)-3 , 3 -dimethyl- 1 -oxobutan-2-yl)carbamate
  • Step 2 (S)-2-amino-N-((3R,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3 -y 1) - 3 , 3 -dimethylbutanamide
  • Step 3 (S)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)-3,3-dimethyl-2-(methylsulfonamido)butanamide
  • (S)-2-amino-N- ((3R,4R)- 1 -(imidazo[ 1 , 5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3 -yl)-3 ,3 - dimethylbutanamide 60 mg, 0.14 mmol
  • MsCl 150 mg, 1.31 mmol
  • TEA 56 mg, 0.55 mmol
  • Example 14 2-acetamido-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)acetamide (Compound 14)
  • Example 16 l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)imidazolidin-2-one (Compound 16)
  • Step 1 (3S,4S)-tert-butyl 3-nitro-4-phenyl-3,4-dihydropyridine-l(2H)-carboxylate
  • Step 3 (3S,4S)-benzyl 3 -nitro-4-phenylpiperidine-l -carboxylate
  • Step 4 (3S,4S)-benzyl 3 -amino-4-phenylpiperidine-l -carboxylate [0340] To a solution of (3S,4S)-benzyl 3 -nitro-4-phenylpiperidine-l -carboxylate (1.00 g, 2.94 mmol) in EtOH (7 mL) and H2O (7 mL) was added Fe (492 mg, 8.81 mmol) and NH4CI (471 mg, 8.81 mmol). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hr. The reaction mixture was filtered via a celite pad.
  • Step 5 (3S,4S)-benzyl 3 -(3 -(2-chloroethyl)ureido)-4-phenylpiperidine-l -carboxylate
  • Step 6 (3S,4S)-benzyl 3 -(2-oxoimidazolidin-l-yl)-4-phenylpiperidine-l -carboxylate
  • Step 7 l-((3S,4S)-4-phenylpiperidin-3-yl)imidazolidin-2-one
  • Step 8 l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)imidazolidin-2-one
  • Example 17 (S)-N-((3R,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamide (Compound 17)
  • Example 18 (S)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- isopropylpiperidin-3-yl)-3,3-dimethyl-2-(methylsulfonamido)butanamide (Compound 18)
  • Step 1 (3S,4R)-tert-butyl 4-isopropyl-3-nitro-3,4-dihydropyridine-l(2H)-carboxylate Boc
  • the pH of the aqueous phase was adjusted to 8 with saturated aqueous NaHCCF.
  • the mixture was extracted with DCM (300 mL x3).
  • the mixture was dried over Na2SO4 and concentrated to give crude product.
  • the title compound (5.80 g, crude) was obtained as a black brown oil which was used directly to the next step without further purification.
  • Step 3 imidazo[l,5-a]pyridin-8-yl((3S,4S)-4-isopropyl-3-nitropiperidin-l- yl)methanone
  • Step 4 ((3S,4S)-3-amino-4-isopropylpiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanoned
  • Step 6 (S)-2-amino-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- isopropylpiperidin-3 -y 1) - 3 , 3 -dimethylbutanamide
  • Step 7 (S)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-isopropylpiperidin-3- yl)-3,3-dimethyl-2-(methylsulfonamido)butanamide
  • Step 1 (3S,4R)-tert-butyl 4-isopropyl-3-nitro-3,4-dihydropyridine-l(2H)-carboxylate
  • Step 3 imidazo[l,5-a]pyridin-8-yl((3S,4S)-4-isopropyl-3-nitropiperidin-l- yl)methanone
  • Step 4 ((3S,4S)-3-amino-4-isopropylpiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 5 tert-butyl ((S)-l-(((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- isopropylpiperidin-3 -yl)amino)-3 , 3 -dimethyl- 1 -oxobutan-2-yl)carbamate
  • Step 6 (S)-2-amino-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- isopropylpiperidin-3 -y 1) - 3 , 3 -dimethylbutanamide
  • Step 7 (S)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-isopropylpiperidin-3- yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamide
  • Example 20 3-amino-l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4 phenylpiperidin-3-yl)pyrrolidin-2-one (Compound 20)
  • Step 1 (3S,4S)-tert-butyl 3 -amino-4-phenylpiperidine-l -carboxylate
  • Step 2 (3S,4S)-tert-butyl 3-(2-(((benzyloxy)carbonyl)amino)-4- (methylthio)butanamido)-4-phenylpiperidine- 1 -carboxylate
  • Step 3 tert-butyl (3S,4S)-3-[[4-BLAH-2-(benzyloxycarbonylamino)butanoyl]amino]- 4-phenyl-piperidine- 1 -carboxylate
  • Step 4 (3S,4S)-tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)-2-oxopyrrolidin-l-yl)- 4-phenylpiperidine- 1 -carboxylate
  • Step 6 benzyl (2-oxo-l-((3S,4S)-4-phenylpiperidin-3-yl)pyrrolidin-3-yl)carbamate
  • Step 7 benzyl (l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-
  • Step 8 3-amino-l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4 phenylpiperidin- 3 -yl)pyrrolidin-2-one
  • Example 21 3-amino-l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)pyrrolidin-2-one (Compound 21)
  • Step 1 benzyl (2-oxo-l-((3S,4S)-4-phenylpiperidin-3-yl)pyrrolidin-3-yl)carbamate
  • Step 2 benzyl (l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin- 3 -yl)-2-oxopyrrolidin-3 -yl)carbamate
  • Step 3 3-amino-l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin- 3 -yl)pyrrolidin-2-one
  • Example 22 l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)tetrahydropyrimidin-2(lH)-one (Compound 22)
  • Step 1 (3S,4S)-benzyl 3-(3-(3-chloropropyl)ureido)-4-phenylpiperidine-l- carboxylate
  • Step 2 (3S,4S)-benzyl 3-(2-oxotetrahydropyrimidin-l(2H)-yl)-4-phenylpiperidine-l- carboxylate
  • Step 3 l-((3S,4S)-4-phenylpiperidin-3-yl)tetrahydropyrimidin-2(lH)-one
  • Step 4 l-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)tetrahydropyrimidin-2( 1 H)-one
  • Step 1 methyl 6- vinyl- lH-indole-2-carboxylate
  • Step 2 methyl 6-formyl-lH-indole-2-carboxylate
  • Step 3 methyl 6-(hydroxymethyl)-lH-indole-2-carboxylate
  • MeOH MeOH
  • NaBT sodium tetrabutyl-lH-indole-2-carboxylate
  • the reaction was stirred at 25 °C for 2 hr.
  • the reaction was quenched with H2O (20 mL).
  • the resulting mixture was extracted with DCM (25 mL x3).
  • the combined organic phase was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude product.
  • Step 5 6-(hydroxymethyl)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3 -y 1) - 1 H-indole-2-carboxamide
  • Example 25 7-fluoro-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)-lH-indole-2-carboxamide (Compound 25)
  • Step 1 ethyl 7-fluoro-lH-indole-2-carboxylate
  • Step 3 7-fhioro-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3 -y 1) - 1 H-indole-2-carboxamide
  • Example 26 4-fluoro-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)-lH-indole-2-carboxamide (Compound 26)
  • Example 28 N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin- 3 -yl)-l -phenylcyclopropanecarboxamide (Compound 28)
  • Example 30 N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)-4-sulfamoyl-lH-indole-2-carboxamide (Compound 30)
  • Step 1 methyl 4-bromo-l -tosyl- lH-indole-2-carboxylate
  • Step 2 methyl 4-((diphenylmethylene)amino)-l -tosyl- lH-indole-2-carboxylate
  • Step 4 methyl 4-sulfamoyl-l -tosyl- lH-indole-2-carboxylate
  • Step 5 methyl 4-sulfamoyl-lH-indole-2-carboxylate, 4-sulfamoyl-lH-indole-2- carboxylic acid
  • the residue was purified by prep-HPLC (column: YMC Triart 30x150 mmx7 pm; mobile phase: [water (HCl)-ACN]; B%: 0%-50%, 40min).
  • the residue was purified by prep- HPLC (column: YMC Triart 30x150 mmx7 pm; mobile phase: [water (HCl)-ACN]; B%:0%- 80%, 40min).
  • Compound 30 (1.9 mg, 2.1%) was obtained as a white solid.
  • Step 1 4-(3,6-dihydro-2H-pyran-4-yl)morpholine
  • Step 2 (Z)-ethyl 3-bromo-2-(hydroxyimino)propanoate
  • Step 3 ethyl l,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2-carboxylate
  • Step 4 l,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2-carboxylic acid
  • Step 5 N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3-yl)- 1 ,4, 6, 7 -tetrahydropyrano [4,3 -b]pyrrole-2-carboxamide
  • Example 35 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-lH-benzo[d]imidazole-2-carboxamide (Compound 35)
  • Step 1 ((3S,4S)-4-(3-chlorophenyl)-3-nitropiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 2 ((3S,4S)-3-amino-4-(3-chlorophenyl)piperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 3 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-lH-benzo[d]imidazole-2-carboxamide
  • the crude product was purified by prep-HPLC (column: Phenomenex C18 75 x30 mm x3 gm; mobile phase: [water (NH3H2O+NH4HCO3)- ACN]; B%: 30%-50%, 10 min). Then the crude product was purified by chiral SFC (column: DAICEL CHIRALPAK AS (250 mm x30 mm, 10 pm); mobile phase: [0.1%NH 3 H 2 O EtOH]; B%: 35%-35%, min) to give Compound 35 (4.0 mg, 18.5%) as a light yellow solid.
  • Example 36 N-((3S, 4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-lH-benzo[d]imidazole-2-carboxamide (Compound 36)
  • the crude product was purified by prep-HPLC (column: Phenomenex C18 75 x30 mm x3 pm; mobile phase: [water (NH3H2O+NH4HCO3)- ACN]; B%: 30%-50%, 10 min). Then the crude product was purified by chiral SFC (column: DAICEL CHIRALPAK AS (250 mm x30 mm, 10 pm); mobile phase: [0.1%NH 3 H 2 O EtOH]; B%: 35%-35%, min) to give Compound 36 (6.0 mg, 28.6%) as a light yellow solid.
  • Example 37 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-5-ethyl-lH-imidazole-2-carboxamide (Compound 37)
  • Example 38 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)thiazole-2-carboxamide_(Compound 38)
  • Example 40 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)benzo[d]thiazole-2-carboxamide (Compound 40)
  • the crude product was purified by prep-HPLC (column: Phenomenex C18 75x30mmx3pm; mobile phase: [water (NH3H2O+NH4HCO3)- ACN]; B%: 33%-63%, 1 Imin). Then the product was separated by chiral SFC (column: DAICEL CHIRALPAK AS (250mmx30mm, 10pm); mobile phase: [0.1%NH3H 2 O ETOH]; B%: 40%-40%, min). Compound 40 (13.2 mg, 30.1%) was obtained as white solid.
  • the crude product was purified by prep-HPLC (column: Phenomenex C18 75x30mmx3pm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 33%-63%, 1 Imin). Then the product was separated by chiral SFC (column: DAICEL CHIRALPAK AS (250mmx30mm, 10pm); mobile phase: [0.1%NH3H2O ETOH]; B%: 40%-40%, min). Compound 40 (2.1 mg, 4.2%) was obtained as white solid.
  • Example 41 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -yl)-4-methyl- 1 H-imidazole-2-carboxamide (Compound 41)
  • the crude product was purified by prep-HPLC (column: Phenomenex C18 75 x30 mm x3 gm; mobile phase: [water (NH3H2O+NH4HCO3)- ACN]; B%: 20%-50%, 14 min). Then the product was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm x30 mm, 10 pm); mobile phase: [0.1%NH3H 2 O IP A]; B%: 55%-55%, min). Compound 41 (1.8 mg, 4.4%) was obtained as a white solid.
  • the crude product was purified by prep-HPLC (column: Phenomenex Cl 8 75 x30 mm x3 pm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 20%-50%, 14 min). Then the product was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm x30 mm, 10 pm); mobile phase: [0.1%NH3H2O IP A]; B%: 55%-55%, min). Compound 41 (8.5 mg, 21.6%) was obtained as a white solid.
  • Example 42 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-4-(hydroxymethyl)-lH-imidazole-2-carboxamide (Compound 42)
  • Step 1 methyl l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-5-carboxylate
  • Step 2 methyl 2-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-5- carboxylate
  • NBS 3.82 g, 21.45 mmol
  • AIBN 160 mg, 0.98 mmol
  • Step 4 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazole
  • Step 5 2 -bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-l-((2-
  • Step 6 5-(((tert-butyldimethylsilyl)oxy)methyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazole-2-carboxylic acid
  • Step 7 4-(((tert-butyldimethylsilyl)oxy)methyl)-N-((3S,4S)-4-(3-chlorophenyl)-l- (imidazo[ 1 , 5-a]pyridine-8-carbonyl)piperidin-3 -yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H- imidazole-2-carboxamide
  • Step 8 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-4-(hydroxymethyl)-lH-imidazole-2-carboxamide
  • Step 8 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-4-(hydroxymethyl)-lH-imidazole-2-carboxamide
  • Example 43 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-4,5-dimethyl-lH-imidazole-2-carboxamide (Compound 43) [0508] Step 1 : 2-bromo-4, 5 -dimethyl- IH-imidazole
  • Step 2 2-bromo-4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole
  • Step 3 methyl 4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-2- carboxylate
  • Step 4 4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-2-carboxylic acid
  • Step 5 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-2- carboxamide
  • Step 6 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-4,5-dimethyl-lH-imidazole-2-carboxamide
  • Step 1 tert-butyl ((R)-l-(((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)amino)-l-oxopropan-2-yl)carbamate
  • Step 2 (R)-2-amino-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)propanamide
  • Step 3 (R)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)-2-(methylsulfonamido)propanamide
  • Example 46 2-(ethylsulfonamido)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8- carbonyl)-4-phenylpiperidin-3-yl)acetamide (Compound 46)
  • Step 1 tert-butyl (2-(((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)amino)-2-oxoethyl)carbamate
  • Step 2 2-amino-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3 -yl)acetamide
  • Step 3 2-(ethylsulfonamido)-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3 -yl)acetamide
  • Example 47 N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-phenylpiperidin-3- yl)-2-(lH-pyrazol-5-yl)acetamide (Compound 47) [0537] To a mixture of ((3S,4S)-3-amino-4-phenylpiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone (30 mg, 0.09 mmol) and 2-(lH-pyrazol-5-yl)acetic acid (12 mg, 0.09 mmol) in DMF (1 mL) was added DIEA (60 mg, 0.47 mmol) and PYBOP (73 mg, 0.14 mmol).
  • Example 48 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-N-methyl-lH-indole-2-carboxamide (Compound 48)
  • Step 1 (3S,4S)-benzyl 4-(3-chlorophenyl)-3 -nitropiperidine- 1 -carboxylate
  • Step 2 (3S,4S)-benzyl 3 -amino-4-(3-chlorophenyl)piperidine-l -carboxylate
  • 3S,4S benzyl 4-(3-chlorophenyl)-3 -nitropiperidine- 1 -carboxylate
  • EtOH 10 mL
  • H2O 10 mL
  • Fe 626 mg, 11.21 mmol
  • NH4CI 599 mg, 11.21 mmol
  • Step 4 (3S,4S)-benzyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(3- chlorophenyl)piperidine- 1 -carboxylate
  • Step 5 (3S,4S)-benzyl 4-(3-chlorophenyl)-3-(methylamino)piperidine-l -carboxylate
  • Step 6 (3S,4S)-benzyl 4-(3-chlorophenyl)-3-(N-methyl-lH-indole-2- carboxamido)piperidine- 1 -carboxylate
  • Step 8 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-N-methyl-lH-indole-2-carboxamide
  • Step 1 (3S,4S)-benzyl 4-(3-chlorophenyl)-3-(N-methyl-lH-imidazole-2- carboxamido)piperidine- 1 -carboxylate
  • Step 2 N-((3S,4S)-4-(3-chlorophenyl)piperidin-3-yl)-N-methyl-lH-imidazole-2- carboxamide
  • Example 50 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-4H-l, 2, 4-triazole-3 -carboxamide (Compound 50)
  • Step 1 ethyl (E)-5,5-dimethylhex-2-enoate
  • DIBALH (1 M, 56 mL) was added dropwise to a solution of (E)-ethyl 5,5- dimethylhex-2-enoate (3.20 g, 18.78 mmol) in DCM (10 mL) at -60°C.
  • the reaction mixture was stirred at -60°C for 30 min and then was stirred at 25°C for 2 hrs.
  • the reaction mixture was poured into saturated aqueous sodium potassium tetrahydrate (100 mL), extracted with DCM (200 mL). The combined organic layer was washed with brine (100 mL x3), dried over Na2SO4, filtered and concentrated to dryness.
  • Step 4 (3S, 4R)-tert-butyl 4-neopentyl-3-nitro-3,4-dihydropyridine-l(2H)-carboxylate
  • Step 5 (3 S,4R)-4-neopentyl-3 -nitropiperidine
  • Step 6 imidazo[l,5-a]pyridin-8-yl((3S,4R)-4-neopentyl-3-nitropiperidin-l- yl)methanone [0578] To a mixture of (3S, 4R)-4-neopentyl-3-nitropiperidine (3.00 g, 14.98 mmol) in DMF (30 mL) was added PYBOP (11.69 g, 22.47 mmol), DIEA (7.74 g, 59.92 mmol) and imidazo[l,5-a]pyridine-8-carboxylic acid (1.58 g, 9.74 mmol) at 25°C. The mixture was stirred at 25°C for 2 hrs.
  • Step 7 ((3S,4R)-3-amino-4-neopentylpiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 8 tert-butyl ((3S,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- neopentylpiperidin-3-yl)carbamate
  • Step 9 ((3S, 4R)-3-amino-4-neopentylpiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 10 N-((3S,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-neopentylpiperidin-3- yl)-lH-imidazole-2-carboxamide
  • Step 6 imidazo[l,5-a]pyridin-8-yl((3S,4R)-4-isobutyl-3-nitropiperidin-l- yl)methanone
  • Step 7 ((3S,4R)-3-amino-4-isobutylpiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 8 tert-butyl ((S)-l-(((3S,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- isobutylpiperidin-3 -yl)amino)-3 ,3 -dimethyl- 1 -oxobutan-2-yl)carbamate
  • Step 9 (S)-2-amino-N-((3S,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- isobutylpiperidin-3 -y 1) - 3 , 3 -dimethylbutanamide
  • Step 10 (S)-N-((3S,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-isobutylpiperidin-3- yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamide
  • Step 1 tert-butyl ((S)-l-(((3S,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- neopentylpiperidin-3 -yl)amino)-3 , 3 -dimethyl- 1 -oxobutan-2-yl)carbamate
  • Step 2 (S)-2-amino-N-((3S,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- neopentylpiperidin-3 -y 1) - 3 , 3 -dimethylbutanamide
  • Step 3 (S)-N-((3S,4R)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4-neopentylpiperidin- 3-yl)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamide
  • Example 54 (S)-N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-3,3-dimethyl-2-(methylsulfonamido)butanamide (Compound 54)
  • Step 1 tert-butyl ((S)-l-(((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -yl)amino)-3 , 3 -dimethyl- 1 -oxobutan-2-yl)carbamate
  • Step 2 (S)-2-amino-N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -y 1) - 3 , 3 -dimethylbutanamide
  • Step 3 (S)-N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -yl)-3 ,3 -dimethyl-2-(methylsulfonamido)butanamide
  • Step 1 (3S,4S)-tert-butyl 4-(3-fluorophenyl)-3-nitro-3,4-dihydropyridine-l(2H)- carboxylate
  • Step 3 ((3S,4S)-4-(3-fhiorophenyl)-3-nitropiperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone
  • Step 4 ((3S,4S)-3-amino-4-(3-fhiorophenyl)piperidin-l-yl)(imidazo[l,5-a]pyridin-8- yl)methanone [0630] To a mixture of ((3S,4S)-4-(3-fluorophenyl)-3-nitropiperidin-l-yl)(imidazo[l,5- a]pyridin-8-yl)methanone (410 mg, 1.11 mmol) in EtOH (3 mL) and H2O (3 mL) was added Fe (249 mg, 4.45 mmol) and NH4CI (238 mg, 4.45 mmol) at 25°C.
  • Step 5 N-((3S,4S)-4-(3-fluorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -yl)- 1 H-indole-2-carboxamide
  • Example 56 7-chloro-5-cyano-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3-yl)-lH-indole-2-carboxamide (Compound 56)
  • Step 1 5-bromo-7-chloro-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3 -yl)- 1 H-indole-2-carboxamide
  • Step 2 7-chloro-5-cyano-N-((3S,4S)-l-(imidazo[l,5-a]pyridine-8-carbonyl)-4- phenylpiperidin-3 -yl)- 1 H-indole-2-carboxamide
  • Example 57 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -yl)-7-fluoro- 1 H-indole-2-carboxamide (Compound 57)
  • Example 58 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-7-fluoro-lH-benzo[d]imidazole-2-carboxamide (Compound 58)
  • Step 1 7-fluoro-2-(trichloromethyl)-lH-benzo[d]imidazole
  • Step 3 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-7-fluoro-lH-benzo[d]imidazole-2-carboxamide
  • Example 59 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -y 1) -4 , 7-difhioro- 1 H-benzo [d]imidazole-2-carboxamide (Compound 59)
  • Step 1 4,7-difluoro-2-(trichloromethyl)-lH-benzo[d]imidazole
  • Step 3 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -y 1) -4 , 7-difluoro- 1 H-benzo [d]imidazole-2-carboxamide
  • ((3S,4S)-3-amino-4-(3-chlorophenyl)piperidin-l-yl)(imidazo[l,5- a]pyridin-8-yl)methanone (30 mg, 0.08 mmol) and 4, 7-difluoro- 1 H-benzo [d]imidazole-2- carboxylic acid (17 mg, 0.08 mmol) in DMF (1 mL) was added PYBOP (66 mg, 0.12 mmol) and DIEA (33 mg, 0.25 mmol).
  • Example 60 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -yl)-4-fluoro-7-methoxy- 1 H-benzo [d] imidazole-2-carboxamide
  • Step 1 4-bromo-7-fluoro-2-(trichloromethyl)-l H-benzo [d] imidazole
  • Step 2 4-bromo-7-fluoro-lH-benzo[d]imidazole-2-carboxylic acid
  • Step 3 methyl 4-bromo-7-fluoro-lH-benzo[d]imidazole-2-carboxylate
  • Step 5 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3 -yl)-4-fluoro-7-methoxy- 1 H-benzo [d] imidazole-2-carboxamide
  • ((3S,4S)-3-amino-4-(3-chlorophenyl)piperidin-l-yl)(imidazo[l,5- a]pyridin-8-yl)methanone 50 mg, 0.14 mmol
  • 4-fluoro-7-methoxy-lH-benzimidazole-2- carboxylic acid 30 mg, 0.14 mmol
  • PYBOP 110 mg, 0.21 mmol
  • DIEA 55 mg, 0.42 mmol
  • Example 61 N-((3S,4S)-4-(3-chlorophenyl)-l-(imidazo[l,5-a]pyridine-8- carbonyl)piperidin-3-yl)-7-methoxy-lH-benzo[d]imidazole-2-carboxamide (Compound 61)
  • Step 1 7-methoxy-lH-benzo[d]imidazole-2-carboxylic acid

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Les composés de formule (I) sont utiles pour traiter une infection à coronavirus par inhibition de la protéase Mpro.
PCT/US2023/079713 2022-11-15 2023-11-14 Nouveaux inhibiteurs de protéase pour le traitement d'infections à coronavirus WO2024107778A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263425609P 2022-11-15 2022-11-15
US63/425,609 2022-11-15

Publications (1)

Publication Number Publication Date
WO2024107778A1 true WO2024107778A1 (fr) 2024-05-23

Family

ID=89224336

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/079713 WO2024107778A1 (fr) 2022-11-15 2023-11-14 Nouveaux inhibiteurs de protéase pour le traitement d'infections à coronavirus

Country Status (1)

Country Link
WO (1) WO2024107778A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2595975A (en) * 2020-06-09 2021-12-15 Pardes Biosciences Inc Inhibitors of cysteine proteases and methods of use thereof
WO2022020242A1 (fr) * 2020-07-20 2022-01-27 Enanta Pharmaceuticals, Inc. Peptides fonctionnalisés en tant qu'agents antiviraux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2595975A (en) * 2020-06-09 2021-12-15 Pardes Biosciences Inc Inhibitors of cysteine proteases and methods of use thereof
WO2022020242A1 (fr) * 2020-07-20 2022-01-27 Enanta Pharmaceuticals, Inc. Peptides fonctionnalisés en tant qu'agents antiviraux

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING CO.
A.L. BINGHAM ET AL., CHEM. COMMUN., 2001, pages 603 - 604
BANERJEE, R. ET AL.: "Potential SARS-CoV-2 main protease inhibitors", DRUG DISCOVERY TODAY, vol. 26, no. 3, 2021, pages 804 - 816
E.C. VAN TENDER ET AL., AAPSPHARM. SCI. TECH., vol. 5, no. 12, 2004
LU, R. ET AL.: "Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding", THE LANCET, vol. 395, no. 10224, 2020, pages 565 - 574, XP055740615, DOI: 10.1016/S0140-6736(20)30251-8
M. CAIRA ET AL., J. PHARMACEUT. SCI., vol. 93, no. 3, pages 601 - 611
OWEN, D. R. ET AL.: "An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19", SCIENCE, vol. 374, no. 6575, 2021, pages 1586 - 1593
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
SHAMSI, A. ET AL.: "Potential drug targets of SARS-CoV-2: From genomics to therapeutics", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, vol. 177, 2021, pages 1 - 9, XP086537146, DOI: 10.1016/j.ijbiomac.2021.02.071
ULLRICH, S.NITSCHE, C.: "The SARS-CoV-2 main protease as drug target", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 30, no. 17, 2020, pages 127377, XP086232485, DOI: 10.1016/j.bmcl.2020.127377
ZUMLA, A. ET AL.: "Coronaviruses-drug discovery and therapeutic options", NATURE REVIEWS DRUG DISCOVERY, vol. 15, no. 5, 2016, pages 327 - 347, XP037065530, DOI: 10.1038/nrd.2015.37

Similar Documents

Publication Publication Date Title
JP5558557B2 (ja) Ｃ型肝炎ウイルス阻害剤
JP5615352B2 (ja) Ｃ型肝炎ウイルス阻害剤
TWI501957B (zh) Ｃ型肝炎病毒抑制劑
JP5612661B2 (ja) Ｃ型肝炎ウイルス阻害剤
US9309231B2 (en) Bridged ring compounds as hepatitis C virus (HCV) inhibitors and pharmaceutical applications thereof
JP5612612B2 (ja) Ｃ型肝炎ウイルス阻害剤
TWI475019B (zh) Ｃ型肝炎病毒抑制劑
US9303061B2 (en) Spiro compounds as Hepatitis C virus inhibitors
JP2023535701A (ja) 抗ウイルス剤としての官能化ペプチド
KR20210073519A (ko) 급속 진행형 섬유육종 폴리펩티드의 표적화 분해를 위한 다중 고리 화합물 및 방법
CN111386118A (zh) 作为rsv抑制剂的组合药物剂
EP2274296B1 (fr) Hydroxyméthylpyrrolidines en tant qu agonistes de récepteur bêta-3-adrénergique
EP2146984A1 (fr) Inhibiteurs du virus de l'hépatite c
KR20140045903A (ko) C형 간염 바이러스 억제제
US9416139B2 (en) Spiro ring compound as hepatitis C virus (HCV) inhibitor and uses thereof
CA2901770A1 (fr) Cyanoethylpyrazolo pyridones acycliques en tant qu'inhibiteurs de janus kinase
WO2015022263A1 (fr) Nouveaux aza-oxo-indoles pour le traitement et la prophylaxie de l'infection par le virus respiratoire syncytial
US11660293B2 (en) Substituted 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane derivatives as orexin receptor antagonists
TW202204338A (zh) 半胱胺酸蛋白酶抑制劑及其使用方法
WO2019241751A1 (fr) Inhibiteurs de ssao et leurs utilisations
CA3023383A1 (fr) 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3- a]pyridin-3(2h)-ones et 2,5,6,7-tetrahydro-3h-pyrrolo[2,1 -c][1,2,4]triazol-3-ones substituees et leur utilisation
US20150232509A1 (en) Spiro ring compounds as hepatitis c virus (hcv) inhibitors
WO2024107778A1 (fr) Nouveaux inhibiteurs de protéase pour le traitement d'infections à coronavirus
JP2024506612A (ja) Ｐａｒｐ７阻害剤として有用な三環式誘導体
WO2024097296A1 (fr) Composés antiviraux