WO2023125825A1 - Composés anti-coronavirus et compositions et utilisations de ceux-ci - Google Patents

Composés anti-coronavirus et compositions et utilisations de ceux-ci Download PDF

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WO2023125825A1
WO2023125825A1 PCT/CN2022/143464 CN2022143464W WO2023125825A1 WO 2023125825 A1 WO2023125825 A1 WO 2023125825A1 CN 2022143464 W CN2022143464 W CN 2022143464W WO 2023125825 A1 WO2023125825 A1 WO 2023125825A1
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compound
pharmaceutically acceptable
acceptable salt
alkyl
cycloalkyl
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PCT/CN2022/143464
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English (en)
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Gongxin HE
Xiaowu Chen
Wenyuan Fan
Kai Hou
Hongtao Liu
Xiubo TANG
Hao Wu
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Shanghai Curegene Pharmaceutical Co., Ltd.
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Publication of WO2023125825A1 publication Critical patent/WO2023125825A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • C07D513/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr

Definitions

  • the present disclosure generally relates to compounds which exhibit activity in the inhibition of 3-chymotrypsin-like protease as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions comprising the same.
  • coronavirus In the past two decades, multiple varieties of coronaviruses have caused several epidemics. Amongst, the global pandemic COVID-19, which is caused by the coronavirus named “severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ” , has caused millions of deaths worldwide. Coronavirus is highly susceptible to mutate into prevalent variants. Although various vaccines have been approved for use since the outbreak of SARS-CoV-2, the vaccinated people are still under risk associated with the emergence of immune escape mutants. Therefore, it is important to develop anti-viral drug to combat existing and emerging coronaviruses.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • coronavirus 3-chymotrypsin-like protease (CLpro; also known as “main protease” or “Mpro” ) is an attractive drug target due to its essential role in processing the polyproteins that are translated from the viral RNA. It cleaves two large overlapping the polyproteins ppla and pplab at more than 11 sites to yield essential nonstructural proteins required for virus replication and pathogenesis. The cleavage is facilitated by the Cys145-His41 catalytic dyad located in a cleft between domain I and domain II of 3CLpro.
  • Cys145-His41 catalytic dyad and substrate binding sites are highly conserved across different varieties of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) that have emerged in 2002 and 2012, respectively. Accordingly, 3CLpro inhibitors is a promising broad-spectrum antiviral for coronavirus infections and other related diseases.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • Pfizer has developed two 3CLpro inhibitors PF-07304814 and PF-07321332 (Nirmatrelvir) .
  • PF-07304814 exhibits rather low oral bioavailability and low tolerance against oxidase even with the addition of oxidase inhibitor.
  • PF-07321332 has not overcome the issue of low tolerance against oxidase, thus requires co-administration with ritonavir tablets, an oxidase inhibitor, to be effective against SARS-CoV-2.
  • the present disclosure provides compounds which are capable of inhibiting 3-chymotrypsin-like protease, the pharmaceutical compositions comprising these compounds and methods for the use of such compounds or pharmaceutical compositions for treatment of viral infections.
  • the present disclosure provides a compound having Formula (I’) :
  • R 1 and R 2 are each independently hydrogen, halogen or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or
  • R 1 and R 2 taken together with the carbon atom to which they are bound form a cycloalkyl or heterocyclyl, the cycloalkyl or heterocyclyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl;
  • R a are optionally substituted with one or more R a ;
  • each R a is selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl or haloalkyl, or
  • L is selected from *-L 1 -or *-L 2 - (CH 2 ) q -L 3 -,
  • each V is independently selected from CR b or N, each Z is independently selected from a bond, -CR b R c -, -O-, or -N (R b ) -; R b and R c are each independently selected from hydrogen, halogen, alkyl, or haloalkyl;
  • Ring A is a 5-or 6-membered heterocyclyl
  • each R 3 is independently hydrogen, halogen or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, alkenyl, or alkynyl, or
  • R 3 one or two pairs of R 3 , each taken together with the carbon atom (s) to which they are bound, form cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl or alkynyl;
  • R 4 is a warhead capable of covalently binding to a 3CL protease
  • G is C or Si
  • R 5A , R 5B and R 6 are each independently selected from hydrogen, halogen, -OR d , alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl and alkylheteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkoxyl, or haloalkyl, and R d is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkylaryl, alkylcycloalkyl, alkylheterocyclyl, alkylheteroaryl, cycloal
  • R 5A and R 5B taken together with the G atom to which they are bound form a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; or
  • R 5B and R 6 taken together with the atoms to which they are bound form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl;
  • R 7 is –R 7-1 -R 7-2 , wherein R 7-1 is selected from a bond, -C (O) O-**, -C (O) -**, -C (O) N (R b ) -**, or -SO 2 -**, R 7-2 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, alkenylcycloalkyl, alkenylheterocyclyl, alkenylaryl, alkenylheteraryl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, alken
  • R 8 is selected from hydrogen, halogen, alkyl, or haloalkyl
  • R 7 and R 8 taken together with the nitrogen atom to which they are bound form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl;
  • R 9 is selected from hydrogen, methyl or ethyl
  • n 0, 1, 2, 3, or 4;
  • n 0, 1, 2, 3, or 4;
  • p 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • q 0, 1 or 2.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating a viral infection in a patient in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.
  • the present disclosure provides a method for inhibiting 3-chymotrypsin-like protease in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a viral infection.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for treating a viral infection.
  • linking substituents are described. It is specifically intended that each linking substituent includes both the forward and backward forms of the linking substituent.
  • -NR (CR’R”) -includes both -NR (CR’R”) -and - (CR’R”) NR-.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • alkyl refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms.
  • alkyl groups contain 1 to 10 carbon atoms.
  • alkyl groups contain 1 to 9 carbon atoms.
  • alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-10 alkyl examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • C 1-6 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.
  • alkylcycloalkyl refers to an alkyl attached to cycloalkyl, including –alkyl-cycloalkyl and alkyl-cycloalkyl-. In some embodiments, alkylcycloalkyl refers to –alkyl-cycloalkyl.
  • alkylheterocyclyl refers to an alkyl attached to heterocyclyl, including –alkyl-heterocyclyl and alkyl-heterocyclyl-. In some embodiments, alkylheterocyclyl refers to –alkyl-heterocyclyl.
  • alkylaryl refers to an alkyl attached to aryl, including –alkyl-aryl and alkyl-aryl-. In some embodiments, alkylaryl refers to –alkyl-aryl.
  • alkylcycloalkyl refers to an alkyl attached to aryl, including –alkyl-cycloalkyl and alkyl-cycloalkyl-. In some embodiments, alkylcycloalkyl refers to –alkyl-cycloalkyl.
  • alkylheteroaryl refers to an alkyl attached to heteroaryl, including –alkyl-heteroaryl and alkyl-heteroaryl-. In some embodiments, alkylheteroaryl refers to –alkyl-heteroaryl.
  • alkenyl refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms.
  • alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms.
  • alkenyl group include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.
  • alkenylcycloalkyl refers to an alkenyl attached to cycloalkyl, including –alkenyl-cycloalkyl and alkenyl-cycloalkyl-. In some embodiments, alkenylcycloalkyl refers to –alkenyl-cycloalkyl.
  • alkenylheterocyclyl refers to an alkenyl attached to heterocyclyl, including –alkenyl-heterocyclyl and alkenyl-heterocyclyl-. In some embodiments, alkenylheterocyclyl refers to –alkenyl-heterocyclyl.
  • alkenylaryl refers to an alkenyl attached to aryl, including –alkenyl-aryl and alkenyl-aryl-. In some embodiments, alkenylaryl refers to –alkenyl-aryl.
  • alkenylheteroaryl refers to an alkenyl attached to heteroaryl, including –alkenyl-heteroaryl and alkenyl-heteroaryl-. In some embodiments, alkenylheteroaryl refers to –alkyl-heteroaryl.
  • alkoxyl refers to an alkyl group attached to oxygen (-O-alkyl) .
  • alkoxyl groups contain 1 to 10 carbon atoms.
  • alkoxyl groups contain 1 to 9 carbon atoms.
  • alkoxyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • Example of alkoxyl group include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
  • alkynyl refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms.
  • alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms.
  • alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • amino refers to —NH 2 group. Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amino groups.
  • aryl refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members.
  • aryl include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl” , as it is used herein, is a group in which an aromatic ring is fused to one or more additional rings.
  • polycyclic ring system In the case of polycyclic ring system, only one of the rings needs to be aromatic (e.g., 2, 3-dihydroindole) , although all of the rings may be aromatic (e.g., quinoline) .
  • the second ring can also be fused or bridged.
  • polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • Aryl groups can be substituted at one or more ring positions with substituents as described above.
  • cycloalkyl refers to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms.
  • the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms.
  • Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic.
  • Examples of monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • polycyclic cycloalkyl group examples include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decanyl, bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, and the like.
  • cyano refers to —CN.
  • halogen refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .
  • haloalkyl refers to an alkyl substituted with one or more halogens.
  • the haloalkyl may contain 1 to 6 carbon atoms.
  • the haloalkyl may contain 1 to 4 carbon atoms.
  • the haloalkyl may contain 1 to 3 carbon atoms. Examples of haloalkyl include, but not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromomethyl, tribromomethyl and tetrafluoroethyl.
  • heteroatom refers to nitrogen, oxygen, sulfur, phosphorus or silicon, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxides) .
  • heteroalkyl refers to an alkyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, S, P or Si.
  • the heteroalkyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl encompasses alkoxy and heteroalkoxy radicals.
  • heteroalkylaryl refers to a heteroalkyl attached to aryl, including –heteroarlkyl-aryl and heteroalkyl-aryl-. In some embodiments, heteroalkylaryl refers to –heteroarlkyl-aryl.
  • heteroalkylcycloalkyl refers to a heteroalkyl attached to cycloalkyl, including –heteroarlkyl-cycloalkyl and heteroalkyl-cycloalkyl-.
  • heteroalkylcycloalkyl refers to –heteroarlkyl-cycloalkyl.
  • heteroalkylheteroaryl refers to a heteroalkyl attached to heteroaryl, including –heteroalkyl-heteroaryl or heteroalkyl-heteroaryl-.
  • heteroalkylheteroaryl refers to –heteroalkyl-heteroaryl.
  • heteroaryl refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms.
  • the heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • the heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • polycyclic heteroaryl include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1, 3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbazolyl, acridiny
  • heterocyclyl refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, silicon and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heterocyclyl also includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring.
  • the heterocyclyl radical may be carbon linked or nitrogen linked where such is possible.
  • the heterocycle is carbon linked.
  • the heterocycle is nitrogen linked.
  • a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) .
  • a group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked) .
  • 3-to 12-membered heterocyclyl refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the fused, spiro and bridged ring systems are also included within the scope of this definition.
  • monocyclic heterocyclyl examples include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.
  • fused heterocyclyl examples include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1, 2-a] pyridinyl, [1, 2, 4] triazolo [4, 3-a
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, and the like.
  • bridged heterocyclyl examples include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo [3.1.0] hexane, 8-aza-bicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane (DABCO) , and the like.
  • hydroxyl refers to —OH.
  • partially unsaturated refers to a radical that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted” , references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the present disclosure provides novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the disclosed compounds.
  • the present disclosure provides a compound having Formula (I’) :
  • R 1 and R 2 are each independently hydrogen, halogen or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or
  • R 1 and R 2 taken together with the carbon atom to which they are bound form a cycloalkyl or heterocyclyl, the cycloalkyl or heterocyclyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl;
  • R a are optionally substituted with one or more R a ;
  • each R a is selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl or haloalkyl, or
  • L is selected from *-L 1 -or *-L 2 - (CH 2 ) q -L 3 -,
  • each V is independently selected from CR b or N, each Z is independently selected from a bond, -CR b R c -, -O-, or -N (R b ) -;
  • R b and R c are each independently selected from hydrogen, halogen, alkyl, or haloalkyl;
  • Ring A is a 5-or 6-membered heterocyclyl
  • each R 3 is independently hydrogen, halogen or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, alkenyl, or alkynyl, or
  • R 3 one or two pairs of R 3 , each taken together with the carbon atom (s) to which they are bound, form cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkenyl or alkynyl;
  • R 4 is a warhead capable of covalently binding to a 3CL protease
  • G is C or Si
  • R 5A , R 5B and R 6 are each independently selected from hydrogen, halogen, -OR d , alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl and alkylheteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkoxyl, or haloalkyl, and R d is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkylaryl, alkylcycloalkyl, alkylheterocyclyl, alkylheteroaryl, cycloal
  • R 5A and R 5B taken together with the G atom to which they are bound form a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; or
  • R 5B and R 6 taken together with the atoms to which they are bound form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl;
  • R 7 is –R 7-1 -R 7-2 , wherein R 7-1 is selected from a bond, -C (O) O-**, -C (O) -**, -C (O) N (R b ) -**, or -SO 2 -**, R 7-2 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, alkenylcycloalkyl, alkenylheterocyclyl, alkenylaryl, alkenylheteraryl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl, alkylheteroaryl, alken
  • R 8 is selected from hydrogen, halogen, alkyl, or haloalkyl
  • R 7 and R 8 taken together with the nitrogen atom to which they are bound form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl;
  • R 9 is selected from hydrogen, methyl or ethyl
  • n 0, 1, 2, 3, or 4;
  • n 0, 1, 2, 3, or 4;
  • p 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • q 0, 1 or 2.
  • R 1 and R 2 are each independently hydrogen, halogen or alkyl.
  • R 1 and R 2 both are hydrogen.
  • R 1 and R 2 both are alkyl. In certain embodiments, R 1 and R 2 both are methyl.
  • R 1 and R 2 are each independently hydrogen or halogen.
  • one of R 1 and R 2 is hydrogen, and the other is halogen. In certain embodiments, one of R 1 and R 2 is hydrogen, and the other is fluoro.
  • R 1 and R 2 taken together with the carbon atom to which they are bound form a cycloalkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • R 1 and R 2 taken together with the carbon atom to which they are bound form a cyclopropyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • each R a is independently selected from halogen, alkyl or haloalkyl. In certain embodiments, each R a is independently fluoro, methyl, ethyl, propyl or trifluoromethyl.
  • R a are optionally substituted with one or more R a , and two R a taken together with the carbon atom (s) to which they are bound form a cycloalkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • two R a taken together with the carbon atom (s) to which they are bound form a cyclopropyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • L is *-L 1 -, and L 1 is a bond.
  • L is *-L 1 -, and L 1 is *-N (R b ) -.
  • R b is selected from hydrogen, halogen, alkyl, or haloalkyl. In certain embodiments, R b is selected from hydrogen, fluoro, methyl or trifluoromethyl.
  • L is *-L 1 -, and L 1 is *-O-.
  • L is *-L 1 -, and L 1 is *-S-.
  • R b and R c are each independently hydrogen or alkyl. In certain embodiments, R b and R c are each independently hydrogen or methyl. In certain embodiments, R b and R c are both hydrogen. In certain embodiments, R b and R c are both methyl. In certain embodiments, one of R b and R c is hydrogen and the other is methyl.
  • L is *-L 1 -, and L 1 is *-C ⁇ C-.
  • L is *-L 1 -, and L 1 is *-S (O) -.
  • L is *-L 1 -, and L 1 is *-SO 2 -.
  • L is *-L 1 -, and L 1 is In certain embodiments, Z is -CR b R c -, -O-, or -N (R b ) -, wherein R b and R c are each independently hydrogen or alkyl.
  • L is *-L 1 -, and L 1 is *-Z-C (O) -Z-.
  • Z is -CR b R c -, -O-, or -N (R b ) -, wherein R b and R c are each independently hydrogen, alkyl or haloalkyl. In certain embodiments, R b and R c are each independently hydrogen, methyl or trifluoromethyl.
  • ring A is selected from wherein X, Y, W and T are each independently selected from -C-, -N-or -O-, and wherein each of optionally comprises a double bond.
  • each R 3 is independently hydrogen, halogen or alkyl optionally substituted with one or more groups independently selected from halogen.
  • one or two pairs of R 3 each taken together with the carbon atom (s) to which they are bound form a cycloalkyl or aryl, wherein the cycloalkyl and aryl are optionally substituted with one or more groups independently selected from halogen or alkyl.
  • ring A is selected from the group consisting of:
  • each R 3 is independently hydrogen, halogen or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl or cyano.
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • each R 3 is independently hydrogen, halogen or alkyl optionally substituted with one or more groups independently selected from halogen, hydroxyl or cyano.
  • one or two pairs of R 3 each taken together with the carbon atom (s) to which they are bound form a cycloalkyl or aryl, wherein the cycloalkyl and aryl are optionally substituted with one or more groups independently selected from halogen or alkyl.
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • ring A is selected from:
  • ring A is selected from:
  • ring A is selected from the group consisting of:
  • ring A is selected from the group consisting of:
  • R 4 is selected from the group consisting of:
  • R 5A , R 5B and R 6 are each independently selected from hydrogen, -OR d , alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, wherein the cycloalkyl, aryl, heteroaryl, alkylaryl and alkylheteroaryl are optionally substituted with one or more groups independently selected from halogen, alkyl, or haloalkyl.
  • R 5A and R 5B taken together with the G atom to which they are bound form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl are optionally substituted with one or more groups independently selected from halogen or alkyl.
  • G is C, and is selected from the group consisting of:
  • G is Si, and is selected from the group consisting of:
  • R 5A is hydrogen, and R 5B and R 6 taken together with the atoms to which they are bound form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one or more groups independently selected from halogen or alkyl.
  • R 7 is –R 7-1 -R 7-2 , R 7-1 is a bond, and R 7-2 is selected from alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, alkyl, alkoxyl, or haloalkyl.
  • R 7-2 is selected from the group consisting of
  • R 7-1 is -C (O) O-**
  • R 7-2 is selected from alkyl, haloalkyl, alkylcycloalkyl, alkylaryl, cycloalkyl, aryl or heteroaryl, wherein the alkyl, alkylcycloalkyl, alkylaryl, and cycloalkyl, aryl and heteroaryl, are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, alkyl, alkoxyl, or haloalkyl.
  • R 7 is selected from the group consisting of:
  • R 7 is –R 7-1 -R 7-2 , R 7-1 is -C (O) -**, R 7-2 is selected from alkyl, haloalkyl, alkylcycloalkyl, alkylaryl, alkenylaryl, heteroalkylcycloalkyl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkylaryl, alkenylaryl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, carbonyl, alkyl, alkoxyl, or haloalkyl.
  • R 7 is selected from the group consisting of:
  • R 7 is –R 7-1 -R 7-2 , R 7-1 is -C (O) N (R b ) -**, R 7-2 is selected from alkyl, haloalkyl, alkylcycloalkyl, alkylaryl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkylcycloalkyl, alkylaryl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, alkyl, alkoxyl, or haloalkyl.
  • R 7 is selected from the group consisting of:
  • R 7 is –R 7-1 -R 7-2 , R 7-1 is -SO 2 -**, and R 7-2 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, alkyl, alkoxyl, or haloalkyl.
  • R 7 is selected from the group consisting of:
  • R 7 is –R 7-1 -R 7-2 , R 7-1 is a bond, and R 7-2 is hydrogen.
  • R 7 is -NH 2 .
  • R 7 and R 8 taken together with the nitrogen atom to which they are bound form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • heterocyclyl formed by R 7 and R 8 taken together with the nitrogen atom to which they are bound selected from the group consisting of:
  • the present disclosure provides compounds of Formula (III) :
  • the present disclosure provides compounds of Formula (IIIa) or (IIIb) :
  • the present disclosure provides compounds of Formula (Ia) :
  • the present disclosure provides compounds of Formula (Ia’) :
  • the present disclosure provides a compound having a formula selected from the group consisting of:
  • the compounds of present disclosure can comprise one or more asymmetric centers depending on substituent selection, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds provided herein may have an asymmetric carbon center, and thus compounds provided herein may have either the (R) or (S) stereo-configuration at a carbon asymmetric center. Therefore, compounds of the present disclosure may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the term “enantiomer” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the term “diastereomer” refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.
  • a particular enantiomer may, in some embodiments be provided substantially free of the opposite enantiomer, and may also be referred to as “optically enriched” .
  • “Optically enriched” means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90%by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99%by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis.
  • a derivatization can be carried out before a separation of stereoisomers.
  • the separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound provided herein or it can be done on a final racemic product.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration.
  • absolute stereochemistry may be determined by Vibrational Circular Dichroism (VCD) spectroscopy analysis.
  • VCD Vibrational Circular Dichroism
  • mixtures of diastereomers for example mixtures of diastereomers enriched with 51%or more of one of the diastereomers, including for example 60%or more, 70%or more, 80%or more, or 90%or more of one of the diastereomers are provided.
  • compounds provided herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
  • the present disclosure additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system (for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole) .
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • the present disclosure is also intended to include all isotopes of atoms in the compounds.
  • Isotopes of an atom include atoms having the same atomic number but different mass numbers.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 I.
  • hydrogen includes protium, deuterium and tritium.
  • carbon includes 12 C and 13 C.
  • Isotopically-enriched compounds of Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as L-glycine, L-lysine, and L-arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • crystal form As used herein, the terms “crystal form” , “crystalline form” , “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present disclosure is also intended to include all isotopes of atoms in the compounds.
  • Isotopes of an atom include atoms having the same atomic number but different mass numbers.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 I.
  • hydrogen includes protium, deuterium and tritium.
  • carbon includes 12 C and 13 C.
  • Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples.
  • the compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the Schemes are for better illustration and can be changed as appropriate.
  • the embodiments of the compounds in examples were synthesized for the purposes of research and potentially submission to regulatory agencies.
  • the reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley &Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) .
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ( “Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) ,
  • the known starting materials of the present disclosure can be synthesized by using or according to the known methods in the art, or can be purchased from commercial suppliers. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification.
  • the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • the Examples section below shows synthetic route for preparing the compounds of the present disclosure as well as key intermediates. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • the present disclosure provides compounds of Formula (I) or pharmaceutically acceptable salts thereof, which are capable of inhibiting 3CL.
  • the compounds of the present disclosure or a pharmaceutically acceptable salt thereof are useful as medicinal drugs, and particularly useful as therapeutic or prophylactic agent that are active against various viruses.
  • the compounds of the present disclosure are therapeutic or prophylactic agent active against caliciviruses, picornaviruses and coronaviruses.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it.
  • Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • treatment is used synonymously with “therapy” .
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof for treatment of viral infection.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating a viral infection.
  • the compounds provided herein shows high tolerance of tolerance against oxidase. This allows the compounds provided herein to resist oxidative metabolism in vivo, thereby showing greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
  • the compounds provided herein can be admininstered to a subject in need thereof without the need of co-administration of oxidase inhibitor, such as ritonavir or cobicistat.
  • oxidase inhibitor such as ritonavir or cobicistat.
  • the compounds provided herein are administered as a raw chemical or are formulated as pharmaceutical compositions.
  • compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure comprise a compound selected from any one of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present disclosure comprise a first compound selected from any one of Formula (I) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula but said first compound and additional compounds are not the same molecules.
  • composition refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical compositions of the present disclosure comprises a therapeutically effective amount of one or more compounds of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.
  • the term “pharmaceutically acceptable excipient” refers to an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient.
  • pharmaceutically acceptable excipient also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.
  • suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, dis
  • suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans.
  • a drug such as the compounds disclosed herein and, optionally, a chemotherapeutic agent
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.
  • compositions provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route.
  • powders, suspensions, granules, tablets (such as orodispersible tablets or orally disintegrating tablets) pills, oral soluble films, capsules, gelcaps, and caplets may be acceptable as solid dosage forms
  • emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms.
  • emulsions and suspensions may be acceptable as liquid dosage forms, and a powder suitable for reconstitution with an appropriate solution as solid dosage forms.
  • solutions, sprays, dry powders, and aerosols may be acceptable dosage form.
  • powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form.
  • pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.
  • the quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved.
  • therapeutically effective amount refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • compositions of the present disclosure may be in a form of formulation for oral administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations.
  • suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) .
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • compositions of the present disclosure may be in a form of formulation for injection administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • compositions of the present disclosure may be in a form of formulation for inhalation administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.
  • the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure.
  • excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005) , which are incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the amount of the compounds provided herein in the unit dosage form will vary depending on the condition to be treated, the subject to be treated (e.g., the age, weight, and response of the individual subject) , the particular route of administration, the actual compound administered and its relative activity, and the severity of the subject's symptoms.
  • dosage levels of the pharmaceutical compositions of the present disclosure can be between 0.001-1000 mg/kg body weight/day, for example, 0.001-1000 mg/kg body weight/day, 0.001-900 mg/kg body weight/day, 0.001-800 mg/kg body weight/day, 0.001-700 mg/kg body weight/day, 0.001-600 mg/kg body weight/day, 0.001-500 mg/kg body weight/day, 0.001-400 mg/kg body weight/day, 0.001-300 mg/kg body weight/day, 0.001-200 mg/kg body weight/day, 0.001-100 mg/kg body weight/day, 0.001-50 mg/kg body weight/day, 0.001-40 mg/kg body weight/day, 0.001-30 mg/kg body weight/day, 0.001-20 mg/kg body weight/day, 0.001-10 mg/kg body weight/day, 0.001-5 mg/kg body weight/day, 0.001-1 mg/kg body weight/day, 0.001-0.5 mg/kg body weight
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure are formulated for oral administration.
  • the unit dosage for oral administration contains one or more compounds provided herein in an amount from about 1 mg to about 1000 mg, for example from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 15 mg to about 1000 mg, from about 20 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 30 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 60 mg to about 1000 mg, from about 70 mg to about 1000 mg, from about 80 mg to about 1000 mg, from about 90 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 1 mg to 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 1000 mg, from about 400 mg
  • the pharmaceutical compositions of the present disclosure are formulated for oral administration in a treatment having a duration of more than 1 week, more than 2 weeks, more than 3 weeks, more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, more than 1 year or even longer.
  • the pharmaceutical compositions of the present disclosure are formulated for parenteral administration, e.g., administered intravenously, subcutaneously or intramuscularly via injection.
  • the unit dosage for parenteral administration contains one or more compounds provided herein in an amount from about 0.1 mg to about 500 mg of one or more compounds provided herein, for example from about 0.2 mg to about 500 mg, from about 0.3 mg to about 500 mg, from about 0.4 mg to about 500 mg, from about 0.5 mg to about 500 mg, from about 1 mg to about 500 mg, from about 5 mg to about 500 mg, from about 10 mg to about 500 mg, from about 20 mg to about 500 mg, from about 30 mg to about 500 mg, from about 40 mg to about 500 mg, from about 50 mg to about 500 mg, from about 0.5 mg to about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg to about 200 mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about 90 mg, from about 0.5 mg to about 80 mg, from about 0.5
  • the pharmaceutical composition intended to be administered by injection can be prepared by combining one or more compounds of the present disclosure with sterile, distilled water, sesame or peanut oil, aqueous propylene glycol, so as to form a solution.
  • the pharmaceutical composition may comprise a surfactant or other solubilizing excipient that is added to facilitate the formation of a homogeneous solution or suspension.
  • the pharmaceutical composition may further comprise one or more additional agents selected from the group consisting of a wetting agent, a suspending agent, a preservative, a buffer, and an isotonizing agent.
  • the pharmaceutical composition intended to be administered by injection can be administered with a syringe.
  • the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the pharmaceutical composition provided herein.
  • compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • an article for distribution can include a container having deposited therein the compositions in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient.
  • the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other.
  • Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • the second active ingredient can be an antibiotic, a protease inhibitor, an anti-viral agent, an anti-inflammatory agent, an immunomodulatory agent, a kinase inhibitor, an anti-metabolite agent, a lysosomotropic agent, a M2 proton channel blocker, a polymerase inhibitor (e.g., EIDD-2801) , a neuraminidase inhibitor, a reverse transcriptase inhibitor, a viral entry inhibitor, an integrase inhibitor, interferons (e.g., types I, II, and III) , or a nucleoside analogue.
  • a polymerase inhibitor e.g., EIDD-2801
  • a neuraminidase inhibitor e.g., a reverse transcriptase inhibitor
  • a viral entry inhibitor e.g., an integrase inhibitor, interferons (e.g., types I, II, and III)
  • interferons e.g
  • the second active ingredient is an antibiotic.
  • the antibiotic can be selected from the group consisting of a penicillin antibiotic, a quinolone antibiotic, a tetracycline antibiotic, a macrolide antibiotic, a lincosamide antibiotic, a cephalosporin antibiotic, or an RNA synthetase inhibitor.
  • the antibiotic is selected from the group consisting of azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, ne
  • the second active ingredient can be a protease inhibitor.
  • the protease inhibitor can be selected from the group consisting of nafamostat, camostat, gabexate, epsilon-aminocapronic acid, aprotinin, amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir.
  • the second active ingredient can be an anti-viral agent.
  • the anti-viral agent can be selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, sime
  • the second active ingredient can be an anti-inflammatory agent.
  • the anti-inflammatory agent can be selected from the group consisting of anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide) , NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast.
  • pranlukast tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists) , adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo) , DPI antagonists, DP2 antagonists, PI3K delta inhibitors, GGK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors, bronchodilators (e.g. .
  • muscarinic antagonists beta-2 agonists
  • methotrexate and similar agents
  • monoclonal antibody therapy such as anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents
  • cytokine receptor therapies e.g. etanercept and similar agents
  • antigen non-specific immunotherapies e.g.
  • cytokines/chemokines interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents
  • suitable anti-infective agents including antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents and antituberculosis agents.
  • the second active ingredient can be an immunomodulatory agent.
  • the immunomodulatory agent can be selected from the group consisting of anti-PD-1 or anti-PDL-1 therapeutics including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab, anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453, anti-LAG3 therapeutics including but not limited to relatlimab, LAG525, or TSR-033, anti-4-1BB (anti-CD37, anti-TNFRSF9) , CD40 agonist therapeutics including but not limited to SGN-40, CP-870, 893 or R07009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists including but not limited to ADU-S100, MK-1454, ASA404, or amidobenz
  • the additional therapeutic agent is a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol.
  • a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol,
  • the second active ingredient can be a kinase inhibitor.
  • the kinase inhibitor can be selected from the group consisting of erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib, Loxo 292, larotrectinib, and quizartinib
  • the present disclosure provides a method for treating a viral infection in a patient in need thereof, comprising administering an effective amount of any compound described herein.
  • the viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a rhinovirous, a norovirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenovirus, a herpes virus, and a hepatovirus.
  • the viral infection is a coronavirus infection.
  • the viral infection is a coronavirus selected from the group consisting of 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV) , severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) , and SARS-CoV-2 (COVID-19) .
  • the viral infection is SARS-CoV-2.
  • the viral infection is from a virus selected from a virus selected from the group consisting of caliciviruses, MD145, murine norovirus, vesicular exanthema of swine virus, abbit hemorrhagic disease virus, porcine teschovirus, bovine coronavirus, feline infectious peritonitis virus, EV-68 virus, EV-71 virus, poliovirus, norovirus, human rhinovirus (HRV) , hepatitis A virus (HAV) and foot-and-mouth disease virus (FMDV) .
  • caliciviruses MD145, murine norovirus, vesicular exanthema of swine virus, abbit hemorrhagic disease virus, porcine teschovirus, bovine coronavirus, feline infectious peritonitis virus, EV-68 virus, EV-71 virus, poliovirus, norovirus, human rhinovirus (HRV) , hepatitis A virus (HAV) and foot-
  • the viral infection is an arenovirus infection.
  • the arenovirus is selected from the group consisting of : Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.
  • the viral infection is influenza infection.
  • the influenza is influenza H1N1, H3N2 or H5N1.
  • methods described herein may inhibit viral replication transmission, replication, assembly, or release, or minimize expression of viral proteins.
  • described herein is a method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting vims release, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, with a virally infected cell.
  • methods described herein do not comprise administrating oxidase inhibitor to the subject. In certain embodiments, methods described herein do not comprise administrating ritonavir or cobicistat in combination with any compounds described herein.
  • the present disclosure provides a method for inhibiting 3-chymotrypsin-like protease in a subject in need thereof, comprising administrating an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein to the subject.
  • Triphenylphosphine (14.2 g, 0.054 mol) was added to a solution of Compound s4-2 (14 g, 0.039 mol) in dry THF (150 mL) , and the reaction was allowed to warm to 65 °C and stirred for 22 h. Then H 2 O (13 mL) was added, and the reaction was allowed to stir for another 2 h. The reaction was concentrated under reduced pressure, and the residue was purified by chromatography to give compound s4 (8.3 g) as colorless oil.
  • Compound 122 was made from intermediate s7.
  • Compound 152 was made from intermediate s7.
  • Compound 153 was made from intermediate s7.
  • Compound 156 was made from intermediate s7.
  • test compounds were 3-fold serially diluted for 10 doses and added to an assay plate (384w format) using ECHO, in duplicate wells. Then 25 ⁇ L of 3CLpro protein was added to the assay plate containing compounds using a Multidrop. The mixture of compounds and 3CLpro protein were pre-incubated at room temperature 30min. Then 5 ⁇ L of substrate was added using a Multidrop. The final concentrations of 3CLpro and substrate are 25 nM and 25 ⁇ M respectively. For 100%inhibition control (HPE, hundred percent effect) , 1 ⁇ M GC376 was added. For no inhibition control (ZPE, zero percent effect) , no compound is added. The final DMSO concentration is 1%.
  • Each activity testing point has a relevant background control to normalize the fluorescence interference of compound.
  • ZPE Zero percent effective controls. Containing enzyme + substrate, no compound. Sample: Compound activity testing wells. Containing compound + enzyme +substrate.
  • BG Compound background control wells. Containing compound + substrate, no enzyme.
  • IC 50 was determined from inhibition plots and the results are shown in Table 1.
  • the working solution was diluted to 1 ⁇ M in potassium phosphate buffer (100 mM, pH 7.4) containing MgCl 2 (3 mM) , NADPH (1 mM) and HLM (1 mg/mL) in a final volume of 200 ⁇ L and incubated in a 37°C shaker. The incubation was performed both in absence and presence of selective CYP3A inhibitor ketoconazole (1 ⁇ M) .
  • Anti-virial activity assay The Huh7 cells were seeded in 96-well plates, in 100 ⁇ l per well of assay medium, at a density of 8000 cells/well and cultured at 37 °C and 5%CO 2 . After incubation for 24 hours, the test compounds and positive control (PF-07321332) were diluted with assay medium and then added into the cells, 50 ⁇ l per well. Then 50 ⁇ l per well of assay medium diluted virus was added. The resulting cell culture are incubated for additional 7 days until virus infection in the virus control (cells infected with virus, without compound treatment) displays significant CPE (cytopathic effects) . The CPE are measured by CellTiter Glo following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.
  • Inhibition (%) (Raw data CPD –Average VC) / (Average CC –Average VC) *100.
  • Cytotoxicity assay The cytotoxicity of compounds is assessed under the same method as in the anti-virial activity assay, but without the step of virus infection.
  • the Huh7 cell viability is measured with Cell-Titer Glo following the manufacturer’s manual.
  • Raw data CPD values of the sample-treated wells.
  • Average VC average value of virus control
  • Average CC average value of cell control (cells without virus infection or compound treatment)
  • Average MC average value of medium control (medium only) wells.
  • Anti-virial activity assay The MRC5 cells were seeded in 96-well plates, in 100 ⁇ l per well of assay medium, at a density of 20000 cells/well and cultured at 37 °C and 5%CO 2 . After incubation for 24 hours, the test compound and positive controls (PF-07321332) were diluted with assay medium and then added into the cells, 50 ⁇ l per well. Then 50 ⁇ l per well of assay medium diluted virus was added. The resulting cell culture are incubated for additional 3 days until virus infection in the virus control (cells infected with virus, without compound treatment) displays significant CPE. The CPE are measured by CellTiter Glo following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.
  • Inhibition (%) (Raw data CPD –Average VC) / (Average CC –Average VC) *100.
  • Raw data CPD values of the sample-treated wells
  • Average VC average value of virus control
  • Average CC average value of cell control (cells without virus infection or compound treatment)
  • Average MC average value of medium control (medium only) wells.
  • the compounds were serially diluted in DMSO and added into 384-well plates 0.3 ⁇ l per well (8 doses, 3 fold, in duplicate wells) .
  • the replicon RNA was generated in vitro transcript.
  • Huh7 cells transfected with purified SARS-CoV-2 replicon RNAs were seeded 4000/well in 384 microplates containing serially diluted compounds, then cultured at 37°C and 5%CO 2 for 1 day. The final volume of the cell culture was 60 ⁇ l per well, and the final concentrations of DMSO in the test plates was 0.5%.
  • Fluorescence intensity was determined using Acumen Cellista (TTP LabTech) , and the antiviral activity of compounds was calculated based on the inhibition of expression of GFP. Cell viability was measured with CellTiter Glo following the manufacturer’s manual.
  • Inhibition (%) (Raw data CPD –Average ZPE) / (Average HPE –Average ZPE) *100
  • Viability (%) (Raw data CPD –Average HPE) / (Average ZPE–Average HPE) *100
  • Raw data CPD values of the sample-treated wells
  • Average ZPE average value of virus control
  • Average HPE average value of medium control (medium only) wells.
  • EC50 and CC50 values was calculated using the GraphPad Prism software using the nonlinear regression model of log (inhibitor) vs. response --Variable slope (four parameters) , and the results are shown in Table 1.
  • the in vitro anti-SARS-COV-2 activity and cytotoxicity were evaluated using vero cell as follows.
  • Anti-virial activity assay The vero cells were seeded in 96-well plates, in 100 ⁇ l per well of assay medium, at a density of vero cells/well and cultured at 37 °C and 5%CO2. After incubation for 24 hours, the test compound and positive controls (PF-07321332) were diluted with assay medium and then added into the cells, 50 ⁇ l per well. Then 50 ⁇ l per well of assay medium diluted virus was added. The resulting cell culture are incubated for additional 3 days until virus infection in the virus control (cells infected with virus, without compound treatment) displays significant CPE. The CPE are measured by CellTiter Glo following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.
  • Inhibition (%) (Raw data CPD –Average VC) / (Average CC –Average VC) *100.
  • Raw data CPD values of the sample-treated wells
  • Average VC average value of virus control
  • Average CC average value of cell control (cells without virus infection or compound treatment)
  • Average MC average value of medium control (medium only) wells.

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Abstract

L'invention concerne des composés qui présentent une activité dans l'inhibition de la protéase de type 3-chymotrypsine ainsi que des compositions pharmaceutiques comprenant ces composés et des méthodes de traitement d'infections virales par l'administration de ces composés ou des compositions pharmaceutiques.
PCT/CN2022/143464 2021-12-29 2022-12-29 Composés anti-coronavirus et compositions et utilisations de ceux-ci WO2023125825A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007001406A2 (fr) * 2004-10-05 2007-01-04 Chiron Corporation Composes macrocycliques contenant un aryle
WO2021250648A1 (fr) * 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile
WO2022020711A1 (fr) * 2020-07-24 2022-01-27 The Texas A&M University System Inhibiteurs de protéase principale de sars-cov-2
US11319325B1 (en) * 2021-05-11 2022-05-03 Enanta Pharmaceuticals, Inc. Macrocyclic spiropyrrolidine derived antiviral agents
WO2022235605A1 (fr) * 2021-05-04 2022-11-10 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux macrocycliques
WO2022240541A1 (fr) * 2021-05-11 2022-11-17 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine macrocycliques
US20220402926A1 (en) * 2021-05-11 2022-12-22 Enanta Pharmaceuticals, Inc. Novel macrocyclic spiropyrrolidine derived antiviral agents

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007001406A2 (fr) * 2004-10-05 2007-01-04 Chiron Corporation Composes macrocycliques contenant un aryle
WO2022020711A1 (fr) * 2020-07-24 2022-01-27 The Texas A&M University System Inhibiteurs de protéase principale de sars-cov-2
WO2021250648A1 (fr) * 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile
WO2022235605A1 (fr) * 2021-05-04 2022-11-10 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux macrocycliques
US11319325B1 (en) * 2021-05-11 2022-05-03 Enanta Pharmaceuticals, Inc. Macrocyclic spiropyrrolidine derived antiviral agents
WO2022240541A1 (fr) * 2021-05-11 2022-11-17 Enanta Pharmaceuticals, Inc. Nouveaux agents antiviraux dérivés de spiropyrrolidine macrocycliques
US20220402926A1 (en) * 2021-05-11 2022-12-22 Enanta Pharmaceuticals, Inc. Novel macrocyclic spiropyrrolidine derived antiviral agents

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