EP4695230A1 - Protease inhibitors and uses thereof - Google Patents

Protease inhibitors and uses thereof

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Publication number
EP4695230A1
EP4695230A1 EP23932400.7A EP23932400A EP4695230A1 EP 4695230 A1 EP4695230 A1 EP 4695230A1 EP 23932400 A EP23932400 A EP 23932400A EP 4695230 A1 EP4695230 A1 EP 4695230A1
Authority
EP
European Patent Office
Prior art keywords
compound
ring
alkyl
pharmaceutically acceptable
solvate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23932400.7A
Other languages
German (de)
French (fr)
Inventor
Hongtao Yu
Qi Hu
Jing Huang
Tingliang WANG
Lijing ZHANG
Dongdong LIANG
Qi Wu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Westlake Pharmaceutical Hangzhou Co Ltd
Original Assignee
Westlake Pharmaceutical Hangzhou Co Ltd
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Filing date
Publication date
Application filed by Westlake Pharmaceutical Hangzhou Co Ltd filed Critical Westlake Pharmaceutical Hangzhou Co Ltd
Publication of EP4695230A1 publication Critical patent/EP4695230A1/en
Pending legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-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
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present disclosure relates to compounds that inhibit proteases such as 3C-like protease (3CLpro) , compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds to treat a disease or a symptom of a disease caused by a coronavirus, e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) , MERS-CoV, or SARS-CoV.
  • a coronavirus e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) , MERS-CoV, or SARS-CoV.
  • the COVID-19 pandemic is caused by a novel coronavirus, SARS-CoV-2.
  • SARS-CoV-2 has more than 70%of its genome encoding 16 non-structural proteins (nsps) , named nsp1 to nsp16 (1, 2) .
  • the 16 nsps are translated as two polyproteins pp1a and pp1ab from which the individual nsps are generated by proteolytic cleavage.
  • pp1a is cleaved into nsp1 to nsp11
  • pp1ab is cleaved into nsp1 to nsp10 and nsp12 to nsp16 (1)
  • the cleavage is carried out by two proteases included in the 16 nsps -nsp3 and nsp5.
  • Nsp3 is a large protein containing several domains among which the papain-like protease (PLpro) domain is responsible for the cleavage of the peptide bonds between nsp1 and 2, nsp2 and 3, and nsp3 and 4 (1, 3) .
  • Nsp5 is 3CLpro, a cysteine protease that cleaves peptide bonds to release nsp4 to nsp16 (1) .
  • 3CLpro has almost the same function in other coronaviruses. Examples of coronavirus 3CLpro protein sequences can be found in table 2 of WO2022150962.
  • 3CLpro After cleaving itself from pp1a and pp1ab, 3CLpro forms a homodimer with a significantly increased protease activity, facilitating it to cleave peptide bonds between other nsps.
  • 3CLpro At the catalytic center of 3CLpro there is a catalytic dyad composed by His41 and Cys145.
  • the working mechanism and the protein sequence of the catalytic domain of 3CLpro are conserved among different coronaviruses.
  • the sequence identity between the 3CLpro of SARS-CoV-2 and that of SARS-CoV reaches 96%.
  • nsp12 and nsp13 also known as the RNA-dependent RNA polymerase (RdRp) and helicase, respectively, are enzymes that catalyze the replication of the virus RNA genome. Therefore, 3CLpro is a promising target for the development of anti-coronavirus drugs.
  • RNA-dependent RNA polymerase RdRp
  • helicase RNA-dependent RNA polymerase
  • 3CLpro is a promising target for the development of anti-coronavirus drugs.
  • Several research teams have spent significant efforts in the development of inhibitors of SARS-CoV 3CLpro and SARS-CoV-2 3CLpro. The majority of these inhibitors are covalent inhibitors optimized from peptidic scaffolds (4) .
  • the present disclosure provides non-covalent inhibitors of proteases such as SARS-CoV-2 3CLpro, as well as pharmaceutical compositions comprising these inhibitors and uses of these inhibitors in the treatment of diseases and/or symptoms thereof caused by a coronavirus infection in a subject.
  • One aspect of this disclosure provides a compound selected from compounds of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, and IX:
  • R 1 is hydrogen, halogen, or C 1 -C 2 alkyl that is optionally substituted with 1 to 3 groups of halogen;
  • R 2 is -NO 2 , -SO 3 H, -SO 2 CH 3 , -CN or -CF 3 ;
  • R a is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R a is optionally substituted with 1-3 groups selected from halogen and deuterium;
  • R b is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R b is optionally substituted with 1-3 groups selected from halogen and deuterium;
  • R c is hydrogen, NH 2 , -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R c is optionally substituted with 1-3 groups selected from halogen, deuterium, and -OH;
  • Ring A 1 is 3-, 4-, 5-or 6-membered cycloalkyl, 3-, 4-, 5-or 6-heterocycloalkyl or 5-or 6-heteroaryl, wherein the heterocycloalkyl or heteroaryl of Ring A 1 contains one or more heteroatoms selected from N and O;
  • X 1 is absent, -CH 2 -, -NH-or -O-;
  • X 2 is CH or N
  • X 3 is -O-, -CH 2 , or -NH-;
  • R 3’ for each occurrence, is independently selected from halogen, -OR d , -NR e R f , and C 1 -C 4 alkyl that is optionally substituted with 1-3 groups of halogen, wherein:
  • R d is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R d is optionally substituted with 1-3 groups of halogen;
  • R e is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R e is optionally substituted with 1-3 groups of halogen;
  • R f is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R f is optionally substituted with 1-3 groups of halogen;
  • R 3’ for each occurrence, may be attached to any of the ring atoms of the Ring A 1 , as long as valence permits;
  • n is an integer selected from 0, 1, 2 and 3;
  • Z is absent, -NR g -, -C (R h R i ) -NR g -, -NR g -C (R h R i ) -, or -O-, wherein:
  • R g is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl of R g is optionally substituted with 1-3 groups of halogen;
  • R h is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl of R h is optionally substituted with 1-3 groups of halogen;
  • R i is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with 1-3 groups of halogen;
  • Ring Y is phenyl or selected from the following rings: wherein:
  • Ring Y 1 is 4-, 5-, 6-, 7-, 8-, or 9-membered cycloalkyl or 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring Y 1 contains one or more heteroatoms selected from N and O;
  • Ring Y 2 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
  • Ring Y 3 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
  • Z 1 , Z 3 , Z 4 , and Z 5 are each independently CH or N;
  • T 1 , T 2 , T 3 , and T 4 are each independently CH or N;
  • R j is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl is optionally substituted with 1-3 groups of halogen;
  • R 4 for each occurrence, may be attached to any of the ring atoms of Ring Y, as long as valence permits;
  • o is an integer selected from 0, 1 and 2;
  • R k , R L , and R n are each independently selected from hydrogen, halogen, and C 1 -C 2 alkyl that is optionally substituted with 1-3 groups of halogen;
  • R m and R o are each independently selected from hydrogen and C 1 -C 2 alkyl that is optionally substituted with 1-3 groups of halogen;
  • Ring A is 5-or 6-membered nitrogen heteroalkyl or nitrogen heteroaryl, or 9-or 10-membered nitrogen heterocyclyl, wherein:
  • Ring A is substituted by t groups of R 5 , and R 5 may be attached to any of the ring atoms of Ring A, as long as valence permits;
  • R 5 for each occurrence, is independently halogen, -CN, -OR p , -NHR p , -CH 2 NHBoc, 5-or 6-membered cycloalkyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R 5 is optionally substituted with 1-3 groups of halogen, wherein:
  • R p for each occurrence, is independently selected from halogen and C 1 -C 4 alkyl
  • t 0, 1, 2, 3, 4, or 5.
  • Another aspect of the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier.
  • a further aspect of the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier in combination with an additional active pharmaceutical agent.
  • a further aspect of the disclosure provides methods of treating a disease and/or a symptom of a disease caused by a coronavirus (e.g., a respiratory tract infectious disease) in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • a coronavirus e.g., a respiratory tract infectious disease
  • a further aspect of the disclosure provides methods of treating a disease and/or a symptom of a disease caused by a coronavirus (e.g., a respiratory tract infectious disease) in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing in combination with a therapeutically effective amount of an additional active pharmaceutical agent, either in the same pharmaceutical composition as the compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound,
  • a further aspect of the disclosure provides a method of reducing or inhibiting the activity of a protease of a coronavirus in a biological sample, comprising contacting said sample, coronavirus or protease with a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • a coronavirus in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • a further aspect of the disclosure provides a method of reducing or inhibiting the replication of a coronavirus in a biological sample, comprising contacting said sample, coronavirus or a protease of the coronavirus with a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • the present disclosure also provides a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, for use as a medicament.
  • the present disclosure also provides a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, for use in treating disorders associated with or caused by a coronavirus.
  • the present disclosure also provides use of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, for the manufacture of a medicament for treating disorders associated with or caused by a coronavirus.
  • the compounds of the disclosure as potent 3CLpro inhibitors have improved antiviral activity and suitable pharmaceutical profile and thus are useful for the treatment a disease and/or a symptom of a disease caused by a coronavirus.
  • FIGURE 1 shows the chemical structures of Compounds 1, 14, 18, 19, 20, 26, 29, 30, 32, 37, 39, 41, 43, 49, 50, 75, 77, 86, 89, 96, 98, 106, 119, 138, 151, 167, 169 and 174.
  • FIGURES 2A and 2B show the docking of Compound 1 to the structure of SARS-CoV-2 3CLpro.
  • FIGURE 2A shows that Compound 1 (sticks) docks well into the catalytic pocket of 3CLpro.
  • the surface electrostatic potential of 3CLpro was calculated by PyMol.
  • FIGURE 2B shows interactions between Compound 1 and 3CLpro. The hydrogen bonds are indicated by dashed lines.
  • FIGURES 3A and 3B show crystal structure of Compound 19 in complex with SARS- CoV-2 3CLpro.
  • FIGURE 3A shows that Compound 19 (sticks) binds into the catalytic pocket of 3CLpro.
  • the surface electrostatic potential of 3CLpro was calculated by PyMol.
  • FIGURE 3B shows interactions between Compound 19 and 3CLpro. The hydrogen bonds are indicated by dashed lines.
  • FIGURES 4A and 4B show crystal structure of Compound 98 in complex with SARS-CoV-2 3CLpro.
  • FIGURE 4A shows that Compound 98 (sticks) binds into the catalytic pocket of 3CLpro.
  • the surface electrostatic potential of 3CLpro was calculated by PyMol.
  • FIGURE 4B shows interactions between Compound 98 and 3CLpro. The hydrogen bonds are indicated by dashed lines.
  • FIGURES 5 shows the binding affinity of Compound Ref-2 (compound P2) , 19 and 30 with SARS-CoV-2 3CLpro determined by isothermal titration calorimetry (ITC) .
  • FIGURE 6 shows the anti-SARS-CoV-2 activity and the cytotoxicity of Compound 1 (FIGURE 6A) and Compound 14 (FIGURE 6B) in A549 cells.
  • FIGURE 7 shows the anti-SARS-CoV-2 activity of Compounds Ref-2 (compound P2) , 18, 19, 26, 29, 30, 37, 41, 43, 75, 89 and 151 in A549 cells.
  • FIGURE 8 shows the anti-Omicron SARS-CoV-2 activity of Compounds Ref-2 and 98 in Caco-2 cells.
  • FIGURE 9 shows the CYP inhibition evaluation of Compounds Ref-2 (compound P2) , 97, 98 and 170 in human liver microsomes.
  • FIGURE 10 shows the free plasma protein binding (PPB) ration of Compounds Ref-2 (compound P2) , 86, 97, 98 and 170 in human and mouse.
  • an additional pharmaceutical agent means a single or two or more additional pharmaceutical agents.
  • coronavirus refers to a group of related RNA viruses that cause diseases in mammals and birds, such as typically respiratory tract infectious diseases in humans and birds that can range from mild to lethal, diarrhea in cows and pigs, and hepatitis and encephalomyelitis in mice.
  • Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid of helical symmetry. They have characteristic club-shaped spikes that project from their surface, which in electron micrographs create an image reminiscience of the solar corona, from which their names.
  • the lethal varieties of coronavirus include those that can cause SARS (severe acute respiratory syndrome) , MERS (Middle East respiratory syndrome) , and COVID-19 (contagious disease caused by severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) .
  • compound when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis/trans stereoisomers, or a collection of (E) and (Z) stereoisomers) , except that there may be isotopic variation among the constituent atoms of the molecules.
  • stereoisomers for example, a collection of racemates, a collection of cis/trans stereoisomers, or a collection of (E) and (Z) stereoisomers
  • the relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors, including, for example, the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9%of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5%of the compound.
  • an alkyl group contains 1 to 2 alkyl carbon atoms.
  • alkyl groups are substituted.
  • alkyl groups are unsubstituted.
  • alkyl groups are linear or straight-chain or unbranched. In some embodiments, alkyl groups are branched.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • Carbocyclyl encompasses the term “cycloalkyl” and refers to a monocyclic C 3-8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14 hydrocarbon that is completely saturated, or is partially saturated as it contains one or more units of unsaturation but is not aromatic, wherein any individual ring in said bicyclic ring system has 3 to 7 members.
  • Bicyclic carbocyclyls include combinations of a monocyclic carbocyclic ring fused to, for example, a phenyl.
  • carbocyclyl groups are substituted.
  • carbocyclyl groups are unsubstituted.
  • the carbocyclyl is a C 3 to C 12 carbocyclyl. In some embodiments, the carbocyclyl is a C 3 to C 10 carbocyclyl. In some embodiments, the carbocyclyl is a C 3 to C 8 carbocyclyl.
  • alkenyl as used herein, means a linear or branched, substituted or unsubstituted hydrocarbon chain that contains one or more double bonds. In some embodiments, alkenyl groups are substituted. In some embodiments, alkenyl groups are unsubstituted. In some embodiments, alkenyl groups are linear, straight-chain, or unbranched. In some embodiments, alkenyl groups are branched. In some embodiments, the term “alkenyl” refers to C 2 -C 10 alkenyl, preferably C 2 -C 6 alkenyl, more preferably C 2 -C 4 alkenyl. Some examples of alkenyls include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and hexenyl.
  • alkynyl refers to a straight or branched alkynyl group of 2 to 24 carbon atoms, such as acetylenyl, n-propynyl, etc., that contains at least one triple bond.
  • the alkynyl group in the disclosure contains 2 to 12 carbon atoms, or 2 to 6 carbon atoms, preferably 4 carbon atoms, more preferably 3 carbons, most preferably 2 carbons.
  • substituted alkynyl refers to an alkynyl group that is replaced by one or more substituting groups
  • hetero-atomic alkynyl and hetero-alkynyl refer to an alkynyl group in which at least one carbon atom is replaced by a heteroatom. If not indicated otherwise, then the term “alkynyl” includes alkynyl groups that are straight, branched, unsubstituted, substituted, and/or contain heteroatoms.
  • heterocyclyl as used herein means non-aromatic (i.e., completely saturated or partially saturated as in it contains one or more units of unsaturation but is not aromatic) , monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems in which one or more ring members is an independently chosen heteroatom.
  • Bicyclic heterocyclyls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl/cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl/cycloalkyl.
  • the “heterocyclyl” group contains 3 to 14 ring members in which one or more ring members is a heteroatom independently chosen, for example, from oxygen, sulfur, nitrogen, and phosphorus.
  • each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members.
  • the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently chosen from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms that are each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms that are each independently selected from nitrogen and oxygen.
  • heterocycles are substituted. In some embodiments, heterocycles are unsubstituted.
  • the heterocyclyl is a 3-to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3-to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-to 9-membered heterocyclyl, for example, a 4-to 9-membered heterocyclyl containing at least one N atom and optionally at least one O atom. In some embodiments, the heterocyclyl is a 5-to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5-to 8-membered heterocyclyl.
  • the heterocyclyl is a 5-or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl.
  • monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1, 1-dioxide, etc.
  • spiro-heterocyclyl refers to a ring system in which a three-to seven-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three-to seven-membered cycloalkyl or three-to seven-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three-to seven-membered heterocyclyl.
  • hetero atom means one or more of oxygen, sulfur, phosphorus, and nitrogen, including, any oxidized form of nitrogen or sulfur; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl) .
  • nitrogen heteroalkyl, ” “nitrogen heteroaryl, ” or “nitrogen heterocyclyl” means the ring atoms of the heteroalkyl, heteroaryl, or heterocyclyl ring contains one or more hetero atoms and the one or more hetero atoms are nitrogen.
  • oxygen heteroalkyl, ” “oxygen heteroaryl, ” or “oxygen heterocyclyl” means the ring atoms of the heteroalkyl, heteroaryl, or heterocyclyl ring contains one or more hetero atoms and the one or more hetero atoms are oxygen.
  • unsaturated means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the state in which not all of the available valence bonds in a compound are satisfied by substituents and thus the compound contains one or more double or triple bonds.
  • alkoxy refers to an alkyl group, as defined above, wherein one carbon of the alkyl group is replaced by an oxygen ( “alkoxy” ) atom, provided that the oxygen atom is linked between two carbon atoms.
  • halogen includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.
  • cyano or “nitrile” group refers to -C ⁇ N.
  • an “aromatic ring” refers to a carbocyclic or heterocyclic ring that contains conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer of 0 to 6.
  • a “non-aromatic” ring refers to a carbocyclic or heterocyclic that does not meet the requirements set forth above for an aromatic ring, and can be either completely or partially saturated.
  • Nonlimiting examples of aromatic rings include aryl and heteroaryl rings that are further defined as follows.
  • aryl used alone or as part of a larger moiety as in “arylalkyl, ” “arylalkoxy, ” or “aryloxyalkyl, ” refers to monocyclic or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems having a total of five to fourteen ring members, wherein every ring in the system is an aromatic ring containing only carbon atoms and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members.
  • aryl groups include phenyl (C 6 ) and naphthyl (C 10 ) rings.
  • aryl groups are substituted.
  • aryl groups are unsubstituted.
  • Non-limiting examples of suitable solvents include water, methanol (MeOH) , ethanol (EtOH) , dichloromethane or “methylene chloride” (CH 2 Cl 2 ) , toluene, acetonitrile (MeCN) , dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , methyl acetate (MeOAc) , ethyl acetate (EtOAc) , heptanes, isopropyl acetate (IPAc) , tert-butyl acetate (t-BuOAc) , isopropyl alcohol (IPA) , tetrahydrofuran (THF) , 2-methyl tetrahydrofuran (2-Me THF) , methyl ethyl ketone (MEK) , tert-butanol, diethyl ether (Et 2 O) , methyl-ter
  • Non-limiting examples of suitable bases include 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) , potassium tert-butoxide (KOtBu) , potassium carbonate (K 2 CO 3 ) , N-methylmorpholine (NMM) , triethylamine (Et 3 N; TEA) , diisopropyl-ethyl amine (i-Pr 2 EtN; DIPEA) , pyridine, potassium hydroxide (KOH) , sodium hydroxide (NaOH) , lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH 3 ) .
  • DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene
  • KtBu potassium tert-butoxide
  • K 2 CO 3 N-methylmorpholine
  • NMM N-methylmorpholine
  • TEA triethylamine
  • i-Pr 2 EtN diiso
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1 to 19.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, carbonic acid, sulfuric acid, sulfurous acid, and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, carbonic acid
  • a compound of this disclosure is a compound of the following structural formula I:
  • R 1 is hydrogen, halogen, or C 1 -C 2 alkyl that is optionally substituted with 1 to 3 groups of halogen;
  • R 2 is -NO 2 , -SO 3 H, -SO 2 CH 3 , -CN or -CF 3 ;
  • R a is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 of R a is optionally substituted with 1-3 groups selected from halogen and deuterium;
  • R b is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R b is optionally substituted with 1-3 groups selected from halogen and deuterium;
  • R c is hydrogen, NH 2 , -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R c is optionally substituted with 1-3 groups selected from halogen, deuterium, and -OH;
  • Ring A 1 is 3-, 4-, 5-or 6-membered cycloalkyl, or 4-, 5-or 6-membered heterocycloalkyl or 5-or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl of Ring A 1 contains one or more heteroatoms selected from N and O;
  • X 1 is absent, -CH 2 -, -NH-or -O-;
  • X 2 is CH or N
  • X 3 is -O-, -CH 2 , or -NH-;
  • R d is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R d is optionally substituted with 1-3 groups of halogen;
  • R f is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R f is optionally substituted with 1-3 groups of halogen;
  • R 3’ for each occurrence, may be attached to any of the ring atoms of the Ring A 1 , as long as valence permits;
  • n is an integer selected from 0, 1, 2 and 3;
  • Z is absent, -NR g -, -C (R h R i ) -NR g -, -NR g -C (R h R i ) -, or -O-, wherein:
  • R g is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl of R g is optionally substituted with 1-3 groups of halogen;
  • R i is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl of R i is optionally substituted with 1-3 groups of halogen;
  • Ring Y is phenyl or selected from the following rings: wherein:
  • Ring Y 2 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
  • Ring Y 3 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
  • Z 1 , Z 3 , Z 4 , and Z 5 are each independently CH or N;
  • U 1 , U 2 , U 3 , and U 4 are each independently CH 2 or NH;
  • T 1 , T 2 , T 3 , and T 4 are each independently CH or N;
  • R j is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R j is optionally substituted with 1-3 groups of halogens;
  • R 4 for each occurrence, may be attached to any of the ring atoms of Ring Y, as long as valence permits;
  • o is an integer selected from 0, 1 or 2;
  • R k , R L , and R n are each independently selected from hydrogen, halogen, and C 1 -C 2 alkyl that is optionally substituted with 1-3 groups of halogen;
  • R m and R o are each independently selected from hydrogen and C 1 -C 2 alkyl that is optionally substituted with 1-3 groups of halogen;
  • Ring A is 5-or 6-membered nitrogen heteroalkyl or nitrogen heteroaryl, or 9-or 10-membered nitrogen heterocyclyl; wherein:
  • Ring A is substituted by t groups of R 5 , and R 5 may be attached to any of the ring atoms of the Ring A, as long as valence permits;
  • R 5 for each occurrence, is independently halogen, -CN, -OR p , -NHR p , -CH 2 NHBoc, 5-or 6-membered cycloalkyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R 5 is optionally substituted with 1-3 groups of halogen;
  • R p for each occurrence, is independently selected from halogen and C 1 -C 4 alkyl
  • t 0, 1, 2, 3, 4, or 5;
  • R 3 is wherein Ring A 1 , X 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -NH-, and Ring A 1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -NH-, and Ring A 1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A 1 contains one or more heteroatoms selected from N and O, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 1 is Br, F or Cl; and all other variables not specifically defined herein are as defined in the first embodiment.
  • R 3 is 5-to 7-membered nitrogen and/or oxygen heterocyclyl; and all other variables not specifically defined herein are as defined in the first embodiment.
  • R 3 is oxazolyl or triazolyl; and all other variables not specifically defined herein are as defined in the first embodiment.
  • R 3 is and all other variables not specifically defined herein are as defined in the first embodiment.
  • R c is H, NH 2 , -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R b is optionally substituted with 1-3 groups selected from halogen, deuterium, and -OH, and all other variables not specifically defined herein are as defined in the first embodiment.
  • a compound of the disclosure is of the following structural Formula II-1, II-2, II-3, II-4, or II-5:
  • R 3 is 4-or 5-membered cycloalkyl, 4-or 5-membered heterocyclyl, or 4-or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl of R 3 contains one or more hetero atoms selected from N and O, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R 3 is 4-or 5-membered heterocyclyl, wherein heterocyclyl of R 3 contains one or more hetero atoms selected from N and O, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R 3 is 5-membered nitrogen heteroaryl, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R 3 is and all other variables not specifically defined herein are as defined in the first embodiment.
  • X 1 when X 1 is -NH-, X 2 is CH; when X 1 is -CH 2 -, X 2 is N, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R d is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R d is optionally substituted with 1-3 groups of halogen, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R e is H
  • R f is H, NH 2 , -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl of R f is optionally substituted with 1-3 groups of halogen, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R g is H, and all other variables not specifically defined herein are as defined in the first embodiment.
  • a compound of the disclosure is of the following structural Formula III:
  • a compound of the disclosure is of the following structural Formula IV:
  • a compound of the disclosure is of the following structural Formula V:
  • Ring Y 1 is 4-, 5-, 6-or 7-membered nitrogen heterocyclyl
  • Z when Z 3 is CH, Z is -NR g -, -C (R h R i ) -NR g -, -NR g -C (R h R i ) -or -O-;
  • R 3 is wherein X 1 is -CH 2 -, -NH-or -O-, and Ring A 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -NH-, and Ring A 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -NH-, and Ring A 1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -NH-, and Ring A 1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A 1 contains one or more heteroatoms selected from N and O, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • Ring A is 10-membered nitrogen heteroaryl
  • R 3 is wherein Ring A 1 , X 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • Ring A is 10-membered nitrogen heteroaryl
  • R 3 is wherein X 1 is -CH 2 -, -NH-or -O-, and Ring A 1 , X 2 , X 3 , R 3’ a nd m are as defined in the first embodiment.
  • Ring A is 10-membered nitrogen heteroaryl
  • R 3 is wherein X 1 is -NH-, and Ring A 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -NH-, and Ring A 1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • Ring A is 10-membered nitrogen heteroaryl
  • R 3 is wherein X 1 is -NH-
  • Ring A 1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A 1 contains one or more heteroatoms selected from N and O, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • a compound of the disclosure is of the following structural Formula VI:
  • Ring Y 2 is 4-or 5-membered nitrogen heterocyclyl
  • Ring Y 3 is 4-, 5-or 6-membered nitrogen heterocyclyl
  • R 4 substitution occurs on any of the ring atoms of Ring Y 2 and/or Ring Y 3 , as long as valence permits;
  • Z when Z 5 is CH, Z is -NR g - ⁇ -C (R h R i ) -NR g - ⁇ -NR g -C (R h R i ) -0-O-;
  • Z 5 when Z 5 is N, Z is absent, and all other variables not specifically defined herein are as defined in the first embodiment. In some embodiments, Z 4 and Z 5 are N, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R 3 is wherein Ring A 1 , X 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -CH 2 -, -NH-or -O-, and Ring A 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -NH-, and Ring A 1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A 1 contains one or more heteroatoms selected from N and O, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • Ring A is 10-membered nitrogen heteroaryl
  • R 3 is wherein Ring A 1 , X 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • Ring A is 10-membered nitrogen heteroaryl
  • R 3 is wherein X 1 is -CH 2 -, -NH-or -O-, and Ring A 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • Ring A is 10-membered nitrogen heteroaryl
  • R 3 is wherein X 1 is -NH-, and Ring A 1 , X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • R 3 is wherein X 1 is -NH-, and Ring A 1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • Ring A is 10-membered nitrogen heteroaryl
  • R 3 is wherein X 1 is -NH-
  • Ring A 1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A 1 contains one or more heteroatoms selected from N and O, and X 2 , X 3 , R 3’ and m are as defined in the first embodiment.
  • Z 4 is in the meta position to the spiro atom, and all other variables not specifically defined herein are as defined in the first embodiment.
  • Z 5 is in the meta position to the spiro atom, and all other variables not specifically defined herein are as defined in the first embodiment.
  • Y is U 1 , U 2 , and U 4 are CH 2 ; U 3 is NH; T 1 and T 2 are N, and all other variables not specifically defined herein are as defined in the first embodiment.
  • Y is T 1 , T 2 and T 4 are N; T 3 is CH; U 1 , U 2 and U 3 are CH 2 , and all other variables not specifically defined herein are as defined in the first embodiment.
  • Ring Y is and all other variables not specifically defined herein are as defined in the first embodiment.
  • Ring Y is and all other variables not specifically defined herein are as defined in the first embodiment.
  • the moiety is and all other variables not specifically defined herein are as defined in the first embodiment.
  • the moiety is and all other variables not specifically defined herein are as defined in the first embodiment.
  • the moiety is and all other variables not specifically defined herein are as defined in the first embodiment.
  • the moiety is and all other variables not specifically defined herein are as defined in the first embodiment.
  • R k is H
  • R L is CF 3
  • all other variables not specifically defined herein are as defined in the first embodiment.
  • R m is -CH 2 -
  • R o is absent, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R o is -CH 2 -
  • R m is absent, and all other variables not specifically defined herein are as defined in the first embodiment.
  • the compound is of the following structural Formula VII:
  • Y is wherein: Z 1 is CH, or Z 4 is CH, and all other variables not specifically defined herein are as defined in the first embodiment.
  • R n is H, and all other variables not specifically defined herein are as defined in the first embodiment.
  • the compound is of the following structural Formula VIII:
  • Z 1 or Z 4 is N
  • Y is wherein: and all other variables not specifically defined herein are as defined in the first embodiment.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • W 1 , W 2 , W 3 , W 4 , W 5 and W 6 are each independently N or CH; for each Ring A group, V 1 and V 2 are each independently NH or CH 2 , and all other variables not specifically defined herein are as defined in the first embodiment.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • W 1 , W 2 , W 3 , W 4 , W 5 and W 6 are each independently N or CH; for each Ring A group, V 1 and V 2 are each independently NH or CH 2 , and all other variables not specifically defined herein are as defined in the first embodiment.
  • Ring A is pyridinyl, pyrimidinyl, pentanolactam, butyrolactam, glutarimide, triazolyl, tetrazolyl, isoquinolinyl, quinolinyl, pyridin-2 (1H) -one, quinolin-2 (1H) -one, 3, 4-dihydroquinolin-2 (1H) -one, naphthyridinyl, pyrrolopyridinyl, or imidazopyridinyl, wherein the pyridinyl, pyrimidinyl, pentanolactam, butyrolactam, glutarimide, triazolyl, tetrazolyl, isoquinolinyl, quinolinyl, pyridin-2 (1H) -one, quinolin-2 (1H) -one, 3, 4-dihydroquinolin-2 (1H) -one, naphthyridinyl, pyrrolopyri
  • Ring A is wherein Ring A is substituted by t groups of R 5 , the substitution occurs on any of atoms of the Ring A, as long as valence permits, and all other variables not specifically defined herein are as defined in the first embodiment.
  • the moiety is and all other variables not specifically defined herein are as defined in the first embodiment.
  • the moiety is and all other variables not specifically defined herein are as defined in the first embodiment.
  • the 5-or 6-membered heteroaryl of R 5 is pyrrolyl, pyrazolyl, or imidazolyl, and all other variables not specifically defined herein are as defined in the first embodiment.
  • the 5-or 6-membered heteroaryl of R 5 is and all other variables not specifically defined herein are as defined in the first embodiment.
  • Ring Y isn’t cyclohexyl, 6-membered nitrogen heterocyclyl, 5-membered nitrogen heterocyclyl or diazaspiro [4.4] , and all other variables not specifically defined herein are as defined in the first embodiment.
  • Ring Y is and all other variables not specifically defined herein are as defined in the first embodiment.
  • the at least one compound of the disclosure is selected from Compounds 1 to 183 depicted in Table 1, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing.
  • compositions comprising at least one compound selected from a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include an additional active pharmaceutical agent.
  • a pharmaceutical composition comprising a compound selected from a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising an additional active pharmaceutical agent.
  • the pharmaceutical compositions disclosed herein comprise a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles.
  • the pharmaceutically acceptable carrier can be chosen, for example, from any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, which are suited to the particular dosage form desired.
  • Remington The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams &Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C.
  • Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin) , buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate) , partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts) , colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose) , starches (such as corn starch and potato starch) , cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate) , powdered tragacanth
  • compositions of the present disclosure may be formulated in the form of tablets, hard or soft gelatin capsules, powders, granules, a solutions or suspension in an aqueous or non-aqueous liquid, sterile injectable preparation, nasal or eye drops, or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the desired dosage forms may be formulated according to the known art using the suitable excipients commonly used in the pharmacy.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for use in treating a disease and/or a symptom of a disease caused by a coronavirus.
  • a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease and/or a symptom or a disease caused by a coronavirus.
  • a method of treating a disease and/or a symptom of a disease in a subject comprising administering to the subject a therapeutically effective amount of a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.
  • the compounds of the present invention can be used in the methods of the invention in combination with an additional active pharmaceutical agent.
  • the additional active pharmaceutical agents that can be used in combination with the compounds of the present invention include but are not limited to one or more of the following: an interferon or a pegylated form thereof, remdesivir, galidesivir, favilavir, favipiravir, tenofivir, boceprevir, Ribavirin, ⁇ -Thymidine, Chlorhexidine, clevudine, dalcetrapib, dexamethasone, hydrocortisone, monoclonal antibodies such as regdanvimab, ravulizumab, bamlanivimab, mdressimab, leronlimab lenzilumab, infliximab, adalimumab, lanadelumab, canakinumab, gimsilumab, otilimab, tocili
  • the disease caused by a coronavirus is a respiratory tract infection. In some embodiments, the disease caused by a coronavirus is a severe acute respiratory syndrome. In one embodiment, the disease caused by a coronavirus is COVID-19. In one embodiment, the disease caused by a coronavirus that is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) .
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the symptom of a disease caused by a coronavirus is selected from fever or chills, cough, shortness of breath or difficulty in breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhea, persistent pain or pressure in the chest, new confusion, inability to wake or stay awake, bluish lips or face, and a combination thereof.
  • a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for reducing or inhibiting the activity of a protease of a coronavirus.
  • a method of reducing or inhibiting the activity of a protease of a coronavirus comprising administering a therapeutically effective amount of a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein to a subject, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.
  • a method of reducing or inhibiting the activity of a protease of a coronavirus comprising contacting said coronavirus or said protease with a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein to a subject, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.
  • the protease of a coronavirus is a 3C-like protease.
  • the coronavirus is SARS-CoV-2.
  • a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for reducing or inhibiting the replication of a coronavirus.
  • a method of reducing or inhibiting the replication of a coronavirus comprising administering a therapeutically effective amount of a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein to a subject, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.
  • a method of reducing or inhibiting the replication of a coronavirus comprising contacting said coronavirus or a protease of the coronavirus with a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein to a subject, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.
  • the protease of a coronavirus is a 3C-like protease.
  • the coronavirus is SARS-CoV-2.
  • a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof may be administered once daily, twice daily, or three times daily, for example, for the treatment of a disease and/or a symptom of a disease caused by a coronavirus, for example, SARS-CoV-2.
  • 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof are administered once daily, twice daily, or three times daily.
  • a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof may be administered, for example, by oral, parenteral, sublingual, topical, rectal, nasal, buccal, vaginal, transdermal, patch, pump administration or via an implanted reservoir, and a pharmaceutical compositions would be formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.
  • Other forms of administration contemplated in this disclosure are as described in International Patent Application Nos. WO 2013/075083, WO 2013/075084, WO 2013/078320, WO 2013/120104, WO 2014/124418, WO 2014/151142, and WO 2015/023915.
  • One or more of the compounds of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof may be administrated in combination with one or more additional pharmaceutical agents, for example, additional anti-SARS-CoV-2 agents or additional inhibitors of proteases of Coronaviridae viruses.
  • the compounds of the disclosure may be made according to standard chemical practices or as described herein, including the following synthetic schemes and in the descriptions for preparing a compound selected from compounds of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing.
  • the synthesis route of compound 57 is similar to that of compound 1 using 5-bromo-2-fluoro-3- (methylsulfonyl) benzoic acid as the start material.
  • intermediate III-1 To a solution of intermediate III-1 in DCM (2 mL) , HCl in dioxane or TFA was added and the reaction was stirred at room temperature for 2 hr. The reaction was concentrated under reduced pressure to give intermediate III-2 without further purification.
  • Method 1 Corresponding amine (1.05 equiv) , TEA (5.0 equiv) and T3P (2.0 equiv) were added to a solution of intermediate VII-1-1 or VII-1-2 (1.0 equiv) in DCM, and stirred at room temperature for 2 hr. The reaction mixture was poured into water and then extracted with DCM three times. The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to give a crude product which was purified by prep-HPLC to give the target compounds as yellow solids.
  • Compound 150 was synthesized from VII-1-2 with two steps (step1: described in method 1 of compound 19, step 2: described in the procedure of I-3) .
  • Compound 160 was obtained by removing protective group Boc using HCl in dioxane described in the procedure of intermediate I-3.
  • the synthetic procedure is similar to the last step of the synthetic route of compound 14.
  • intermediate XII-7 The synthesis of intermediate XII-7 is similar to that of intermediate XII-4.
  • the synthetic procedure is similar to the last step of the synthetic procedure of compound 1.
  • the 3CLpro enzymes of SARS-CoV-2, SARS-CoV and MERS-CoV were over-expressed in E. coli and purified to homogeneity following protocols described previously (6) .
  • Crystals were grown at 20 °C in a 96-well plate using the sitting-drop vapor-diffusion method.
  • the diffraction data was collected at 100 K on a Rigaku XtaLAB Synergy Custom diffractometer and solved by molecular replacement using Phaser-MR (7) in the Phenix software suite (8) .
  • the crystal structure of the SARS-CoV-2 3CLpro (PDB code: 7EN8) was used as the initial model.
  • the 3CLpro/inhibitor complex structures were manually refined with Coot (9) and Phenix (8) .
  • the ability of the compounds in Table 1 to inhibit 3CLpro was tested using a fluorescence resonance energy transfer (FRET) -based continuous kinetic assay (6) .
  • FRET fluorescence resonance energy transfer
  • a fluorescent peptide Dabcyl-KTSAVLQ ⁇ SGFRKM-E (Edans) was used as the substrate of purified 3CLpro. After cleavage by 3CLpro, the fragment SGFRKM-E (Edans) was released and its fluorescence could be monitored with the excitation and emission wavelengths of 355 nm and 538 nm, respectively.
  • the final concentration of 3CLpro and the fluorogenic substrate were 15 nM and 25 ⁇ M, respectively.
  • the final concentration of 3CLpro and the fluorogenic substrate were 500 nM and 100 ⁇ M, respectively.
  • ITC experiments were done with an isothermal titration calorimeter MicroCal PEAQ-ITC (Malvern Panalytical) .
  • the inhibitor with a concentration of 20 ⁇ M in the ITC buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 0.5%DMSO) was titrated by 200 ⁇ M 3CLpro in the ITC buffer at 25 °C.
  • Control experiments in which the inhibitors were titrated by the ITC buffer were performed and the data was used to correct the 3CLpro titration data. The data was processed using the MicroCal PEAQ-ITC analysis software. Each measurement was repeated three times.
  • the anti-SARS-CoV-2 activity was measured in A549 cells expressing the human ACE2 receptor following protocols described previously (6) . Briefly, the cells were first treated with DMSO or various concentrations of the compounds (Table 1) for 1 hour, then infected by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) for 24 hours. After paraformaldehyde fixation, the cells were stained with SARS-CoV-2 nucleocapsid (N) protein antibody and DAPI. The percentage of the cells infected by SARS-CoV-2 was measured by imaging using a high-content imaging system.
  • the anti-Omicron SARS-CoV-2 activity was measured in Caco-2 cells using similar protocol.
  • the reactions were terminated by adding 400 ⁇ L cold stop solution (200 ng/mL Tolbutamide and Labetalol in ACN) .
  • the samples are centrifuged at 4000 rpm for 20 minutes to precipitate protein.
  • 200 ⁇ L of the supernatant of each sample was transferred to 100 ⁇ L HPLC water and shaken for 10 minutes, and then analyzed by LC/MS/MS.
  • a loading matrix was prepared by diluting of a 400 ⁇ M stock of each of the compounds in DMSO by the plasma matrix.
  • T 0 time zero
  • 50 ⁇ L of the loading matrix were transferred in triplicate to the sample collection plate, immediately matched with opposite blank buffer to obtain a final volume of 100 ⁇ L of 1: 1 matrix/dialysis buffer (v/v) in each well, followed by the addition of 500 ⁇ L of stop solution (200 ng/mL of tolbutamide, 200 ng/mL of labetalol, and 50 ng/mL of metformin in acetonitrile) and then stored at 2-8°C pending further processes along with other post-dialysis samples.
  • 150 ⁇ L of the loading matrix and 150 ⁇ L of the dialysis buffer were transferred to the donor side and the receiver side of each well, respectively.
  • the dialysis plate was placed in a humidified incubator at 37 °C with 5%CO 2 on a shaking platform that rotated slowly (about 100 rpm) for 4 hours, then 50 ⁇ L of samples were taken from both the buffer side and the matrix side, and transferred into new 96-well plates. Each sample was mixed with an equal volume of opposite blank buffer (or matrix) to reach a final volume of 100 ⁇ L, followed by the addition of 500 ⁇ L of stop solution.
  • the mixture was vortexed and centrifuged at 4000 rpm for about 20 minutes, then 100 ⁇ L of the supernatant of each sample was removed for LC-MS/MS analysis.
  • the single blank samples were prepared by transferring 50 ⁇ L of blank matrix to a 96 well plate and adding 50 ⁇ L of blank PBS buffer to each well. The blank plasma must match the species of plasma used in the plasma side of the well. Then the matrix-matched samples were further processed by adding 500 ⁇ L of stop solution, following the same sample processing method as the dialysis samples.
  • the %Unbound, %Bound and %Recovery were calculated using the following equations:
  • F is the analyte concentration or peak area ratio of analyte/internal standard on the buffer (receiver) side of the membrane
  • T is the analyte concentration or peak area ratio of analyte/internal standard on the matrix (donor) side of the membrane
  • T 0 is the analyte concentration or the peak area ratio of analyte/internal standard in the loading matrix sample at time zero.

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Abstract

The disclosure provides compounds of Formula I, compositions comprising the same, and methods of using the same, including use in treating a disease and/or a symptom of a disease caused by a coronavirus.

Description

    PROTEASE INHIBITORS AND USES THEREOF
  • Field of the Disclosure
  • The present disclosure relates to compounds that inhibit proteases such as 3C-like protease (3CLpro) , compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds to treat a disease or a symptom of a disease caused by a coronavirus, e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) , MERS-CoV, or SARS-CoV.
  • Background of the Disclosure
  • The COVID-19 pandemic is caused by a novel coronavirus, SARS-CoV-2. There is a great need for drugs that specifically treat diseases caused by SARS-CoV-2 or other coronaviruses. The positive-sense RNA virus SARS-CoV-2 has more than 70%of its genome encoding 16 non-structural proteins (nsps) , named nsp1 to nsp16 (1, 2) . The 16 nsps are translated as two polyproteins pp1a and pp1ab from which the individual nsps are generated by proteolytic cleavage. Specifically, pp1a is cleaved into nsp1 to nsp11, while pp1ab is cleaved into nsp1 to nsp10 and nsp12 to nsp16 (1) . The cleavage is carried out by two proteases included in the 16 nsps -nsp3 and nsp5. Nsp3 is a large protein containing several domains among which the papain-like protease (PLpro) domain is responsible for the cleavage of the peptide bonds between nsp1 and 2, nsp2 and 3, and nsp3 and 4 (1, 3) . Nsp5 is 3CLpro, a cysteine protease that cleaves peptide bonds to release nsp4 to nsp16 (1) . 3CLpro has almost the same function in other coronaviruses. Examples of coronavirus 3CLpro protein sequences can be found in table 2 of WO2022150962.
  • After cleaving itself from pp1a and pp1ab, 3CLpro forms a homodimer with a significantly increased protease activity, facilitating it to cleave peptide bonds between other nsps. At the catalytic center of 3CLpro there is a catalytic dyad composed by His41 and Cys145. The working mechanism and the protein sequence of the catalytic domain of 3CLpro are conserved among different coronaviruses. The sequence identity between the 3CLpro of SARS-CoV-2 and that of SARS-CoV reaches 96%.
  • Inhibition of the protease activity of 3CLpro would block the release of nsp4 to nsp16 that are necessary for coronavirus replication. For example, nsp12 and nsp13, also known as the RNA-dependent RNA polymerase (RdRp) and helicase, respectively, are enzymes that catalyze the replication of the virus RNA genome. Therefore, 3CLpro is a promising target for the development of anti-coronavirus drugs. Several research teams have spent significant efforts in the development of inhibitors of SARS-CoV 3CLpro and SARS-CoV-2 3CLpro. The majority of these inhibitors are covalent inhibitors optimized from peptidic scaffolds (4) . A large number of  non-covalent inhibitors were also reported, however, most of them only showed moderate activity in cell-free or cell-based assays. Recently a noncovalent oral SARS-CoV-2 3CLpro inhibitor S-217622 was reported (5) . Certain 3CLpro inhibitors are described in WO2022150962 and WO2023036140.
  • Accordingly, there is a need for compounds that are 3CLpro inhibitors with improved antiviral activity for the treatment a disease and/or a symptom of a disease caused by a coronavirus, for example, an infection caused by SARS-Cov-2, MERS-CoV, or SARS-CoV.
  • Summary of the Disclosure
  • The present disclosure provides non-covalent inhibitors of proteases such as SARS-CoV-2 3CLpro, as well as pharmaceutical compositions comprising these inhibitors and uses of these inhibitors in the treatment of diseases and/or symptoms thereof caused by a coronavirus infection in a subject.
  • One aspect of this disclosure provides a compound selected from compounds of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, and IX:


  • a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, wherein:
  • R1 is hydrogen, halogen, or C1-C2 alkyl that is optionally substituted with 1 to 3 groups of halogen;
  • R2 is -NO2, -SO3H, -SO2CH3, -CN or -CF3;
  • R3 is 5-or 6-membered heteroaryl, -C (=O) Ra, -C (=O) ORa, -C (=O) NRbRc or wherein:
  • Ra is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Ra is optionally substituted with 1-3 groups selected from halogen and deuterium;
  • Rb is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rb is optionally substituted with 1-3 groups selected from halogen and deuterium;
  • Rc is hydrogen, NH2, -OH, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rc is optionally substituted with 1-3 groups selected from halogen, deuterium, and -OH;
  • Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, 3-, 4-, 5-or 6-heterocycloalkyl or 5-or 6-heteroaryl, wherein the heterocycloalkyl or heteroaryl of Ring A1 contains one or more heteroatoms selected from N and O;
  • X1 is absent, -CH2-, -NH-or -O-;
  • X2 is CH or N;
  • X3 is -O-, -CH2, or -NH-;
  • R3’, for each occurrence, is independently selected from halogen, -ORd, -NReRf, and C1-C4 alkyl that is optionally substituted with 1-3 groups of halogen, wherein:
  • Rd is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rd is optionally substituted with 1-3 groups of halogen;
  • Re is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Re is optionally substituted with 1-3 groups of halogen;
  • Rf is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rf is optionally substituted with 1-3 groups of halogen;
  • R3’, for each occurrence, may be attached to any of the ring atoms of the Ring A1, as long as valence permits; and
  • m is an integer selected from 0, 1, 2 and 3;
  • Z is absent, -NRg-, -C (RhRi) -NRg-, -NRg-C (RhRi) -, or -O-, wherein:
  • Rg is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl of Rg is optionally substituted with 1-3 groups of halogen;
  • Rh is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl of Rh is optionally substituted with 1-3 groups of halogen;
  • Ri is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with 1-3 groups of halogen;
  • Ring Y is phenyl or selected from the following rings: wherein:
  • Ring Y1 is 4-, 5-, 6-, 7-, 8-, or 9-membered cycloalkyl or 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring Y1 contains one or more heteroatoms selected from N and O;
  • Ring Y2 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
  • Ring Y3 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
  • Z1, Z3, Z4, and Z5, for each occurrence, are each independently CH or N;
  • U1, U2, U3, and U4, for each occurrence, are each independently CH2 or NH;
  • T1, T2, T3, and T4, for each occurrence, are each independently CH or N;
  • R4, for each occurrence, is independently halogen, -OH, -C (=O) Rj, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with 1-3 groups of halogens, wherein:
  • Rj is C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with 1-3 groups of halogen;
  • R4, for each occurrence, may be attached to any of the ring atoms of Ring Y, as long as valence permits;
  • o is an integer selected from 0, 1 and 2;
  • X is absent, -CRkRL-, -C (=O) -, -C (=O) NRn-, or -Rm-C (=O) NRn-Ro-, wherein:
  • Rk, RL, and Rn, for each occurrence, are each independently selected from hydrogen, halogen, and C1-C2 alkyl that is optionally substituted with 1-3 groups of halogen;
  • Rm and Ro, for each occurrence, are each independently selected from hydrogen and C1-C2 alkyl that is optionally substituted with 1-3 groups of halogen;
  • Ring A is 5-or 6-membered nitrogen heteroalkyl or nitrogen heteroaryl, or 9-or 10-membered nitrogen heterocyclyl, wherein:
  • Ring A contains -N=, or =N-in the meta position to the ring atom to which X is attached, or -NH-in the meta position or para position to the ring atom to which X is attached;
  • the -NH-in the meta position is attached to -C (=O) -in the ortho position, or the -NH-in the para position is attached to -C (=O) -in the meta position;
  • Ring A is substituted by t groups of R5, and R5 may be attached to any of the ring atoms of Ring A, as long as valence permits;
  • R5, for each occurrence, is independently halogen, -CN, -ORp, -NHRp, -CH2NHBoc, 5-or 6-membered cycloalkyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of R5 is optionally substituted with 1-3 groups of halogen, wherein:
  • Rp, for each occurrence, is independently selected from halogen and C1-C4 alkyl; and
  • t is 0, 1, 2, 3, 4, or 5.
  • Another aspect of the disclosure provides a pharmaceutical composition comprising a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier.
  • A further aspect of the disclosure provides a pharmaceutical composition comprising a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof,  a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier in combination with an additional active pharmaceutical agent.
  • A further aspect of the disclosure provides methods of treating a disease and/or a symptom of a disease caused by a coronavirus (e.g., a respiratory tract infectious disease) in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • A further aspect of the disclosure provides methods of treating a disease and/or a symptom of a disease caused by a coronavirus (e.g., a respiratory tract infectious disease) in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing in combination with a therapeutically effective amount of an additional active pharmaceutical agent, either in the same pharmaceutical composition as the compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing or in a separate composition.
  • Also disclosed herein are methods of reducing or inhibiting the activity of a protease of a coronavirus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • A further aspect of the disclosure provides a method of reducing or inhibiting the activity of a protease of a coronavirus in a biological sample, comprising contacting said sample, coronavirus or protease with a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • Further disclosed herein are methods of reducing or inhibiting the replication of a coronavirus in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV,  V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • A further aspect of the disclosure provides a method of reducing or inhibiting the replication of a coronavirus in a biological sample, comprising contacting said sample, coronavirus or a protease of the coronavirus with a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
  • The present disclosure also provides a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, for use as a medicament.
  • The present disclosure also provides a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, for use in treating disorders associated with or caused by a coronavirus.
  • The present disclosure also provides use of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, or VIII, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, for the manufacture of a medicament for treating disorders associated with or caused by a coronavirus.
  • The compounds of the disclosure as potent 3CLpro inhibitors have improved antiviral activity and suitable pharmaceutical profile and thus are useful for the treatment a disease and/or a symptom of a disease caused by a coronavirus.
    • Brief Description of the Drawings
  • FIGURE 1 shows the chemical structures of Compounds 1, 14, 18, 19, 20, 26, 29, 30, 32, 37, 39, 41, 43, 49, 50, 75, 77, 86, 89, 96, 98, 106, 119, 138, 151, 167, 169 and 174.
  • FIGURES 2A and 2B show the docking of Compound 1 to the structure of SARS-CoV-2 3CLpro. FIGURE 2A shows that Compound 1 (sticks) docks well into the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. FIGURE 2B shows interactions between Compound 1 and 3CLpro. The hydrogen bonds are indicated by dashed lines.
  • FIGURES 3A and 3B show crystal structure of Compound 19 in complex with SARS- CoV-2 3CLpro. FIGURE 3A shows that Compound 19 (sticks) binds into the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. FIGURE 3B shows interactions between Compound 19 and 3CLpro. The hydrogen bonds are indicated by dashed lines.
  • FIGURES 4A and 4B show crystal structure of Compound 98 in complex with SARS-CoV-2 3CLpro. FIGURE 4A shows that Compound 98 (sticks) binds into the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. FIGURE 4B shows interactions between Compound 98 and 3CLpro. The hydrogen bonds are indicated by dashed lines.
  • FIGURES 5 shows the binding affinity of Compound Ref-2 (compound P2) , 19 and 30 with SARS-CoV-2 3CLpro determined by isothermal titration calorimetry (ITC) .
  • FIGURE 6 shows the anti-SARS-CoV-2 activity and the cytotoxicity of Compound 1 (FIGURE 6A) and Compound 14 (FIGURE 6B) in A549 cells.
  • FIGURE 7 shows the anti-SARS-CoV-2 activity of Compounds Ref-2 (compound P2) , 18, 19, 26, 29, 30, 37, 41, 43, 75, 89 and 151 in A549 cells.
  • FIGURE 8 shows the anti-Omicron SARS-CoV-2 activity of Compounds Ref-2 and 98 in Caco-2 cells.
  • FIGURE 9 shows the CYP inhibition evaluation of Compounds Ref-2 (compound P2) , 97, 98 and 170 in human liver microsomes.
  • FIGURE 10 shows the free plasma protein binding (PPB) ration of Compounds Ref-2 (compound P2) , 86, 97, 98 and 170 in human and mouse.
  • FIGURES 11A, 11B and 11C show the inhibitory activities of the Compounds Ref-2 and 98 against the 3CLpro (P132H) of SARS-CoV-2 (FIGURE 11A) , the 3CLpro of MERS-CoV (FIGURE 11B) , and the 3CLpro of SARS-CoV (FIGURE 11C) . Using an in vitro enzymatic assay, the half maximal inhibitory concentrations (IC50s) of Compounds Ref-2 and 98 were measured.
  • Detailed Description of the Disclosure
  • I. Definitions
  • The term “a” or “an” when referring to a noun as used herein encompasses the expression “at least one” and therefore encompasses both singular and plural units of the noun. For example, “an additional pharmaceutical agent” means a single or two or more additional pharmaceutical agents.
  • The term “coronavirus” as used herein refers to a group of related RNA viruses that cause diseases in mammals and birds, such as typically respiratory tract infectious diseases in humans and birds that can range from mild to lethal, diarrhea in cows and pigs, and hepatitis and  encephalomyelitis in mice. Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid of helical symmetry. They have characteristic club-shaped spikes that project from their surface, which in electron micrographs create an image reminiscience of the solar corona, from which their names. The lethal varieties of coronavirus include those that can cause SARS (severe acute respiratory syndrome) , MERS (Middle East respiratory syndrome) , and COVID-19 (contagious disease caused by severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) .
  • The term “inhibitor” as used herein refers to an organic chemistry small molecule compound (≤ 10 kDa) that has the ability to reduce or inhibit the expression of, and/or to reduce or inhibit the activity of any one or more proteases (e.g., by blocking the active site of the protease) of a coronavirus as defined above, including but not limited to the 3C-like protease (3CLpro or 3CLpro) or formally known as C30 endopeptidase that is the main protease of coronaviruses. The 3C-like protease cleaves the coronavirus polyprotein at multiple conserved sites having a glutamine-serine/glutamine-alanine/glutamine-glycine peptide bond, and is important in the processing of the coronavirus replicase polyprotein P0C6U8. Other examples of coronavirus proteases include the papain-like protease PLpro that is required for processing viral polyproteins to generate a functional replicase complex and enable viral spread.
  • The term “compound, ” when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis/trans stereoisomers, or a collection of (E) and (Z) stereoisomers) , except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors, including, for example, the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9%of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5%of the compound.
  • As used herein, the phrase “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted. ” In general, the term “substituted, ” refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an “optionally substituted” group may have a 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 chosen from a specified group, the substituent may be either the same or different at every position.
  • Combinations of certain chemical components (e.g., substituents, ring structures, and or heteroatoms) envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds. For abbreviation or according to common practice, certain hydrogen atoms attached to a certain atom (e.g., a carbon atom C or a nitrogen atom N) are not specifically spelled out in a chemical structure, formula, or notation; hydrogen atoms are deemed to be present to the extent the valences of the certain atom (e.g., C or N) are completed.
  • The term “isotopologue” refers to a species in which the chemical structure differs from only in the isotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C or 14C are also within the scope of this disclosure.
  • Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis/trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
  • The term “solvate” as used herein, refers to a molecular complex comprising the compound of the present disclosure and one or more pharmaceutically acceptable solvent molecules, for example, ethanol, DMSO or water. When the solvent is water, the term “hydrate” may optionally be used interchangeable with the term “solvate. ”
  • The term “tautomer” as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an atom, e.g., a hydrogen atom, or a group within the molecule.
  • The term “stereoisomer” as used herein refers to enantiomers and diastereomers.
  • As used herein, “deuterated derivative” refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ( “D” or “2H” ) . It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable  isotopic substitution of deuterated derivatives described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated derivative” of a compound of the disclosure, at least one hydrogen is replaced with deuterium at a level that is well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5%deuterium incorporation at each designated deuterium) , at least 4500 (67.5 %deuterium incorporation at each designated deuterium) , at least 5000 (75%deuterium incorporation at each designated deuterium) , at least 5500 (82.5%deuterium incorporation at each designated deuterium) , at least 6000 (90%deuterium incorporation at each designated deuterium) , at least 6333.3 (95%deuterium incorporation at each designated deuterium) , at least 6466.7 (97%deuterium incorporation at each designated deuterium) , or at least 6600 (99%deuterium incorporation at each designated deuterium) .
  • The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • The term “alkyl” as used herein, means a linear or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated. Unless otherwise specified, an alkyl group contains 1 to 20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 4 alkyl carbon atoms. In other embodiments, an alkyl group contains 1 to 3 alkyl carbon atoms. And in yet other embodiments, an alkyl group contains 1 to 2 alkyl carbon atoms. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are linear or straight-chain or unbranched. In some embodiments, alkyl groups are branched. For example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • The term “cycloalkyl” refers to a monocyclic C3-8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C8-14 hydrocarbon that is completely saturated, wherein any individual ring in said bicyclic ring system has 3 to 7 members. In some embodiments, cycloalkyl groups are substituted. In some embodiments, cycloalkyl groups are unsubstituted. In some embodiments, the cycloalkyl is a C3 to C12 cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.
  • The term “carbocyclyl” encompasses the term “cycloalkyl” and refers to a monocyclic C3-8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C8-14 hydrocarbon that is completely saturated, or is partially saturated as it contains one or more units of unsaturation but is not aromatic, wherein any individual ring in said bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyls include combinations of a monocyclic carbocyclic ring fused to, for example, a phenyl. In some embodiments, carbocyclyl groups are substituted. In some embodiments, carbocyclyl groups are unsubstituted. In some embodiments, the carbocyclyl is a C3 to C12 carbocyclyl. In some embodiments, the carbocyclyl is a C3 to C10 carbocyclyl. In some embodiments, the carbocyclyl is a C3 to C8 carbocyclyl.
  • The term “alkenyl” as used herein, means a linear or branched, substituted or unsubstituted hydrocarbon chain that contains one or more double bonds. In some embodiments, alkenyl groups are substituted. In some embodiments, alkenyl groups are unsubstituted. In some embodiments, alkenyl groups are linear, straight-chain, or unbranched. In some embodiments, alkenyl groups are branched. In some embodiments, the term “alkenyl” refers to C2-C10 alkenyl, preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl. Some examples of alkenyls include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and hexenyl.
  • The term "alkynyl" refers to a straight or branched alkynyl group of 2 to 24 carbon atoms, such as acetylenyl, n-propynyl, etc., that contains at least one triple bond. Usually, but not necessarily, the alkynyl group in the disclosure contains 2 to 12 carbon atoms, or 2 to 6 carbon atoms, preferably 4 carbon atoms, more preferably 3 carbons, most preferably 2 carbons. The terms "substituted alkynyl" refer to an alkynyl group that is replaced by one or more substituting groups, and the terms "hetero-atomic alkynyl" and "hetero-alkynyl" refer to an alkynyl group in which at least one carbon atom is replaced by a heteroatom. If not indicated otherwise, then the term "alkynyl" includes alkynyl groups that are straight, branched, unsubstituted, substituted, and/or contain heteroatoms.
  • The term “heterocyclyl” as used herein means non-aromatic (i.e., completely saturated or partially saturated as in it contains one or more units of unsaturation but is not aromatic) , monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems in which one or more ring members is an independently chosen heteroatom. Bicyclic heterocyclyls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl/cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl/cycloalkyl. In some embodiments, the “heterocyclyl” group contains 3 to 14 ring members in which one or more ring members is a heteroatom independently chosen, for example, from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a  bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently chosen from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms that are each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms that are each independently selected from nitrogen and oxygen. In some embodiments, heterocycles are substituted. In some embodiments, heterocycles are unsubstituted. In some embodiments, the heterocyclyl is a 3-to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3-to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-to 9-membered heterocyclyl, for example, a 4-to 9-membered heterocyclyl containing at least one N atom and optionally at least one O atom. In some embodiments, the heterocyclyl is a 5-to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5-to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5-or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1, 1-dioxide, etc.
  • Also used herein, the term “spiro-heterocyclyl” refers to a ring system in which a three-to seven-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three-to seven-membered cycloalkyl or three-to seven-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three-to seven-membered heterocyclyl.
  • The term “hetero atom” means one or more of oxygen, sulfur, phosphorus, and nitrogen, including, any oxidized form of nitrogen or sulfur; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl) . The term “nitrogen heteroalkyl, ” “nitrogen heteroaryl, ” or “nitrogen heterocyclyl” means the ring atoms of the heteroalkyl, heteroaryl, or heterocyclyl ring contains one or more hetero atoms and the one or more hetero atoms are nitrogen. The term “oxygen heteroalkyl, ” “oxygen heteroaryl, ” or “oxygen heterocyclyl” means the ring atoms of the heteroalkyl, heteroaryl, or heterocyclyl ring contains one or more hetero atoms and the one or more hetero atoms are oxygen.
  • The term “unsaturated” , as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the state in which not all of the available valence bonds  in a compound are satisfied by substituents and thus the compound contains one or more double or triple bonds.
  • The term “alkoxy” as used herein, refers to an alkyl group, as defined above, wherein one carbon of the alkyl group is replaced by an oxygen ( “alkoxy” ) atom, provided that the oxygen atom is linked between two carbon atoms.
  • The term “halogen” includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.
  • As used herein, a “cyano” or “nitrile” group refers to -C≡N.
  • As used herein, an “aromatic ring” refers to a carbocyclic or heterocyclic ring that contains conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer of 0 to 6. A “non-aromatic” ring refers to a carbocyclic or heterocyclic that does not meet the requirements set forth above for an aromatic ring, and can be either completely or partially saturated. Nonlimiting examples of aromatic rings include aryl and heteroaryl rings that are further defined as follows.
  • The term “aryl” used alone or as part of a larger moiety as in “arylalkyl, ” “arylalkoxy, ” or “aryloxyalkyl, ” refers to monocyclic or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems having a total of five to fourteen ring members, wherein every ring in the system is an aromatic ring containing only carbon atoms and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Nonlimiting examples of aryl groups include phenyl (C6) and naphthyl (C10) rings. In some embodiments, aryl groups are substituted. In some embodiments, aryl groups are unsubstituted.
  • The term “heteroaryl” refers to monocyclic or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Bi-cyclic heteroaryls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. Non-limiting examples of bi-cyclic heteroaryls are isoquinolinyl, quinolinyl, quinazolinyl, phthalazinyl, purinyl, and 1H-pyrrolo [2, 3-c] pyridinyl. In some embodiments, heteroaryl groups are substituted. In some embodiments, heteroaryl groups have one or more heteroatoms chosen, for example, from nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl groups have one heteroatom. In some embodiments, heteroaryl groups have two heteroatoms. In some embodiments, heteroaryl groups are monocyclic ring systems having five ring members. In some embodiments, heteroaryl groups are monocyclic ring systems having six ring members. In some embodiments, heteroaryl groups are unsubstituted. In some embodiments, the heteroaryl is a 3-to 12-membered heteroaryl. In some embodiments, the  heteroaryl is a 3-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3-to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5-or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls are pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, etc.
  • Non-limiting examples of suitable solvents that may be used in this disclosure include water, methanol (MeOH) , ethanol (EtOH) , dichloromethane or “methylene chloride” (CH2Cl2) , toluene, acetonitrile (MeCN) , dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , methyl acetate (MeOAc) , ethyl acetate (EtOAc) , heptanes, isopropyl acetate (IPAc) , tert-butyl acetate (t-BuOAc) , isopropyl alcohol (IPA) , tetrahydrofuran (THF) , 2-methyl tetrahydrofuran (2-Me THF) , methyl ethyl ketone (MEK) , tert-butanol, diethyl ether (Et2O) , methyl-tert-butyl ether (MTBE) , 1, 4-dioxane, and N-methyl pyrrolidone (NMP) .
  • Non-limiting examples of suitable bases that may be used in this disclosure include 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) , potassium tert-butoxide (KOtBu) , potassium carbonate (K2CO3) , N-methylmorpholine (NMM) , triethylamine (Et3N; TEA) , diisopropyl-ethyl amine (i-Pr2EtN; DIPEA) , pyridine, potassium hydroxide (KOH) , sodium hydroxide (NaOH) , lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH3) .
  • Disclosed herein are pharmaceutically acceptable salts of the disclosed compounds. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • The term “pharmaceutically acceptable, ” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1 to 19.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, carbonic acid, sulfuric acid, sulfurous acid, and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-l, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+ (C1-4alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.
  • The term “subject” refers to an animal including a human.
  • The term "biological sample" , as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • The term “therapeutically effective amount” refers to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in a disease and/or a symptom of a disease caused by a coronavirus, lessening the severity of a disease and/or a symptom of a disease caused by a coronavirus, and/or reducing progression of a disease and/or a symptom caused by a coronavirus) . The exact amount of a therapeutically effective amount will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) , The Art, Science and Technology of Pharmaceutical Compounding) .
  • As used herein, the term “treatment” and its cognates refer to slowing or stopping disease progression. “Treatment” and its cognates as used herein include, but are not limited to the  following: complete or partial remission, curing a disease caused by a coronavirus, lower risk of a disease and/or a symptom of a disease caused by a coronavirus. Improvements in or lessening the severity of any of these symptoms can be assessed according to methods and techniques known in the art.
  • The terms “about” and “approximately, ” when used in connection with a number such as a percentage include the number as specified, and a range of the number (e.g., a range of percentages) that is recognized by one of ordinary skill in the art.
  • II. Compounds and Compositions
  • In a first embodiment, a compound of this disclosure is a compound of the following structural formula I:
  • a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, wherein:
  • R1 is hydrogen, halogen, or C1-C2 alkyl that is optionally substituted with 1 to 3 groups of halogen;
  • R2 is -NO2, -SO3H, -SO2CH3, -CN or -CF3;
  • R3 is 5-or 6-membered heteroaryl, -C (=O) Ra, -C (=O) ORa, -C (=O) NRbRc or
  • wherein:
  • Ra is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 of Ra is optionally substituted with 1-3 groups selected from halogen and deuterium;
  • Rb is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rb is optionally substituted with 1-3 groups selected from halogen and deuterium;
  • Rc is hydrogen, NH2, -OH, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rc is optionally substituted with 1-3 groups selected from halogen, deuterium, and -OH;
  • Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, or 4-, 5-or 6-membered heterocycloalkyl or 5-or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl of Ring A1 contains one or more heteroatoms selected from N and O;
  • X1 is absent, -CH2-, -NH-or -O-;
  • X2 is CH or N;
  • X3 is -O-, -CH2, or -NH-;
  • R3’, for each occurrence, is independently selected from halogen, -ORd, -NReRf, and C1-C4 alkyl that is optionally substituted with 1-3 groups of halogen; wherein:
  • Rd is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rd is optionally substituted with 1-3 groups of halogen;
  • Re is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Re is optionally substituted with 1-3 groups of halogen;
  • Rf is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rf is optionally substituted with 1-3 groups of halogen;
  • R3’, for each occurrence, may be attached to any of the ring atoms of the Ring A1, as long as valence permits; and
  • m is an integer selected from 0, 1, 2 and 3;
  • Z is absent, -NRg-, -C (RhRi) -NRg-, -NRg-C (RhRi) -, or -O-, wherein:
  • Rg is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl of Rg is optionally substituted with 1-3 groups of halogen;
  • Rh is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl of Rh is optionally substituted with 1-3 groups of halogen;
  • Ri is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl of Ri is optionally substituted with 1-3 groups of halogen;
  • Ring Y is phenyl or selected from the following rings:  wherein:
  • Ring Y1 is 4-, 5-, 6-, 7-, 8-, or 9-membered cycloalkyl or 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring Y1 contains one or more heteroatoms selected from N and O;
  • Ring Y2 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
  • Ring Y3 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
  • Z1, Z3, Z4, and Z5, for each occurrence, are each independently CH or N;
  • U1, U2, U3, and U4, for each occurrence, are each independently CH2 or NH;
  • T1, T2, T3, and T4, for each occurrence, are each independently CH or N;
  • R4, for each occurrence, is independently halogen, -OH, or -C (=O) Rj, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of R4 is optionally substituted with 1-3 groups of halogens; wherein:
  • Rj is C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rj is optionally substituted with 1-3 groups of halogens;
  • R4, for each occurrence, may be attached to any of the ring atoms of Ring Y, as long as valence permits;
  • o is an integer selected from 0, 1 or 2;
  • X is absent, -CRkRL-, -C (=O) -, -C (=O) NRn-, or -Rm-C (=O) NRn-Ro-; wherein:
  • Rk, RL, and Rn, for each occurrence, are each independently selected from hydrogen, halogen, and C1-C2 alkyl that is optionally substituted with 1-3 groups of halogen;
  • Rm and Ro, for each occurrence, are each independently selected from hydrogen and C1-C2 alkyl that is optionally substituted with 1-3 groups of halogen;
  • Ring A is 5-or 6-membered nitrogen heteroalkyl or nitrogen heteroaryl, or 9-or 10-membered nitrogen heterocyclyl; wherein:
  • Ring A contains -N=, or =N-in the meta position to the ring atom to which X is attached, or -NH-in the meta position or para position to the ring atom to which X is attached;
  • the -NH-in the meta position is attached to -C (=O) -in the ortho position, or the -NH-in the para position is attached to -C (=O) -in the meta position;
  • Ring A is substituted by t groups of R5, and R5 may be attached to any of the ring atoms of the Ring A, as long as valence permits;
  • R5, for each occurrence, is independently halogen, -CN, -ORp, -NHRp, -CH2NHBoc, 5-or 6-membered cycloalkyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of R5 is optionally substituted with 1-3 groups of halogen;
  • Rp, for each occurrence, is independently selected from halogen and C1-C4 alkyl; and
  • t is 0, 1, 2, 3, 4, or 5;
  • provided that the compound is not any one of Compounds P1 through P23:


  • In one embodiment of formula I, wherein R3 iswherein Ring A1, X1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula I, wherein R3 iswherein X1 is -CH2-, -NH-or -O-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula I, wherein R3 iswherein X1 is -NH-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula I, wherein R3 iswherein X1 is -NH-, and Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula I, wherein R3 iswherein X1 is -NH-, and Ring A1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A1 contains one or more heteroatoms selected from N and O, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula I, R1 is Br, F or Cl; and all other variables not specifically defined herein are as defined in the first embodiment.
  • In one embodiment of formula I, R3 is 5-to 7-membered nitrogen and/or oxygen heterocyclyl; and all other variables not specifically defined herein are as defined in the first  embodiment.
  • In one embodiment of formula I, R3 is oxazolyl or triazolyl; and all other variables not specifically defined herein are as defined in the first embodiment.
  • In one embodiment of formula I, R3 isand all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, R3’ is -NHCH3, -NHCD3, -NHCHD2, or -NHCH2D, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, when Rb is H, Rc is H, NH2, -OH, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rb is optionally substituted with 1-3 groups selected from halogen, deuterium, and -OH, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, a compound of the disclosure is of the following structural Formula II-1, II-2, II-3, II-4, or II-5:

  • In some embodiments, R3 is 4-or 5-membered cycloalkyl, 4-or 5-membered heterocyclyl, or 4-or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl of R3 contains one or more hetero atoms selected from N and O, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, R3 is -C (=O) NHCH3, -C (=O) NH2, -C (=O) N (CH3) 2, -C (=O) OCH3, -C (=O) NHCH3, -C (=O) NHCH2CH=CH2, -COOH, -C (=O) NHNH2, -C (=O) NHCH2CF3, -C (=O) NHCH (CH3) CF3, -C (=O) NHCH2CHF2, -C (=O) NHCH3, -C (=O) NHCD3, -C (=O) NHCH (CH3) CF3, -C (=O) NHC (CH3) 3, -C (=O) NHCH2 (CH3) 2CH2OH,  and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, R3 is -C (=O) OCH3, -C (=O) NHCH2CH=CH2, -COOH, -C (=O) NHNH2, -C (=O) NHCH (CH3) CF3, -C (=O) NHCH2CHF2, -C (=O) NHCH3, -C (=O) NHCD3, -C (=O) NHCH (CH3) CF3, -C (=O) NHCH2 (CH3) 2CH2OH, 
  • In some embodiments, R3 is 4-or 5-membered heterocyclyl, wherein heterocyclyl of R3 contains one or more hetero atoms selected from N and O, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, R3 is 5-membered nitrogen heteroaryl, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, R3 isand all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, when X1 is -NH-, X2 is CH; when X1 is -CH2-, X2 is N, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Rd is H, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rd is optionally substituted with 1-3 groups of halogen, and all other variables not specifically defined herein are as defined in the first  embodiment.
  • In some embodiments, Re is H, Rf is H, NH2, -OH, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rf is optionally substituted with 1-3 groups of halogen, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Rg is H, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, a compound of the disclosure is of the following structural Formula III:
  • , and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, a compound of the disclosure is of the following structural Formula IV:
  • , and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Ri is C1-C6 branched alkyl that is optionally substituted with 1-3 groups of halogen, or C4-C8 alkyl with C3-C6 carbocyclyl side chain and optionally substituted with 1-3 groups of halogen, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Z1 is in ortho position or meta position to Z3, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, a compound of the disclosure is of the following structural Formula V:
  • Ring Y1 is 4-, 5-, 6-or 7-membered nitrogen heterocyclyl;
  • when Z1 is CH, X is -C (=O) NRn-or -Rm-C (=O) NRnRo-;
  • when Z1 is N, X is absent, -CRkRL-, or -C (=O) -; and
  • when Z3 is CH, Z is -NRg-, -C (RhRi) -NRg-, -NRg-C (RhRi) -or -O-;
  • when Z3 is N, Z is absent,
  • and all other variables not specifically defined herein are as defined in the first embodiment.
  • In one embodiment of formula V, wherein R3 iswherein Ring A1, X1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula V, wherein R3 iswherein X1 is -CH2-, -NH-or -O-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula V, wherein R3 iswherein X1 is -NH-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula V, wherein R3 iswherein X1 is -NH-, and Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula V, wherein R3 iswherein X1 is -NH-, and Ring A1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the  heterocycloalkyl of Ring A1 contains one or more heteroatoms selected from N and O, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula V, wherein Ring A is 10-membered nitrogen heteroaryl, and R3 iswherein Ring A1, X1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula V, wherein Ring A is 10-membered nitrogen heteroaryl, and R3 iswherein X1 is -CH2-, -NH-or -O-, and Ring A1, X2, X3, R3’a nd m are as defined in the first embodiment.
  • In one embodiment of formula V, wherein Ring A is 10-membered nitrogen heteroaryl, and R3 iswherein X1 is -NH-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula V, R3 iswherein X1 is -NH-, and Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula V, wherein Ring A is 10-membered nitrogen heteroaryl, and R3 iswherein X1 is -NH-, and Ring A1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A1 contains one or more heteroatoms selected from N and O, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In some embodiments, a compound of the disclosure is of the following structural Formula VI:
  • Formula VI
  • Ring Y2 is 4-or 5-membered nitrogen heterocyclyl;
  • Ring Y3 is 4-, 5-or 6-membered nitrogen heterocyclyl;
  • R4 substitution occurs on any of the ring atoms of Ring Y2 and/or Ring Y3, as long as valence permits; 
  • when Z4 is CH, X is -C (=O) NRn-or -Rm-C (=O) NRn-Ro-;
  • when Z4 is N, X is absent, -CRkRL-, or -C (=O) -; and
  • when Z5 is CH, Z is -NRg-、-C (RhRi) -NRg-、-NRg-C (RhRi) -０-O-;
  • when Z5 is N, Z is absent, and all other variables not specifically defined herein are as defined in the first embodiment. In some embodiments, Z4 and Z5 are N, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein R3 iswherein Ring A1, X1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein R3 iswherein X1 is -CH2-, -NH-or -O-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein R3 iswherein X1 is -NH-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein R3 iswherein X1 is -NH-, and Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein R3 iswherein X1 is -NH-, and Ring A1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the  heterocycloalkyl of Ring A1 contains one or more heteroatoms selected from N and O, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein Ring A is 10-membered nitrogen heteroaryl, and R3 iswherein Ring A1, X1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein Ring A is 10-membered nitrogen heteroaryl, and R3 iswherein X1 is -CH2-, -NH-or -O-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein Ring A is 10-membered nitrogen heteroaryl, and R3 iswherein X1 is -NH-, and Ring A1, X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, R3 iswherein X1 is -NH-, and Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In one embodiment of formula VI, wherein Ring A is 10-membered nitrogen heteroaryl, and R3 is wherein X1 is -NH-, and Ring A1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A1 contains one or more heteroatoms selected from N and O, and X2, X3, R3’ and m are as defined in the first embodiment.
  • In some embodiments, Z4 is in the meta position to the spiro atom, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Z5 is in the meta position to the spiro atom, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Y isU1, U2, and U4 are CH2; U3 is NH; T1 and T2 are N, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Y isT1, T2 and T4 are N; T3 is CH; U1, U2 and U3 are CH2, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Ring Y is and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Ring Y is and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the moietyis and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the moietyis  and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the moietyis and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the moietyis and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Rk is H, RL is CF3, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Rm is -CH2-, Ro is absent, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Ro is -CH2-, Rm is absent, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the compound is of the following structural Formula VII:
  • Y iswherein: Z1 is CH, or Z4 is CH, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Rn is H, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the compound is of the following structural Formula VIII:

  • Z1 or Z4 is N, Y iswherein: and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Ring A is
  • for each Ring A group, W1, W2, W3, W4, W5 and W6 are each independently N or CH; for each Ring A group, V1 and V2 are each independently NH or CH2, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Ring A is
  • for each Ring A group, W1, W2, W3, W4, W5 and W6 are each independently N or CH; for each Ring A group, V1 and V2 are each independently NH or CH2, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Ring A is pyridinyl, pyrimidinyl, pentanolactam, butyrolactam, glutarimide, triazolyl, tetrazolyl, isoquinolinyl, quinolinyl, pyridin-2 (1H) -one, quinolin-2 (1H) -one, 3, 4-dihydroquinolin-2 (1H) -one, naphthyridinyl, pyrrolopyridinyl, or imidazopyridinyl, wherein the pyridinyl, pyrimidinyl, pentanolactam, butyrolactam, glutarimide, triazolyl, tetrazolyl, isoquinolinyl, quinolinyl, pyridin-2 (1H) -one, quinolin-2 (1H) -one, 3, 4-dihydroquinolin-2 (1H) -one, naphthyridinyl, pyrrolopyridinyl, or imidazopyridinyl substituted by t groups of R5, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, Ring A is wherein Ring A is substituted by t groups of R5, the substitution occurs on any of atoms of the Ring A, as long as valence permits, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the moietyis and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the moietyis and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the 5-or 6-membered heteroaryl of R5 is pyrrolyl, pyrazolyl, or imidazolyl, and all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, the 5-or 6-membered heteroaryl of R5 isand all other variables not specifically defined herein are as defined in the first embodiment.
  • In some embodiments, when R3 is -C (=O) NHCH3, Ring A isn’t isoquinolinyl; or when Ring A is isoquinolinyl, R3 isn’t -C (=O) NHCH3, and all other variables not specifically defined herein are as defined in the first embodiment.
  • Ring Y isn’t cyclohexyl, 6-membered nitrogen heterocyclyl, 5-membered nitrogen heterocyclyl or diazaspiro [4.4] , and all other variables not specifically defined herein are as  defined in the first embodiment.
  • In some embodiments, When X is absent, Ring Y is and all other variables not specifically defined herein are as defined in the first embodiment.
  • In certain embodiments, the at least one compound of the disclosure is selected from Compounds 1 to 183 depicted in Table 1, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing.
  • Table 1. Compounds 1 to 183













  • Table 2. Activities of Compounds 1-183 (inhibition of SARS-CoV-2 3CLpro (IC50) and inhibition of SARS-CoV-2 replication (EC50) in mammalian cells)

    ****: IC50< 100 nM ***: 100 nM≤ IC50< 1 μM **: 1μM≤IC50< 10 μM *: IC50≥10 μM
    ++++: EC50< 100 nM +++: 100 nM≤ EC50< 1 μM ++: 1μM≤EC50< 10 μM +: EC50≥10 μM
  • Another aspect of the disclosure provides a pharmaceutical composition comprising at least one compound selected from a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, and at least one pharmaceutically acceptable carrier.
  • In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.
  • It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising an additional active pharmaceutical agent. For example, the additional active pharmaceutical agents that can be used in combination with a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt according to the present invention include but are not limited to one or more of the following: an interferon or a pegylated form thereof, remdesivir, galidesivir, favilavir, favipiravir, tenofivir, boceprevir, Ribavirin, β-Thymidine, Chlorhexidine, clevudine, dalcetrapib, dexamethasone, hydrocortisone, monoclonal antibodies such as regdanvimab, ravulizumab, bamlanivimab, mavrilimab, leronlimab lenzilumab, infliximab, adalimumab, lanadelumab, canakinumab, gimsilumab, otilimab, tocilizumab, and sarilumab, abivertinib, bemcentinib, acalabrutinib, baricitinib, tofacitinib, chloroquine, hydroxychloroquine, and azithromycin.
  • As described above, the pharmaceutical compositions disclosed herein comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The pharmaceutically acceptable carrier, as used herein, can be chosen, for example, from any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, which are suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams &Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component (s) of the pharmaceutical  composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin) , buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate) , partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts) , colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose) , starches (such as corn starch and potato starch) , cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate) , powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes) , oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil) , glycols (such as propylene glycol and polyethylene glycol) , esters (such as ethyl oleate and ethyl laurate) , agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide) , alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) , coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.
  • The pharmaceutical compositions of the present disclosure may be formulated in the form of tablets, hard or soft gelatin capsules, powders, granules, a solutions or suspension in an aqueous or non-aqueous liquid, sterile injectable preparation, nasal or eye drops, or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The desired dosage forms may be formulated according to the known art using the suitable excipients commonly used in the pharmacy. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • III. Methods of Treatment and Uses
  • In another aspect of this disclosure, provided is a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for use in treating a disease and/or a symptom of a disease caused by a coronavirus. In another aspect, disclosed herein is use of a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or  Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease and/or a symptom or a disease caused by a coronavirus. In yet another aspect, disclosed herein is a method of treating a disease and/or a symptom of a disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof. The compounds of the present invention can be used in the methods of the invention in combination with an additional active pharmaceutical agent. For example, the additional active pharmaceutical agents that can be used in combination with the compounds of the present invention include but are not limited to one or more of the following: an interferon or a pegylated form thereof, remdesivir, galidesivir, favilavir, favipiravir, tenofivir, boceprevir, Ribavirin, β-Thymidine, Chlorhexidine, clevudine, dalcetrapib, dexamethasone, hydrocortisone, monoclonal antibodies such as regdanvimab, ravulizumab, bamlanivimab, mavrilimab, leronlimab lenzilumab, infliximab, adalimumab, lanadelumab, canakinumab, gimsilumab, otilimab, tocilizumab, and sarilumab, abivertinib, bemcentinib, acalabrutinib, baricitinib, tofacitinib, chloroquine, hydroxychloroquine, and azithromycin.
  • In some embodiments, the disease caused by a coronavirus is a respiratory tract infection. In some embodiments, the disease caused by a coronavirus is a severe acute respiratory syndrome. In one embodiment, the disease caused by a coronavirus is COVID-19. In one embodiment, the disease caused by a coronavirus that is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . In some embodiments, the symptom of a disease caused by a coronavirus is selected from fever or chills, cough, shortness of breath or difficulty in breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhea, persistent pain or pressure in the chest, new confusion, inability to wake or stay awake, bluish lips or face, and a combination thereof.
  • In another aspect of this disclosure, a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, is for use in reducing or inhibiting the activity of a protease of a coronavirus. In another aspect, disclosed herein is use of a compound, solvate, tautomer,  stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for reducing or inhibiting the activity of a protease of a coronavirus. In yet another aspect, disclosed herein is a method of reducing or inhibiting the activity of a protease of a coronavirus, comprising administering a therapeutically effective amount of a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein to a subject, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof. In yet another aspect, disclosed herein is a method of reducing or inhibiting the activity of a protease of a coronavirus, comprising contacting said coronavirus or said protease with a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein to a subject, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof. In one embodiment, the protease of a coronavirus is a 3C-like protease. In one embodiment, the coronavirus is SARS-CoV-2.
  • In another aspect of this disclosure, a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, is for use in reducing or inhibiting the replication of a coronavirus. In another aspect, disclosed herein is use of a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for reducing or inhibiting the replication of a coronavirus. In yet another aspect, disclosed herein is a method of reducing or inhibiting the replication of a coronavirus, comprising administering a therapeutically effective amount of a compound, solvate, tautomer, stereoisomer, deuterated derivative, or  pharmaceutically acceptable salt as described herein to a subject, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof. In yet another aspect, disclosed herein is a method of reducing or inhibiting the replication of a coronavirus, comprising contacting said coronavirus or a protease of the coronavirus with a compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt as described herein to a subject, including a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof. In one embodiment, the protease of a coronavirus is a 3C-like protease. In one embodiment, the coronavirus is SARS-CoV-2.
  • A compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof may be administered once daily, twice daily, or three times daily, for example, for the treatment of a disease and/or a symptom of a disease caused by a coronavirus, for example, SARS-CoV-2.
  • In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof are administered once daily, twice daily, or three times daily.
  • A compound of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof may be administered, for example, by oral, parenteral, sublingual, topical, rectal, nasal, buccal, vaginal, transdermal, patch, pump administration or via an implanted reservoir, and a pharmaceutical compositions would be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time. Other forms of administration contemplated in this disclosure are as described in International Patent Application Nos. WO 2013/075083, WO 2013/075084, WO 2013/078320, WO 2013/120104, WO 2014/124418, WO 2014/151142, and WO 2015/023915.
  • One or more of the compounds of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof may be administrated in combination with one or more additional pharmaceutical agents, for example, additional anti-SARS-CoV-2 agents or additional inhibitors of proteases of Coronaviridae viruses.
    • Examples
  • In order that the disclosure described herein may be more fully understood, the following examples are disclosed herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any way.
  • Example 1. Design of 3CLpro inhibitors
  • A series of non-covalent inhibitors of SARS-CoV-2 3CLpro (Table 1) were designed based on the compounds identified in a previous study (6) .
  • Example 2. Synthesis of Exemplary Compounds
  • The compounds of the disclosure may be made according to standard chemical practices or as described herein, including the following synthetic schemes and in the descriptions for preparing a compound selected from compounds of Formulae I, II-1, II-2, II-3, II-4, II-5, III, IV, V, VI, VII, VIII, or Compounds 1 to 183, a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing.
  • Synthesis of compounds 1 to 5, 7 to 9, 55 and 72
  • Intermediate I-1: 5-bromo-2-fluoro-N-methyl-3-nitrobenzamide
  • To a solution of 5-bromo-2-fluoro-3-nitrobenzoic acid (2.64 g, 10 mmol) in DCM (20.0 mL) , DIPEA (5.0 mL, 30 mmol) , HATU (5.7 g, 15 mmol) and methylamine hydrochloride (0.81 g, 12 mmol) were added and the reaction was stirred at 0 ℃ for 2 hr. The reaction mixture was poured into H2O (50.0 mL) and then extracted with DCM (50.0 mL*3) . The combined organic layer was washed with brine (50.0 mL*2) , dried over Na2SO4 and concentrated to give crude product which was purified by Flash Chromatography eluting with ethyl acetate in petroleum ether to afford the title compound (2.6 g, 94%yield) as a yellow solid. LC-MS (ESI) (M+H) + = 277.1.
  • Intermediate I-2: tert-butyl ( (1S, 2R) -2- ( (4-bromo-2- (methylcarbamoyl) -6-nitrophenyl) amino) cyclohexyl) carbamate
  • To a solution of 5-bromo-2-fluoro-N-methyl-3-nitrobenzamide (2.6 g, 9.4 mmol) in DMF (30 mL) , tert-butyl ( (1S, 2R) -2-aminocyclohexyl) carbamate (2.22 g, 10.4 mmol) and DIPEA (4.66 mL, 28.2 mmol) were added and the reaction was stirred at 80 ℃ for 14 hr. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL*3) . The combined organic layer was washed with brine (50 mL*2) , dried over Na2SO4 and concentrated under reduced pressure to obtain crude product (yellow solid) . The residue was used directly without further purification.
  • Intermediate I-3: 2- ( ( (1R, 2S) -2-aminocyclohexyl) amino) -5-bromo-N-methyl-3-nitrobenzamide
  • To a solution of tert-butyl ( (1S, 2R) -2- ( (4-bromo-2- (methylcarbamoyl) -6-nitrophenyl) amino) cyclohexyl) carbamate (400 mg, 0.84 mmol) in DCM (4.0 mL) , 4 N HCl in dioxane (2.6 mL) was added and the reaction was stirred at 25 ℃ for 2 hr. The reaction mixture was dried in vacuo to afford the 2- ( ( (1R, 2S) -2-aminocyclohexyl) amino) -5-bromo-N-methyl-3-nitrobenzamide (290 mg, 0.78 mmol, 73%yield) as a yellow solid. LC-MS (ESI) (M+H) + = 371.1
  • Compounds 1-5, 7-9, 55 and 72:
  • To a solution of 2- ( ( (1R, 2S) -2-aminocyclohexyl) amino) -5-bromo-N-methyl-3-nitrobenzamide (1.0 equiv) in DMF (5 mL) , DIPEA (5.0 equiv) , corresponding acid R1COOH (1.0 equiv) and HATU (2.0 equiv) were added and the reaction was stirred at 25 ℃ for 12 hr. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL*3) . The combined organic layer was washed with saturated salt water (3*20 mL) . The organic layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The residue was purified by Prep-HPLC to give the target compound as a yellow solid.

  • Synthesis of compounds 108, 121, 122, 179 and 180
  • Intermediates I-4 and I-5:
  • Intermediates I-4 and I-5 were synthesized using the same route of intermediate I-3.
  • Compound 108 and intermediate I-6:
  • The procedure for making compounds 108 and intermediate I-6 is similar to the synthetic procedure of compound 1.
  • Compounds 121, 122, 179 and 180:
  • Intermediate I-6 was further separated by SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um) ) to give compounds 121, 122, 179 and 180.

  • Synthesis of compound 57
  • The synthesis route of compound 57 is similar to that of compound 1 using 5-bromo-2-fluoro-3- (methylsulfonyl) benzoic acid as the start material.
  • Synthesis of compound 6
  • Compound 6: 5- (aminomethyl) -N- ( (1S, 2R) -2- ( (4-bromo-2- (methylcarbamoyl) -6-nitrophenyl) amino) cyclohexyl) nicotinamide
  • Compound 5 (45 mg, 0.07 mmol) was dissolved in 5 mL of DCM, and 2 ml of TFA was added. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed  and the residue was neutralized with aqueous NaHCO3 and extracted with ethyl acetate, followed by washing with saturated brine solution. The organic layer was dried on anhydrous Na2SO4. The solution was concentrated and purified by flash silica chromatography to give the target product (35 mg, 93%yield) as a yellow solid.
  • Synthesis of compounds 10, 13, 18, 20, 58, 62, 63, 64, 66, 70, 75, 77, 87, 88, 99, 127, 129, 131, 132 and 141
  • Intermediate II-1:
  • DIPEA (3.0 equiv) was added to a solution of 5-bromo-2-fluoro-N-methyl-3-nitrobenzamide (1.0 equiv) and a corresponding linker (1.2 equiv) in DMF (1 mL) , and the reaction was stirred at 80 ℃ for 12 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3*10 mL) . The organic layer was separated, washed with water and further saturated NaCl solution (3*10 mL) , and dried over Na2SO4, then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to afford intermediate II-1 as a yellow solid.
  • Intermediate II-2:
  • To a solution of intermediate II-1 (0.2～0.5 mmol) in DCM (1 mL) was added TFA (1 mL) , and the reaction was stirred at room temperature for 2 hr. The reaction was concentrated under reduced pressure to give intermediate II-2 as a yellow solid.
  • Compounds 10, 13, 18, 20, 58, 62, 63, 64, 66, 70, 75, 77, 87, 88, 99, 127, 129, 131, 132 and 141:
  • To a solution of intermediate II-2 (1.0 equiv) in DMF, isoquinoline-4-carboxylic acid (1.2 equiv) , DIPEA (3.0 equiv) and HATU (2.0 equiv) were added and the reaction was stirred at room temperature for 12 hr. The reaction was diluted with water and extracted with EtOAc three times. The organic layer was separated, washed with water and further saturated NaCl solution, and dried over Na2SO4, then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to afford the target compounds as yellow solids.




  • Synthesis of compounds 12, 15, 28 and 31
  • Compound 99 or 77 was separated by chiral SFC (column: ChiralPak AD (250 mm*30 mm, 10 μm) ; mobile phase: [CO2-EtOH] ; B%: 15%-15%, 1.556; 20 min) to give compound 12 and compound 15 or compound 28 and compound 31 as yellow solids. 

  • Synthesis of compound 21
  • The synthesis route of compound 21 is similar to that of compound 10.
  • Synthesis of compounds 11, 25, 67, 74 and 138
  • Intermediate III-1:
  • To a solution of corresponding linker (1.0 equiv) , isoquinoline-4-carboxylic acid (1.2 equiv) and DIPEA (3.0 equiv) in DMF (1 mL) , HATU (1.1 equiv) was added and the reaction was stirred at room temperature for 12 hr. The reaction was diluted with water (5 mL) and extracted with EtOAc (3*10 mL) . The organic layer was separated, washed with water and further saturated NaCl solution (3*10 mL) , and dried over Na2SO4, and then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to afford intermediate III-1.
  • Intermediate III-2:
  • To a solution of intermediate III-1 in DCM (2 mL) , HCl in dioxane or TFA was added and the reaction was stirred at room temperature for 2 hr. The reaction was concentrated under reduced pressure to give intermediate III-2 without further purification.
  • Compounds 11, 25, 67, 74 and 138:
  • To a solution of intermediates III-2 (1.0 equiv) and 5-bromo-2-fluoro-N-methyl-3-nitrobenzamide (1.2 equiv) in DMF (2 mL) , DIPEA (3.0 equiv) was added and the reaction as stirred at 80 ℃ for 12 hr. The reaction was diluted with water (5 mL) and extracted with EtOAc (3*10 mL) . The organic layer was separated, washed with water and further saturated NaCl solution (3*10 mL) , and dried over Na2SO4, and then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to afford the target compounds as yellow solids.

  • Synthesis of compounds 14, 16, 51, 52, 53, 54, 56, 59, 60, 61, 68 and 85
  • Intermediate IV-1: methyl 5-bromo-2-fluoro-3-nitrobenzoate
  • Thionyl chloride (0.4 mL, 5.68 mmol) was added to a solution of 5-bromo-2-fluoro-3-nitrobenzoic acid (500 mg, 1.89 mmol) in MeOH (5.0 mL) , and the reaction was stirred at room temperature for 16 hr. The reaction was concentrated in vacuo to get a solid, which was triturated  with PE to afford the title compound (450 mg, 85%yield) as a yellow solid.
  • LC-MS (ESI) (M+H) + = 278.0.
  • Intermediate IV-2: methyl 5-bromo-2- ( ( (1R, 2S) -2- ( (tert-butoxycarbonyl) amino) cyclohexyl) amino) -3-nitrobenzoate
  • To a solution of methyl 5-bromo-2-fluoro-3-nitrobenzoate (50 mg, 0.18 mmol) in DMF (2.0 mL) , tert-butyl ( (1S, 2R) -2-aminocyclohexyl) carbamate (58 mg, 0.27 mmol) and DIPEA (0.1 mL, 0.54 mmol) were added and the reaction was stirred at 80 ℃ for 16 hr. The reaction was diluted with water (50.0 mL) and extracted with EtOAc (3*50.0 mL) . The organic layer was separated, washed with water and further saturated NaCl solution (3*30.0 mL) , and dried over Na2SO4, and then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (EtOAc : PE=1 : 2) to afford the title compound (75 mg, 88%yield) as a yellow solid.
  • LC-MS (ESI) (M+H) + = 472.1.
  • Intermediate IV-3: methyl 2- ( ( (1R, 2S) -2-aminocyclohexyl) amino) -5-bromo-3-nitrobenzoate
  • To a solution of methyl 5-bromo-2- ( ( (1R, 2S) -2- ( (tert-butoxycarbonyl) amino) cyclohexyl) amino) -3-nitrobenzoate (75 mg, 0.16 mmol) in DCM (2.0 mL) , 4N HCl in dioxane (4.0 mL, 4.0 mol/L) was added and the reaction was stirred at room temperature for 2 hr. The reaction was dried in vacuo to afford the title compound (80 mg, crude) as a yellow solid.
  • LC-MS (ESI) (M+H) + = 372.1.
  • Intermediate IV-4 (compound 51) : methyl 5-bromo-2- ( ( (1R, 2S) -2- (isoquinoline-4-carboxamido) cyclohexyl) amino) -3-nitrobenzoate
  • To a solution of methyl 2- ( ( (1R, 2S) -2-aminocyclohexyl) amino) -5-bromo-3-nitrobenzoate (80 mg, Crude) in DMF (2.0 mL) , isoquinoline-4-carboxylic acid (118 mg, 0.68 mmol) , DIPEA (0.3 mL, 1.71 mmol) and HATU (194 mg, 0.51 mmol) were added and the reaction was stirred at room temperature for 16 hr. The reaction was diluted with water (50.0 mL) and extracted with EtOAc (3*20.0 mL) . The combined organic layer was washed with NH4Cl solution (20.0 mL) , NaHCO3 solution (20.0 mL) , water (20.0 mL) and further saturated NaCl solution (20.0 mL) , and it was dried over Na2SO4, and then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (EtOAc : PE=1 : 2) to afford the title compound (100 mg, 88%yield, 2 steps) as a yellow solid.
  • Intermediate IV-5 (compounds 52) : 5-bromo-2- ( ( (1R, 2S) -2- (isoquinoline-4-carboxamido) cyclohexyl) amino) -3-nitrobenzoic acid
  • To a solution of methyl 5-bromo-2- ( ( (1R, 2S) -2- (isoquinoline-4-carboxamido) cyclohexyl) amino) -3-nitrobenzoate (100 mg, 0.19 mmol) in MeOH/H2O (v/v = 5/1,  6 mL) , NaOH (82 mg, 2.05 mmol) was added and the reaction was stirred at 55 ℃ for 16 hr. The reaction mixture was quenched with 1N HCl to pH 3 and then extracted with EtOAc (50 mL) . The EtOAc layer was dried over Na2SO4 and dried in vacuo to afford the title compound (71 mg, 73%yield) as a yellow solid.
  • Compounds 14, 16, 56, 59, 60, 61, 68 and 85:
  • To a solution of 5-bromo-2- ( ( (1R, 2S) -2- (isoquinoline-4-carboxamido) cyclohexyl) amino) -3-nitrobenzoic acid (1.0 equiv) in DMF (2.5 mL) , corresponding amine (1.2 equiv) , HATU (1.5 equiv) and DIPEA (3.0 equiv) were added and the reaction was stirred at room temperature overnight. The reaction was diluted with water (50.0 mL) and extracted with EtOAc (3*20.0 mL) . The organic layer was separated, washed with water, NH4Cl solution (20 mL) , NaHCO3 solution (20 mL) and further saturated NaCl solution (20 mL) , and it was dried over Na2SO4 and concentrated in vacuo. The residue was purified using prep-TLC with ethyl acetate in petroleum ether and Prep-HPLC to give the target compounds as yellow solids.
  • Compound 53
  • Compound 51 (53 mg, 0.1 mmol) was added to 7 N NH3 in method (5.0 mL) and the reaction was stirred at 55 ℃ overnight under Ar atmosphere. The reaction was concentrated in vacuo and then purified using silica gel column chromatography eluting with methanol in DCM to give compound 53 (17 mg, 33.3%yield) as a yellow solid.
  • Compound 54
  • Hydrazine monohydrate (2.0 mL) was added to a solution of compound 51 (100 mg, 0.19 mmol) in methanol (10.0 mL) . The solution was stirred at room temperature for 4 hr. The solvent was removed under vacuum. The residue was resuspended with EtOAc and washed with NaHCO3 solution and further saturated NaCl solution. The organic layer dried over Na2SO4 was concentrated in vacuo and purified by silica gel column chromatography eluting with methanol in DCM to give compound 54 (40 mg, 40%yield) as a yellow solid.



  • Synthesis of compounds 27, 29 and 78
  • The synthesis route of compound 27 and 78 is similar to that of compound 14.
  • Synthesis of compounds 116, 117, 124, 128 and 130
  • Intermediates V-1～V-4:
  • The synthetic procedures of intermediates V-1～V-4 are similar to that of intermediates IV-2～ IV-5.
  • Compounds 116, 117, 124, 128 and 130
  • The synthetic procedure is similar to the last step of the synthesis route of compound 14.

  • Synthesis of compound 17
  • Intermediate V-5: 5-bromo-2- ( (1- (1- (isoquinoline-4-carbonyl) azetidin-3-yl) -2-methylpropyl) amino) -3-nitrobenzamide
  • To a solution of intermediate V-4 (200 mg, 0.38 mmol) and NH4Cl (41 mg, 0.76 mmol) in DMF (5.0 mL) , DIPEA (147 mg, 1.14 mmol) and HATU (173 mg, 0.46 mmol) were added and the reaction was stirred at room temperature for 4 h. The reaction mixture was poured into water (50.0 mL) and then extracted with EtOAc (30.0 mL*3) . The combined organic layer was washed with brine (30.0 mL*3) , dried over Na2SO4 and concentrated to give a crude product, which was purified by Flash Chromatography eluting with methanol in DCM (MeOH : DCM=1 :  40) to afford the title compound (190 mg, 95%yield) as a light yellow liquid. LC-MS (ESI) (M+H) + = 526.1.
  • Intermediate V-6: (E) -5-bromo-N- ( (dimethylamino) methylene) -2- ( (1- (1- (isoquinoline-4-carbonyl) azetidin-3-yl) -2-methylpropyl) amino) -3-nitrobenzamide
  • A solution of 5-bromo-2- ( (1- (1- (isoquinoline-4-carbonyl) azetidin-3-yl) -2-methylpropyl) amino) -3-nitrobenzamide (190 mg, 0.36 mmol) in DMF-DMA (5.0 mL) was stirred at 120 ℃ for 4 hr. The reaction mixture was poured into water (50.0 mL) and then extracted with EtOAc (30.0 mL*3) . The combined organic layer was washed with brine (30.0 mL*3) , dried over Na2SO4 and concentrated to give a crude product, which was purified by Flash Chromatography eluting with methanol in DCM (MeOH : DCM=1 : 40) to afford the title compound (200 mg, 95%yield) as a light yellow liquid. LC-MS (ESI) (M+H) + = 581.2.
  • Compound 17: (3- (1- ( (4-bromo-2-nitro-6- (4H-1, 2, 4-triazol-3-yl) phenyl) amino) -2 -methylpropyl) azetidin-1-yl) (isoquinolin-4-yl) methanone
  • Hydrazine monohydrate (13 mg, 0.41 mmol) was added to a solution of intermediate V-6 (200 mg, 0.34 mmol) in HOAc (5.0 mL) . The solution was stirred at 120 ℃ for 2 h. The solvent was removed under vacuum. The residue was purified by prep-HPLC to give compound 17 (67.0 mg, 36%yield) as a yellow solid.
  • Synthesis of compound 65
  • Intermediate VI-1: 5-bromo-N- (2, 2-dimethoxyethyl) -2-fluoro-3-nitrobenzamide
  • EDCI (1.09 g, 5.69 mmol) , HOBT (767 mg, 5.69 mmol) and DIPEA (1.47 g, 11.37 mmol) were added to a solution of 5-bromo-2-fluoro-3-nitrobenzoic acid (1.00 g, 3.79 mmol) and 2, 2-dimethoxyethan-1-amine (478 mg, 4.55 mmol) in DMF (15 mL) . The reaction mixture was stirred for 2 hr. The reaction mixture was poured into water (20 mL) , and extracted with EtOAc (20 mL x 2) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by Flash Chromatography eluting with ethyl acetate in petroleum ether (EtOAc : PE=1 : 5) to afford the title compound (480 mg, 36%yield) as a yellow solid. LC-MS (ESI) (M+H) + = 351.1.
  • Intermediate VI-2: 2- (5-bromo-2-fluoro-3-nitrophenyl) oxazole
  • To a solution of intermediate VI-1 (480 mg, 1.37 mmol) in MeSO3H (5 mL) , P2O5 (777 mg, 5.48 mmol) was added. The reaction mixture was heated and stirred at 140 ℃ for 6 hr. After cooling to room temperature, the reaction mixture was poured into ice-water (20 mL) and extracted with EtOAc (20 mL x 2) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by Flash Chromatography eluting with ethyl acetate in petroleum ether (EtOAc : PE=1 : 3) to afford the title compound (180 mg, 45%yield) as a yellow solid. LC-MS (ESI) (M+H) + =287.1.
  • Intermediates VI-3～VI-4:
  • The synthetic procedures of intermediate VI-3～VI-4 are similar to that of intermediate I-2～ I-3.
  • Compound 65: (3- (1- ( (4-bromo-2-nitro-6- (oxazol-2-yl) phenyl) amino) -2-methylpropyl) azetidin-1-yl) (isoquinolin-4-yl) methanone
  • The synthesis of compound 65 is similar to that of intermediate IV-4.
  • Synthesis of compounds 71 and 73

  • Synthesis of compounds 19, 33, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 91, 93, 94, 95, 111, 112, 139, 142, 143, 147, 148, 149, 151, 152, 153, 154, 155, 156, 157, 158 and 159
  • Intermediates VII-1-1 and VII-1-2 (compound 153) :
  • The synthetic procedures of intermediates VII-1-1 and VII-1-2 are similar to that of intermediate IV-5.
  • Compounds 19, 33, 36, 37, 38, 40, 41, 42, 43, 44, 45, 47, 48, 91, 93, 94, 111, 112, 139, 142, 143, 147, 148, 149, 151, 152, 154, 155, 156, 157, 158 and 159:
  • Method 1: Corresponding amine (1.05 equiv) , TEA (5.0 equiv) and T3P (2.0 equiv) were added to a solution of intermediate VII-1-1 or VII-1-2 (1.0 equiv) in DCM, and stirred at room temperature for 2 hr. The reaction mixture was poured into water and then extracted with DCM three times. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give a crude product which was purified by prep-HPLC to give the target compounds as yellow solids.
  • Method 2: To a solution of intermediate VII-1-1 or VII-1-2 (1.0 equiv) in DMF (2.5 mL) , corresponding amine (1.2 equiv) , HATU (1.5 equiv) and DIPEA (3.0 equiv) were added and the reaction was stirred at room temperature overnight. The reaction was diluted with water (50.0 mL) and extracted with EtOAc (3*20.0 mL) . The organic layer was separated, washed with water, NH4Cl solution (20 mL) , NaHCO3 solution (20 mL) and further saturated NaCl solution (20 mL) , and it was dried over Na2SO4 and concentrated in vacuo. The residue was purified using prep-TLC with ethyl acetate in petroleum ether and Prep-HPLC to give the target compounds as yellow solids.
  • Compounds 46 and 95:
  • Compounds 46 and 95 were synthesized from VII-1-2 with two steps (step1: described in method 1 of compound 19, step 2: described in the procedure of I-3) .





  • Synthesis of compounds 150
  • Intermediate VII-2: 5-bromo-2- [ [ (3S) -4, 4-difluoro-1- (isoquinoline-4-carbonyl) pyrrolidin-3-yl] amino] -3-nitro-benzoic acid
  • The synthetic procedure of intermediate VIII-2 is similar to that of intermediate IV-5.
  • Compounds 150:
  • Compound 150 was synthesized from VII-1-2 with two steps (step1: described in method 1 of compound 19, step 2: described in the procedure of I-3) .
  • Synthesis of compounds 35, 82, 83, 84, 118, 144, 160, 164, 165, 172, 173 and 182
  • Intermediates VIII-1～ VIII-3:
  • The synthetic procedures of intermediates VIII-1～ VIII-3 are similar to that of intermediate IV-2～ IV-4.
  • Intermediate VIII-4:
  • To a solution of intermediate VIII-3 (1.0 equiv) in EtOH/H2O=4: 1 (10 mL) , Fe (8.0 equiv) and NH4Cl (8.0 equiv) were added and the reaction was stirred at 40 ℃ for 16 hr. The reaction was filtered through a celite pad, and the filtrate was concentrated to give the crude product. The crude product was resuspended with water and extracted with EtOAc (50 mL*3) . The organic layer was separated, and washed with saturated NaCl solution. The combined organic layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel chromatography eluted with ethyl acetate in petroleum ether to afford intermediate VIII-4.
  • Intermediate VIII-5:
  • t-BuONO (3.0 equiv) was slowly added to a solution of intermediate VIII-4 (1.0 equiv) in CH3CN (2 mL) for 20 min, then CuX (5.0 equiv) was added and the reaction mixture was stirred at 70 ℃ for 2 hr. The reaction was concentrated under vacuum then added water (20 mL) and extracted with EtOAc (30 mL*3) . The organic layer was separated, and washed with saturated NaCl solution. The combined organic layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel chromatography eluted with ethyl acetate in petroleum ether to afford intermediate VIII-5.
  • Intermediate VIII-6:
  • The synthetic procedure of intermediate VIII-6 is similar to that of intermediate IV-5.
  • Compounds 35, 82, 83, 84, 118, 144, 160-1, 164, 165, 172, 173 and 182:
  • The synthetic procedure is similar to the last step of the synthesis route of compound 14.
  • Compound 160: 5-bromo-2- [ [ (3S) -4, 4-difluoro-1- (isoquinoline-4-carbonyl) -3-piperidyl] amino] -N- [ (3R) -pyrrolidin-3-yl] -3- (trifluoromethyl) benzamide
  • Compound 160 was obtained by removing protective group Boc using HCl in dioxane described in the procedure of intermediate I-3.



  • Synthesis of compounds 109, 110, 145, 146, 167 and 183
  • Intermediates VIII-7, VIII-8 and VIII-9:
  • The synthetic procedures of intermediate VIII-7, VIII-8 and VIII-9 are similar to that of intermediate VIII-6.
  • Compounds 109, 110, 145, 146, 167 and 183:
  • The synthetic procedure is similar to the last step of the synthesis route for compound 14.

  • Synthesis of compounds 22, 23, 24, 26, 76 and 115
  • The synthetic procedures are similar to compound 1.

  • Synthesis of compounds 79 and 80
  • Compounds 79 and 80 were synthesized using a similar synthetic route for compound 22.
  • Synthesis of compounds 134 and 137
  • Compounds 134 and 137 were synthesized using a similar synthesis route of compound 22.
  • Synthesis of compound 30
  • Compound 30: (R) -5-bromo-N- (3, 3-difluorocyclobutyl) -2- ( (5- (isoquinoline-4-carbonyl) -5-azaspiro [2.4] heptan-7-yl) amino) -3-nitrobenzamide
  • To a solution of intermediate IX-1 (95 mg, 0.27 mmol) and (R) - (7-amino-5-azaspiro [2.4] heptan-5-yl) (isoquinolin-4-yl) methanone (60 mg, 0.22 mmol) in DMF (2.0 mL) , DIPEA (0.1 mL, 0.67 mmol) was added and the reaction was stirred at 80 ℃ at N2 atmosphere for 16 hr. The reaction mixture was poured into water and then extracted with EtOAc (20.0 mL*3) . The combined organic layer was washed with brine (20.0 mL*3) , dried over Na2SO4 and concentrated to give a crude product, which was purified by Flash Chromatography eluting with EtOAc in PE (PE: EtOAc=2 : 1) and prep-HPLC to give compound 30 (2.0 mg, 2%yield) as a yellow solid.
  • Synthesis of compound 32
  • Intermediate X-1: tert-butyl (S) - (4, 4-difluoro-1- (isoquinolin-4-ylmethyl) piperidin-3-yl) carbamate
  • To a solution of tert-butyl (S) - (4, 4-difluoropiperidin-3-yl) carbamate (2.0 g, 8.47 mmol) and isoquinoline-4-carbaldehyde (1.30 g, 8.47 mmol) in MeOH (30.0 mL) , HOAc (60 mg, 1 mmol) and NaBH3CN (1.06 g, 16.94 mmol) were added and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water and then extracted with EtOAc (50.0 mL*3) . The combined organic layer was washed with brine (50.0 mL*3) , dried over Na2SO4 and concentrated to give a crude product which was purified by Flash Chromatography eluting with ethyl acetate in petroleum ether (EtOAc : PE=1 : 10) to afford the title compound (3.0 g, 97%yield) as a light yellow liquid. LC-MS (ESI) (M+H) + = 378.1.
  • Intermediate X-2: (S) -4, 4-difluoro-1- (isoquinolin-4-ylmethyl) piperidin-3-amine
  • The synthetic procedure is similar to that of intermediate I-3.
  • Compound 32: (S) -5-bromo-2- ( (4, 4-difluoro-1- (isoquinolin-4-ylmethyl) piperidin-3-yl) amino) -N-methyl-3-nitrobenzamide
  • DIPEA (136 mg, 1.05 mmol) was added to a solution of intermediate X-2 (60 mg, 0.21 mmol) and 5-bromo-2-fluoro-N-methyl-3-nitrobenzamide (59 mg, 0.21 mmol) in DMF (2.0 mL) . The solution was stirred at 80 ℃ for 16 hr. The reaction mixture was poured into water and then extracted with EtOAc (30.0 mL*3) . The combined organic layer was washed with brine (30.0 mL*3) , dried over Na2SO4 and concentrated to give a crude product which was purified by prep-HPLC to give compound 32 (39.4 mg, 35%yield) as a yellow solid.

  • Synthesis of compounds 34, 81 and 125
  • Intermediate XI-1: tert-butyl (R) - (1- (isoquinoline-4-carbonyl) piperidin-3-yl) carbamate
  • The synthetic procedure is similar to that of intermediate III-1.
  • Intermediate XI-2: (R) - (3-aminopiperidin-1-yl) (isoquinolin-4-yl) methanone
  • The synthetic procedure is similar to that of intermediate I-3.
  • Intermediate XI-3: methyl (R) -5-bromo-2- ( (1- (isoquinoline-4-carbonyl) piperidin-3-yl) amino) -3-nitrobenzoate
  • The synthetic procedure is similar to that of intermediate I-2.
  • Intermediate XI-4: (R) -5-bromo-2- ( (1- (isoquinoline-4-carbonyl) piperidin-3-yl) amino) -3-nitrobenzoic acid
  • The synthetic procedure is similar to that of intermediate IV-5.
  • Compounds 34, 81 and 125:
  • The synthetic procedure is similar to the last step of the synthetic route of compound 14.

  • Synthesis of compounds 39, 49, 86, 92, 97, 98, 100, 101, 103, 104, 105, 106, 107, 113, 114, 119, 120, 123, 140, 168, 169, 174, 175 and 176
  • Intermediate XII-1:
  • The synthetic procedure is similar to that of intermediate IV-2.
  • Intermediate XII-2:
  • The synthetic procedure is similar to that of intermediate IV-5.
  • Intermediate XII-3:
  • The synthetic procedure is similar to that of intermediate I-1.
  • Intermediate XII-4 and XII-6:
  • The synthetic procedure is similar to that of intermediate I-3.
  • Intermediate XII-5:
  • A mixture of 5-bromo-2- [ [ (3S) -1-tert-butoxycarbonyl-4, 4-difluoro-3-piperidyl] amino] -3-nitro-benzoic acid (2.00 g, 4.16 mmol) , TEA (2.53 g, 24.9 mmol, 3.48 mL) , HATU (3.17 g, 8.33 mmol) and NH4Cl (1.34 g, 24.9 mmol) in DMF (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 ℃ for 2 hrs under N2 atmosphere. The reaction mixture was washed with water and filtered to give a residue. The residue was purified by reversed-phase HPLC (column: C18-6 100 *30 mm *5 μm; mobile phase: [water (FA) -ACN] ; B%: 10%-70%, 15 min) . Intermediate XII-5 (620 mg, 1.29 mmol, 31.1%yield) was obtained as a white solid.
  • Compounds 39, 49, 86, 92, 97, 98, 100, 101, 103, 104, 105, 106, 107, 113, 114, 120, 123, 168, 169, 174, 175 and 176:
  • The synthetic procedure is similar to the last step of the synthetic route for compound 1.
  • Compounds 140: 5-bromo-2- ( ( (3S) -4, 4-difluoro-1- (2, 2, 2-trifluoro-1- (isoquinolin-4-yl) ethyl) piperidin-3-yl) amino) -N-methyl-3-nitrobenzamide
  • To a solution of 4- (1-chloro-2, 2, 2-trifluoroethyl) isoquinoline (110 mg, 0.45 mmol) in dioxane (2 mL) , (S) -5-bromo-2- ( (4, 4-difluoropiperidin-3-yl) amino) -N-methyl-3-nitrobenzamide (350 mg, 0.89 mmol) and TEA (135 mg, 1.34 mmol) were added, and the reaction was stirred at 80 ℃ for 12 hr. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified using prep-TLC with ethyl acetate in petroleum ether (EtOAc : PE=1: 2) and Prep-HPLC to give compound 140 (48 mg, 18%yield) as a yellow solid.




  • Synthesis of compounds 50 and 166
  • The synthesis routes of compounds 50 and 166 are similar to last step synthesis route of compound 39.

  • Synthesis of compounds 170, 171 and 178
  • Intermediate XII-7:
  • The synthesis of intermediate XII-7 is similar to that of intermediate XII-4.
  • Compounds 170, 171 and 178:
  • The synthetic procedure is similar to the last step of the synthetic procedure of compound 1.

  • Synthesis of compound 69
  • Intermediate XIII-1: 5-bromo-2- (3-iodo-1, 4, 6, 7-tetrahydro-5H-pyrazolo [4, 3-c] pyridin-5-yl) -N-methyl-3-nitrobenzamide
  • To a solution of 3-iodo-4, 5, 6, 7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine (100 mg, 0.40 mmol) in DMF (5 mL) , 5-bromo-2-fluoro-N-methyl-3-nitrobenzamide (133 mg, 0.48 mmol) and DIPEA (156 mg, 1.20 mmol) were added, and the reaction mixture was heated and stirred at 120 ℃ for 18 hr. After cooling to room temperature, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (30 mL*3) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to get a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0%to 10%) in petroleum ether to afford the title product (45 mg, 22%yield) as a white solid. LC-MS (ESI) (M+H) + = 506.0
  • Compound 69: 5-bromo-2- (3- (isoquinolin-4-yl) -1, 4, 6, 7-tetrahydro-5H-pyrazolo [4, 3-c] pyridin-5-yl) -N-methyl-3-nitrobenzamide
  • Isoquinolin-4-ylboronic acid (19 mg, 0.11 mmol) , K2CO3 (37 mg, 0.27 mmol) and Pd (dppf) Cl2 (7 mg, 0.01 mmol) were added to a solution of intermediate XIII-1 (45 mg, 0.09 mmol) in dioxane (3 mL) and H2O (1 mL) , and the reaction mixture was heated and stirred at 100 ℃ for 12 hr under a N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (30 mL*3) . The organic layer was separated, washed with water, NH4Cl solution (20 mL) , NaHCO3 solution (20 mL) and further saturated NaCl solution (20 mL) , and it was dried over Na2SO4, and concentrated in vacuo. The residue was purified using prep-TLC with ethyl acetate in petroleum ether (EtOAc : PE=1: 2) and Prep-HPLC to give compound 69 (1 mg, 1%yield) as a yellow solid.
  • Synthesis of compounds 89 and 90
  • Intermediate XIV-1: tert-butyl (3S, 4S) -3-hydroxy-4- (isoquinoline-4-carboxamido) piperidine-1-carboxylate
  • Isoquinoline-4-carboxylic acid (841 mg, 4.86 mmol) , TEA (2.34 g, 23.12 mmol) and T3P (5.88 g, 9.25 mmol, 50%wt in EtOAc) were added to a solution of tert-butyl (3S, 4S) -4-amino-3-hydroxypiperidine-1-carboxylate (1.0 g, 4.62 mmol) in DCM (30 mL) , and the reaction was stirred at 25 ℃ for 2 hr. The reaction was added water (40 mL) and extracted with DCM (40 mL*3) . The organic layer was separated, and washed with saturated NaCl solution. The combined organic layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel chromatography eluted with methanol in DCM (DCM/Methanol = 10/1) to afford intermediate XIV-1 (1.0 g, 58%yield) as a colorless oil. LC-MS (ESI) (M+H) + = 372.2.
  • Intermediate XIV-2: tert-butyl (3S, 4S) -4- (isoquinoline-4-carboxamido) -3- ( (methylsulfonyl) oxy) piperidine-1-carboxylate
  • To a solution of intermediate XIV-1 (1.0 g, 2.69 mmol) in DCM (20 mL) , TEA (818 mg, 8.08 mmol) and MsCl (617 mg, 5.38 mmol) were added, and the reaction was stirred at 25 ℃ for 16 hr. The reaction was added water (40 mL) and extracted with DCM (40 mL*3) . The organic layer was separated, and washed with saturated NaCl solution. The combined organic  layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel chromatography eluted with methanol in DCM (DCM/Methanol = 20/1) to afford intermediate XIV-2 (1000 mg, 83%yield) as a red solid. LC-MS (ESI) (M+H) + = 450.4.
  • Intermediate XIV-3: tert-butyl (3S, 4S) -3- (1, 3-dioxoisoindolin-2-yl) -4- (isoquinoline-4-carboxamido) piperidine-1-carboxylate
  • To a solution of intermediate XIV-2 (1000 mg, 2.22 mmol) in DMF (20 mL) , potassium 1, 3-dioxoisoindolin-2-ide was added (824 mg, 4.44 mmol) and the reaction was stirred at 100 ℃ for 16 hr. The reaction was added water (40 mL) and extracted with EtOAc (40 mL*3) . The organic layer was separated, washed with saturated NaCl solution and concentrated in vacuo. The crude product was purified by silica gel chromatography eluted with methanol in DCM (MeOH : DCM = 1/20) to afford intermediate XIV-3 (700 mg, 62%yield) as a colorless solid. LC-MS (ESI) (M+H) + = 501.3.
  • Intermediate XIV-4: tert-butyl (3R, 4S) -3-amino-4- (isoquinoline-4-carboxamido) piperidine-1-carboxylate
  • Hydrazine hydrate (350 mg, 7.0 mmol) was added to a solution of intermediate XIV-3 (700 mg, 1.40 mmol) in MeOH (10 mL) , and the reaction was stirred at 70 ℃ for 16 hr. The reaction was concentrated under vacuum, then added water (30 mL) and extracted with EtOAc (30 mL*3) . The organic layer was separated, and washed with saturated NaCl solution. The combined organic layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel chromatography eluted with methanol in DCM (MeOH : DCM = 1/20) to afford intermediate XIV-4 (400 mg, 77%yield) as a colorless oil. LC-MS (ESI) (M+H) + = 371.3.
  • Intermediate XIV-5: tert-butyl (3R, 4S) -3- ( (4-bromo-2- (methylcarbamoyl) -6-nitrophenyl) amino) -4- (isoquinoline-4-carboxamido) piperidine-1-carboxylate
  • 5-bromo-2-fluoro-N-methyl-3-nitrobenzamide (359 mg, 1.30 mmol) and DIPEA (698 mg, 5.40 mmol) were added to a solution of intermediate XIV-4 (400 mg, 1.08 mmol) in NMP (10 mL) , and the reaction was stirred at 80 ℃ for 16 hr. The reaction was added water (40 mL) and extracted with EtOAc (40 mL*3) . The organic layer was separated, and washed with saturated NaCl solution. The combined organic layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel chromatography eluted with ethyl acetate in petroleum ether (PE : EtOAc=1 : 1) to afford intermediate XIV-5 (550 mg, 81%) as a black solid. LC-MS (ESI) (M+H) + = 627.2.
  • Intermediate XIV-6: N- ( (3R, 4S) -3- ( (4-bromo-2- (methylcarbamoyl) -6-nitrophenyl) amino) piperidin-4-yl) isoquinoline-4-carboxamide
  • The synthetic procedure of intermediate XIV-6 is similar to that of intermediate I- 3.
  • Compound 89: N- ( (3R, 4S) -3- ( (4-bromo-2- (methylcarbamoyl) -6-nitrophenyl) amino) -1-methylpiperidin-4-yl) isoquinoline-4-carboxamide
  • TEA (57.6 mg, 0.57 mmol) and CH3I (26.9 mg, 0.19 mmol) were added to a solution of intermediate XIV-6 (100 mg, 0.19 mmol) in DCM (5 mL) , and the reaction was stirred at room temperature for 2 hr. The reaction was concentrated under vacuum, then added water (20 mL) and extracted with EtOAc (20 mL*3) . The organic layer was separated, washed with saturated NaCl solution and concentrated in vacuo. The combined organic layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC to afford compound 89 (16.4 mg, 16%yield) as a yellow solid.
  • Compound 90:
  • CH3COCl (18 mg, 0.23 mmol) and TEA (47 mg, 0.46 mmol) were added to a solution of intermediate XIV-6 (80 mg, 0.15 mmol) in DCM (2 mL) , and the reaction was stirred at 25 ℃ for 2 hr. The reaction was added water (20 mL) and extracted with EtOAc (20 mL*3) . The organic layer was separated, and washed with saturated NaCl solution. The combined organic layers dried over Na2SO4 was filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC to afford compound 90 (30 mg, 34%) as a yellow solid.
  • Synthesis of compounds 96, 126, 133, 135, 136 and 177
  • Intermediates XV-1 and XV-2: 5-bromo-2- ( ( (3S, 4S) -4- (isoquinoline-4-carboxamido) tetrahydro -2H-pyran-3-yl) amino) -3-nitrobenzoic
  • The synthesis routes of intermediate XV-1 and XV-2 are similar to that of intermediate IV-5.
  • Compounds 96, 126, 133, 135, 136 and 177:
  • The synthetic routes of compounds 96, 126, 133, 135, 136 and 177 are similar to the last step of the synthesis route of compound 14.

  • Synthesis of compound 102
  • Intermediate XVI-1: N- [ (1S, 2R) -2-hydroxycyclohexyl] isoquinoline-4-carboxamide
  • To a solution of isoquinoline-4-carboxylic acid (100 mg, 0.58 mmol) in DCM (5.00  mL) was added HATU (329 mg, 0.87 mmol) and DIPEA (373 mg, 2.89 mmol) . After addition, the mixture was stirred for 30 min, and then (1R, 2S) -2-aminocyclohexanol (87.6 mg, 0.58 mmol) was added. The mixture was stirred at 25 ℃ for 12 hrs. The reaction mixture was added to the water and stirred for 30 minutes, and extracted with DCM. The combined organic layer was concentrated under reduced pressure to give intermediate XVI-1 (125 mg, 80.1%yield) as a yellow solid. LC-MS (ESI) (M+H) + = 271.1.
  • Compounds 102: N- [ (1S, 2R) -2- [4-bromo-2- (methylcarbamoyl) -6-nitro-phenoxy] cyclohexyl] isoquinoline-4-carboxamide
  • To a solution of intermediate XVI-1 (50.0 mg, 0.18 mmol) in THF (2.00 mL) was added one portion NaH (18.5 mg, 0.46 mmol, 60.0%purity) at 0 ℃. After addition, the mixture was stirred at this temperature for 30 min, and then 5-bromo-2-fluoro-N-methyl-3-nitro-benzamide (51.2 mg, 0.18 mmol) was added at 25 ℃. The resulting mixture was stirred at 25℃ for 2 hrs. The reaction mixture was added to water and stirred for 30 minutes, and extracted with DCM. The combined organic layer was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 100 *30 mm *10 um; mobile phase: [water (FA) -ACN] ; B%: 40%-70%, 10 min) . Compound 102 (20.0 mg, 20.3%yield) was obtained as a yellow solid. 
  • Synthesis of compounds 161, 162 and 163
  • Intermediate XVI-1: 5-bromo-2- [ [ (3S) -1-tert-butoxycarbonyl-4, 4-difluoro-pyrrolidin-3-yl] amino] -3-nitro-benzoic acid
  • A mixture of 5-bromo-2-fluoro-3-nitro-benzoic acid (300 mg, 1.14 mmol) , tert-butyl (4S) -4-amino-3, 3-difluoro-pyrrolidine-1-carboxylate (252 mg, 1.14 mmol) and DIEA (440 mg, 3.41 mmol, 593 uL) in ACN (10.0 mL) was stirred at 85 ℃ for 8 hrs. The reaction mixture was concentrated under reduced pressure to remove ACN. The residue was washed with water and extracted with DCM (30.0 Ml*3) . The combined organic layers were concentrated under reduced pressure to give intermediate XVI-1 (500 mg, crude) as a yellow solid.
  • Intermediate XVI-2:
  • The synthetic procedure of intermediate XVI-2 is similar to the last step of the synthetic procedure of compound 14.
  • Intermediate XVI-3:
  • The synthetic procedure of intermediate XVI-3 is similar to that of intermediate I-3.
  • Compounds 161, 162 and 163:
  • The synthetic procedure of compounds 161, 162 and 163 is similar to the last step of the synthetic procedure of compound 1.

  • Synthesis of compound 181
  • Intermediate XVI-4:
  • The synthetic procedure of intermediate XVI-4 is similar to that of compound 161.
  • Intermediate XVI-5:
  • The synthetic procedure of intermediate XVI-5 is similar to that of compound VIII-4.
  • Compounds 181: 5-bromo-2- ( ( (3S, 4R) -4-fluoro-1- (isoquinoline-4-carbonyl) piperidin-3-yl) amino) -N-methyl-3- (trifluoromethyl) benzamide
  • NaNO2 (29.60 mg, 0.43 mmol) was slowly added to a solution of intermediate XVI-5 (140 mg, 0.29 mmol) in HBr (3.00 mL) at 0℃. The resulting mixture was stirred at 50 ℃ for 12 hr. The reaction mixture was poured into ice-water, and the pH was adjusted to 8 with Na2CO3 solution, and reaction mixture was then extracted with DCM (10 mL*3) , dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: C18-6 100*30 mm*5 um; mobile phase: [water (FA) -ACN] ; B%: 10%-70%, 15min) to give compound 181 (10.0 mg, 6.28%yield) as a white solid.
  • Example 3. Purification of 3CLpro enzymes
  • The 3CLpro enzymes of SARS-CoV-2, SARS-CoV and MERS-CoV were over-expressed in E. coli and purified to homogeneity following protocols described previously (6) .
  • Example 4. Structural Biology Studies
  • To understand how the compounds as disclosed herein bind to and inhibit the  enzymatic activity of 3CLpro, certain inhibitors were co-crystalized with SARS-CoV-2 3CLpro. Before crystallization, a 10 mg/mL stock of the purified SARS-CoV-2 3CLpro in a buffer containing 20 mM HEPES pH 7.4 and 150 mM NaCl was incubated with 1.5 mM of the inhibitor at room temperature for 2 hours then the precipitate was removed by centrifugation. For crystallization, 0.2 μL of the 3CLpro/inhibitor complex was mixed with 0.2 μL of well buffers from commercially crystallization kits. Crystals were grown at 20 ℃ in a 96-well plate using the sitting-drop vapor-diffusion method. The diffraction data was collected at 100 K on a Rigaku XtaLAB Synergy Custom diffractometer and solved by molecular replacement using Phaser-MR (7) in the Phenix software suite (8) . The crystal structure of the SARS-CoV-2 3CLpro (PDB code: 7EN8) was used as the initial model. The 3CLpro/inhibitor complex structures were manually refined with Coot (9) and Phenix (8) .
  • The crystal structure of 3CLpro/Compound 19 complex was determined by molecular replacement and refined to Compound 19 formed a 1: 1 complex with 3CLpro. In the crystal structure, one molecule of Compound 19 bound into the catalytic pocket of 3CLpro thus competitively inhibiting the binding of 3CLpro substrates (FIGURE 3A) . Five hydrogen bonds formed between Compound 19 and 3CLpro: two were between the nitrogen atom in the isoquinoline ring of Compound 19 and the side chains of His163 and Ser144; two were between the carbonyl group attached to the isoquinoline ring of Compound 19 and the side chain of Asn142 and the main chain of Gly143; one was between the carbonyl oxygen in the methylcarbamoyl group of Compound 2 and the main chain amide of Glu166 (FIGURE 3B) .
  • The crystal structure of 3CLpro/Compound 98 complex was refined to (FIGURE 4A) . Compound 98 was found to bind to 3CLpro similar to that of Compound 19 (FIGURE 4B) .
  • Example 5. In vitro Enzymatic Assay Results
  • The ability of the compounds in Table 1 to inhibit 3CLpro was tested using a fluorescence resonance energy transfer (FRET) -based continuous kinetic assay (6) . A fluorescent peptide Dabcyl-KTSAVLQ↓SGFRKM-E (Edans) was used as the substrate of purified 3CLpro. After cleavage by 3CLpro, the fragment SGFRKM-E (Edans) was released and its fluorescence could be monitored with the excitation and emission wavelengths of 355 nm and 538 nm, respectively.
  • For SARS-CoV-2 3CLpro and SARS-CoV 3CLpro, the final concentration of 3CLpro and the fluorogenic substrate (Dabcyl-KTSAVLQ↓SGFRKM-E (Edans) were 15 nM and 25 μM, respectively. For MERS-CoV 3CLpro, the final concentration of 3CLpro and the fluorogenic substrate (Dabcyl-KTSAVLQ↓SGFRKM-E (Edans) were 500 nM and 100 μM, respectively. Briefly, 15 μL of the recombinant 3CLpro in the assay buffer (20 mM HEPES 7.4,  150 mM NaCl, 0.01%Triton X-100, 1 mM DTT) was incubated with 1.5 μL of a serial dilution of each compound at room temperature for 1 hour. A 384-well plate (Corning, CLS3575) was pre-warmed for 5 min at 37 ℃. Then 11 μL of the 3CLpro/inhibitor mixture was transferred to the 384-well plate. The reaction was initiated by adding 29 μL of the fluorogenic substrate in the assay buffer. After that, the fluorescence signal was immediately measured every 1 min at 37 ℃ using a Thermol Varioskan LUX plate reader with 355 nm excitation and 538 nm emission.
  • The inhibitory activity data of some of the representative compounds was shown in Table 2 and FIGURE 11.
  • Example 6. Isothermal titration calorimetry (ITC)
  • ITC experiments were done with an isothermal titration calorimeter MicroCal PEAQ-ITC (Malvern Panalytical) . The inhibitor with a concentration of 20 μM in the ITC buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 0.5%DMSO) was titrated by 200 μM 3CLpro in the ITC buffer at 25 ℃. Control experiments in which the inhibitors were titrated by the ITC buffer were performed and the data was used to correct the 3CLpro titration data. The data was processed using the MicroCal PEAQ-ITC analysis software. Each measurement was repeated three times.
  • The ITC data of some of the representative compounds was shown in FIGURE 5. From the ITC data, compounds 19 and 30 showed a higher binding affinity (dissociation constant, Kd) than compound Ref-2 (compound P2) in previously filed patent (WO2022150962) .
  • Example 7. Anti-SARS-CoV-2 Activity of 3CLpro Inhibitors in Cellular Assays
  • The anti-SARS-CoV-2 activity was measured in A549 cells expressing the human ACE2 receptor following protocols described previously (6) . Briefly, the cells were first treated with DMSO or various concentrations of the compounds (Table 1) for 1 hour, then infected by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) for 24 hours. After paraformaldehyde fixation, the cells were stained with SARS-CoV-2 nucleocapsid (N) protein antibody and DAPI. The percentage of the cells infected by SARS-CoV-2 was measured by imaging using a high-content imaging system.
  • The anti-Omicron SARS-CoV-2 activity was measured in Caco-2 cells using similar protocol.
  • The above testing results showed that the non-covalent small molecule inhibitors of SARS-CoV-2 3CLpro effectively blocked coronavirus replication in host cells (FIGURE 6, FIGURE 7, FIGURE 8, and Table 2) . These inhibitors can be used for the treatment of a disease, or a symptom of a disease caused by a coronavirus, such as COVID-19.
  • Comparing to compound Ref-2 in previously filed patent application (WO2022150962) , compounds 19, 29, 30, 37, 41, 43 and 151 showed a better antiviral potency  in A549 cells (FIGURE 7) . Compound 98 demonstrated a stronger activity against Omicron SARS-CoV-2 in Caco-2 cells (FIGURE 8) .
  • Example 8. CYP inhibition evaluation of representative compounds in human liver microsomes
  • 20 μL of the substrate solutions of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 were each mixed with 2 μL of the test compounds (final concentrations: 50 μM, 15 μM, 5 μM, 1.5 μM, 0.5 μM, 0.15 μM, 0.05 μM, 0 μM) , followed by the addition of 158 μL of the HLM (Human liver microsome) working solution. Each of the mixtures was incubated at 37 ℃ for 10 minutes, and then mixed with 20 μL of NADPH cofactor, followed by incubation at 37 ℃ for additional 10 minutes. The reactions were terminated by adding 400 μL cold stop solution (200 ng/mL Tolbutamide and Labetalol in ACN) . The samples are centrifuged at 4000 rpm for 20 minutes to precipitate protein. Next, 200 μL of the supernatant of each sample was transferred to 100 μL HPLC water and shaken for 10 minutes, and then analyzed by LC/MS/MS.
  • The above testing results showed that compounds 97, 98 and 170 have little effect on different CYP isoforms (FIGURE 9) .
  • Example 9. Plasma protein binding (PPB)
  • The binding of compounds Ref-2, 86, 97, 98 and 170 to human and mouse plasma were measured using equilibrium dialysis. A loading matrix was prepared by diluting of a 400 μM stock of each of the compounds in DMSO by the plasma matrix. To prepare the time zero (T0) samples to be used for recovery determination, 50 μL of the loading matrix were transferred in triplicate to the sample collection plate, immediately matched with opposite blank buffer to obtain a final volume of 100 μL of 1: 1 matrix/dialysis buffer (v/v) in each well, followed by the addition of 500 μL of stop solution (200 ng/mL of tolbutamide, 200 ng/mL of labetalol, and 50 ng/mL of metformin in acetonitrile) and then stored at 2-8℃ pending further processes along with other post-dialysis samples. To load the dialysis device, 150 μL of the loading matrix and 150 μL of the dialysis buffer were transferred to the donor side and the receiver side of each well, respectively. The dialysis plate was placed in a humidified incubator at 37 ℃ with 5%CO2 on a shaking platform that rotated slowly (about 100 rpm) for 4 hours, then 50 μL of samples were taken from both the buffer side and the matrix side, and transferred into new 96-well plates. Each sample was mixed with an equal volume of opposite blank buffer (or matrix) to reach a final volume of 100 μL, followed by the addition of 500 μL of stop solution. The mixture was vortexed and centrifuged at 4000 rpm for about 20 minutes, then 100 μL of the supernatant of each sample was removed for LC-MS/MS analysis. The single blank samples were prepared by transferring 50 μL of blank matrix to a 96 well plate and adding 50 μL of blank PBS buffer to each well. The blank plasma  must match the species of plasma used in the plasma side of the well. Then the matrix-matched samples were further processed by adding 500 μL of stop solution, following the same sample processing method as the dialysis samples. The %Unbound, %Bound and %Recovery were calculated using the following equations:
  • %Unbound = 100×F/T
  • %Bound = 100-%Unbound
  • %Recovery = 100× (F+T) /T0
  • in which F is the analyte concentration or peak area ratio of analyte/internal standard on the buffer (receiver) side of the membrane, T is the analyte concentration or peak area ratio of analyte/internal standard on the matrix (donor) side of the membrane, and T0 is the analyte concentration or the peak area ratio of analyte/internal standard in the loading matrix sample at time zero.
  • The above testing results showed that compounds 86, 97, 98 and 170 have better free PPB ratios in comparison with compound Ref-2 (FIGURE 10) .
  • REFERENCES
  • 1. A.R. Fehr, S. Perlman, Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 1282, 1-23 (2015) .
  • 2. P. Zhou et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270-273 (2020) .
  • 3. J. Lei, Y. Kusov, R. Hilgenfeld, Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein. Antiviral Res 149, 58-74 (2018) .
  • 4. D.R. Owen et al., An oral SARS-CoV-2 M (pro) inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586-1593 (2021) .
  • 5. Y. Unoh et al., Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19. J Med Chem 65, 6499-6512 (2022) .
  • 6. N. Hou et al., Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro. ACS Cent Sci 9, 217-227 (2023) .
  • 7. A. J. McCoy et al., Phaser crystallographic software. J Appl Crystallogr 40, 658-674 (2007) .
  • 8. D. Liebschner et al., Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr D Struct Biol 75, 861-877 (2019) .
  • 9. P. Emsley, B. Lohkamp, W.G. Scott, K. Cowtan, Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66, 486-501 (2010) .
  • One skilled in the art will readily recognize from the disclosure and claims that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims.

Claims (40)

  1. A compound represented by Formula I:
    a solvate thereof, a tautomer thereof, a stereoisomer thereof, a deuterated derivative of the compound, or a pharmaceutically acceptable salt of the foregoing, wherein:
    R1 is hydrogen, halogen, or C1-C2 alkyl that is optionally substituted with 1 to 3 groups of halogen;
    R2 is -NO2, -SO3H, -SO2CH3, -CN or -CF3;
    R3 is 5-or 6-membered heteroaryl, -C (=O) Ra, -C (=O) ORa, -C (=O) NRbRc or
    wherein:
    Ra is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 of Ra is optionally substituted with 1-3 groups selected from halogen and deuterium;
    Rb is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rb is optionally substituted with 1-3 groups selected from halogen and deuterium;
    Rc is hydrogen, NH2, -OH, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rc is optionally substituted with 1-3 groups selected from halogen, deuterium, and -OH;
    Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, or 4-, 5-or 6-membered heterocycloalkyl or 5-or 6-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl of Ring A1 contains one or more heteroatoms selected from N and O;
    X1 is absent, -CH2-, -NH-or -O-;
    X2 is CH or N;
    X3 is -O-, -CH2, or -NH-;
    R3’, for each occurrence, is independently selected from halogen, -ORd, -NReRf, and C1-C4 alkyl that is optionally substituted with 1-3 groups of halogen; wherein:
    Rd is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rd is optionally substituted with 1-3 groups of halogen;
    Re is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Re is optionally substituted with 1-3 groups of halogen;
    Rf is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rf is optionally substituted with 1-3 groups of halogen;
    R3’, for each occurrence, may be attached to any of the ring atoms of the Ring A1, as long as valence permits; and
    m is an integer selected from 0, 1, 2 and 3;
    Z is absent, -NRg-, -C (RhRi) -NRg-, -NRg-C (RhRi) -, or -O-, wherein:
    Rg is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl of Rg is optionally substituted with 1-3 groups of halogen;
    Rh is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl of Rh is optionally substituted with 1-3 groups of halogen;
    Ri is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl of Ri is optionally substituted with 1-3 groups of halogen;
    Ring Y is phenyl or selected from the following rings:
    wherein:
    Ring Y1 is 4-, 5-, 6-, 7-, 8-, or 9-membered cycloalkyl or 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring Y1 contains one or more heteroatoms selected from N and O;
    Ring Y2 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
    Ring Y3 is 4-, 5-, 6-, or 7-membered cycloalkyl or 4-, 5-, 6-, or 7-membered nitrogen heterocycloalkyl;
    Z1, Z3, Z4, and Z5, for each occurrence, are each independently CH or N;
    U1, U2, U3, and U4, for each occurrence, are each independently CH2 or NH;
    T1, T2, T3, and T4, for each occurrence, are each independently CH or N;
    R4, for each occurrence, is independently halogen, -OH, -C (=O) Rj, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of R4 is optionally substituted with 1-3 groups of halogen; wherein:
    Rj is C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rj is optionally substituted with 1-3 groups of halogen;
    R4, for each occurrence, may be attached to any of the ring atoms of Ring Y, as long as valence permits;
    o is an integer selected from 0, 1 or 2;
    X is absent, -CRkRL-, -C (=O) -, -C (=O) NRn-, or -Rm-C (=O) NRn-Ro-; wherein:
    Rk, RL, and Rn, for each occurrence, are each independently selected from hydrogen, halogen, and C1-C2 alkyl that is optionally substituted with 1-3 groups of halogen;
    Rm and Ro, for each occurrence, are each independently selected from hydrogen and C1-C2 alkyl that is optionally substituted with 1-3 groups of halogen;
    Ring A is 5-or 6-membered nitrogen heteroalkyl or nitrogen heteroaryl, or 9-or 10-membered nitrogen heterocyclyl; wherein:
    Ring A contains -N=, or =N-in the meta position to the ring atom to which X is attached , or -NH-in the meta position or para position to the ring atom to which X is attached;
    the -NH-in the meta position is attached to -C (=O) -in the ortho position, or the -NH-in the para position is attached to -C (=O) -in the meta position;
    Ring A is substituted by t groups of R5, and R5 may be attached to any of the ring atoms of Ring A, as long as valence permits;
    R5, for each occurrence, is independently halogen, -CN, -ORp, -NHRp, -CH2NHBoc, 5-or 6-membered cycloalkyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of R5 is optionally substituted with 1-3 groups of halogen; wherein:
    Rp, for each occurrence, is independently selected from halogen and C1-C4 alkyl; and
    t is 0, 1, 2, 3, 4, or 5.
  2. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R3 iswherein Ring A1, X1, X2, X3, R3’ and m are as defined in claim 1.
  3. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R3 iswherein X1 is -CH2-, -NH-or -O-, and Ring A1, X2, X3, R3’ and m are as defined in claim 1.
  4. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R3 iswherein X1 is -NH-, and Ring A1, X2, X3, R3’ and m are as defined in claim 1.
  5. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R3 iswherein X1 is -NH-, and Ring A1 is 3-, 4-, 5-or 6-membered cycloalkyl, and X2, X3, R3’ and m are as defined in claim 1.
  6. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein R3 iswherein X1 is -NH-, and Ring A1 is 4-, 5-or 6-membered heterocycloalkyl, wherein the heterocycloalkyl of Ring A1 contains one or more heteroatoms selected from N and O, and X2, X3, R3’ and m are as defined in claim 1.
  7. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein:
    Re is H, Rf is H, NH2, -OH, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rf is optionally substituted with 1-3 groups of halogen.
  8. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein:
    when Rb is H, Rc is H, NH2, -OH, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl of Rc is optionally substituted with 1-3 groups selected from halogen, deuterium, and -OH.
  9. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein:
    R3 is -C (=O) NHCH3, -C (=O) NH2, -C (=O) N (CH3) 2, -C (=O) OCH3, -C (=O) NHCH3, -C (=O) NHCH2CH=CH2, -COOH, -C (=O) NHNH2, -C (=O) NHCH2CF3, -C (=O) NHCH (CH3) CF3, -C (=O) NHCH2CHF2, -C (=O) NHCH3, -C (=O) NHCD3, -C (=O) NHCH (CH3) CF3, -C (=O) NHC (CH3) 3, -C (=O) NHCH2 (CH3) 2CH2OH,
    preferably, R3 is -C (=O) OCH3, -C (=O) NHCH2CH=CH2, -COOH, -C (=O) NHNH2, -C (=O) NHCH (CH3) CF3, -C (=O) NHCH2CHF2, -C (=O) NHCH3, -C (=O) NHCD3, -C (=O) NHCH (CH3) CF3, -C (=O) NHCH2 (CH3) 2CH2OH,
  10. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein:
    the compound is of the following structural Formula II-1, II-2, II-3, II-4, or II-5:
  11. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein R1 is Br, F or Cl.
  12. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein:
    the compound is of the following structural Formula III or Formula IV:
    wherein:
    Ri is C1-C6 branched alkyl that is optionally substituted with 1-3 groups of halogen, or C4-C8 alkyl with a C3-C6 carbocyclyl side chain and optionally substituted with 1-3 groups of halogen.
  13. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt of the foregoing according to any one of claims 1 to 11, wherein:
    the compound is of the following structural Formula V:
    Ring Y1 is 4-, 5-, 6-or 7-membered nitrogen heterocyclyl; wherein:
    when Z1 is CH, X is -C (=O) NRn-or -Rm-C (=O) NRnRo-;
    when Z1 is N, X is absent, -CRkRL-, or -C (=O) -; and
    when Z3 is CH, Z is -NRg-, -C (RhRi) -NRg-, -NRg-C (RhRi) -, or-O-; and
    when Z3 is N, Z is absent.
  14. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 or 13, wherein:
    Z1 is next to Z3, or Z1 is next but one to Z3.
  15. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein:
    the compound is of the following structural Formula VI:
    wherein:
    Ring Y2 is 4-or 5-membered nitrogen heterocyclyl;
    Ring Y3 is 4-, 5-or 6-membered nitrogen heterocyclyl;
    R4 occurs on any of ring atoms of Ring Y2 and/or Ring Y3, as long as valence permits;
    when Z4 is CH, X is -C (=O) NRn-or -Rm-C (=O) NRnRo-;
    when Z4 is N, X is absent, -CRkRL-, or -C (=O) -; and
    when Z5 is CH, Z is -NRg-, -C (RhRi) -NRg-, -NRg-C (RhRi) -or -O-; and
    when Z5 is N, Z is absent.
  16. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 15, wherein:
    Z4 and Z5 are N; and
    Z4 is in the meta position to the spiro atom, and/or:
    Z5 is in the meta position to the spiro atom.
  17. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 13, wherein:
    Rk is H, and RL is CF3.
  18. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 13 or 17, wherein:
    Rm is -CH2-, and Ro is absent.
  19. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 13 or 17, wherein:
    Ro is -CH2-, and Rm is absent.
  20. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein:
    the compound is of the following structural Formula VII:
    Y iswherein: Z1 is CH, or Z4 is CH, preferably, Rn is H.
  21. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein:
    the compound is of the following structural Formula VIII:
    Y iswherein: Z1 or Z4 is N.
  22. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-11, wherein:
    the moietyis
    preferably, the moietyis
    more preferably, the moietyis
    most preferably, the moietyis
  23. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-22, wherein:
    Ring A is pyridinyl, pyrimidinyl, pentanolactam, butyrolactam, glutarimide, triazolyl, tetrazolyl, isoquinolinyl, quinolinyl, pyridin-2 (1H) -one, quinolin-2 (1H) -one, 3, 4-dihydroquinolin-2 (1H) -one, naphthyridinyl, pyrrolopyridinyl, or imidazopyridinyl, wherein the pyridinyl, pyrimidinyl, pentanolactam, butyrolactam, glutarimide, triazolyl, tetrazolyl, isoquinolinyl, quinolinyl, pyridin-2 (1H) -one, quinolin-2 (1H) -one, 3, 4-dihydroquinolin-2 (1H) -one, naphthyridinyl, pyrrolopyridinyl, or imidazopyridinyl substituted by t groups of R5.
  24. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-23, wherein:
    Ring A is
    wherein Ring A is substituted by t groups of R5, and the substitution occurs on any of the ring atoms of Ring A, as long as valence permits.
  25. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-24, wherein:
    the 5-or 6-membered heteroaryl of R5 is nitrogen heteroaryl,
    preferably, the 5-or 6-membered heteroaryl of R5 is pyrrolyl, pyrazolyl, or imidazolyl, more preferably, the 5-or 6-membered heteroaryl of R5 is
  26. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1-25, wherein:
    the moietyis
    preferably, the moietyis
  27. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein the compound is selected from the group consisting of:













  28. A pharmaceutical composition comprising the compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 27 and at least one pharmaceutically acceptable carrier.
  29. The pharmaceutical composition according to claim 28, further comprising one or more additional active pharmaceutical agents useful for treating a coronavirus infection.
  30. A method of treating a disease or a symptom of a disease caused by a coronavirus in a subject, comprising administering to the subject, a therapeutically effective amount of the compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 27 or the pharmaceutical composition according to claim 28 or 29.
  31. The method according to claim 29, wherein the disease is a respiratory tract infectious disease, preferably a severe acute respiratory syndrome.
  32. The method according to claim 30 or 31, wherein one or more additional active pharmaceutical agents useful for treating a coronavirus infection are administered to the subject.
  33. A method of reducing or inhibiting the activity of a protease of a coronavirus, comprising contacting the protease with the compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 27 or the pharmaceutical composition according to claim 28 or 29, wherein the protease is a 3C-like protease.
  34. A method of reducing or inhibiting the replication of a coronavirus, contacting the coronavirus with the compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 27 or the pharmaceutical composition according to claim 28 or 29.
  35. The method according to any one of claims 30 to 34, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) , MERS-CoV, or SARS-CoV.
  36. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 27, for use as a medicament.
  37. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 27, for the treatment of a coronavirus infection in a subject.
  38. The compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt for use according to claim 37, wherein the coronavirus infection is an infection caused by SARS-Cov-2, MERS-CoV, or SARS-CoV.
  39. Use of the compound, solvate, tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 27 or the pharmaceutical composition according to claim 28 or 29 in the manufacture of a medicament for the treatment of a coronavirus infection in a subject.
  40. The use according to claim 39, wherein the coronavirus infection is an infection caused by SARS-Cov-2, MERS-CoV, or SARS-CoV.
EP23932400.7A 2023-04-11 2023-04-11 Protease inhibitors and uses thereof Pending EP4695230A1 (en)

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