WO2022265577A2 - Modulateurs d'enzyme du coronavirus, leurs procédés de synthèse et leurs utilisations - Google Patents

Modulateurs d'enzyme du coronavirus, leurs procédés de synthèse et leurs utilisations Download PDF

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WO2022265577A2
WO2022265577A2 PCT/SG2022/050408 SG2022050408W WO2022265577A2 WO 2022265577 A2 WO2022265577 A2 WO 2022265577A2 SG 2022050408 W SG2022050408 W SG 2022050408W WO 2022265577 A2 WO2022265577 A2 WO 2022265577A2
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optionally substituted
compound
mmol
equiv
alkyl
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WO2022265577A3 (fr
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Cheng San Brian Chia
Qian Wen TAN
Subramanyam VANKADARA
Yi Yang SEE
Shuyi Pearly NG
Weijun Xu
Choon Heng LOW
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Agency For Science, Technology And Research
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates, in general terms, to coronavirus 3CL protease enzyme modulators, their methods of synthesis and uses thereof.
  • the enzyme modulators can be used for inhibiting coronavirus 3CL protease and thereby prevent replication of the virus.
  • Coronaviruses are enveloped, single-stranded, positive-sense RNA viruses with the largest known viral RNA genomes (26 to 32 kilobases).
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
  • OC43, NL63, HKU1, 229E four human coronaviruses commonly cause mild-to moderate respiratory diseases in humans. It is therefore of strategic importance to increase the number of effective antivirals against coronaviruses by developing drugs against viral targets that are highly conserved within the family and crucial for virus replication.
  • the SARS-CoV-2 genome encodes for more than 20 proteins, with two proteases, the papain-like protease (PLpro) and 3C-like protease (3CLpro) that are vital for virus replication.
  • the first two open reading frames (ORFs) of the coronavirus genome encode for overlapping replicase polyproteins la (PP1A) and lab (PP1AB) that are approximately 450 kD and 750 kD respectively.
  • PP1A and PP1AB contain proteins that are required for virus replication and transcription.
  • Both PLpro and 3CLpro cleave PP1A and PP1AB into individual proteins.
  • Both virus polyproteins are cleaved at more than 10 junctions by 3CLpro to produce individual non-structural proteins critical for virus replication. It has been demonstrated that inhibiting 3CLpro and thus, proteolytic processing of virus polyproteins blocks viral replication effectively.
  • 3CLpro is a virally encoded protein that has no close human analogs, reducing the likelihood of drug
  • 3CLpro also known as the main protease
  • 3CLpro also known as the main protease
  • 3CLpro is considered a promising drug target since it is highly conserved across known coronavirus strains. Accordingly, designing inhibitors that are active against 3CLpro of various coronaviruses is highly desirable for future pandemic readiness.
  • Remdesivir is currently the only Food and Drug Administration-approved drug for the treatment of COVID-19. There is currently a lack of anti-viral drugs for use in treating COVID-19.
  • the present invention relates to modulators (and in particular inhibitors) of coronavirus 3-chymotrypsin-like protease (3CLpro).
  • the peptide-like modulators have an a-ketoamide moiety.
  • the peptide-like modulators also demonstrate inhibitory activity against various coronaviruses, including SARS-CoV-2, MERS, HCoV- 229E, HCoV-OC43 and MHVA59, by preventing replication.
  • the inhibitors also demonstrate inhibitory activity against the picornavirus 3Cpro, specifically coxsackievirus 3B 3Cpro which are cysteine proteases.
  • the present invention provides a compound of Formula (la) or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 1 is selected from cyano, or optionally substituted amidoacyl; R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted sulfonyl or optionally substituted sulfonylalkyl; R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally
  • the compound is a compound of Formula (I'a) or a pharmaceutically acceptable salt, solvate or prodrug thereof: ( l'a) wherein R 1 is selected from cyano, or optionally substituted amidoacyl; R 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and R 6 is selected from optionally substituted alkyl, optionally substituted aryl, or optionally substituted cycloalky
  • the compound is a compound of Formula (ll'a) pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 6 is selected from optionally substituted alkyl, optionally substituted aryl, or optionally substituted cycloalkyl; and R 7 is selected from optionally substituted amino, optionally substituted N-heterocyclyl or optionally
  • R 7 is -N H 2 , -NH(methyl), -NH(ethyl), -NH(propyl), -NH(iso- propyl), -NH(cyclopropyl), -NH(cyclobutyl), -NH(cyclopentyl), -NH(cyclohexyl), - NH(benzyl), -N(methyl) 2 , -N(ethyl) 2 , -N(propyl) 2 , -N(iso-propyl) 2 , pyrrolidinyl, piperidinyl, azetidinyl, or aziridinyl.
  • R 2 is selected from optionally substituted cycloalkyl having an amide moiety, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonyla Ikyl, optionally substituted aminosulfonyl and optionally substituted aminosulfonylalkyl.
  • the compound is a compound of Formula (Ill'b) or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 3a , R 4 , R 5 , R 6 and R 7 are as disclosed herein; R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 to 3.
  • R 3 is selected from:
  • R 3a is selected from:
  • R 4 is selected from H, methyl, ethyl, propyl, isopropyl, and cyclopropyl.
  • R 5 is selected from:
  • R 6 is selected from:
  • the compound is a compound of Formula (IV'a) or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl; R 4 is selected from H, optionally substituted alkyl; R 5 is selected from optionally substituted cycloalkyl; R 10 and R 11 are each independently selected from halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 and 2.
  • the present invention also provides a method of synthesising a compound of Formula (I), (I'), (II), (ll'), (III), (lll'), (IV), (IV'), (V) or (V') or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising : a) sequentially reacting a C-terminus an amino acid like compound comprising R 5 and an amino moiety of a compound comprising R 2 with a C-terminus and/or N-terminus of an amino acid like compound comprising R 3 ; and b) oxidising the intermediate of step a) with an oxidising agent in order to form R 1 .
  • a N-terminus of the amino acid like compound comprising R 5 is reacted with a carboxylate compound comprising R 6 .
  • the compound comprising R 2 comprises a lactamide moiety.
  • the method further comprises: a) oxidising a hydroxyl moiety of a compound comprising R 2 to an aldehyde; and b) reacting the aldehyde with an isocvano compound in order to form a lactamide compound comprising R 2 .
  • the present invention also provides a method of treating or preventing a virus infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (l'), (II), (ll'), (III), (lll'), (IV), (IV'), (V) or (V') or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the present invention also provides a use of a compound of Formula (I), (l'), (II), (ll'), (lll ), (lll' ), (IV), (IV'), (V) or (V') or a pharmaceutically acceptable salt, solvate or prodrug thereof in the manufacture of a medicament for treating or preventing a virus infection in a patient in need thereof.
  • the present invention also provides a compound of Formula (I), (l'), a (II), (ii), (III), (IIl ), (IV), (IV'), (V) or (V') or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in treating or preventing a virus infection in a patient in need thereof.
  • the virus infection is caused or associated with a virus selected from rhinovirus, Middle East Respiratory Syndrome coronavirus (MMRS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), common coronaviridae (including but not limited to OC43, HKU1, 229E and NL63), enterovirus, poliovirus, coxsackievirus, hepatitis A virus, foot-and-mouth disease virus (FMDV) belonging to the picornaviridae family and calicivirus from the caliciviridae family.
  • MMRS-CoV Middle East Respiratory Syndrome coronavirus
  • SARS-CoV Severe Acute Respiratory Syndrome coronavirus
  • common coronaviridae including but not limited to OC43, HKU1, 229E and NL63
  • enterovirus poliovirus
  • coxsackievirus hepatitis A virus
  • FMDV foot-and-mouth disease virus
  • Alkyl refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso- butyl, n-hexyl, and the like.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo.
  • Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms.
  • aryl groups include phenyl, naphthyl and the like.
  • eroaryl refers to a monovalent aromatic heterocyclic group which fulfils the Huckel criteria for aromaticity (i.e. contains 4n + 2 n electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within thS ring (and includes oxides of sulfur, selenium and nitrogen).
  • heteroaryl groups can have a single ring (e.g. pyridyl, pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (e.g. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).
  • a single ring e.g. pyridyl, pyrrolyl or N-oxides thereof or furyl
  • multiple condensed rings e.g. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl.
  • heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiophene, benzo[b]thiophene, triazole, imidazopyridine,
  • Arylalkyl refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such arylalkyl groups are exemplified by benzyl, phenethyl and the like.
  • Acyl refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxyacyl refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Amino refers to the group -NR"R" where each R" is independently hydrogen, sulfonyl, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of sulfonyl, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminoalkyl refers to the group -alkyl-NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminoacyl refers to the group -C(0)NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Acylamino refers to the group -NR"C(0)R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • “Amidoacyl” refers to the group -C(0)C(0)NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein, or R"R" can be linked to form a N-heteroaryl or N-heterocyclyl.
  • Acyloxy refers to the groups -0C(0)-alkyl, -0C(0)-aryl, -C(0)0-heteroaryl, and -C(0)0-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Aminoacyloxy refers to the groups -OC(0)NR"-alkyl, -0C(0)NR"-aryl, -0C(0)NR"- heteroaryl, and -OC(0)NR"-heterocyclyl where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Oxyacylamino refers to the groups -NR"C(0)0-alkyl, -NR"C(0)0-aryl, -NR"C(0)0- heteroaryl, and NR"C(0)0-heterocyclyl where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Cycloalkyl refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 11 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, indanyl, 1,2,3,4-tetrahydronapthalenyl and the like.
  • Heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen. It will be understood that where, for instance, R 2 or R 1 is an optionally substituted heterocyclyl which has one or more ring heteroatoms, the heterocyclyl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.
  • heterocyclyl and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1, 2, 3, 4-tetra hydroisoquinoline, 4,5,6,7-t
  • Sulfonyl refers to groups H-S(0) 2 -, amino-S(0) 2 -, alkyl-S(0) 2 -, cycloalkyl-S(0) 2 -, aryl-S(0) 2 -, heteroaryl-S(0) 2 -, and heterocyclyl-S(0) 2 -, where amino, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • “Sulfonylalkyl” refers to group sulfonyl-alkyl-, where sulfonyl and alkyl are as described herein.
  • a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from halo, hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalo
  • an "optionally substituted amino” group may include amino acid and peptide residues.
  • sequence analysis of SARS-CoV and SARS-CoV- 2 3CLpro shows about 96% identity in the protease amino acid sequences.
  • 3CLpro almost exclusively cleaves substrates after a Pl-Gln and its P2 substrate residue is typically a Leu, with exceptions such as Met, Val, lie and Phe.
  • the truncated protein fragments then fold into functional proteins/enzymes needed for viral replication.
  • a consensus cleavage site of P3-XLQ-(S/G/A/N)-P1' has been identified for 3CLpro across known coronaviruses.
  • the inventors have utilised this high sequence conservation and cleavage specificity amongst 3CLpro of known human coronaviruses to develop a pan- coronavirus 3CLpro inhibitor by i) mimicking the structure of Leu-Gin and ii) attaching an electrophilic moiety at its C-terminus which covalently binds to the protease's Cysl45, 3CLpro activity can be modulated, or at least inhibited.
  • the compounds are found to inhibit alpha and beta coronavirus including SARS Cov-2 virus.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 1 is selected from cyano, or optionally substituted amidoacyl; R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted sulfonyl or optionally substituted sulfonylalkyl; R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally
  • the compound of Formula (I) is a compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 1 is selected from cyano, or optionally substituted amidoacyl; R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted sulfonyl or optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally
  • R 6 is selected from optionally substituted alkyl, optionally substituted aryl, or optionally substituted cycloalkyl.
  • the compound of Formula (I) is a compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 1 is selected from cyano, or optionally substituted amidoacyl; R 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and R 6 is selected from optionally substituted alkyl, optionally substituted aryl, or optionally substituted cycloalkyl.
  • the compound of Formula (I) is a compound of Formula (la) or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 1 is selected from cyano, or optionally substituted amidoacyl; R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted sulfonyl or optionally substituted sulfonylalkyl; R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted
  • the compound of Formula (I') is a compound of Formula (I'a) or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • R 1 is selected from cyano, or optionally substituted amidoacyl
  • R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted sulfonyl or optionally substituted sulfonylalkyl
  • R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl
  • R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl
  • R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl
  • R 6 is selected from optionally substituted alky
  • the compound of Formula (I') is a compound of Formula (I'a) or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein R 1 is selected from cyano, or optionally substituted amidoacyl; R 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and R 6 is selected from optionally substituted alkyl, optionally substituted aryl, or optionally substituted cycloalky
  • R 1 is cyano. In other embodiment, R 1 is optionally substituted amidoacyl.
  • the optionally substituted amidoacyl can have a a-ketoamide structure or a structure selected from wherein R 7 , R 8 and R9 are as defined herein.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (II): wherein R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted sulfonyl or optionally substituted sulfonylalkyl; R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 6 is selected from optionally substitute
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (Il): wherein R 2 , R 3a , R 4 , R 5 , R 6 , and R 7 are as disclosed herein.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (Ila): wherein R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted sulfonyl or optionally substituted sulfonylalkyl; R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R 6 is selected from optionally substitute
  • R 7 is selected from optionally substituted amino, optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (ll'a)
  • R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted sulfonyl or optionally substituted sulfonylalkyl
  • R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl
  • R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl
  • R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl
  • R 6 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (ll'a): wherein R 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 6 is selected from optionally substituted alkyl, optionally substituted aryl, or optionally substituted cycloalkyl; and R 7 is selected from optionally substituted amino, optionally substituted N-
  • R 7 is optionally substituted amino, or optionally substituted N- heterocyclyl.
  • R 7 is selected from -IMH 2 , optionally substituted alkylamino, optionally substituted cycloalkylamino, optionally substituted arylamino, optionally substituted arylalkylamino, optionally substituted heteroarylalkylamino, optionally substituted heterocycylalkylamino and optionally substituted N-heterocyclyl.
  • R 7 is selected from -NH 2 , optionally substituted C 1 -C 5 alkylamino, optionally substituted C 3 -C 6 cycloalkylamino, optionally substituted arylamino, optionally substituted aryl(C 1 -C 5 alkyl)amino, optionally substituted heteroaryl (C 1 -C 5 alkyl)amino, optionally substituted heterocycyl(C 1 -C 5 alkyl)amino and optionally substituted C 3 -C 6 N-heterocyclyl.
  • the amino is -NH 2 , or optionally substituted one or two times with methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexanyl, benzyl, phenyl, tetrahydropyrany I methyl, oxazolylmethyl.
  • substituents can be further substituted by 1, 2 or 3 halogens such as fluoride, chloride and bromide.
  • the optionally substituted N-heterocyclyl is optionally substituted N- cyclobutyl or optionally substituted N-cyclohexanyl.
  • R 7 is -NH 2 , optionally substituted -NH(alkyl), optionally substituted -N(alkyl) 2 , optionally substituted -NH(cycloalkyl), or optionally substituted N-heterocyclyl.
  • R 7 is -NH 2 , optionally substituted -NH(C 1 -C 5 alkyl), optionally substituted -N(C 1 -C 5 alkyl>2, optionally substituted -NH(C3-Cs cycloalkyl), optionally substituted - NH(aryl-C 1 -C 5 alkyl) or optionally substituted C 3 -C 6 N-heterocyclyl.
  • R 7 is -NH 2 , -NH(methyl), -NH(ethyl), -NH(propyl), -NH(iso-propyl), - NH(cyclopropyl), -NH(cyclobutyl), -NH(cyclopentyl), -NH(cyclohexyl), -NH(benzyl), - NH(phenyl), -NH(tetrahydropyranylmethyl), -NH(oxazolylmethyl), -N(methyl) 2 , - N(ethyl) 2 , -N(propyl) 2 , -N(iso-propyl) 2 , or C3-Cs N-heterocyclyl.
  • the C 3 -C 6 N- heterocyclyl can be pyrrolidinyl, piperidinyl, azetidinyl, or aziridinyl.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (lib):
  • R 2 , R 3 , R , R 5 and R 6 are as disclosed herein;
  • R 8 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl;
  • R9 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl; or R 6 and R9 are linked to form an optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (ll'b): wherein R 2 , R 3a , R 4 , R 5 and R 6 are as disclosed herein;
  • R 8 is selected from H , optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl;
  • R9 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl; or R 8 and R9 are linked to form an optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • R 8 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl. In some embodiments, R 8 is selected from H , C 1 -C 5 alkyl, optionally substituted C 3 -C 6 cycloalkyl. In other embodiments, R 8 is selected from H, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexanyl, benzyl, or phenyl. In other embodiments, R 8 is H.
  • R9 is selected from optionally substituted C 1 -C 5 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted aryl, optionally substituted aryl(C 1 - C 5 alkyl). In other embodiments, R9 is selected from methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexanyl, benzyl, or phenyl.
  • R 8 and R9 are linked to form an optionally substituted C 3 -C 6 heterocyclyl. In other embodiments, R 8 and R9 are linked to form optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azetidinyl, or optionally substituted aziridinyl.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (lie): wherein R 2 , R 3 , R 4 , R 5 and R 6 are as disclosed herein.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (II'c): wherein R , R 3a , R , R 5 and R 6 are as disclosed herein.
  • the a-ketoamide moiety can act as a targeting ligand to reversibly bind with Cysl45 in the active site of 3CLpro to inhibit the protease activity, but having a higher binding affinity relative to the viral peptides.
  • Inhibition of 3CL proteases is expected to reduce the ability of the coronavirus to replicate inside a host cell. By disrupting the ability of the coronavirus to process its polyprotein precursors after the viral genome has been translated in a host cell, disease and symptoms resulting from rhinovirus and coronavirus infections can be treated and/or prevented.
  • the a-ketoamide moiety are also expected to similarly reversibly bind with 3Cpro, and thus can be also used for treating viruses in the picornaviridae family. This is based on the understanding that both 3CLpro and 3Cpro recognize the Gln- (Ser/Ala/Gly) sequence and also have a cysteine-histidine catalytic dyad at its active site that participate in peptide bond cleavage. In particular, the cyclopropylamino moiety of Formula (lie) and/or (II'ç) was found to be especially effective.
  • R 2 is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocyclyl, optionally substituted C 4 -C 8 heteroaryl, optionally substituted aryl, optionally substituted amino, optionally substituted amino(C 1 -C 6 alkyl), optionally substituted sulfonyl, and optionally substituted sulfonyl(C 1 -C 5 alkyl).
  • R 2 is selected from optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocyclyl, optionally substituted C 4 -C 8 heteroaryl, optionally substituted sulfonylamino, optionally substituted sulfonylamino(C 1 -C 6 alkyl), optionally substituted aminosulfonyl and optionally substituted aminosulfonyl(C 1 -C 5 alkyl).
  • R 2 is selected from optionally substituted cycloalkyl having an amide moiety, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonylalkyl, optionally substituted sulfonylamino, optionally substituted sulfonylaminoalkyl, optionally substituted aminosulfonyl and optionally substituted aminosulfonylalkyl.
  • R 2 is selected from optionally substituted cycloalkyl having an amide moiety, optionally substituted alkylsulfonylalkyl, and optionally substituted aminosulfonylalkyl.
  • R 2 is selected from optionally substituted C 3 -C 6 cycloalkyl having an amide moiety, optionally substituted (C 1 -C 5 alkyl)sulfonyl(C 1 -C 5 alkyl), optionally substituted sulfonylamino, optionally substituted sulfonylamino(C 1 -C 5 alkyl), optionally substituted aminosulfonyl and optionally substituted aminosulfonyl(C 1 -C 5 alkyl).
  • R 2 is selected from optionally substituted C 3 -C 6 cycloalkyl having an amide moiety, optionally substituted (C 1 -C 5 alkyl)sulfonyl(C 1 -C 5 alkyl), and optionally substituted aminosulfonyl(C 1 -C 5 alkyl).
  • R 2 is selected from optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted sulfonylmethyl, optionally substituted cyclopentyl, and optionally substituted cycloalkyl having an amide moiety.
  • R 2 is optionally substituted cycloalkyl having an amide moiety.
  • R 2 is optionally substituted cycloalkyl having an amide moiety at the 2' position.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (III):
  • R 1 , R 3 , R 4 , R 5 and R 6 are as disclosed herein;
  • R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 to 3.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (IIl): wherein R 1 , R 3a , R 4 , R 5 and R 6 are as disclosed herein; R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 to 3.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (Ilia): wherein R 1 , R 3 , R 4 , R 5 and R 6 are as disclosed herein; R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 to 3.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (Ill'a): wherein R 1 , R 3a , R 4 , R 5 and R 6 are as disclosed herein; R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 to 3.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (Illb): wherein R 3 , R 4 , R 5 , R 6 and R are as disclosed herein; R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 to 3.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (Ill'b):
  • R 3a , R 4 , R 5 , R 6 and R 7 are as disclosed herein;
  • R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 to 3.
  • R 10 and R 11 are each independently selected from F, Cl, Br, methyl, ethyl, propyl or iso-propyl. In other embodiments, R 10 and R 11 are each independently selected from F, methyl, ethyl, propyl or iso-propyl.
  • R 10 and R 11 are linked to form an optionally substituted cycloalkyl. In other embodiments, R 10 and R 11 are linked to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • n 1 or 2.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (IIIc): wherein R 3 , R 4 , R 5 , R 6 , R 10 and R 11 and n are as disclosed herein.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (III'c):
  • R 3a , R 4 , R 5 , R 6 , R 10 and R 11 and n are as disclosed herein.
  • R 3 is selected from optionally substituted C 1 -C 5 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocyclyl, optionally substituted C 4 -C 8 heteroaryl. In other embodiments, R 3 is selected from optionally substituted C 1 -C 5 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • the cycloalkyl can be selected from cyclopentyl, cyclobutyl, cyclopropyl, and cyclohexyl.
  • the optional substituent can be halo, or C 1 -C 4 alkyl.
  • the alkyl can be optionally substituted with optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • the optional substituent can be halo, or C 1 -C 4 alkyl.
  • R 3 is selected from methyl, ethyl, trifluoroethyl, cyclohexanyl, cyclobutyl, cyclopropyl, cyclopentyl, and bicyclo[l.l.l]pentyl.
  • R 3 is selected from:
  • R 3 is selected from: In some embodiments, R 3a is selected from optionally substituted C 1 -C 5 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocyclyl, optionally substituted C 4 -C 8 aryl, optionally substituted C 4 -C 8 heteroaryl. In other embodiments, R 3a is selected from optionally substituted C 1 -C 5 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • the cycloalkyl can be selected from cyclopentyl, cyclobutyl, cyclopropyl, and cyclohexyl.
  • the optional substituent can be halo, or C 1 -C 4 alkyl.
  • the alkyl can be optionally substituted with optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
  • the optional substituent can be halo, or C 1 -C 4 alkyl.
  • R 3a is selected from methyl, ethyl, trifluoroethyl, cyclohexanyl, cyclobutyl, cyclopropyl, cyclopentyl, and bicyclo[l.l.l]pentyl.
  • R 3a is selected from: In other embodiments, R 3a is selected from:
  • R 4 is selected from H, optionally substituted C 1 -C 5 alkyl, and optionally substituted C 3 -C 6 cycloalkyl. In other embodiments, R 4 is selected from H, and optionally substituted C 1 -C 5 alkyl. In other embodiments, R 4 is selected from H, optionally substituted methyl, optionally substituted ethyl, and optionally substituted cyclopropyl. In other embodiments, R 4 is selected from H, methyl, ethyl, propyl, isopropyl, and cyclopropyl.
  • N-alkylation for example, N-methylation
  • EC 50 values show that the EC 50 values are improved.
  • R 4 is selected from optionally substituted C 1 -C 5 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocyclyl, optionally substituted aryl, optionally substituted C 4 -C 8 heteroaryl.
  • the aryl is phenyl.
  • R 4 is selected from optionally substituted C 1 -C 5 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocyclyl, optionally substituted C 4 -C 8 heteroaryl.
  • R 4 is selected from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, indanyl, phenyl, benzyl, phenylethyl, diphenylmethyl, naphthalenyl, thiophenyl, pyridinyl, methylphenylmethyl, bisphenylmethyl, or phenylmethyl.
  • R 5 is selected from:
  • R 5 is selected from:
  • R 6 is selected from optionally substituted C 1 -C 5 alkyl, optionally substituted C 4 -C 8 aryl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 4 - C 8 heteroaryl, optionally substituted C 3 -C 6 heterocycyl.
  • R 6 is selected from optionally substituted methyl, optionally substituted ethyl, optionally substituted iso-propyl, optionally substituted iso-butyl, optionally substituted tert-butyl, optionally substituted cyclopropyl, optionally substituted phenyl, and optionally substituted phenylethyl.
  • R 6 is selected from:
  • R 6 is selected from:
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (IV):
  • R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl
  • R 4 is selected from H, optionally substituted alkyl
  • R 5 is selected from optionally substituted aryl, or optionally substituted cycloalkyl
  • R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl
  • n is an integer from 1 and 2.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (IVa): wherein R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl; is selected from H, optionally substituted alkyl; R 5 is selected from optionally substituted aryl, or optionally substituted cycloalkyl; R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 and 2.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (IV'):
  • R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl
  • R 4 is selected from H, optionally substituted alkyl
  • R 5 is selected from optionally substituted cycloalkyl
  • R 10 and R 11 are each independently selected from H, halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl
  • n is an integer from 1 and 2.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (IV'a): wherein R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl; R 4 is selected from H, optionally substituted alkyl; R 5 is selected from optionally substituted cycloalkyl; R 10 and R 11 are each independently selected from H , halo or optionally substituted alkyl; or R 10 and R 11 are linked to form an optionally substituted cycloalkyl, optionally substituted halocycloalkyl, or optionally substituted heterocyclyl; and n is an integer from 1 and 2.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (V):
  • R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted sulfonyl, optionally substituted sulfonylalkyl
  • R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl
  • R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl
  • R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl
  • R 6 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycyl, optionally substituted cycloalkyl.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (Va): wherein R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted sulfonyl, optionally substituted sulfonylalkyl; R 3 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; and R 6 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl,
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (V'): wherein R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted sulfonyl, optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; and R 6 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl; and R
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (V'): wherein R 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl; and R 6 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl.
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (V'a): wherein R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted sulfonyl, optionally substituted sulfonylalkyl; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; and R 6 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted hetero
  • the compound of Formula (I') or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of Formula (V'a): wherein R 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted sulfonyla Ikyl ; R 3a is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl; R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl; R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl; and R 6 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl.
  • the compound of Formula (I) is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the present invention also provides a method of synthesising a compound of Formula (I), (I'), (II), (ll'), (III), (lll'), (IV), (IV'), (V) or (V') or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising: a) sequentially reacting a C-terminus an amino acid like compound comprising R 5 and an amino moiety of a compound comprising R 2 with a C-terminus and/or N-terminus of an amino acid like compound comprising R 3 ; and b) oxidising the intermediate of step a) with an oxidising agent in order to form R 1 .
  • the method of synthesis can be via a general scheme as shown in general route A, B, D, E, F, H, and I.
  • the compound comprising R 2 comprises a lactamide moiety.
  • a N-terminus of the amino acid like compound comprising R 5 is reacted with a carboxylate compound comprising R 6 .
  • the amino acid like compounds can be coupled using amide coupling reagents.
  • amide coupling reagents For example,H ATU and DIPEA can be used.
  • the oxidation step is performed using Dess-Martin periodinane (DMP).
  • DMP Dess-Martin periodinane
  • primary alcohols are oxidised to aldehydes and secondary alcohols to ketones.
  • the method further comprises: a) oxidising a hydroxyl moiety of a compound comprising R 2 to an aldehyde; and b) reacting the aldehyde with an isocyano compound in order to form a lactamide compound comprising R 2 .
  • the isocyano compound has the functional group -N oC.
  • amino acid like compounds and intermediates can be protected using protecting groups.
  • the present invention also provides a method of treating and/or preventing a virus infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (l'), (II), (ll'), (III), (lll'), (IV), (IV'), (V) or (V') or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the present invention also provides a use of a compound of Formula (I), (l'), (II), (ll'), (III), (Ill'), (IV), (IV'), (V) or (V') or a pharmaceutically acceptable salt, solvate or prodrug thereof in the manufacture of a medicament for treating and/or preventing a virus infection in a patient in need thereof.
  • the present invention also provides a compound of Formula (I), (T), (II), (ll'), (III), (Ill'), (IV), (IV'), (V) or (V') or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in treating and/or preventing a virus infection in a patient in need thereof.
  • the virus infection is caused at least in part by a virus in the picornaviridae family or coronaviridae family.
  • the virus infection is caused by a virus belonging to the following families: levi-, narna-, picorna-, dicistro- , marna-, sequi-, como-, poty-, calici-, astro-, noda-, tetra-, luteo-, tombus-, corona-, arteri-, roni-, flavi-, toga-, bromo-, tymo-, clostero-, flexi-, seco-, barna, ifla-, sadwa-, chera-, hepe-, sobemo- , umbra-, tobamo-, tobra-, hordei-, furo-, porno-, peclu-, beny- , ourmia-, and id
  • the virus infection is caused at least in part by the coxsackievirus from the family picornaviridae. Variations in virus family are also included within this scope.
  • the World Health Organisation recommends using a Greek naming system for SARS-CoV-2 variants.
  • the virus infection can be COVID-19, caused by SARS-CoV-2 and its variants thereof.
  • Viruses constantly change through mutation and these mutations can result in a new variant of the virus. Due to the mutations, some variants emerge and disappear, others persist, while some variants spread more easily and quickly.
  • Some variants of the SARS-CoV-2 coronavirus to date are alpha, beta, gamma, delta and omicron.
  • the variants can have sub-variants. For example, omicron has a few major offshoots (sublineages), including BA.l, BA.2 and BA.3.
  • the virus infection is caused or associated with a virus selected from rhinovirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), common coronaviridae (including but not limited to OC43, HKU1, 229E and NL63), enterovirus, poliovirus, coxsackievirus, hepatitis A virus, foot-and-mouth disease virus (FMDV) belonging to the picornaviridae family and calicivirus from the caliciviridae family.
  • the virus is alpha human coronaviruses.
  • the virus is beta human coronaviruses.
  • the virus is human enteroviruses A-D. In other embodiments, the virus is poliovirus. In other embodiments, the virus is coxackievirus. In other embodiments, the virus is echovirus. In other embodiments, the virus is hepatitis A virus. In other embodiments, the virus is calicivirus. In other embodiments, the virus is norovirus. In other embodiments, the virus is Norwalk virus.
  • the virus infection is caused or associated with coronavirus; i.e. coronavirus infection. In other embodiments, the virus infection is associated with rhinovirus. In other embodiments, the virus infection is from an RNA-based virus. In other embodiments, the virus infection is from a single-stranded RNA virus.
  • RNA virus is a virus that has RNA (ribonucleic acid) as its genetic material. This nucleic acid is usually single-stranded RNA (ssRNA). RNA viruses can be further classified according to the sense or polarity of their RNA into negative-sense and positive-sense. Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation. As such, purified RNA of a positive-sense virus can directly cause infection though it may be less infectious than the whole virus particle. Purified RNA of a negative-sense virus is not infectious by itself as it needs to be transcribed into positive- sense RNA; each virion can be transcribed to several positive-sense RNAs.
  • ssRNA single-stranded RNA
  • the virus infection is caused by a positive-sense, single-stranded RNA virus. In other embodiments, the virus infection is caused by a negative-sense, single-stranded RNA virus.
  • the method is a method of inhibiting progression of a virus infection in a patient in need thereof.
  • the use is a use in the manufacture of a medicament for inhibiting progression of a virus infection in a patient in need thereof.
  • the compound is for inhibiting progression of a virus infection in a patient in need thereof.
  • the compound of Formula (I), (I'), (II), (ll'), (III), (lll'), (IV), (IV'), (V) or (V') is an inhibitor of 3CL protease.
  • Suitable pharmaceutically acceptable salts include, but are not limited to salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • the present invention includes within its scope cationic salts e.g. sodium or potassium salts, or alkyl esters (e.g. methyl, ethyl) of the phosphate group.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • prodrug any compound that is a prodrug of the compound of formula (I) is also within the scope and spirit of the invention.
  • the compound of the invention can be administered to a subject in the form of a pharmaceutically acceptable pro-drug.
  • pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compound of the invention. Such derivatives would readily occur to those skilled in the art.
  • Other texts which generally describe prodrugs (and the preparation thereof) include: Design of Prodrugs, 1985, H. Bundgaard (Elsevier); The Practice of Medicinal Chemistry, 1996, Camille G.
  • prodrugs of the compound can include a protecting group protecting the amino group, including but not limited to, Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, Acetyl (Ac) group, Benzoyl (Bz) group, Benzyl (Bn) group, Carbamate group, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-Methoxyphenyl (PMP) group, Tosyl (Ts) group, Troc (trichlor
  • the compound of the invention may be in crystalline form either as the free compound or as a solvate (e.g. hydrate) and it is intended that both forms are within the scope of the present invention.
  • Methods of solvation are generally known within the art.
  • a therapeutically effective amount is intended to include at least partially attaining the desired effect, or delaying the onset of, or inhibiting the progression of, or halting or reversing altogether the onset or progression of macular degeneration.
  • the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods.
  • Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
  • Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the severity of the condition as well as the general age, health and weight of the patient to be treated.
  • the compound of the invention may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition.
  • the formulation of such compositions is well known to those skilled in the art.
  • the composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • injectables for such use can be prepared in conventional forms, either as a liquid solution or suspension or in a solid form suitable for preparation as a solution or suspension in a liquid prior to injection, or as an emulsion.
  • Carriers can include, for example, water, saline (e.g. normal saline (NS), phosphate-buffered saline (PBS), balanced saline solution (BSS)), sodium lactate Ringer's solution, dextrose, glycerol, ethanol, and the like; and if desired, minor amounts of auxiliary substances, such as wetting or emulsifying agents, buffers, and the like can be added.
  • saline e.g. normal saline (NS), phosphate-buffered saline (PBS), balanced saline solution (BSS)
  • sodium lactate Ringer's solution sodium lactate Ringer's solution
  • dextrose dextrose
  • glycerol glycerol
  • ethanol ethanol
  • auxiliary substances such as wetting or emulsifying agents, buffers, and the like
  • Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining
  • the compound, composition or combination can be dissolved in a pharmaceutically effective carrier and be injected into the vitreous of the eye with a fine gauge hollow bore needle (e.g., 30 gauge, 1/2 or 3/8 inch needle) using a temporal approach (e.g., about 3 to about 4 mm posterior to the limbus for human eye to avoid damaging the lens).
  • a fine gauge hollow bore needle e.g., 30 gauge, 1/2 or 3/8 inch needle
  • a temporal approach e.g., about 3 to about 4 mm posterior to the limbus for human eye to avoid damaging the lens.
  • a person skilled in the art will appreciate that other means for injecting and/or administering the compound, composition or combinations to the vitreous of the eye can also be used.
  • These other means can include, for example, intravitreal medical delivery devices.
  • These devices and methods can include, for example, intravitreal medicine delivery devices, and biodegradable polymer delivery members that are inserted in the eye for long term delivery of medicaments.
  • These devices and methods can further include transscleral delivery devices.
  • solutions or suspensions of the compound, composition or combinations of the invention may be formulated as eye drops, or as a membranous ocular patch, which is applied directly to the surface of the eye.
  • Topical application typically involves administering the compound of the invention in an amount between 0.1 ng and 10 mg.
  • the compound, composition or combinations of the invention may also be suitable for intravenous administration.
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof may be administered intravenously at a dose of up to 16 mg/m 2 .
  • the compound, composition or combinations of the invention may also be suitable for oral administration and may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • the compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt, solvate or prodrug is orally administrable.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • a binder e.g. inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • the compound, composition or combinations of the invention may be suitable for topical administration in the mouth including lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum
  • pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum
  • mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compound, composition or combinations of the invention may be suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like.
  • suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Transdermal patches may also be used to administer the compounds of the invention.
  • the compound, composition or combination of the invention may be suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the compound, composition or combination isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compound, composition or combination may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage composition or combinations are those containing a daily dose or unit, daily sub-dose, as herein above described, or an appropriate fraction thereof, of the active ingredient.
  • composition or combination of this invention may include other agents conventional in the art having regard to the type of composition or combination in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
  • suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
  • Suitable disintegrating agents include cornstarch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
  • Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
  • Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • intermediate iii as a light yellow solid (1.85 g, 5.21 mmol).
  • intermediate iii (1.85 mg, 5.21 mmol) was added HCI (4M in 1,4-dioxane, 10 equiv.). The mixture was stirred for 1 h, before concentration under pressure to afford intermediate 1-C (1.52 g, 5.21 mmol) as a white solid.
  • intermediate v was purified by reversed-phase prep-HPLC to afford intermediate v as a colourless solid (123.20 mg, 49.5%).
  • acetone 3 mL
  • 5% aqueous NaHCCH 1.30 mL
  • TEMPO 69.92 mg, 0.447 mmol, 1.1 equiv.
  • a 5% aqueous solution of NaOCI 1.2 mL, 0.814 mmol, 2 equiv.
  • intermediate xv (175 mg, 0.47 mmol) was added HCI (4M in 1,4-dioxane, 10 equiv). The mixture was stirred for 1 h, before concentration under pressure to afford intermediate 1-H (119 mg, 0.47 mmol) as a white solid.
  • intermediate A-3 60 mg, 0.14 mmol, 1.0 equiv.
  • intermediate 1-A 40 mg, 0.14 mmol, 1.0 equiv.
  • /V,/V-diisopropylethylamine 126 ⁇ L, 0.72 mmol, 5.0 equiv.
  • HATU 55 mg, 0.14 mmol, 1.0 equiv.
  • reaction mixture was diluted with DMF (1 mL), filtered and the crude product was purified by Waters MDAP preparative H PLC reverse phase chromatography (20-70% MeCN/H 2 O, 0.1% formic acid) to afford compound 107 as white solid upon lyophilization (7.5 mg, 0.012 mmol).
  • intermediate 1-7 (39.9 mg, 0.117 mmol, 1.0 equiv.), HATU (53.5 mg, 0.141 mmol, 1.2 equiv.) and N,N V-diisopropylethylamine (0.14 ml, 0.821 mmol, 7.0 equiv.) at 0 °C and stirred at rt for 30 min.
  • the reaction mixture was diluted with EtOAc (5 mL) and washed with water (2 mL).
  • intermediate J-4 270 mg, 0.417 mmol, 1.0 equiv.
  • THF 2.1 mL
  • diethylamine 864 ⁇ L, 8.35 mmol, 20 equiv.
  • the reaction was stirred at room temperature for 0.5 h.
  • the reaction was concentrated under reduced pressure and purified by silica gel column chromatography (0-20% MeOH/CH 2 Cl 2 ) to afford intermediate J-5 as a yellow solid (195 mg, 0.459 mmol); MS (ESI) m/z 425.3 [C21H36N4O5 + H] + .
  • intermediate J-8 (126 mg, 0.236 mmol, 1.0 equiv.) in EtOAc (2.4 mL) was added acetic acid (16 ⁇ L, 0.284 mmol, 1.2 equiv.) followed by isocyanocyclopropane (19 ⁇ L, 0.284 mmol, 1.2 equiv.) at 0 °C.
  • acetic acid (16 ⁇ L, 0.284 mmol, 1.2 equiv.
  • isocyanocyclopropane (19 ⁇ L, 0.284 mmol, 1.2 equiv.) at 0 °C.
  • the reaction was warmed to room temperature and stirred for 17 h.
  • the reaction was concentrated under reduced pressure and the crude was purified by silica gel column chromatography (0- 10% MeOH/CH 2 Cl 2 ) to afford intermediate J-9 as a white solid (125 mg, 0.189 mmol);
  • intermediate L-1 130 mg, 0.456 mmol
  • 1,4-dioxane 0.4 mL
  • HCI 4 M in 1,4-dioxane, 1.5 mL
  • the reaction was reduced under pressure and dried under high vacuum overnight to afford intermediate L-2 as an off-white solid.
  • Some compounds herein may exist as mixtures of diastereomers with diastereomeric ratios of at least 9: 1.
  • the full-length gene encoding SARS-CoV-2 3CLpro from strain BetaCoV/Wuhan/WIV04/2019 was synthesized and cloned into Ndel and Xhol site of pET29a(+) vector by Genscript (Piscataway, NJ, USA), as described previously. 2
  • the full-length gene encoding a Human Coronavirus 229E (HCoV-229E, Accession X69721.1) was cloned in pET29a( + ) with a C-terminus His tag.
  • the codon optimized plasmid for E. coli expression was transformed into competent BL21(DE3) cells.
  • a single colony was picked to inoculate 10 mL of Terrific Broth (TB) supplemented with 50 mg/L Kanamycin and grown at 37 °C with shaking at 200 rpm.
  • the 10-mL inoculum was added to 1 L of TB with 50 mg /L Kanamycin and grown to an optical density at 600 nm of 2.5.
  • the culture was induced using 0.5mM Isopropyl b-D-l-thiogalactopyranoside (IPTG) and grown at 37 °C for an additional 2 hrs.
  • IPTG Isopropyl b-D-l-thiogalactopyranoside
  • the cell pellet was resuspended in lysis buffer (20mM Tris, pH 7.5, lOOmM NaCI, 2mM dithiothreitol (DTT) and 10 pg/mL DNase I), and lysed by sonication (25% amplitude, 2 seconds on/ 2 seconds off). Cell debris were removed by centrifugation at 39,191x g for 30 min at 4°C. The supernatant was loaded onto equilibrated HisTrap HP column (Cytiva). The column was washed with lysis buffer containing 5mM imidazole, followed by another wash with 30mM imidazole.
  • lysis buffer 20mM Tris, pH 7.5, lOOmM NaCI, 2mM dithiothreitol (DTT) and 10 pg/mL DNase I
  • Protein was eluted using buffer with 300mM imidazole and further purified by gel filtration chromatography on HiLoad 16/600 Superdex 200 prep grade column (Cytiva) with 20mM Tris, pH 7.5, lOOmM NaCI, 2mM DTT. Fractions from resulted peak were pooled and concentrated using centrifugal filter unit of 10,000-molecular-weight-cutoff. The purity and molecular weight of the protein was confirmed with SDS-PAGE and Mass Spectrometry (MS). A predominant peak at 34863 Da was observed by MS which matched with the calculated molecular weight of SARS-CoV-2 C-His-3CLpro without the N-terminal Methionine residue.
  • MS Mass Spectrometry
  • Recombinant MERS-CoV 3CLpro (accession K9N638) expressed in E.coli was purchased from R&D Systems (Cat No. E-719). The purity and molecular size of commercial MERS- CoV 3CL was confirmed in our lab by SDS-PAGE. Further validation by MS showed a predominant peak at 33361 Da that matched with theoretical molecular weight of 33360.3 Da.
  • the 3C protease domain from Non-Coronaviruses, Human Coxsackievirus B3, strain Beijing0811 (Accession GQ141875.1) and Norovirus Hu/GIi.6/GZ2010- L96/Guangzhou/CHN/2011 (Accession JX989075.1) were cloned into pET29a(+) and pET28a(+) vector, respectively.
  • the gene synthesis and protein purification were conducted by Genscript (Piscataway, NJ, USA). Briefly, the codon optimized plasmids for E. coli expression was transformed into competent BL21(DE3) cells.
  • the culture was induced at 0.5 mM IPTG and grown at 37°C for 4 hrs for CVB3 and overnight at 15°C for Norovirus. Both proteins were purified from soluble fraction using His affinity and size exclusion chromatography.
  • the CVB3 protease was stored in 50 mM Tris-HCI, 100 mM NaCI, 2 mM dithiothreitol, pH 7.5 and a similar storage buffer was used for Norovirus except the Tris-HCI concentration was 20mM with pH 8.0.
  • HRV-3C protease with a N-terminus His tag was purchased from Sigma-Aldrich (Cat no: SAE0045).
  • a highly sensitive FRET based protease assay was developed to identify inhibitors of 3CL proteases.
  • the substrate, Peptide 1 (Dabcyl)KTSAVLQSGFRKM(Glu)(EDANS) (2) was synthesized by Genscript.
  • the test compounds were 3-fold serially diluted in 100% DMSO to 15 concentrations, starting at 3.33 mM. 1.5 mI of the serially diluted compounds were transferred to a black 384 well assay plate (Cat. 781900, Greiner). 23.5 mI of 2.13X concentration of SARS-CoV-2 Chis-3CLpro, 229E-CoV Chis-3CLpro or MERS-CoV 3CLpro prepared in assay buffer was added to the compounds and incubated for 30 mins at 25°C.
  • the final assay contained 12.5 nM of SARS-CoV-2 Chis-3CLpro or 6 nM 229E-CoV Chis-3CLpro or 75 nM MERS-CoV 3CLpro with 6 mM peptide 1 substrate and 3% DMSO in assay buffer containing 50 mM HEPES at pH 7.5, 100 mM NaCI, and 0.01% Triton X-100 and ImM DTT.
  • the FRET signal was measured using an excitation wavelength of 340 nm (UV(TRF) 340/60 nm, Barcode 101), emission wavelength of 490 nm (DSPPsion 486/10 filter, Barcode 220) and Lance/DELFIA D400 single mirror (Barcode 412) on Envision plate reader (2104 Envision Multilabel Plate Readers, Perkin Elmer).
  • the dose-dependent inhibition curves were fitted with a variable slope using GraphPad Prism software (GraphPad, USA) to determine a compound's IC50.
  • a similar FRET assay was developed for the non-coronavirus 3C proteases.
  • the substrate peptides, Peptide 13: ⁇ Glu(Edans) ⁇ LEVLFQGP ⁇ Lys(Dabcyl) ⁇ , Peptide 12 ⁇ Glu(Edans) ⁇ DFHLQGP ⁇ Lys(Dabcyl) ⁇ 3 and Peptide 1 all synthesized by GenScript were used for HRV 3C, Norovirus 3C and CVB3 3C protease assays, respectively.
  • the compound dilution and assay buffer were similar to SARS-CoV-2 Chis-3CLpro assay.
  • the final assay condition for HRV 3C protease contained 100 nM of enzyme, 6 mM Peptide 13 with 1 hr incubation at 25°C.
  • the final assay condition for Norovirus 3C protease contained 1.25 mM of enzyme and 12.5 mM Peptide 12 and 1.5 hr incubation at 37°C.
  • the final assay condition for CVB3 protease contained 2.5 mM enzyme, 6 mM peptide 1 substrate 4 with 2 hrs incubation at 25°C.
  • MRC-5 ATCC® CCL-171TM cells. MRC-5 cells were seeded at a density of 10,000 cells per well into black, clear flat-bottom 96- well plates (Greiner) on the day before virus inoculation. Cells were infected with 229E or OC43 virus at multiplicity of infection (MOI) of 0.01 using 50 ⁇ l of virus inoculum.
  • MOI multiplicity of infection
  • virus inoculum was removed and 50mI of diluted test compounds in EMEM + 2% FBS, was added to each well.
  • the cells were then incubated at 35°C with 5% CO 2 for 4 days (229E) or 5 days (OC43).
  • Cell viability was measured with CellTiter Glo (Promega), post 4 or 5-day incubation according to manufacturer's protocol, using Tecan infinite M200 pro plate reader. Cytotoxicity of compounds was assessed in parallel on uninfected cells plated together with the cells for virus infection. The percent effect of test compounds at each concentration was calculated with the DMSO-treated uninfected control wells set as 100% cell viability and untreated virus-containing control wells as 0% virus inhibition.
  • Relative Cell-Titer Glo signals were plotted against log10 values of compound concentration.
  • concentration required for 50% inhibition of virus CPE (EC50 value) was determined using a 4-parameter logistic model in Prism 8.
  • Percent effect for cytotoxicity of test compounds on uninfected cells was calculated using values for DMSO-treated uninfected control wells set as 100% cell viability.
  • CC50 values were calculated using a 4-parameter logistic model in Prism 8 and selectivity index (SI) was calculated by dividing CC50 value over EC50 value for each compound.
  • A549-hACE2 cells that stably express the human angiotensin-converting enzyme 2 (hACE2) were plated at a density of 10,000 - 12,000 cells per well in white opaque 96- well plates (Corning). On the next day, cells were inoculated with SARS-CoV2-Nluc viruses (MOI 0.1) (Xie et a I . , 2020) together with diluted compounds in phenol red-free medium containing 2% FBS. 50pl of virus-compound mixture was added to each well and plates were incubated at 37°C with 5% C02for 48 hours. At 48 hours post-infection, 50mI of Nano-Glo luciferase substrates (Promega) were added to each well.
  • SARS-CoV2-Nluc viruses MOI 0.1
  • Xie et a I . , 2020 SARS-CoV2-Nluc viruses
  • 50pl of virus-compound mixture was added to each well and plates were incubated at 37°
  • Luciferase signals were measured using BioTek Synerge Neo2 plate reader (lid-on, Gain 100). The relative luciferase signals were calculated by normalizing the luciferase signals of compound-treated cells to that of the DMSO control wells (set as 100%). The relative luciferase signal was plotted against the loglO values of compound concentration. EC50 (compound concentration causing 50% reduction of luciferase signal) values were calculated using a 4-parameter logistic model in Prism 8.

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Abstract

La présente invention concerne, en général, des modulateurs de l'enzyme protéase 3CL du coronavirus, leurs procédés de synthèse et leurs utilisations. En particulier, les modulateurs d'enzyme peuvent être utilisés pour inhiber la protéase 3CL du coronavirus et empêcher ainsi la réplication du virus.
PCT/SG2022/050408 2021-06-15 2022-06-14 Modulateurs d'enzyme du coronavirus, leurs procédés de synthèse et leurs utilisations WO2022265577A2 (fr)

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US6291640B1 (en) * 1996-12-27 2001-09-18 Boehringer Ingelheim Ltd. Peptidomimetic inhibitors of the human cytomegalovirus protease
GB9809664D0 (en) * 1998-05-06 1998-07-01 Hoffmann La Roche a-Ketoamide derivatives
JP2003526634A (ja) * 1999-12-03 2003-09-09 ブリストル−マイヤーズ スクイブ ファーマ カンパニー Ｃ型肝炎ウイルスＮＳ３プロテアーゼのα−ケトアミド阻害剤
CN1446201A (zh) * 2000-07-21 2003-10-01 先灵公司 用作丙型肝炎病毒ns3－丝氨酸蛋白酶抑制剂的新型肽
WO2007041775A1 (fr) * 2005-10-10 2007-04-19 The University Of Queensland Inhibiteurs de cystéine protéase incorporant des groupements azide
EP2760827A4 (fr) * 2011-09-27 2015-06-24 Univ Kansas State Antiviraux à large spectre contre des protéases 3c ou 3c-associées du super-groupe des picornavirus-associés : picornavirus, calicivirus et coronavirus
TW201817714A (zh) * 2016-08-30 2018-05-16 英商葛蘭素史密斯克藍智慧財產權有限公司 抑制3c及3cl蛋白酶之化合物及其使用方法
US20230148179A1 (en) * 2020-04-08 2023-05-11 Arizona Board Of Regents On Behalf Of The University Of Arizona SMALL MOLECULE INHIBITORS OF SARS-CoV-2 VIRAL REPLICATION AND USES THEREOF

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