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WO2022221686A1 - Inhibiteurs de protéases à cystéine et leurs méthodes d'utilisation - Google Patents

Inhibiteurs de protéases à cystéine et leurs méthodes d'utilisation Download PDF

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WO2022221686A1
WO2022221686A1 PCT/US2022/025064 US2022025064W WO2022221686A1 WO 2022221686 A1 WO2022221686 A1 WO 2022221686A1 US 2022025064 W US2022025064 W US 2022025064W WO 2022221686 A1 WO2022221686 A1 WO 2022221686A1
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group
alkyl
compound
virus
oxo
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Lee D. Arnold
Walter Keung
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Pardes Biosciences Inc
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Pardes Biosciences Inc
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/61—Halogen atoms or nitro radicals
    • 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

Definitions

  • the Coronaviridae family of viruses are enveloped, single-stranded, positive- sense RNA viruses and include 141 species that are classified into four genera according to their phylogenetic relationships: ⁇ -, ⁇ -, ⁇ -, and ⁇ -coronavirus.
  • Coronaviruses are zoonotic viruses that infect a variety of animals from whales to birds, bats, cats, and humans. Typically, CoV infection results in mild to moderate respiratory tract infections; however, some CoV species are extremely virulent and can result in widespread fatality.
  • Severe acute respiratory syndrome coronavirus SARS-CoV
  • SARS-CoV Severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • COVID-19 (SARS CoV2) coronaviruses have raised a global pandemic since they had been first identified in late 2019. Therefore, it is important to identify coronavirus drug targets that can be utilized for the development of broad-spectrum anti-coronaviral therapeutics to combat infections of existing and emerging coronaviruses.
  • All CoVs express a >800 kDa replicase polyprotein that contains either two or three cysteine proteases, the papain-like protease(s) (PLPpro, or PLP1 and PLP2) and the 3C- like protease (3CLpro, nsp5, or Mpro).
  • CoV replicase polyprotein processes the CoV replicase polyprotein by cleaving it into 16 non-structural proteins, which are responsible for a variety of aspects of CoV replication.
  • the CoV 3CLpro is responsible for processing 11 cleavage sites of within the replicase polyprotein and is essential for CoV replication, making it a highly valuable target for therapeutic development.
  • the overall active site architecture and substrate recognition pockets are structurally conserved across CoV 3CLpros, increasing its attractiveness as a target for the development of broad-spectrum anti-CoV therapeutics.
  • high sequence conservation in the vicinity of active site among CoV 3CLpros from different coronavirus subclasses make them an excellent target for the development of broad-spectrum therapeutics for coronavirus infections.
  • compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.
  • Y is selected from -C(O)-, -S(O)-, and -S(O) 2 -
  • R W is selected from N(R U1 R U2 ) and a 3-10 membered N-heterocyclyl, wherein R W is optionally substituted by one, two or three substituents each selected from R a , or R W is a warhead
  • R 2 is selected from the group consisting of C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, wherein R 2 is optionally substituted by one, two or three substituents each selected from the group consisting of halogen,
  • Y is selected from -C(O)-, -S(O)-, and -S(O) 2 -
  • R 6a is selected from the group consisting of hydrogen, halogen, cyano, SF 5 , C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl
  • R 6b is selected from the group consisting of hydrogen, halogen, cyano, SF 5 , C 1 -C 6 alkyl, and C 3 - C 10 cycloalkyl
  • R 7a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl
  • R 7b is selected from the group consisting of hydrogen, halogen, C 1 - C 6 alkyl, and C 1 -C 6 haloalkyl
  • R 8 is selected from the group consisting of hydrogen, deuterium,
  • kits for ameliorating or treating a viral infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of any of the compounds described herein.
  • methods of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release comprising administering a therapeutically effective amount of a compound described herein to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein with a virally infected cell.
  • treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like, including a reduction of viral shedding in asymptomatic individuals and prophylaxis of exposed individuals, independent of symptoms.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C 1 -C 5 alkenyl, C 2 -C 6 alkenyl, and C 3 -C 4 alkenyl, respectively.
  • Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • alkoxy refers to a straight or branched alkyl group attached to oxygen (alkyl-O-).
  • alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C 1 -C 5 alkoxy, C 1 -C 6 alkoxy, and C 2 -C 6 alkoxy, respectively.
  • Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C 1-6 alkyl, C 1-4 alkyl, and C 1-3 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • alkylene bridge refers to a straight or branched divalent hydrocarbon bridge, linking two different carbons of the same ring structure.
  • the alkylene bridge may link any two carbons within the ring structure.
  • alkylene bridges can be an indicated number of carbon atoms, for example, C 1 -C 6 alkylene bridge, C 1 -C 5 alkylene bridge, C 1 -C 4 alkylene bridge, C 1 -C 3 alkylene bridge, or C 1 -C 2 alkylene bridge.
  • each instance of an alkylene bridge is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkylene bridge”) or substituted (a “substituted alkylene bridge”) with one or more substituents (for instance from 1 to 4 substituents, 1 to 3 substituents, or 1 substituent) which may be halo, -NO 2 , -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, or C 1 -C 6 cycloalkyl.
  • substituents for instance from 1 to 4 substituents, 1 to 3 substituents, or 1 substituent
  • alkylene bridge include, but are not limited to, methylene, ethylene, propylene, tetramethylene, and n-butylene.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”).
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 -C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl
  • R 60 and R 61 are each independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl.
  • carbonyl refers to the radical -C(O)-.
  • cyano as used herein refers to the radical -CN.
  • cycloalkyl or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C 3 -C 10 cycloalkyl, C 3-6 cycloalkyl or C 4-6 cycloalkyl, respectively.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.
  • halo or “halogen” as used herein refer to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl radical in which the alkyl group is substituted with one or more halogens.
  • Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e. CF 3 ), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.
  • Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e.
  • C 1-6 haloalkyl C 1-4 haloalkyl
  • C 1-3 haloalkyl C 1-3 haloalkyl
  • the term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,.
  • heteroaryl or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur.
  • heteroatoms for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur.
  • the term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen.
  • heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.
  • Examples of representative heteroaryls include the following: wherein each Z is selected from carbonyl, N, NR 65 , O, and S; and R 65 is each independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.
  • heterocyclyl refers to saturated or partially unsaturated 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen.
  • heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.
  • the heterocyclyl group is a bridged heterocyclyl, a bicyclic heterocyclyl, or a spirocyclic heterocyclyl.
  • the heterocycle is a spiro heterocycle (e.g.2,8-diazaspiro[4.5]decane).
  • the heterocycle is a bridged heterocycle (e.g. octahydro-1H-4,7-methanoisoindole).
  • “Spiro heterocyclyl,” or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O) m (wherein m is an integer of 0 to 2) as ring atoms.
  • Representative examples of heterocyclyl include, for example: , , , , , , In some embodiments, the heterocycle is a N-heterocyclyl.
  • N-heterocyclyl or “N-linked heterocyclyl” refers to a heterocyclyl group as defined above containing at least one nitrogen, wherein the point of attachment of the heterocyclyl group to the rest of the molecule is the nitrogen atom of the heterocyclyl group.
  • hydroxy and “hydroxyl” as used herein refers to the radical -OH.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • compositions for human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • pharmaceutical composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • Modulation includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g. mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards.
  • structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.
  • Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a single polymorph.
  • the compound is a mixture of polymorphs.
  • the compound is in a crystalline form.
  • the disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • a compound of the disclosure may have one or more H atom replaced with deuterium.
  • Certain isotopically-labeled disclosed compounds e.g., those labeled with 3 H and 14 C are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255).
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1-8 )alkyl, (C 2-12 )alkylcarbonyloxymethyl, 1- (alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)- ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)e
  • a group such as (C 1-8 )alkyl, (C 2-12 )alkylcarbonyloxymethyl, 1- (alkyl
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1-6 )alkylcarbonyloxymethyl, 1-((C 1-6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C 1-6 )alkylcarbonyloxy)ethyl (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1- 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkylcarbonyl, ⁇ -amino(C 1-4 )alkylcarbonyl, arylalkylcarbonyl and ⁇ -aminoalkylcarbonyl, or ⁇ -aminoalkylcarbonyl- ⁇ - aminoalkylcarbonyl, where each ⁇ -aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O),
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N- alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine.
  • warhead refers to a functional group present on a compound wherein that functional group is capable of reversibly or irreversibly participating in a reaction with a protein, e.g., 3C or 3CL protease (e.g., with a cysteine on the protease such as Cys 145).
  • Warheads may, for example, form covalent bonds with the protein, or may create stable transition states, or be a reversible or an irreversible alkylating agent.
  • the warhead moiety can be a functional group on an inhibitor that can participate in a bond-forming reaction, wherein a new covalent bond is formed between a portion of the warhead and a donor, for example an amino acid residue of a protein.
  • the warhead is an electrophile and the “donor” is a nucleophile such as the side chain of a cysteine residue.
  • a warhead may include a nitrile or halo group.
  • a warhead may include an aldehyde, ketoamides, hydroxybisulfite salts, heterocyclic moieties, aziridine, oxirane, epoxy ketones, halomethyl ketones, hydroxymethyl ketones, electrophilic ketones (e.g. trifluoromethyl ketones), acyloxymethyl ketones, benzothiazolyl ketones and a Michael acceptor.
  • nitriles may be reversible covalent warheads for cysteine protease inhibition., for example, where the mechanism of action may involve aformation of reversible covalent bond between the nitrile and the active cysteine to form a thioimidate adduct.
  • Reaction of cysteine of glutathione or other proteins is generally reversible, while the reaction with cysteine or aminoethylthiols generally irreversibly forms a thiazolidine adduct. It can be appreciated that contemplated compounds herein may be a reversible or an irreversible inhibitor.
  • Examples of exemplary warheads include, but not limited to, a moiety with a cyano or halo moiety, e.g.: independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -SO 2 , -SF 5 , and R 13a ;
  • R 13a is selected from the group consisting of -OR 13b , C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, -N(R e R f ), -N(R e )-C(O)-(R f ), 3-10 membered heterocyclyl, C 6 -C 14 aryl and 5-10 membered heteroaryl; wherein R 13a may be optionally substituted by one, two or three substituents each selected from R h ; R e and R f are each selected from
  • the compounds disclosed herein that include the warheads above also contemplate the precursors to those compounds, for example, where a cyano moiety involved in a warheads may be replaced with e.g., a halo moiety.
  • the compounds disclosed herein can also irreversibly bind, or may otherwise inhibit e.g., a virus protein via any other mechanism of action.
  • the term "inhibitor” as used herein refers to a compound that binds to and /or inhibits a target protease with measurable affinity.
  • reversible or "reversible inhibitor” as used herein refers to a protease inhibitor that associates with a protease in such a way as to inhibit the activity of the protease while the protease and inhibitor are bound, but does not associate with a protease in such a way as to inhibit the activity of the protease when the protease and inhibitor are no longer bound.
  • Reversible inhibitors can effect inhibition by competing with substrate for binding to the active site of the protease (competitive reversible inhibitor), or by associating with the protease bound to its substrate in a way to make the complex inactive (uncompetitive reversible inhibitor), or by associating with the protease and/or protease-substrate complex in a way that inhibits the activity of either and/or both.
  • competitive reversible inhibitor refers to an inhibitor (i.e. a compound) that is able to be covalently bonded to a target protease in a substantially non-reversible manner.
  • An irreversible inhibitor will remain substantially bound to the target protease once covalent bond formation has occurred.
  • Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the time with which the inhibitor is in contact with the enzyme.
  • an irreversible inhibitor will remain substantially bound to target protease once covalent bond formation has occurred and will remain bound for a time period that is longer than the life of the protein.
  • viral proteases include, but not limited to, Cathepsin K, coronavirus main protease (Mpro), Caspase 3, Calpain 1, and Cathepsin S.
  • a compound of the present disclosure e.g. a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc.
  • the viral protease is selected from the group consisting of Cathepsin K, coronavirus main protease (Mpro), Caspase 3, Calpain 1, and Cathepsin S.
  • the viral protease is a coronavirus main protease (Mpro).
  • the viral protease is Cathepsin K. In some embodiments, the viral protease is Caspase 3. In some embodiments, the viral protease is Calpain 1. In some embodiments, the viral protease is Cathepsin S.
  • Y is selected from -C(O)-, -S(O)-, and -S(O) 2 -
  • R W is selected from N(R U1 R U2 ) and a 3-10 membered N-heterocyclyl, wherein R W is optionally substituted by one, two or three substituents each selected from R a , or R W is a warhead
  • R 2 is selected from the group consisting of C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, wherein R 2 is optionally substituted by one, two or three substituents each selected from the group consisting of halogen, -C(O)-N(R b R c ), and R 5
  • mR 3 is selected from the group consisting of C 3 -C 10 cycloalkyl, C 6 -C 14
  • the compound of Formula I is represented by: (Formula I-A). [00056] In some embodiments, the compound of Formula I is represented by: (Formula I-B). [00057] In some embodiments, the compound of Formula I is represented by: (Formula I-C).
  • the compound of Formula I is represented by: (Formula I-D), wherein: Y 1 , Y 2 and Y 3 are independently selected, for each occurrence, from the group consisting of C(R Y1 R Y2 ), N(R Y1 R Y2 ), O, S(O) and S(O) 2 , or two of Y 1 , Y 2 and Y 3 may form, together with the carbons to which they are attached, a C 1 -C 3 alkylene bridge, wherein the alkylene bridge may optionally be substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, oxo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R Y1 and R Y2 are independently selected, for each occurrence, from the group consisting of R 13aa , hydrogen, cyano, halogen, hydroxyl, oxo, -CH(
  • the compound of Formula I is represented by: wherein: Y 1 , Y 2 and Y 3 are independently selected, for each occurrence, from the group consisting of C(R Y1 R Y2 ), N(R Y1 R Y2 ), O, S(O), and S(O) 2 ; or two of Y 1 , Y 2 and Y 3 may form, together with the carbons to which they are attached, a C 1 -C 3 alkylene bridge, wherein the alkylene bridge may optionally be substituted by one, two or three substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, oxo, hydroxyl, and halogen; R Y1 and R Y2 are independently selected, for each occurrence, from the group consisting of R 13aa , hydrogen, cyano, halogen, hydroxyl, oxo, -CH(CN)(OH), -SR
  • Y 1 2 3 , Y and Y are independently selected, for each occurrence, from the group consisting of C(R Y1 R Y2 ), N(R Y1 R Y2 ), O, S(O), and S(O) 2 ; or two of Y 1 , Y 2 and Y 3 may form, together with the carbons to which they are attached, a C 1 -C 3 alkylene bridge, wherein the alkylene bridge may optionally be substituted by one, two or three substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, oxo, hydroxyl and halogen;
  • R Y1 and R Y2 are independently selected, for each occurrence, from the group consisting of R 13aa , hydrogen, cyano, halogen, hydroxyl, oxo, -CH(CN)(OH), -SR 13ee , -S(R 13
  • Y 1 , Y 2 and Y 3 are each independently C(R Y1 R Y2 ), wherein each R Y1 and R Y2 is independently hydrogen or cyano.
  • Y 1 is O
  • Y 2 and Y 3 are each independently C(R Y1 R Y2 ), wherein each R Y1 and R Y2 is independently hydrogen or cyano.
  • n is 1, 2 or 3.
  • n is 3.
  • n is 2.
  • n is 1.
  • R W is an optionally substituted 3-10 membered N- heterocyclyl.
  • R W is a 3-10 membered N-heterocyclyl, wherein R W is optionally substituted by one, two or three substituents each independently selected from R a .
  • R a is cyano.
  • R a is halogen.
  • R W is optionally substituted N(R U1 R U2 ).
  • R W is N(R U1 R U2 ), wherein R W is optionally substituted by one, two or three substituents each independently selected from R a .
  • R a is cyano.
  • R a is halogen.
  • R U1 is hydrogen or C 1- C 3 alkyl, wherein the C 1- C 3 alkyl is optionally substituted with one, two or three substituents each independently selected from R a , wherein R a is cyano, -CF 3 or halogen.
  • R U2 is C 3 -C 6 cycloalkyl optionally substituted with one, two or three substituents each independently selected from R a , wherein R a is cyano or halogen.
  • R W is a warhead selected from the group consisting of:
  • R W is a warhead selected from the group consisting of: .
  • R 2 is selected from C 3 -C 6 cycloalkyl and C 6 -C 8 aryl, wherein the cycloalkyl or aryl is optionally substituted by one, two or three substituents each independently selected from R a .
  • R a is selected from the group consisting of SF 5 , halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy.
  • R a is selected from the group consisting of SF 5 , halogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl.
  • R 2 is selected from the group consisting of: [00068]
  • R 3 is 5-6 membered heteroaryl optionally substituted by one, two or three substituents each independently selected from R a .
  • R 3 is pyridyl optionally substituted by one, two or three substituents each independently selected from R a .
  • R a is selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 3 -C 10 cycloalkyl. In some embodiments, R a is halogen or C 1 -C 6 haloalkyl. In some embodiments, R a is -CF 3 . [00069] In some embodiments, R 3 is selected from the group consisting of: [00070] In some embodiments, R 3a is selected from the group consisting of hydrogen, deuterium, and C 1 -C 3 alkyl. In some embodiments, R 3a is selected from the group consisting of hydrogen and methyl.
  • R 3a is hydrogen. In some embodiments, R 3a is deuterium. In some embodiments, R 3a is methyl.
  • R 4 is C 3 -C 6 cycloalkyl optionally substituted by one, two or three substituents each independently selected from R a .
  • R a is selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 3 -C 10 cycloalkyl. In some embodiments, R a is halogen. In some embodiments, R a is F.
  • R 4a is hydrogen.
  • R 5 is selected from the group consisting of halogen, SF 5 , C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl. In some embodiments, R 5 is selected from the group consisting of halogen, SF 5 , C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl. In some embodiments, R 5 is selected from the group consisting of F, SF 5 , tert-butyl, and cyclopropyl.
  • Y is -C(O)-. In some embodiments, Y is -S(O)-. In some embodiments, Y is -S(O) 2 -.
  • R a is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, SF 5 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, and C 3 -C 10 cycloalkyl. In some embodiments, R a is independently selected, for each occurrence, from the group consisting of halogen, cyano, and C 1 -C 6 haloalkyl.
  • R a is halogen or cyano.
  • Formula II (Formula II), wherein: Y is selected from -C(O)-, -S(O)-, and -S(O) 2 -; R 6a is selected from the group consisting of hydrogen, halogen, cyano, SF 5 , C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl; R 6b is selected from the group consisting of hydrogen, halogen, cyano, SF 5 , C 1 -C 6 alkyl, and C 3 - C 10 cycloalkyl; R 7a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; R 7b is selected from the group consisting of hydrogen, halogen, C 1 - C 6 alkyl, and C 1 -C 6 haloalkyl;
  • R 6a is selected from the group consisting of hydrogen
  • R 6b is selected from hydrogen and halogen.
  • R 7a is selected from hydrogen and -CF 3 .
  • R 7b is selected from hydrogen and halogen.
  • Y is -C(O)-.
  • Y is -S(O)-.
  • Y is -S(O) 2 -.
  • the compound is selected from the group consisting of the compounds identified in Table 1 below: Table 1. Exemplary compounds.
  • Another aspect of the disclosure provides methods of treating patients suffering from a viral infection, e.g., a coronaviral infection.
  • the disclosure provides a method of treating the below medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-B, I-C, I-D, I-E, I-F, or II.
  • the disclosure provides a method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein.
  • the viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenavirus, a herpes virus, and a hepatovirus.
  • the viral infection is a coronavirus infection.
  • the viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus,
  • OC43 beta coronavirus HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS- CoV), and SARS-CoV-2 (COVID-19).
  • the viral infection is SARS-CoV-2.
  • the viral infection is from a virus selected from the group consisting of caliciviruses, MD145, murine norovirus, vesicular exanthema of swine virus, abbit hemorrhagic disease virus, porcine teschovirus, bovine coronavirus, feline infectious peritonitis virus, EV-68 virus, EV-71 virus, poliovirus, norovirus, human rhinovirus (HRV), hepatitis A virus (HAV) and foot-and-mouth disease virus (FMDV).
  • caliciviruses MD145, murine norovirus, vesicular exanthema of swine virus, abbit hemorrhagic disease virus, porcine teschovirus, bovine coronavirus, feline infectious peritonitis virus, EV-68 virus, EV-71 virus, poliovirus, norovirus, human rhinovirus (HRV), hepatitis A virus (HAV) and foot-and-mouth disease virus (FMDV).
  • the viral infection is an arenovirus infection.
  • the arenovirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.
  • the viral infection is an influenza infection.
  • the influenza is influenza H1N1, H3N2 or H5N1.
  • Another aspect of the disclosure provides methods of treating patients suffering from a viral infection, e.g., a noroviral infection.
  • the disclosure provides a method of treating a viral infection from a norovirus in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein.
  • a method of inhibiting transmission of a virus comprising administering a therapeutically effective amount of a compound described herein to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein with a virally infected cell.
  • the method further comprises administering another therapeutic.
  • the method further comprises administering an additional anti-viral therapeutic.
  • the anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentas
  • the another therapeutic is selected from the group consisting of protease inhibitors, fusion inhibitors, M2 proton channel blockers, polymerase inhibitors, 6- endonuclease inhibitors, neuraminidase inhibitors, reverse transcriptase inhibitor, aciclovir, acyclovir, protease inhibitors, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor, interferons, lopinavir, loviride, moroxydine, nexavir, nucleoside analogues, penciclo
  • the additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti -idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir
  • Contemplated patients include not only humans, but other animals such as companion animals (e.g. dogs, cats), domestic animals (e.g. cow, swine), and wild animals (e.g. monkeys, bats, snakes).
  • companion animals e.g. dogs, cats
  • domestic animals e.g. cow, swine
  • wild animals e.g. monkeys, bats, snakes.
  • described herein is a method of ameliorating or treating a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of a compound of Formula I, I-B, I-C, I-D, I-E, I-F, or II, described herein) or a pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., a compound of a compound of Formula I, I-B, I-C, I-D, I-E, I-F, or II, described herein
  • a pharmaceutically acceptable salt thereof e.g., a compound of a compound of Formula I, I-B, I-C, I-D, I-E, I-F, or II, described herein
  • Other contemplated methods of treatment include method of treating or ameliorating a virus infection condition or co-morbidity, by administering a compound disclosed herein to a subject.
  • Exemplary co-morbidities include lung diseases, cardiac disorders, endocrine disorders, respiratory disorders, hepatic disorders, skeletal disorders, psychiatric disorders, metabolic disorders, and reproductive disorders.
  • the viral infection is from a virus selected from the group consisting of an RNA virus, a DNA virus, a coronavirus, a papillomavirus, a pneumovirus, a picomavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebola virus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, arenovirus, a herpes virus, and a hepatovirus.
  • the viral infection is a coronavirus infection.
  • the viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).
  • the viral infection is SARS-CoV-2.
  • the viral infection is an arenovirus infection.
  • the arenovirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.
  • the viral infection is an influenza infection. In some embodiments, the influenza is influenza H1N1, H3N2 or H5N1. In some embodiments, the viral infection is a respiratory viral infection. In some embodiments, the viral infection is an upper respiratory viral infection or a lower respiratory viral infection. In some embodiments, the method further comprises administering another therapeutic.
  • the virus is selected from the group consisting of a retrovirus (e.g ., human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), human T-cell lymphotropic virus (HTLV)-l, HTLV-2, HTLV-3, HTLV-4), Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, a herpes simplex virus (HSV)
  • a retrovirus e.g ., human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), human T-cell lymphotropic virus (HTLV)-l, HTLV-2, HTLV-3, HTLV-4
  • Ebola virus hepatitis A virus
  • hepatitis B virus hepatitis C virus
  • HSV herpes simplex virus
  • HSV-1, HSV-2, varicella zoster virus, cytomegalovirus an adenovirus, an orthomyxovirus (e.g, influenza virus A, influenza virus B, influenza virus C, influenza virus D, thogotovirus), a flavivirus (e.g, dengue virus, Zika virus), West Nile virus, Rift Valley fever virus, an arenavirus, Crimean-Congo hemorrhagic fever virus, an echovirus, a rhinovirus, coxsackie virus, a coronavirus (e.g, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), a respiratory syncytial virus, a mumps virus, a rotavirus, measles virus, rubella virus, a parvovirus (e.g, an adeno- associated virus), a vaccinia virus, a variola virus, a molluscum virus, bovine
  • Louis encephalitis virus Japanese encephalitis virus, a tick-borne encephalitis virus, Murray Valley virus, Powassan virus, Rocio virus, louping-ill virus, Banzi virus, Ilheus virus, Kokobera virus, Kunjin virus, Alfuy virus, a rabies virus, a polyomavirus (e.g, JC virus, BK virus), an alphavirus, and a rubivirus (e.g, rubella virus).
  • a polyomavirus e.g, JC virus, BK virus
  • an alphavirus e.g, rubella virus
  • the disease or disorder is a viral infection, e.g, a disease or disorder selected from the group consisting of acquired immune deficiency syndrome (AIDS), HTLV-1 associated myelopathy/tropical spastic paraparesis, Ebola virus disease, hepatitis A, hepatitis B, hepatitis C, herpes, herpes zoster, acute varicella, mononucleosis, respiratory infections, pneumonia, influenza, dengue fever, encephalitis (e.g, Japanese encephalitis, St.
  • AIDS acquired immune deficiency syndrome
  • HTLV-1 associated myelopathy/tropical spastic paraparesis Ebola virus disease
  • hepatitis A hepatitis B
  • hepatitis C herpes
  • herpes herpes zoster
  • acute varicella mononucleosis
  • respiratory infections pneumonia, influenza, dengue fever, encephalitis (e.g, Japanese encephalitis, St
  • the vims is an RNA vims (having a genome that is composed of RNA).
  • RNA vimses may be single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA).
  • ssRNA single-stranded RNA
  • dsRNA double-stranded RNA
  • RNA vimses have high mutation rates compared to DNA vimses, as RNA polymerase lacks proofreading capability (see Steinhauer DA, Holland JJ (1987). "Rapid evolution of RNA viruses”. Annu. Rev. Microbiol. 41: 409 33).
  • the RNA vims is a positive-strand RNA vims (e.g., a SARS-CoV vims, polio vims, Coxsackie vims, Enterovims, Human rhinovims, Foot/Mouth disease vims, encephalomyocarditis vims, Dengue vims, Zika vims, Hepatitis C vims, or New Castle Disease vims).
  • a positive-strand RNA vims e.g., a SARS-CoV vims, polio vims, Coxsackie vims, Enterovims, Human rhinovims, Foot/Mouth disease vims, encephalomyocarditis vims, Dengue vims, Zika vims, Hepatitis C vims, or New Castle Disease vims.
  • RNA vimses are classified by the type of genome (double-stranded, negative (-), or positive (+) single-stranded). Double-stranded RNA vimses contain a number of different RNA molecules, each coding for one or more viral proteins. Positive-sense ssRNA vimses utilize their genome directly as mRNA; ribosomes within the host cell translate mRNA into a single protein that is then modified to form the various proteins needed for viral replication. One such protein is RNA-dependent RNA polymerase (RNA replicase), which copies the viral RNA in order to form a double-stranded, replicative form.
  • RNA replicase RNA-dependent RNA polymerase
  • Negative-sense ssRNA vimses have their genome copied by an RNA replicase enzyme to produce positive- sense RNA for replication. Therefore, the vims comprises an RNA replicase enzyme. The resultant positive-sense RNA then acts as viral mRNA and is translated by the host ribosomes.
  • the vims is a dsRNA vims. In some embodiments, the vims is a negative ssRNA vims. In some embodiments, the vims is a positive ssRNA vims. In some embodiments, the positive ssRNA vims is a coronavims.
  • SARS-CoV2 also sometimes referred to as the novel coronavims of 2019 or 2019-nCoV, is a positive-sense single-stranded RNA vims.
  • SARS-CoV-2 has four stmctural proteins, known as the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins.
  • the N protein holds the RNA genome together; the S, E, and M proteins form the viral envelope.
  • Spike allows the vims to attach to the membrane of a host cell, such as the ACE2 receptor in human cells (Kmse R.L. (2020), Therapeutic strategies in an outbreak scenario to treat the novel coronavims originating in Wuhan, China (version 2). FlOOOResearch , 9:72).
  • SARS-CoV2 is the highly contagious, causative viral agent of coronavims disease 2019 (COVID19), a global pandemic.
  • the vims is a DNA vims (having a genome that is composed of DNA).
  • DNA vimses include, without limitation, parvoviruses (e.g., adeno-associated viruses), adenoviruses, asfarviruses, herpesviruses (e.g ., herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV)), papillomoviruses (e.g., HPV), polyomaviruses (e.g, simian vacuolating virus 40 (SV40)), and poxviruses (e.g, vaccinia virus, cowpox virus, smallpox virus, fowlpox virus, sheeppox virus, myxoma virus).
  • parvoviruses e.g., adeno-associated viruses
  • adenoviruses e.g ., asfarvirus
  • RNA viruses include, without limitation, bunyaviruses (e.g, hantavirus), coronaviruses, flaviviruses (e.g, yellow fever virus, west nile virus, dengue virus), hepatitis viruses (e.g, hepatitis A virus, hepatitis C virus, hepatitis E virus), influenza viruses (e.g, influenza virus type A, influenza virus type B, influenza virus type C), measles virus, mumps virus, noroviruses (e.g, Norwalk virus), poliovirus, respiratory syncytial virus (RSV), retroviruses (e.g, human immunodeficiency virus- 1 (HIV-1)) and toroviruses.
  • bunyaviruses e.g, hantavirus
  • coronaviruses e.g, flaviviruses (e.g, yellow fever virus, west nile virus, dengue virus)
  • hepatitis viruses e.g,
  • the methods described herein may inhibit viral replication transmission, replication, assembly, or release, or minimize expression of viral proteins.
  • described herein is a method of inhibiting transmission of a virus, a method of inhibiting viral replication, a method of minimizing expression of viral proteins, or a method of inhibiting virus release, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, with a virally infected cell.
  • a method of treating a respiratory disorder in a subject in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. described herein) or a pharmaceutically acceptable salt thereof.
  • the respiratory disorder is selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, fibrosis, chronic asthma, acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis and an autoimmune disease.
  • the respiratory disorder is associated with a heart attack.
  • a method of treating a disorder associated with cathepsin comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. described herein) or a pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. described herein
  • the disorder is a cathepsin dependent condition or disease.
  • the disorder is selected from the group consisting of breast cancer, pycnodysostosis, glioblastoma, osteosclerosis, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, atherosclerosis, obesity, glaucoma, chronic obstructive pulmonary disease, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
  • Compounds described herein e.g., a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. as defined herein, can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein, such as an infection by a pathogen described herein, e.g., a virus, fungus, or protozoan.
  • a pathogen described herein e.g., a virus, fungus, or protozoan.
  • contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic.
  • a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula I as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient.
  • a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, as defined herein and one additional therapeutic agent is administered.
  • a disclosed compound as defined herein and two additional therapeutic agents are administered.
  • a disclosed compound as defined herein and three additional therapeutic agents are administered.
  • Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately.
  • a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. as defined herein and an additional therapeutic agent can be formulated and administered separately.
  • Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a compound of Formula I as one therapeutic agent and one or more additional therapeutic agents such as an antibiotic, a viral protease inhibitor, or an anti -viral nucleoside anti -metabolite.
  • a compound of Formula I as defined herein and an additional therapeutic agent can be administered in a single formulation.
  • Other combinations are also encompassed by combination therapy.
  • the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y- X-Y, Y-Y-X, X-X-Y- Y, etc.
  • the one or more additional therapeutic agents that may be administered in combination with a compound provided herein can be an antibiotic, a viral protease inhibitor, an anti-viral anti-metabolite, a lysosomotropic agent, a M2 proton channel blocker, a polymerase inhibitor (e.g., EIDD-2801, which is also known as MOLNUPIRAVIR), aneuraminidase inhibitor, a reverse transcriptase inhibitor, a viral entry inhibitor, an integrase inhibitor, interferons (e.g., types I, II, and III), or a nucleoside analogue.
  • EIDD-2801 which is also known as MOLNUPIRAVIR
  • aneuraminidase inhibitor e.g., EIDD-2801, which is also known as MOLNUPIRAVIR
  • aneuraminidase inhibitor e.g., EIDD-2801, which is also known as MOLNUPIRAVIR
  • aneuraminidase inhibitor e
  • the one or more additional therapeutic agents that may be administered in combination wiht a compounds provided herein can be a steroid (e.g., corticosteroids, such as bethamethasone, prednisone, prednisolone, triamcinolone, methylprednisolone, dexamethasone; mineralcorticoid such as fludrocortisone; glucocorticoids, such as hydrocortisone, cortisone, ethamethasoneb, prednisone, prednisolone, triamcinolone, dexamethasone; vitamin D such as dihydrotachysterol; androgens such as apoptone, oxandrolone, oxabolone, testosterone, nandrolone (also known as anabolic steroids), oestrogens such as diethylstilbestrol, progestins such as danazol, norethindrone, medroxypro
  • the one or more additional therapeutic agent is Cathepsin L. In some embodiments, the one or more additional therapeutic agent is dehydrodidemnin B (also known as Plitidepsin or APLIDIN) or Zotatifm (eFT226).
  • methods described herein further comprise administering an additional anti-viral therapeutic.
  • the anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, parit
  • the another therapeutic is selected from the group consisting of protease inhibitors (e.g., nafamostat, camostat, gabexate, epsilon-aminocapronic acid and aprotinin), fusion inhibitors (e.g., BMY-27709, CL 61917, and CL 62554), M2 proton channel blockers (e.g., amantadine and rimantadine), polymerase inhibitors (e.g., 2-deoxy-2'fluoroguanosides (2'-fluoroGuo), 6- endonuclease inhibitors (e.g., L-735,822 and flutamide) neuraminidase inhibitors (e.g., zanamivir (Relenza), oseltamivir, peramivir and ABT-675 (A-315675), reverse transcriptase inhibitor (e.g., abacavir, adefovir, delavird
  • the additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a VAP anti-idiotypic antibody, enfuvirtide, amantadine, rimantadine, pleconaril, aciclovir, zidovudine, fomivirsen, a morpholino, a protease inhibitor, double-stranded RNA activated caspase oligomerizer (DRACO), rifampicin, zanamivir, oseltamivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir
  • the another therapeutic is selected from the group consisting of quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives (e.g., artemether, artesunate, dihydroartemisinin, arteether), doxycycline, pyrimethamine, mefloquine, halofantrine, hydroxychloroquine, eflomithine, nitazoxanide, ornidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), a sulfonamide (e.g., sulfadoxine, sulfamethoxypyridazine), tafenoquine, tinidazole and aPPTl inhibitor (including Lys05 and DC661).
  • quinine optionally in combination with clindamycin
  • chloroquine
  • the another therapeutic is an antibiotic.
  • the antibiotic is a penicillin antibiotic, a quinolone antibiotic, a tetracycline antibiotic, a macrolide antibiotic, a lincosamide antibiotic, a cephalosporin antibiotic, or an RNA synthetase inhibitor.
  • the antibiotic is selected from the group consisting of azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, ne
  • the antibiotic is azithromycin.
  • the one or more additional therapeutic agents that may be administered in combination with a compound provided herein can be selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, ril
  • the compounds described herein may be used in combination with one or more other agents which may be useful in the prevention or treatment of respiratory disease, inflammatory disease, autoimmune disease, for example; anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast.pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors
  • corticosteroids e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mome
  • LP lysophosphatidic
  • FLAP FLAP
  • LP lysophosphatidic
  • FLAP FLAP
  • LP lysophosphatidic
  • FLAP FLAP
  • LP lysophosphatidic
  • FLAP FLAP
  • LP lysophosphatidic
  • FLAP FLAP
  • bronchodilators e.g., sodium 3-(3-(tert-butylthio)-l -(4-(6- ethoxypyridin-3-yl)benzyl)-5-((5-ethylpyridin-2- yl)methoxy)-l H-indol-2-yl)-2,2- dimethylpropanoate
  • bronchodilators e.g..
  • muscarinic antagonists beta-2 agonists
  • methotrexate and similar agents
  • monoclonal antibody therapy such as anti-lgE, anti- TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents
  • cytokine receptor therapies e.g. etanercept and similar agents
  • antigen non-specific immunotherapies e.g.
  • cytokines/chemokines interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents), suitable anti-infective agents including antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents and antituberculosis agents.
  • the additional therapeutic agents can be kinase inhibitors including but not limited to erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib, Loxo 292, larotrectinib, and quizartinib.
  • kinase inhibitors including but not limited to erlotinib,
  • the additional therapeutic agents can be therapeutic anti- viral vaccines.
  • the additional therapeutic agents can be immunomodulatory agents including but not limited to anti-PD-1or anti-PDL-1 therapeutics including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab, anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453, anti-LAG3 therapeutics including but not limited to relatlimab, LAG525, or TSR- 033, anti-4-1BB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutics including but not limited to SGN-40, CP-870,893 or RO7009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists including but not limited to ADU-S100, MK-1454
  • the additional therapeutic agent is a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol.formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol.flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1 -hydroxy-2- naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol.
  • a p2-adrenoreceptor agonist including, but not limited to, vilanterol, salmeterol, salbutamol.formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbut
  • the additional therapeutic agent is an anticholinergic agent, including, but not limited to, umeclidinium (for example, as the bromide), ipratropium (for example, as the bromide), oxitropium (for example, as the bromide) and tiotropium (for example, as the bromide).
  • umeclidinium for example, as the bromide
  • ipratropium for example, as the bromide
  • oxitropium for example, as the bromide
  • tiotropium for example, as the bromide
  • the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein, such as a disclosed compound.
  • boosting amount or “boosting dose” is the amount of a compound needed to improve the pharmacokinetics of a second compound (or increase availability or exposure).
  • the boosting amount or boosting dose may improve the pharmacokinetics (or increase availability or exposure) of the second compound to a level to therapeutic levels in a subject.
  • the disclosure provides for a disclosed compound to be administered together with an antiviral therapeutic such as disclosed herein, and e.g., thereby boosting the dose of the anti-viral therapeutic or therapeutics.
  • Such a boost combination may be used, e.g., as prophylactic or therapeutic treatment of a viral infection in a subject in need thereof.
  • the protease inhibitor is a compound described herein (e.g. a compound of Formula I, I-B, I-C, I-D, I-E, I-F, II, etc. III.
  • compositions and Kits [000116] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier.
  • the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alg
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • a pharmaceutically acceptable carrier such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such
  • the disclosure also provides kits for use by a e.g. a consumer in need of 3CL inhibitor.
  • kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, ... etc.... Second Week, Monday, Tuesday, ... “ etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • a subject or patient can further have viral infection- or virus-related co- morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected by a virus.
  • viral infection- or virus-related co- morbidities i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected by a virus.
  • Contemplated herein are disclosed compounds in combination with at least one other agent that has previously been shown to treat these virus-related conditions.
  • EXAMPLES [000134] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art.
  • reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated.
  • the starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. [000135]
  • the compounds described herein can be synthesized using methods disclosed in Tanaka, Y.; Hasui, T.; Suginome, M.
  • Scheme 1 illustrates an exemplary preparation of ureido-acetamide E-I. Reacting a solution of aldehyde C-I and amine A-I with a catalyst/reagent, for example a propylphosphonic anhydride solution, and then reacting the solution with isocyanide B-I in the presence of a solvent affords amino acetamide D-I. Then, adding a solution of the amino acetamide D-I to a solution of triphosgene with amine F-I affords ureido-acetamide E-I.
  • a catalyst/reagent for example a propylphosphonic anhydride solution
  • examples of R 1a include optionally substituted phenyl
  • examples of R 1b include optionally substituted cycloalkyl
  • R 1c include optionally substituted heteroaryl
  • examples of each R 1d and R 1e include hydrogen, optionally substituted alkyl, optionally substitued cycloalkyl, or R 1d and R 1e may form, together with the nitrogen to which they are attached, a heterocyclyl.
  • Scheme 2 base G-I H-I I-I
  • Scheme 2 illustrates an exemplary preparation of ureido-acetamide I-I. Reacting a solution of nitrile G-I and triphosgene affords isocyanate H-I.
  • Step 1 2-(4-tert-butylanilino)-N-(4,4-difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide
  • 5-fluoropyridine-3-carbaldehyde 838.29 mg, 6.70 mmol, 1 eq
  • EtOAc 15 mL
  • 4-tert-butylaniline 1 g, 6.70 mmol, 1.06 mL, 1 eq
  • T3P (2.13 g, 3.35 mmol, 1.99 mL, 50% purity, 0.5 eq)
  • Step 2 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide
  • triphosgene 113.19 mg, 381.42 umol, 0.8 eq
  • DCM 3 mL
  • 1-aminocyclopropanecarbonitrile 169.59 mg, 1.43 mmol, 3 eq, HCl
  • DIEA 369.71 mg, 2.86 mmol, 498.27 uL, 6 eq
  • Example 2 (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyclohexyl)amino)- 1-(5-fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamide (Compound 18) and (2S)-N1-(4-(tert-butyl)phenyl)-N1-(2-((4,4-difluorocyclohexyl)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxamide (Compound 57) Step 1: 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acetonitrile [000153] To a mixture of 4-tert-butylaniline (5 g, 33.50
  • Step 2 methyl 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acetate
  • Step 3 methyl 2-((S)-N-(4-(tert-butyl)phenyl)-2-cyanopyrrolidine-1-carboxamido)-2-(5- fluoropyridin-3-yl)acetate
  • DCM methyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate
  • DIEA 7.77 mg, 4.74 mmol, 825.83 uL, 3 eq
  • triphosgene 468.99 mg, 1.58 mmol, 1 eq
  • reaction mixture was diluted with water (10 mL) and extracted with DCM (5 mL * 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was diluted with sat.
  • Step 5 (2S)-N-(4-(tert-butyl)phenyl)-2-cyano-N-(2-((4,4-difluorocyclohexyl)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxamide
  • 2-(4-tert-butyl-N-[(2S)-2-cyanopyrrolidine-1-carbonyl]anilino)- 2-(5-fluoro-3-pyridyl)acetic acid 0.05 g, 58.90 umol, 50% purity, 1 eq
  • 2-(4-tert-butyl- N-[(2S)-2-carbamoylpyrrolidine-1-carbonyl]anilino)-2-(5-fluoro-3-pyridyl)acetic acid 0.05 g, 56.50 umol, 50% purity, 9.59e-1 eq
  • Step 2 methyl 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acetate
  • Step 3 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acetic acid [000171] To a mixture of methyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate (2 g, 6.32 mmol, 1 eq) in THF (20 mL) and H 2 O (7 mL) was added LiOH.H 2 O (397.89 mg, 9.48 mmol, 1.5 eq), the solution was stirred at 20 °C for 2 h.
  • Step 4 benzyl 2-((4-(tert-butyl)phenyl)amino)-2-(5-fluoropyridin-3-yl)acetate
  • 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetic acid 1.5 g, 4.96 mmol, 1 eq
  • phenylmethanol 3.22 g, 29.77 mmol, 3.10 mL, 6 eq
  • DCM 20 mL
  • Step 6 2-((R)-N-(4-(tert-butyl)phenyl)-2-(methoxycarbonyl)pyrrolidine-1-carboxamido)-2- (5-fluoropyridin-3-yl)acetic acid
  • Step 7 2-((R)-N-(4-(tert-butyl)phenyl)-2-(methoxycarbonyl)pyrrolidine-1-carboxamido)-2- (5-fluoropyridin-3-yl)acetic acid
  • Step 8 (2R)-methyl 1-((4-(tert-butyl)phenyl)(2-((4,4-difluorocyclohexyl)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)carbamoyl)pyrrolidine-2-carboxylate [000176] A solution of methyl (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]carbamoyl]pyrrolidine-2- carboxylate (0.2 g, 348.05 umol, 1 eq) in NH 3 .MeOH (7M, 4 mL, 80.45 eq) was stirred at 50 °C for 16
  • Step 9 (2R)-N1-(4-(tert-butyl)phenyl)-N1-(2-((4,4-difluorocyclohexyl)amino)-1-(5- fluoropyridin-3-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxamide
  • (2R)-N1-(4-tert-butylphenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]pyrrolidine-1,2-dicarboxamide (0.16 g, 285.91 umol, 1 eq) in DCM (3 mL) was added burgess reagent (204.40 mg, 857.72 umol, 3 eq), and then the solution was stirred at 20 °C for 1 h.
  • Step 1 methyl 1-[[2-benzyloxy-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]-(4-tert- butylphenyl)carbamoyl]azetidine-2-carboxylate
  • a solution of benzyl 2-(4-tert-butylanilino)-2-(5-fluoro-3-pyridyl)acetate (300 mg, 764.40 umol, 1 eq) and DIEA (296.37 mg, 2.29 mmol, 399.42 uL, 3 eq) in DCM (5 mL) was cooled to 0 °C and triphosgene (680.51 mg, 2.29 mmol, 3 eq) in DCM (2 mL) was added drop-wise at 0 °C, the solution was stirred at 0 °C for 1 h under N 2 .
  • Step 2 2-(4-tert-butyl-N-(2-methoxycarbonylazetidine-1-carbonyl)anilino)-2-(5-fluoro-3- pyridyl)acetic acid
  • Step 3 methyl 1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)amino]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]carbamoyl]azetidine-2-carboxylate
  • Step 1 methyl (2R)-1-chlorosulfonylpyrrolidine-2-carboxylate [000189] DMAP (2.50 g, 20.46 mmol, 1.69e-1 eq) and TEA (12.70 g, 125.51 mmol, 17.47 mL, 1.04 eq) were added to a stirred solution of methyl (2R)-pyrrolidine-2-carboxylate (20 g, 120.76 mmol, 1 eq, HCl) in dry toluene (200 mL) at 20 °C and the resulting mixture was stirred for 10 mins.
  • reaction mixture was cooled to -20 ° C, followed by dropwise addition of sulfuryl chloride (16.50 g, 122.25 mmol, 12.22 mL, 1.01 eq) over a period of 30 mins and the stirring was continued for 1 hr at -10 °C. and for a further 2 h at 20 °C.
  • sulfuryl chloride (16.50 g, 122.25 mmol, 12.22 mL, 1.01 eq
  • the stirring was continued for 1 hr at -10 °C. and for a further 2 h at 20 °C.
  • the reaction mass was diluted with DCM (300 mL) and washed with aqueous NH 4 Cl solution (200 mL * 2).
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to dryness give methyl (2R)-1-chlorosulfonylpyrrolidine-2-carboxylate (8 g, crude) as a yellow solid.
  • Step 2 methyl (2R)-1-[(4-tert-butylphenyl)sulfamoyl]pyrrolidine-2-carboxylate
  • a solution of methyl (2R)-1-chlorosulfonylpyrrolidine-2-carboxylate (2 g, 8.78 mmol, 1 eq) in lutidine (5 mL) was added 4-tert-butylaniline (1.40 g, 9.40 mmol, 1.48 mL, 1.07 eq) in DCM (5 mL). Then the reaction was stirred at 50 °C for 16 h.
  • Step 3 bromo-(2-tert-butoxy-2-oxo-ethyl)zinc [000191] Under N 2 atmosphere, to a 500 mL round-bottom flask were added Zn (16.71 g, 255.57 mmol, 1.99 eq), dry THF (160 mL), and TMSCl (1.39 g, 12.82 mmol, 1.63 mL, 0.1 eq). The suspension was warmed to 75 °C, and tert-butyl 2-bromoacetate (25 g, 128.17 mmol, 18.94 mL, 1 eq) in THF (100 mL) was added dropwise to the suspension.
  • Step 4 tert-butyl 2-(5-fluoro-3-pyridyl)acetate
  • Pd(dba) 2 653.47 mg, 1.14 mmol, 0.02 eq
  • ditert- butyl(cyclopentyl)phosphane;iron;(2,3,4,5-tetraphenylcyclopentyl)benzene 807.68 mg, 1.14 mmol, 0.02 eq).
  • Step 5 2-bromo-2-(5-fluoro-3-pyridyl)acetate
  • NBS 3.37 g, 18.94 mmol, 2 eq
  • BPO 229.35 mg, 946.83 umol, 0.10 eq
  • Step 6 (2R)-1-[[2-tert-butoxy-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]-(4-tert- butylphenyl)sulfamoyl]pyrrolidine-2-carboxylate [000194] To a solution of tert-butyl 2-bromo-2-(5-fluoro-3-pyridyl)acetate (500 mg, 1.72 mmol, 1.47 eq) in MeCN (10 mL) was added methyl (2R)-1-[(4-tert- butylphenyl)sulfamoyl]pyrrolidine-2-carboxylate (400 mg, 1.17 mmol, 1 eq) and K 2 CO 3 (194.86 mg, 1.41 mmol, 1.2 eq).
  • reaction was stirred at 20 °C for 24 h. Upon completion, the reaction mixture was quenched by addition H 2 O 40 mL at 20 °C, and extracted with EtOAc 60 mL (20 mL * 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 7 2-(4-tert-butyl-N-[(2R)-2-methoxycarbonylpyrrolidin-1-yl]sulfonyl-anilino)-2-(5- fluoro-3-pyridyl)acetic acid [000195] To a solution of methyl (2R)-1-[[2-tert-butoxy-1-(5-fluoro-3-pyridyl)-2-oxo- ethyl]-(4-tert-butylphenyl)sulfamoyl]pyrrolidine-2-carboxylate (200 mg, 363.87 umol, 1 eq) in DCM (2 mL) was added TFA (0.4 mL).
  • Step 8 methyl (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)amino]-1-(5-fluoro- 3-pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-carboxylate [000196] To a solution of 2-(4-tert-butyl-N-[(2R)-2-methoxycarbonylpyrrolidin-1- yl]sulfonyl-anilino)-2-(5-fluoro-3-pyridyl)acetic acid (145 mg, 293.79 umol, 1 eq) in MeCN (4 mL) was added 4,4-difluorocyclohexanamine (59.56 mg, 440.69 umol, 1.5 eq), 1- methylimidazole (72.36 mg, 881.37 umol, 70.25 uL,
  • reaction was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H 2 O 20 mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 9 (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)amino]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-carboxylic acid [000197] To a solution of methyl (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2- carboxylate (60.00 mg, 98.25 umol, 1 eq) in dioxane (0.6 mL) was added 4 M of HCl aq.
  • Step 10 (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4-difluorocyclohexyl)amino]-1-(5-fluoro-3- pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2-carboxamide [000198] To a solution of (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2- carboxylic acid (50.00 mg, 83.80 umol, 1 eq) in DCM (2.5 mL) was added ammonium;1- oxidobenzotriazole (25.50 mg, 167.60 umol, 2 eq
  • reaction mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was diluted with H 2 O 40 mL and extracted with EtOAc 40 mL (20 mL * 2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 11 2-(4-tert-butyl-N-[(2R)-2-cyanopyrrolidin-1-yl]sulfonyl-anilino)-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide
  • (2R)-1-[(4-tert-butylphenyl)-[2-[(4,4- difluorocyclohexyl)amino]-1-(5-fluoro-3-pyridyl)-2-oxo-ethyl]sulfamoyl]pyrrolidine-2- carboxamide (Isomer 1) (15 mg, 25.18 umol, 1 eq) in DCM (0.6 mL) was added Burgess reagenT (12.00 mg, 50.35 umol, 2.00 eq).
  • Example 7 2-[4-tert-butyl-N-[(1-cyano-1-methyl-ethyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide
  • Step 1 2-[4-tert-butyl-N-[(1-cyano-1-methyl-ethyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide
  • a solution of triphosgene (212.23 mg, 715.17 umol, 1.5 eq) in DCM (3 mL) was cooled to 0 °C, and then 2-amino-2-methyl-propanenitrile (200.53 mg, 2.38 mmol, 5 eq) and DIEA (369.71 mg, 2.
  • Example 8 2-[4-tert-butyl-N-[(1-cyanocyclopropyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-[4-(trifluoromethyl)-3-pyridyl]acetamide
  • Step 1 2-(4-tert-butylanilino)-N-(4,4-difluorocyclohexyl)-2-[4-(trifluoromethyl)-3- pyridyl]acetamide
  • Step 2 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine-1-carbonyl]anilino)- 2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000212]
  • methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]azetidine-2-carboxylate (0.1 g, 170.78 umol, 1 eq) in EA (3 mL) was added Pd/C (170.78 umol, 10% purity, 1 eq), and then the solution was stirred at 20 °C for 1 h under H 2 (344.98 ug, 170.78 umol, 1 eq) at 15 Psi.
  • Step 3 methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyclohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]azetidine-2-carboxylate [000213] To a solution of 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine- 1-carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid (0.07 g, 141.29 umol, 1 eq) and 4,4-difluorocyclohexanamine (38.19 mg, 282.59 umol, 2 eq) in ACN (2 mL) was added 1-methylimidazole (23.20 mg, 282.59
  • Step 1 benzyl 2-(N-[(2S)-2-cyanopyrrolidine-1-carbonyl]-4-cyclopropyl-2-fluoro-anilino)-2- [4-(trifluoromethyl)-3-pyridyl]acetate
  • a solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.4 g, 900.05 umol, 1 eq) and DIEA (348.97 mg, 2.70 mmol, 470.31 uL, 3 eq) in DCE (5 mL) was cooled to 0 °C, and then triphosgene (801.27 mg, 2.70 mmol, 3 eq) in DCE (1 mL) was added drop-wise, the solution was stirred at 70 °C for 13 h.
  • Step 2 2-(4-cyclopropyl-2-fluoro-N-[(2S)-2-methoxycarbonylpyrrolidine-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid
  • Step 2 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylpyrrolidine-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000226]
  • methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]pyrrolidine-2-carboxylate 200 mg, 333.57 umol, 1 eq
  • Pd/C 393.61 mg, 333.57 umol, 10% purity, 1 eq
  • Step 1 methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]piperidine-2-carboxylate
  • Step 2 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylpiperidine-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000235] To a solution of methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]piperidine-2-carboxylate (130 mg, 211.87 umol, 1 eq) in EA (2 mL) was added Pd/C (250.00 mg, 211.87 umol, 10% purity, 1 eq) under N 2 atmosphere.
  • reaction mixture was quenched by addition H 2 O (25 mL) and extracted with DCM (8 mL * 5). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to get crude product (2R)-N1-(4-cyclopropyl-2-fluoro-phenyl)-N1-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]piperidine-1,2- dicarboxamide (60 mg, crude) as yellow oil.
  • Step 1 methyl (3R)-4-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]morpholine-3-carboxylate
  • Step 2 2-(4-cyclopropyl-2-fluoro-N-[(3R)-3-methoxycarbonylmorpholine-4- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000245] To a solution of methyl (3R)-4-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]morpholine-3-carboxylate (104 mg, 168.95 umol, 1 eq) in EA (1 mL) was added Pd/C (199.36 mg, 168.95 umol, 10% purity, 1 eq) under N 2 atmosphere.
  • Example 14 (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)-N-[2-[(4,4- difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-2-formyl- azetidine-1-carboxamide (Compound 62) and (2R)-N-(4-cyclopropyl-2-fluoro-phenyl)- N-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-2- (hydroxymethyl)azetidine-1-carboxamide (Compound 61) Step 1: benzyl 2-(N-chlorocarbonyl-4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3-
  • Step 2 methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]azetidine-2-carboxylate
  • Step 3 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylazetidine-1-carbonyl]anilino)- 2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000256]
  • methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]azetidine-2-carboxylate (0.17 g, 290.33 umol, 1 eq) in EA (3 mL) was aaded Pd/C (290.33 umol, 10% purity, 1 eq), and the solution was stirred at 25 °C for 1 h under H 2 (586.46 ug, 290.33 umol, 1 eq) at 15 Psi
  • Step 4 methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyclohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]azetidine-2-carboxylate [000257]
  • reaction mixture was diluted with Na 2 S 2 O 3 (aq, 10 %) and NaHCO 3 (aq, sat) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with Na 2 S 2 O 3 (aq, 10 %) and NaHCO 3 (aq, sat) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 1 benzyl 2-(N-chlorocarbonyl-4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate
  • a solution of benzyl 2-(4-cyclopropyl-2-fluoro-anilino)-2-[4-(trifluoromethyl)-3- pyridyl]acetate (0.35 g, 787.54 umol, 1 eq) and DIEA (610.69 mg, 4.73 mmol, 823.03 uL, 6 eq) in DCE (7 mL) was cooled to 0 °C, and then triphosgene (934.81 mg, 3.15 mmol, 4 eq) in DCE (2 mL) was added drop-wise at 0 °C.
  • Step 2 methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]-(4- cyclopropyl-2-fluoro-phenyl)carbamoyl]pyrrolidine-2-carboxylate
  • a solution of benzyl 2-(N-chlorocarbonyl-4-cyclopropyl-2-fluoro-anilino)-2-[4- (trifluoromethyl)-3-pyridyl]acetate (0.4 g, 789.15 umol, 1 eq) in DCE (5 mL) was cooled to 0 °C, and then methyl (2R)-pyrrolidine-2-carboxylate (653.49 mg, 3.95 mmol, 5 eq, HCl) and DIEA (611.94 mg, 4.73 mmol, 824.71 uL, 6 eq) in DCE (5 mL)
  • reaction mixture was diluted with sat. NaHCO 3 (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 3 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2-methoxycarbonylpyrrolidine-1- carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid [000269]
  • methyl (2R)-1-[[2-benzyloxy-2-oxo-1-[4-(trifluoromethyl)-3- pyridyl]ethyl]-(4-cyclopropyl-2-fluoro-phenyl)carbamoyl]pyrrolidine-2-carboxylate (0.15 g, 250.18 umol, 1 eq) in EA (3 mL) was added Pd/C (250.18 umol, 10% purity, 1 eq), the solution was stirred at 25 °C for 2 h under H 2 (505.36 ug, 250.18 umol, 1 eq) at 15 Psi.
  • Step 4 methyl (2R)-1-[(4-cyclopropyl-2-fluoro-phenyl)-[2-[(4,4-difluorocyclohexyl)amino]- 2-oxo-1-[4-(trifluoromethyl)-3-pyridyl]ethyl]carbamoyl]pyrrolidine-2-carboxylate [000270] To a solution of 2-(4-cyclopropyl-2-fluoro-N-[(2R)-2- methoxycarbonylpyrrolidine-1-carbonyl]anilino)-2-[4-(trifluoromethyl)-3-pyridyl]acetic acid (0.12 g, 235.55 umol, 1 eq) in ACN (3 mL) was added 4,4-difluorocyclohexanamine (63.67 mg, 471.10 umol, 2 eq), 1-methylimidazole (38.68 mg, 471.10 umol,
  • Step 1 N-(4-tert-butylphenyl)-N-[2-[(4,4-difluorocyclohexyl)amino]-2-oxo-1-[4- (trifluoromethyl)-3-pyridyl]ethyl]-3,3-dimethyl-2-oxo-butanamide
  • 4-tert-butylaniline 0.3 g, 2.01 mmol, 317.46 uL, 1 eq
  • 4- (trifluoromethyl)pyridine-3-carbaldehyde (352.02 mg, 2.01 mmol, 1 eq) in t-BuOH (5 mL) was stirred at 25 °C for 1 h, and then 1,1-difluoro-4-isocyano-cyclohexane (291.79 mg, 2.01 mmol, 1 eq), 3,3-dimethyl-2-oxo-butanoic acid (261.62 mg, 2.0
  • Example 17 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide
  • Step 1 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide
  • triphosgene (318.34 mg, 1.07 mmol, 1.5 eq) in DCM (5 mL) was cooled to 0 °C, and then 1-aminocyclobutanecarbonitrile (343.75 mg, 2.59 mmol, 3.63 eq, HCl) and DIEA (554.57 mg, 4.29
  • Step 2 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide
  • 2-[4-tert-butyl-N-[(1-cyanocyclobutyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (0.06 g, 110.78 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [Neu-ETOH];B%: 20%-20%,9min) to give 2-[4-tert-butyl-N-[(1- cyanocyclobutyl)carb
  • Example 18 2-[4-tert-butyl-N-[(1-cyanocyclopentyl)carbamoyl]anilino]-N-(4,4- difluorocyclohexyl)-2-(5-fluoro-3-pyridyl)acetamide (Compound 64) [000283] A solution of triphosgene (318.34 mg, 1.07 mmol, 1.50 eq) in DCM (3 mL) was cooled to 0 °C, and then 1-aminocyclopentanecarbonitrile (524.28 mg, 3.58 mmol, 5 eq, HCl) and DIEA (554.57 mg, 4.29 mmol, 747.40 uL, 6 eq) in DCM (3 mL) was added drop-wise, the solution was stirred at 0 °C for 1 h.
  • triphosgene 318.34 mg, 1.07 mmol, 1.50 eq
  • Example 19 Evaluation of antiviral activity of compounds against COVID-19 (nCoV- 2019, SARS-CoV2) Mpro in the enzymatic assay [000285] Compounds are assayed using standard methods to assess compound activity and IC50.
  • the C-His6-tagged Mpro (NC_045512) is cloned, expressed in E. coli and purified.
  • the assay buffer contains 20 mM of Tris-HCl (pH 7.3), 100 mM of NaCl, 1 mM of EDTA, 5mM of TCEP and 0.1%BSA.
  • the final concentrations of the Mpro protein and substrate are 25 nM and 25 ⁇ M, respectively, in the Mpro enzymatic assay.
  • the Km of the Mpro substrate for the protease is 13.5 ⁇ M.
  • the compounds are added to an assay plate. For 100% inhibition control (HPE, hundred percent effect), 1 ⁇ M GC376 is added. For no inhibition control (ZPE, zero percent effect), no compound is added. Each activity testing point has a relevant background control to normalize the fluorescence interference of compound.
  • IC50 values of compounds are calculated with the GraphPad Prism software using the nonlinear regression model of log(inhibitor) vs. response -- Variable slope (four parameters).
  • Inhibition% [ (Sample- Average ZPE )/(Average HPE-Average ZPE)] * 100% # # HEP: Hundred percent effect controls. Containing substrate + enzyme + 1 ⁇ M GC376. ZPE: Zero percent effective controls. Containing enzyme + substrate, no compound. Sample: Compound activity testing wells. Containing compound + enzyme + substrate. BG: Compound background control wells. Containing compound + substrate, no enzyme.
  • Example 20 Evaluation of antiviral activity of compounds against human coronavirus (HCov) 229E and OC43 in the cytopathic effect (CPE) assays
  • CPE cytopathic effect
  • Virus - HCoV 229E Cytopathic effect (CPE) is measured by CellTiter Glo following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.
  • Virus - HCov OC43 Reference compound used is remdesivir; detection reagent: CellTiter Glo.) The CPE are measured by CellTiter Glo following the manufacturer’s manual. The antiviral activity of compounds is calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control. [000292] The cytotoxicity of compounds is assessed under the same conditions, but without virus infection, in parallel.

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La divulgation concerne des composés avec des charges et leur utilisation dans le traitement de maladies ou de troubles médicaux, tels que des infections virales. Des compositions pharmaceutiques et des procédés de préparation de divers composés avec des charges sont également décrits. Les composés sont envisagés pour inhiber des protéases, telles que la protéase de type 3C, CL ou 3CL.
PCT/US2022/025064 2021-04-15 2022-04-15 Inhibiteurs de protéases à cystéine et leurs méthodes d'utilisation Ceased WO2022221686A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11731944B2 (en) 2021-11-02 2023-08-22 Insilico Medicine Ip Limited SARS-CoV-2 inhibitors for treating coronavirus infections
WO2025101881A1 (fr) * 2023-11-08 2025-05-15 Emory University Peptidomimétiques contenant des hétéroatomes ciblant des protéases virales

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005056528A1 (fr) * 2003-12-15 2005-06-23 Merck Patent Gmbh Derives d'amide d'acide carboxylique
WO2009065906A2 (fr) * 2007-11-20 2009-05-28 Cognis Oleochemicals Gmbh Procédé de fabrication d'une composition organique contenant un n-nonyléther
WO2012009678A1 (fr) * 2010-07-16 2012-01-19 Agios Pharmaceuticals, Inc. Compositions thérapeutiquement actives et méthode d'utilisation correspondante
US20170313685A1 (en) * 2016-04-28 2017-11-02 Purdue Research Foundation Broad-spectrum non-covalent coronavirus protease inhibitors
CN110143911A (zh) * 2019-06-17 2019-08-20 浙江大学 一种N-(吲哚-N-甲酰基)-α-氨基酰胺衍生物的制备方法
WO2021212039A1 (fr) * 2020-04-17 2021-10-21 Pardes Biosciences, Inc. Inhibiteurs de protéases à cystéine et leurs procédés d'utilisation
WO2021219089A1 (fr) * 2020-04-30 2021-11-04 Insilico Medicine Ip Limited Inhibiteurs de sras-cov-2 ayant des modifications covalentes pour le traitement d'infections à coronavirus

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005056528A1 (fr) * 2003-12-15 2005-06-23 Merck Patent Gmbh Derives d'amide d'acide carboxylique
WO2009065906A2 (fr) * 2007-11-20 2009-05-28 Cognis Oleochemicals Gmbh Procédé de fabrication d'une composition organique contenant un n-nonyléther
WO2012009678A1 (fr) * 2010-07-16 2012-01-19 Agios Pharmaceuticals, Inc. Compositions thérapeutiquement actives et méthode d'utilisation correspondante
US20170313685A1 (en) * 2016-04-28 2017-11-02 Purdue Research Foundation Broad-spectrum non-covalent coronavirus protease inhibitors
CN110143911A (zh) * 2019-06-17 2019-08-20 浙江大学 一种N-(吲哚-N-甲酰基)-α-氨基酰胺衍生物的制备方法
WO2021212039A1 (fr) * 2020-04-17 2021-10-21 Pardes Biosciences, Inc. Inhibiteurs de protéases à cystéine et leurs procédés d'utilisation
WO2021219089A1 (fr) * 2020-04-30 2021-11-04 Insilico Medicine Ip Limited Inhibiteurs de sras-cov-2 ayant des modifications covalentes pour le traitement d'infections à coronavirus

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
ASPELUND HELGE: "Reaction of urea derivatives with ethyl phenylchloroacetate, phenylchloroacetamide and phenylchloroacetomethylamide", FINSKA KEMISTSAM-FUNDETS MEDD., 1 January 1962 (1962-01-01), pages 123 - 132, XP055939616, Retrieved from the Internet <URL:www.stn.org> [retrieved on 20220707] *
CARREIRAKVAERNO: "Classics in Stereoselective Synthesis", 2009, WILEY-VCH
CHUCK CHI-PANG ET AL: "Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, 1 January 2013 (2013-01-01), AMSTERDAM, NL, pages 1 - 6, XP055826852, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2012.10.053 *
JON JACOBS ET AL: "Discovery, Synthesis, And Structure-Based Optimization of a Series of N -( tert -Butyl)-2-( N -arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease", JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, no. 2, 24 January 2013 (2013-01-24), US, pages 534 - 546, XP055333594, ISSN: 0022-2623, DOI: 10.1021/jm301580n *
PAN, S. C.LIST, B., ANGEW. CHEM. INT. ED., vol. 47, 2008, pages 3622 - 3625
RAUTIO, KUMPULAINEN ET AL., NATURE REVIEWS DRUG DISCOVERY, vol. 7, 2008, pages 255
SAETTONE MARCO F ET AL: "Reactions of 3,4-Disubstituted 4-Oxazolin-2-ones. I. A Novel Route to 1,3,5-Trisubstituted Hydantoins", J. ORG. CHEM, 1 June 1966 (1966-06-01), pages 1959 - 1962, XP055937243, Retrieved from the Internet <URL:www.stn.org> [retrieved on 20220630] *
SIMPLICIO ET AL., MOLECULES, vol. 13, 2008, pages 519
ST. JOHN SARAH E. ET AL: "Discovery, Synthesis, And Structure-Based Optimization of a Series of N -( tert -Butyl)-2-( N -arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease", BIOORGANIC, vol. 23, no. 17, 1 September 2015 (2015-09-01), AMSTERDAM, NL, pages 6036 - 6048, XP055826372, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2015.06.039 *
STEINHAUER DAHOLLAND JJ: "Rapid evolution of RNA viruses", ANNU. REV. MICROBIOL., vol. 41, 1987, pages 409 - 33
TANAKA, Y.HASUI, T.SUGINOME, M., ORGANIC LETTERS, vol. 9, no. 22, 2007, pages 4407 - 4410

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11731944B2 (en) 2021-11-02 2023-08-22 Insilico Medicine Ip Limited SARS-CoV-2 inhibitors for treating coronavirus infections
WO2025101881A1 (fr) * 2023-11-08 2025-05-15 Emory University Peptidomimétiques contenant des hétéroatomes ciblant des protéases virales

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