WO2023139402A1 - Inhibiteurs de cystéine protéases et leurs procédés d'utilisation - Google Patents

Inhibiteurs de cystéine protéases et leurs procédés d'utilisation Download PDF

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WO2023139402A1
WO2023139402A1 PCT/IB2022/000751 IB2022000751W WO2023139402A1 WO 2023139402 A1 WO2023139402 A1 WO 2023139402A1 IB 2022000751 W IB2022000751 W IB 2022000751W WO 2023139402 A1 WO2023139402 A1 WO 2023139402A1
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alkyl
independently selected
aryl
cycloalkyl
compound
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PCT/IB2022/000751
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English (en)
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Bailing YANG
Bin Liang
Yang Lai
Jinzi Jason Wu
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Ascletis Bioscience Co., Ltd.
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Priority claimed from US17/806,371 external-priority patent/US11760722B2/en
Application filed by Ascletis Bioscience Co., Ltd. filed Critical Ascletis Bioscience Co., Ltd.
Publication of WO2023139402A1 publication Critical patent/WO2023139402A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • FIELD This application generally relates to inhibitors of cysteine proteases, as well as compositions and methods of use related thereto.
  • Cysteine proteases also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad. Inhibitors of cysteine protease have been used as antiviral drugs for the treatment of HIV/AIDS and hepatitis C.
  • the 3C-like protease is a cysteine protease and a member of the PA clan of proteases.3CL protease is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved site and is important in the processing of the coronavirus replicase polyprotein (P0C6U8). While a number of 3CL protease inhibitors have been used or are under clinical trial for treating coronavirus infections, such as COVID19, there is still a need for new cysteine protease inhibitors that that can effectively inhibit coronavirus replication.
  • a pharmaceutical agent which may be in the form of a salt or prodrug, is administered in methods disclosed herein that is specified by a weight.
  • Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as b- camphorsulfonic acid.
  • optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as b- camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, TV- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
  • each of the chiral centers in the compound may be independently ( R ) or (S), unless otherwise indicated.
  • Compounds of the application also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine -imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1 H- and 3/f-imidazole, 1 H-, 2H- and 4 H- 1,2, 4- triazole, ⁇ H- and 211-isoindole and 1 H- and 2//-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the application can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • One or more constituent atoms of the compounds of the application can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
  • the compound includes at least one deuterium atom.
  • one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
  • the compound includes two or more deuterium atoms.
  • the term, "compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.
  • the term is also meant to refer to compounds of the applications, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.
  • All compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates.
  • the compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
  • the compounds of the application, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds of the application.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the application, or salt thereof.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20 °C to about 30 °C.
  • present application also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present application include the non-toxic salts of the parent compound formed, e.g., from non toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p.1418, Berge et al., J. Pharm.
  • the compounds described herein include the N-oxide forms.
  • subject “individual” and “patient,” used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • therapeutically effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • solvate refers to the compound formed by the interaction of a solvent and an EPI, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • substituted or optionally substituted as used in the present invention means that one or more hydrogen atoms of the group to which the term “substitute” or “optionally substituted” refers is replaced with one of the substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, -car
  • alkyl refers to a straight or branched or cyclic chain hydrocarbon radical with only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted.
  • aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
  • Heterocyclyl and “heterocycle’ are used interchangeably and refer to heterocyclic groups, including heteroaryl groups. Heterocyclyl groups may be attached through a nitrogen or through a carbon atom in the ring.
  • Heterocyclic groups are groups having 3-14 ring atoms, wherein 1 to 4 ring atoms are heteroatoms and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium.
  • Heterocyclic groups include unsaturated cyclic, fused cyclic and spirocyclic groups.
  • Heteroaryl groups are heterocyclic groups derived from heteroarenes.
  • Heteroaryl groups may have 5-14 ring atoms, wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms.
  • Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N- lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
  • the term “biaryl” represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups.
  • Suitable biaryl groups include naphthyl and biphenyl.
  • substituted aryl and substituted heteroaryl refers to aryl and heteroaryl groups substituted with 1-3 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.
  • -aralkyl refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted.
  • heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • alkylaryl- refers to an aryl group substituted with an alkyl group. “Lower alkylaryl-” refers to such groups where alkyl is lower alkyl.
  • the carbon atom designations may have the indicated integer and any intervening integer. For example, the number of carbon atoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that these designations refer to the total number of atoms in the corresponding hetero group, including carbon atoms and heteroatoms.
  • the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.
  • the term “lower” referred to herein in connection with organic radicals or compounds respectively refers to 6 carbon atoms or less. Such groups may be straight chain, branched, or cyclic.
  • the term “higher” referred to herein in connection with organic radicals or compounds respectively refers to 7 or more carbon atoms. Such groups may be straight chain, branched, or cyclic.
  • cyclic alkyl or “cycloalkyl” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 carbon atoms Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
  • arylamino (a), and “aralkylamino” (b), respectively, refer to the group— NRR' wherein respectively, (a) R is aryl and R' is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R' is aralkyl and R' is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl.
  • acyl refers to— C(O)-R where R is alkyl, heterocycloalkyl, or aryl.
  • carboxy esters refers to— C(O)-OR where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted.
  • carboxyl refers to— C(O)-OH.
  • amino refers to -NRR' where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H are optionally substituted; and R and R' can form a cyclic ring system.
  • -carboxylamido refers to –C(O)NR 2 where each R is independently hydrogen or alkyl.
  • halogen or“halo” refers to -F, -Cl, -Br and -I.
  • alkylaminoalkylcarboxy refers to the group alkyl-NR-alk- C(O)- O- where “alk” is an alkylene group, and R is a H or lower alkyl.
  • sulphonyl or “sulfonyl” refers to -SO 2 R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • sulphonate or “sulfonate” refers to— SO2-OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • alkenyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched- chain and cyclic groups. Alkenyl groups may be optionally substituted.
  • Suitable alkenyl groups include allyl.
  • “1-Alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • the term “alkynyl” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight-chain, branched- chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.
  • alkynyl refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1 -alkynyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • alkylene refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene group contains up to and including 6 atoms. In a further aspect the alkylene group contains up to and including 4 atoms. The alkylene group can be either straight, branched or cyclic.
  • acyloxy refers to the ester group –O-C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.
  • aminoalkyl- refers to the group NR 2 -alk- wherein“alk” is an alkylene group and R is selected from -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • alkylaminoalkyl- refers to the group alkyl-NR-alk- wherein each“alk” is an independently selected alkylene, and R is H or lower alkyl. “Lower alkylaminoalkyl-” refers to groups where the alkyl and the alkylene group is lower alkyl and alkylene, respectively.
  • arylaminoalkyl- refers to the group aryl-NR-alk- wherein “alk” is an alkylene group and R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • alkylene group is lower alkylene.
  • alkylaminoaryl- refers to the group alkyl-NR-aryl- wherein “aryl” is a divalent group and R is -H, alkyl, aralkyl, or heterocycloalkyl.
  • aryl is a divalent group and R is -H, alkyl, aralkyl, or heterocycloalkyl.
  • alkyl group is lower alkyl.
  • alkoxyaryl- refers to an aryl group substituted with an alkyloxy group. In“lower alkyloxyaryl-,” the alkyl group is lower alkyl.
  • aryloxyalkyl- refers to an alkyl group substituted with an aryloxy group.
  • aralkyloxyalkyl- refers to the group aryl-alk-O-alk- wherein “alk” is an alkylene group. “Lower aralkyloxyalkyl-” refers to such groups where the alkylene groups are lower alkylene.
  • alkoxy- or“alkyloxy-” refers to the group alkyl-O- .
  • alkoxyalkyl- or“alkyloxyalkyl-” refers to the group alkyl-O-alk- wherein“alk” is an alkylene group. In “lower alkoxyalkyl-,” each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • alkylthio- refers to the group alkyl-S-.
  • alkylthioalkyl- refers to the group alkyl-5-alk- wherein“alk” is an alkylene group. In “lower alkylthioalkyl-,” each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • alkoxycarbonyloxy- refers to alkyl-O-C(O)-O-
  • aryloxycarbonyloxy- refers to aryl-O-C(O)-O- .
  • alkylthiocarbonyloxy- refers to alkyl-S-C(O)-O-
  • alkylthiocarbonyloxy- refers to alkyl-S-C(O)-O-
  • carboxy refers to NR2-C(O)- and RC(O)-NR 1 - , where R and R 1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • urea does not include urea, - NR- C(O)-NR-.
  • R and R 1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Carboxamidoalkylaryl or “carboxamidoaryl” refers to an aryl-alk- NR 1 -C(O), and ar-NR 1 -C(O)-alk-, respectively where “ar” is aryl, “alk” is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • hydroxyalkyl refers to an alkyl group substituted with one -OH.
  • haloalkyl refers to an alkyl group substituted with halo.
  • cyano refers to -CN.
  • acylalkyl refers to an alkyl-C(O)-alk-, where“alk” is alkylene.
  • aminocarboxamidoalkyl- refers to the group NR 2- C(O)-N(R)-alk- wherein R is an alkyl group or H and “alk” is an alkylene group. “Lower aminocarboxamidoalkyl-” refers to such groups wherein“alk” is lower alkylen
  • heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced. [0085] As used herein, the term “combination with” when used to describe administration with an additional treatment means that the agent can be administered prior to, together with, or after the additional treatment, or a combination thereof. II.
  • One aspect of the present application relates to compounds derived from a generic structure as shown in Formula A: Formula A wherein X in each occurrence is independently selected from O and S; wherein Y is selected from a bond, O, CH2, and NR b ; wherein A is a warhead, which is selected from ; wherein R a is independently selected from H, C1-C6 alkyl, C2-C6 alkylene, C2-C6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycle, C 4 -C 10 bridged alkyl, C 5 -C 12 spiro alkyl, C 5 - C 10 aryl, and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, wherein R a can optionally be substituted with one or more R a1 ; wherein each R a1 is independently selected
  • F ormula B wherein X in each occurrence is independently selected from O and S; wherein Y is selected from a bond, O, CH2, and NR b ; wherein A is a warhead, which is selected from wherein R a is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkylene, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C3-C10 heterocycle, C4-C10 bridged alkyl, C5-C12 spiro alkyl, C5-C10 aryl, and 5-10 membered heteroaryl, wherein the heteroaryl moiety comprises one to four heteroatoms, each independently selected from N, O and S, wherein R a can optionally be substituted with one or more R a1 ; wherein each R a1 is independently selected from halo, oxo, cyano, SF5, -NR m R m , - NR m (C
  • the C 5 -C 10 aryl and 5-10 membered heteroaryl in Formula A, B, C, or D in each occurrence is one or more R d ;
  • Another aspect of the present application relates to a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable carrier.
  • Another aspect of the present application relates to a method of treating or preventing a virus infection in a subject. The method comprises the step of administering to the subject an effective amount of the compound of the present application or the pharmaceutical composition of the present application.
  • the virus infection is an infection of SARS-CoV-2 or a variant thereof. III.
  • the method comprises the step of administering an effective amount of the compound of the present application to a subject in need thereof.
  • the viral infection is a coronavirus infection.
  • the viral infection is SARS-CoV-2 infection.
  • the viral infection is caused by alphavirus, flavivirus coronavirus, RSV, influenza virus, Powassan virus, Ebola virus, or viruses of filoviridae, orthomyxovirudae or paramyxoviridae..
  • the viral infection is caused by a virus selected from MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Ross River virus, Barmah Forest virus, Powassan virus, Zika virus, and Chikungunya virus.
  • a virus selected from MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Ross River virus, Barmah Forest virus, Powassan virus, Zika virus, and Chikungunya virus.
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with influenza A virus including subtype H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), Dengue virus, Zika virus, chikungunya, Eastern equine encephalitis virus (IL), INF, INF,
  • the subject is at risk of exhibiting symptoms of, or diagnosed with a Zika virus infection.
  • influenza A virus including subtypes H1N1, H3N2, H7N9, H5N1 (low path), and H5N1 (high path) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, coxsackie A virus, norovirus, Rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, me
  • influenza A virus including subtypes H1N1, H3N
  • the subject is diagnosed with a Zika virus infection.
  • the subject is at risk of, exhibiting symptoms of, or diagnosed with, infection of subgroup 1a or 1b alphacoronaviruses, subgroup 2a, 2b, 2c or 2d betacoronaviruses, or subgroup 3 gammscoronaviruses.
  • subgroup 1a alphacoronaviruses and their GenBank Accession Nos.
  • FCov.FIPV.79.1146.VR.2202 (NV_007025), transmissible gastroenteritis virus (TGEV) (NC_002306; Q811789.2; DQ811786.2; DQ811788.1; DQ811785.1; X52157.1; AJ011482.1; KC962433.1; AJ271965.2; JQ693060.1; KC609371.1; JQ693060.1; JQ693059.1; JQ693058.1; JQ693057.1; JQ693052.1; JQ693051.1; JQ693050.1); porcine reproductive and respiratory syndrome virus (PRRSV) (NC_001961.1; DQ811787), as well as any subtype, clade or sub-clade thereof, including any other subgroup 1a coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database.
  • TGEV transmissible gastroenteritis virus
  • Nonlimiting examples of a subgroup 1b alphacoronaviruses and their GenBank Accession Nos. include HCoV.NL63.Amsterdam.I (NC_005831), BtCoV.HKU2.HK.298.2006 (EF203066), BtCoV.HKU2.HK.33.2006 (EF203067), BtCoV.HKU2.HK.46.2006 (EF203065), BtCoV.HKU2.GD.430.2006 (EF203064), BtCoV.1A.AFCD62 (NC_010437), BtCoV.1B.AFCD307 (NC_010436), BtCov.HKU8.AFCD77 (NC_010438), BtCoV.512.2005 (DQ648858); porcine epidemic diarrhea viruses (NC_003436, DQ355224.1, DQ355223.1, DQ355221.1, JN601062.1, JN601061.1, JN601060.1, JN60105
  • Nonlimiting examples of subgroup 2a betacoronaviruses and their GenBank Accession Nos. include HCoV.HKU1.C.N5 (DQ339101), MHV.A59 (NC_001846), PHEV.VW572 (NC_007732), HCoV.OC43.ATCC.VR.759 (NC_005147), bovine enteric coronavirus (BCoV.ENT) (NC_003045), as well as any subtype, clade or sub-clade thereof, including any other subgroup 2a coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database.
  • HCoV.HKU1.C.N5 DQ339101
  • MHV.A59 NC_001846)
  • PHEV.VW572 NC_007732
  • HCoV.OC43.ATCC.VR.759 NC_005147
  • bovine enteric coronavirus BCo
  • Nonlimiting examples of subgroup 2b betacoronaviruses and their GenBank Accession Nos. include human SARS CoV-2 isolates, such as Wuhan-Hu-1 (NC_045512.2) and any CoV-2 isolates comprising a genomic sequence set forth in GenBank Accession Nos., such as MT079851.1, MT470137.1, MT121215.1, MT438728.1, MT470115.1, MT358641.1, MT449678.1, MT438742.1, LC529905.1, MT438756.1, MT438751.1, MT460090.1, MT449643.1, MT385425.1, MT019529.1, MT449638.1, MT374105.1, MT449644.1, MT385421.1, MT365031.1, MT385424.1, MT334529.1, MT466071.1, MT461669.1, MT449639.1, MT415321.1, MT38
  • Nonlimiting examples of subgroup 2c betacoronaviruses and their GenBank Accession Nos. include Middle East respiratory syndrome coronavirus (MERS) isolates, such as Riyadh 22012 (KF600652.1), Al-Hasa_18_2013 (KF600651.1), Al-Hasa_17_2013 (KF600647.1), Al-Hasa_152013 (KF600645.1), Al-Hasa_16_2013 (KF600644.1), Al- Hasa_21_2013 (KF600634), Al-Hasa 19_2013 (KF600632), Buraidah_1_2013 (KF600630.1), Hafr-Al-Batin_1_2013 (KF600628.1), Al-Hasa_122013 (KF600627.1), Bisha.ltoreq.1_2012 (KF600620.1), Riyadh_3_2013 (KF600613.1), Riyadh_1_2012 (KF60062
  • Nonlimiting examples of subgroup 2d betacoronaviruses and their GenBank Accession Nos. include BtCoV.HKU9.2 (EF065514), BtCoV.HKU9.1 (NC_009021), BtCoV.HkU9.3 (EF065515), BtCoV.HKU9.4 (EF065516), as well as any subtype, clade or sub-clade thereof, including any other subgroup 2d coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database.
  • Nonlimiting examples of subgroup 3 gammacoronaviruses include IBV.Beaudette.IBV.p65 (DQ001339) or any other subgroup 3 coronavirus now known (e.g., as can be found in the GenBank® Database) or later identified in the GenBank® Database.
  • a coronavirus defined by any of the isolates or genomic sequences in the aforementioned subgroups 1a, 1b, 2a, 2b, 2c, 2d and 3 can be targeted for decontamination in accordance with the methods and compositions of the present application.
  • the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fever, acquired immunodeficiency syndrome or hepatitis.
  • the compound of the present application is administered orally or by inhalation. In certain embodiments, the compound is administered by inhalation through the lungs.
  • the compound of the present application is administered at a daily dosage in the range of 10-8000 mg, 10-4000 mg, 10-2000 mg, 10- 1000 mg, 10-800 mg, 10-400 mg, 10-200 mg, 10-100 mg, 10-80 mg, 10-40 mg, 10-20 mg, 20-8000 mg, 20-4000 mg, 20-2000 mg, 20-1000 mg, 20-800 mg20-400 mg, 20-200 mg, 20- 100 mg, 20-80 mg, 20-40 mg, 40-8000 mg, 40-4000 mg, 40-2000 mg, 40-1000 mg, 40-800 mg, 40-400 mg, 40-200 mg, 40-100 mg, 40-80 mg, 80-8000 mg, 80-4000 mg, 80-2000 mg, 80-1000 mg, 80-800 mg, 80-400 mg, 80-200 mg, 80-100 mg, 100-8000 mg, 100-4000 mg, 100-2000 mg, 100-1000 mg, 100-800 mg, 100-400 mg, 100-200 mg, 200-8000 mg, 200-4000 mg, 200-2000 mg, 200
  • the compound of the present application is administered at a daily dosage in the range of 50-1000 mg, 100-800 mg, 200-600 mg or 300- 500 mg. IV.
  • Pharmaceutical compositions [0119] Another aspect of the present application relates to pharmaceutical compositions comprising the compounds of the present application.
  • a pharmaceutical composition comprises a compound of the present application and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises, or is in the form of, a pharmaceutically acceptable salt of the compound of the present application, as generally described below.
  • Suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).
  • the exemplary compounds contain an acidic group as well as a basic group, the compounds can form internal salts, which can also be used in the compositions and methods described herein.
  • an exemplary compound contains a hydrogen-donating heteroatom (e.g., NH), salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • a hydrogen-donating heteroatom e.g., NH
  • Pharmaceutically acceptable salts of the exemplary compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphat
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference.
  • Physiologically acceptable salts of the exemplary compounds are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts.
  • the exemplary compounds can be administered in the form of prodrugs.
  • a prodrug can include a covalently bonded carrier which releases the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include, for example, compounds wherein a hydroxyl group is bonded to any group that, when administered to a subject, cleaves to form a free hydroxyl group.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds. Methods of structuring a compound as prodrugs can be found in the book of Testa and Mayer, Hydrolysis in Drug and Prodrug Metabolism, Wiley (2006).
  • Typical prodrugs form the active metabolite by transformation of the prodrug by hydrolytic enzymes, the hydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxides or the cleavage of esters of inorganic acids.
  • the pharmaceutical composition comprises an effective amount of an exemplary compound and a pharmaceutically acceptable carrier.
  • the compounds can be formulated as a pharmaceutical preparation comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent, or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • the preparations can be prepared in a manner known per se, which usually involves mixing the at least one compound according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary, under aseptic conditions. Reference is again made to U.S. Pat.
  • compositions can be in a unit dosage form, and can be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which can be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • such unit dosages will contain from 1 and 1000 mg, and usually from 5 and 500 mg, of the at least one compound of the disclosure, e.g., about 50, 100, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750 or 800 mg per unit dosage.
  • the compound or pharmaceutical composition can be administered by a variety of routes including the oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used.
  • the compound or pharmaceutical composition will generally be administered in an "effective amount", by which is meant any amount of a compound that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered.
  • such an effective amount will usually be from 0.01 to 1000 mg per kilogram body weight of the patient per day, more often from 0.1 and 500 mg, such as from 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight of the patient per day, which can be administered as a single daily dose, divided over one or more daily doses.
  • the amount(s) to be administered, the route of administration and the further treatment regimen can be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to U.S. Pat.
  • Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, lotions, or aerosols and the like.
  • the formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages.
  • Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets.
  • liquid dosage forms such as solutions, syrups, suspension, shakes, etc. can also be utilized.
  • the formulation is administered topically.
  • Suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels.
  • the topical formulation is a gel.
  • the formulation is administered intranasally.
  • Formulations containing one or more of the compounds described herein can be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and can be administered to an individual without causing undesirable biological side effects or unwanted interactions.
  • the carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • carrier includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, pH modifying agents, preservatives, antioxidants, solubility enhancers, and coating compositions.
  • Carrier also includes all components of the coating composition, which can include plasticizers, pigments, colorants, stabilizing agents, and glidants.
  • Delayed release, extended release, and/or pulsatile release dosage formulations can be prepared as described in standard references such as "Pharmaceutical dosage form tablets”, eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), "Remington--The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6th Edition, Ansel et al., (Media, Pa.: Williams and Wilkins, 1995). These references provide information on carriers, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.
  • suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGITTM (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.
  • the coating material can contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
  • Optional pharmaceutically acceptable excipients present in the drug- containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.
  • Diluents also referred to as "fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
  • Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
  • Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as crosslinked PVP (Polyplasdone XL from GAF Chemical Corp).
  • Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
  • Surfactants can be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMERTM 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate
  • amphoteric surfactants include sodium N-dodecyl-beta.-alanine, sodium N-lauryl-.beta.- iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
  • the tablets, beads, granules, or particles can also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.
  • concentration of the exemplary compound to pharmaceutically acceptable carrier, excipient and/or other substances can vary from about 0.5 to about 100 wt. % (weight percent).
  • the pharmaceutical composition can generally contain from about 5 to about 100% by weight of the active material.
  • the pharmaceutical composition can generally have from about 0.5 to about 50 wt. % of the active material.
  • the compositions described herein can be formulated for modified or controlled release. Examples of controlled release dosage forms include extended release dosage forms, delayed release dosage forms, pulsatile release dosage forms, and combinations thereof.
  • the extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington--The science and practice of pharmacy” (20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000).
  • a diffusion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds.
  • Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
  • Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and CARBOPOLTM 934, polyethylene oxides and mixtures thereof.
  • Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.
  • the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl me
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the trade name EUDRAGIT.
  • the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names EUDRAGIT RL30D and EUDRAGIT RS30D, respectively.
  • EUDRAGIT RL30D and EUDRAGIT RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT RL30D and 1:40 in EUDRAGIT RS30D.
  • the mean molecular weight is about 150,000.
  • EUDRAGIT S-100 and EUDRAGIT L-100 are also preferred.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • EUDRAGIT RL/RS mixtures are insoluble in water and in digestive fluids.
  • multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the polymers described above such as EUDRAGIT RL/RS can be mixed together in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable dissolution profile. Desirable sustained-release multiparticulate systems can be obtained, for instance, from 100% EUDRAGIT RL, 50% EUDRAGIT RL and 50% EUDRAGIT RS, and 10% EUDRAGIT RL and 90% EUDRAGITRS.
  • acrylic polymers can also be used, such as, for example, EUDRAGIT L.
  • extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion.
  • the devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads, or granules.
  • An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders.
  • a lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In the congealing method, the drug is mixed with a wax material and either spraycongealed or congealed and screened and processed.
  • Delayed release formulations are created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material.
  • the drug-containing composition can be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and can be conventional "enteric" polymers.
  • Enteric polymers as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastro-intestinal tract, particularly in the colon.
  • Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the trade name EUDRAGITTM (Rohm Pharma; Westerstadt, Germany), including EUDRAGITTM L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGITTM L-100 (
  • the coating composition can include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
  • a plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer.
  • plasticizers examples include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides.
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt.
  • the formulation can provide pulsatile delivery of the one or more compounds.
  • pulsatile is meant that a plurality of drug doses is released at spaced apart intervals of time. Generally, upon ingestion of the dosage form, release of the initial dose is substantially immediate, i.e., the first drug release "pulse" occurs within about one hour of ingestion.
  • This initial pulse is followed by a first time interval (lag time) during which very little or no drug is released from the dosage form, after which a second dose is then released.
  • a second nearly drug release-free interval between the second and third drug release pulses can be designed.
  • the duration of the nearly drug release-free time interval will vary depending upon the dosage form design e.g., a twice daily dosing profile, a three times daily dosing profile, etc.
  • the nearly drug release- free interval has a duration of approximately 3 hours to 14 hours between the first and second dose.
  • the nearly drug release-free interval has a duration of approximately 2 hours to 8 hours between each of the three doses.
  • the pulsatile release profile is achieved with dosage forms that are closed and preferably sealed capsules housing at least two drug-containing "dosage units" wherein each dosage unit within the capsule provides a different drug release profile.
  • Control of the delayed release dosage unit(s) is accomplished by a controlled release polymer coating on the dosage unit, or by incorporation of the active agent in a controlled release polymer matrix.
  • Each dosage unit can comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different drug release profile. For dosage forms mimicking a twice a day dosing profile, a first tablet releases drug substantially immediately following ingestion of the dosage form, while a second tablet releases drug approximately 3 hours to less than 14 hours following ingestion of the dosage form.
  • each dosage unit in the capsule can comprise a plurality of drug- containing beads, granules or particles.
  • drug-containing "beads" refer to beads made with drug and one or more excipients or polymers.
  • Drug-containing beads can be produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by creating a "core" comprising both drug and one or more excipients.
  • drug-containing "granules” and “particles” comprise drug particles that can or cannot include one or more additional excipients or polymers.
  • granules and particles do not contain an inert support.
  • Granules generally comprise drug particles and require further processing. Generally, particles are smaller than granules, and are not further processed.
  • the compound is formulated for topical administration.
  • suitable topical dosage forms include lotions, creams, ointments, and gels.
  • a "gel” is a semisolid system containing a dispersion of the active agent, i.e., compound, in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle.
  • the liquid can include a lipophilic component, an aqueous component or both.
  • Some emulsions can be gels or otherwise include a gel component.
  • Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components.
  • the compound described herein can be administered adjunctively with other active compounds.
  • active compounds include but are not limited to analgesics, anti- inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro- intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, anti-narcoleptics, and antiviral agents.
  • antiviral agents include, but are not limited to, RNA-dependent RNA polymerase (RdRp) inhibitors, protease drugs, anti-viral neutralizing antibodies and other antiviral drugs.
  • the antiviral agent is a non-CNS targeting antiviral compound.
  • Adjunctive administration means the compound can be administered in the same dosage form or in separate dosage forms with one or more other active agents.
  • the additional active agent(s) can be formulated for immediate release, controlled release, or combinations thereof.
  • compounds that can be adjunctively administered with the compounds include, but are not limited to, aceclofenac, acetaminophen, adomexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine,
  • the exemplary compounds and pharmaceutical compositions can be administered in combination with another antiviral agent(s) such as abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-5734, ibacitabine, imunovir, idoxuridine, imiquimod
  • another antiviral agent such
  • Typical embodiments of compounds in accordance with the present disclosure may be synthesized using the general reaction schemes and/or examples described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds which are embodiments of the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.
  • Group labels e.g., R1, R2 used in the reaction schemes herein are for illustrative purposes only and unless otherwise specified do not necessarily match by name or function the labels used elsewhere to describe compounds of formula (A), formula (B),formula (C) and formula (D) or aspects or fragments thereof.
  • Synthetic Reaction Parameters [0165]
  • the compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated.
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers.
  • stereoisomers i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0169] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • solvent refers to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), N, N- dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like).
  • solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.
  • the term “q.s.” means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
  • Compounds as provided herein may be synthesized according to the general schemes provided below. In the Schemes below, it should be appreciated that each of the compounds shown therein may have protecting groups as required present at any step. Standard protecting groups are well within the pervue of one skilled in the art.
  • the present invention provides a method for preparing a compound of the formula (A), formula (B), formula (C) and formula (D), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof.
  • IntA-4 (85 g,0.230 mol, 1.0 eq) was added into DCM (1500 ml) and stirred for 5 min, then IntA-5 (52.4 g,0.253 mol, 1.1 eq), HOBt (38.9 g, 0.288 mol, 1.25 eq), and EDCI (48.6 g, 0.253 mol, 1.1 eq) were added, then TEA (81.3 g, 0.805 mol, 3.5 eq) was added dropwisely to form a reaction mixture. The reaction mixture was stirred for 1 days at 20 °C. The reaction mixture was diluted with water (1000 ml) and extracted with DCM (2x1000 ml).
  • Int B [0176] Int B-1 (2.72 g, 10mmol, 1.0 eq), and N,O-dimethylhydroxylamine (0.92g, 15mmol,1.5eq) were added into DCM (25ml) and stirred for 5 min, then HOBt (2.03 g, 15mmol, 1.5eq), EDCI (2.29 g, 12mmol, 1.2 eq), and TEA (2.02 g, 20mmol, 2 eq) were added to form a reaction mixture. The reaction mixture was stirred for 6 hours at 20 °C. The reaction mixture was diluted with water (50 ml) and extracted with DCM (2x50 ml).
  • Int B-2 (2.0 g, 6.34mmol, 1.0 eq) was added, and stirred for 2 hours.
  • the reaction mixture was heated to room temperature, and ammonium chloride solution was added to quench the reaction.
  • DCM 50ml was added to extract.
  • the organic phase was collected and concentrated under vacuum to produce Int B-3(1.3g) as an oil without purification for next reaction.
  • Int B-3 (1.3g) was added in EA (20ml, 2M HCl in EA) and stirred for 4 hour at room temperature. A white solid was precipitated.
  • reaction mixture was stirred at room temperature for 1h and then extracted with EA (2 x 10 ml).
  • the combined organic phase was washed with brine (10 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum.
  • 3.1.10 Doses Compounds were diluted for 10 doses and added to an assay plate (384w format) using ECHO, in duplicate wells. [0200] 3.2.25 ⁇ L of 30 nM of Mpro protein was added to an assay plate containing compounds using a Multidrop. The compounds and Mpro protein were pre-incubated at room temperature 30min. Then 5 ⁇ L of 150 ⁇ M of substrate was added to an assay plate using a Multidrop. The final concentrations of Mpro and substrate were 25 nM and 25 ⁇ M respectively. For 100% inhibition control (HPE, hundred percent effect), no enzyme and compound was added. For no inhibition control (ZPE, zero percent effect), no compound was added.
  • HPE 100% inhibition control
  • ZPE zero percent effect
  • Huh7 cells were acquired from the JCRB cell bank, and maintained in the Dulbecco's Modified Eagle Medium supplemented with 10% FBS, 1% L-glutamine, 1% NEAA, and 1% penicillin-streptomycin. [0209] 2.3. Reagents and instruments [0210] The main reagent used in this assay was luminescent cell viability assay kit CellTiter Glo (Promega) [0211] The main instrument used in this assay was Acumen Cellista (TTP LabTech). 3. METHODS [0212] The SARS-CoV-2 replicon RNA was generated by the mMACHINE T7 Ultra Kit.
  • Huh7 cells were transfected with purified replicon RNAs and then seeded in plates containing serially diluted compounds, then cultured at 37°C and 5% CO2 for 1 day. The final volume of the cell culture was 60 ⁇ l per well, and the final concentrations of DMSO in the test plates were 0.5%.
  • Fluorescence intensity was determined using Acumen Cellista (TTP LabTech), and the antiviral activity of compounds was calculated based on the inhibition of expression of GFP. Cell viability was measured with CellTiter Glo following the manufacturer’s manual.
  • EC 50 and CC 50 values was calculated using the GraphPad Prism software using the nonlinear regression model of log(inhibitor) vs. response -- Variable slope (four parameters).
  • Virus strain [0219] HCoV 229E strain was obtained from the ATCC. [0220] 2.3. Cell line [0221] MRC5 cells were obtained from the ATCC, and maintained in the Minimum Essential Medium supplemented with 10% FBS, 1% L-glutamine, 1% NEAA and 1% penicillin-streptomycin. Minimum Essential Medium supplemented with 5% FBS, 1% L- glutamine, 1% NEAA and 1% penicillin-streptomycin was used as the assay medium. [0222] 2.4.
  • the main reagent used in this assay was luminescent cell viability assay kit CellTiter Glo (Promega) [0224] The main instrument used in this assay was Microplate Reader Synergy2 (BioTek). 3. METHODS [0225] Cells were seeded in 96 well plates, in 100 ⁇ l per well of assay medium, and cultured at 37 °C and 5% CO2 overnight. Next day, test compound was diluted with assay medium and then added into the cells, 50 ⁇ l per well. Then 50 ⁇ l per well of assay medium diluted virus was added. The final volume of the cell culture was 200 ⁇ l per well.
  • the resulting cell culture were incubated at 35 °C and 5% CO 2 for additional 3 days until virus infection in the virus control (cells infected with virus, without compound treatment) displays significant CPE.
  • the CPE were measured by CellTiter Glo following the manufacturer’s manual.
  • the antiviral activity of compounds was calculated based on the protection of the virus-induced CPE at each concentration normalized by the virus control.
  • the cytotoxicity of compounds was assessed under the same conditions, but without virus infection, in parallel. Cell viability was measured with CellTiter Glo following the manufacturer’s manual.
  • EC50 and CC50 values were calculated using the GraphPad Prism software using the nonlinear regression model of log(inhibitor) vs. response -- Variable slope (four parameters).
  • Virus Inoculation Doses The dose-dependent antiviral effect was studied at a target MOI of 0.005 TCID50/cell after 48 ⁇ 4 hours post infection. For the omicron variant the MOI is TBD and will be added through amendment. 3. EXPERIMENTAL DESIGN: [0231] Antiviral activity was determined for each test article at the concentrations of using a post treatment regimen. TA was mixed with virus and incubated to allow for viral adsorption for 60-90 min. Following the adsorption, cells were washed with 1x PBS or media and 1x media with TA was placed on top of the cells.
  • TEST SYSTEM [0232] Cell Culture: African green monkey kidney (Vero E6) cells were maintained in Dulbecco’s Minimum Essential Medium with 10% Fetal Bovine Serum and antibiotics. For the efficacy and cytotoxicity assay the FBS was reduced to 2%. [0233] Challenge Virus: The viruses listed in the following table were used for the study. Viruses were stored at approximately ⁇ -65°C prior to use. Viruses 5. METHODS: [0234] African green monkey kidney (Vero E6) cells were maintained in Dulbecco’s Minimum Essential Medium with 10% Fetal Bovine Serum and antibiotics. For the efficacy and cytotoxicity assay the FBS was reduced to 2%.
  • a volume of 50 ⁇ L of each 2x test article dilution mixed with 50 ⁇ L of 1x media containing the virus was transferred to a monolayer of confluent Vero E6 cells to allow for viral adsorption for 60-90 min. All groups were added with CP-100356 at a final concentration of 2 ⁇ M.
  • CP-100356 is a P-glycoprotein (P-gp) inhibitor, which can prevent P- gp from pumping Mpro inhibitors out of cells.
  • P-gp P-glycoprotein
  • the concentrations of TAs range from 10 ⁇ M to 0.003 ⁇ M with 3-fold dilutions and 8 doses in total. All incubations were performed in a humidified chamber at 37 ⁇ 2 °C in 5 ⁇ 2% CO2. Remdesivir free-base was evaluated in parallel as a positive control compound. Cell controls with DMSO and CP-100356 were evaluated in parallel. The dose-dependent antiviral effect was studied at a target MOI of 0.005 TCID50/cell after 48 ⁇ 4 hours post infection.
  • Controls The virus control (VC) wells contained only SARS-CoV-2 and Vero E6 cells and acted as the infection control.
  • the cell control (CC) wells contained cells only, no virus, and were used as a background control. VC and CC were loaded in 12 replicates of each 96 well-plate used.
  • Data Analysis Absorbance readings for each well were collected by Softmax Pro software (version 7.0.3; GXP; San Jose, CA) and imported into a Microsoft Excel spreadsheet for further calculations.
  • the IC50 was defined as the reciprocal log10 dilution that caused 50% reduction of the absorbance value of the virus control (50% A405 reduction).
  • the date of Evaluation of the in vitro bioactivity was summarized in Table 3. Table 3.
  • In vitro inhibitory activity of the test against SARS-CoV-2 wildtype, P132H mutant (Mpro), and human coronavirus 229E [0244]

Abstract

L'invention concerne certains composés antiviraux, des compositions pharmaceutiques et des procédés associés. Formule (C)
PCT/IB2022/000751 2022-01-18 2022-12-09 Inhibiteurs de cystéine protéases et leurs procédés d'utilisation WO2023139402A1 (fr)

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