WO2024129963A1 - Analogues nucléosidiques biodisponibles par voie orale - Google Patents

Analogues nucléosidiques biodisponibles par voie orale Download PDF

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WO2024129963A1
WO2024129963A1 PCT/US2023/084006 US2023084006W WO2024129963A1 WO 2024129963 A1 WO2024129963 A1 WO 2024129963A1 US 2023084006 W US2023084006 W US 2023084006W WO 2024129963 A1 WO2024129963 A1 WO 2024129963A1
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alkyl
compound
cycloalkyl
alkylene
heterocycloalkyl
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Steven A. Boyd
Stephen M. Condon
Glen A. COBURN
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VenatoRx Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • Remdesivir is a parenterally administered prodrug that was previously developed for the treatment of Ebola virus disease and more recently received emergency use authorization for the treatment of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection (Eastman, R.T., Roth, J.S., Brimacombe, K.R., Simeonov, A., Shen, M., Patnaik, S., and Hall, M.D. (2020). Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci 6, 672-683).
  • SARS-CoV-2 severe acute respiratory syndrome-coronavirus 2
  • the parent compound is a 1′-cyano modified adenosine C- nucleoside analog (GS-441524) that is phosphorylated by intracellular nucleotide kinases to the active tri-phosphorylated form (GS-443902).
  • GS-443902 inhibits viral replication by competing with adenosine 5’-triphosphate for incorporation into nascent RNA chains by the virally-encoded RNA-dependent RNA polymerase leading to a delayed chain termination that can occur three nucleotides downstream from its position (Kokic et a., 2021; Nature Communications 12:279).
  • GS-443902 residues in the template strand significantly compromises the incorporation of uridine residues during second-strand synthesis (Tchesnokov et al.2020 Journal of Biological Chemistry 295(47):16156-16165).
  • Remdesivir is a monophosphoramidate prodrug of GS-441524 and demonstrates broad spectrum antiviral activity against a wide range of different RNA virus families including: filoviruses (e.g. Ebola viruses, Marburg virus), paramyxoviruses (e.g.
  • Coronaviruses are a large family of viruses that typically infect the upper respiratory tract causing mild to moderate disease in humans. Infections with human coronaviruses: 229E, NL63, OC43 and HKU1 account for approximately 5-30% of “common” colds. There are several hundred coronaviruses that circulate in animals such as pigs, camels, bats, and cats. In the past twenty years, at least three coronaviruses have jumped from one or more of these animal reservoirs into humans in what is known as a spillover event.
  • MERS-CoV Middle East Respiratory Syndrome Coronavirus
  • SARS-CoV the coronavirus responsible for “Severe Acute Respiratory Syndrome” (SARS) that was first identified in China in 2002.
  • SARS-CoV-2 the causative agent of COVID-19 WSGR Docket No. 41223-754.601 (Coronavirus Disease of 2019). All three of these beta-coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, have shown the potential to replicate in the lower respiratory tract and cause more serious illnesses in humans giving rise to a viral pneumonia that can be fatal.
  • the present disclosure relates to small-molecule compounds that can be used as a monotherapy or in combination with additional antivirals and/or other agents in the treatment of a viral infection.
  • the present disclosure relates to small-molecule compounds that block coronavirus and filovirus replication with the potential to be used as a monotherapy or in combination with additional antivirals and/or other agents.
  • Disclosed herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (IIa) as defined herein.
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.
  • a method of treating a viral infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.
  • the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-CoV-2), Yellow Fever, Eastern Equine Encephalitis virus, Human Immunodeficiency virus (HIV), “African Swine Fever Viruses,” Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Bimaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Ebolavirus, Deltaviridae, Filoviridae, Flaviviridae, Iridoviridae, Mononegavirus, Myoviridae, Papillomavirus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Pox
  • the viral infection is caused by coronavirus disease 2019 (SARS-CoV- 2).
  • the viral infection is caused by the Middle East respiratory syndrome coronavirus (MERS-CoV).
  • the viral infection is caused by one Ebolavirus.
  • the method further comprises administering at least one antiviral agent.
  • the at least one antiviral agent is nirmatrelvir/ritonavir.
  • Haldroxy refers to -OH; [0022] “Carboxyl” refers to -COOH. [0023] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms.
  • Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 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, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like
  • a numerical range such as “C 1 -C 6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl.
  • the alkyl is a C 1 -C 6 alkyl.
  • the alkyl is a C 1 -C 5 alkyl.
  • the alkyl is a C 1 -C 4 alkyl.
  • the alkyl is a C 1 -C 3 alkyl.
  • an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkyl is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as “C 2 -C 6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl).
  • Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl.
  • an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or WSGR Docket No. 41223-754.601 heteroaryl, and the like.
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and/or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl), from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl), from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl), from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl), from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl), or three to four carbon atoms (e.g.,
  • the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to -O-haloalkyl, with haloalkyl as defined above.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. [0035] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium.
  • the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 .
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus , or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , - CH(CH 3 )OCH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N(CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or - NO 2 .
  • a heteroalkyl is optionally substituted with one or more oxo , halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked.
  • the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three WSGR Docket No. 41223-754.601 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), from two to five carbon atoms (e.g., C
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyrany
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • the heterocycloalkyl is a 3 - to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3 - to 6-membered WSGR Docket No. 41223-754.601 heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF 3 , -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl is C-linked.
  • the heteroaryl is N-linked.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may b e optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4 -benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indo
  • pyrazolyl pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).
  • a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • halogen methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heteroaryl is optionally substituted with halogen.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , - CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible.
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • the term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • “Treatment” of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
  • treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
  • Coronavirus infection refers to any and all conditions deriving from infection with coronaviruses, including but not limited to SARS-CoV, SARS-CoV-2, and MERS-CoV, preferably SARS-CoV-2.
  • the viral infection is a coronavirus infection.
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 - C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a ;
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxy
  • the compound of Formula (I) gets metabolized in vivo.
  • the compound of Formula (I) gets metabolized in vivo to a compound of Formula (I-M).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 - C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a ; R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C
  • X is hydrogen. In some embodiments of a compound of Formula (I) or (I-M), X is -CN. [0051] In some embodiments of a compound of Formula (I) or (I-M), R 13 is hydrogen. In some embodiments of a compound of Formula (I) or (I-M), R 13 is C 1 -C 6 alkyl. [0052] In some embodiments of a compound of Formula (I) or (I-M), R 14 is -OH. In some embodiments of a compound of Formula (I) or (I-M), R 14 is fluoro.
  • R 11 is hydrogen.
  • each R 11a is independently halogen, -CN, -OH, -OR a , or -NR c R d . In some embodiments of a compound of Formula (I) or (I-M), each R 11a is independently halogen.
  • R 21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 21a .
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R 21 is C 1 -C 6 alkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • each R 21a is independently halogen, -OH, - OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • R 22 is C 1 -C 6 alkyl or C 1 - C 6 alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl.
  • R 23 is hydrogen, C 1 -C 6 alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), WSGR Docket No. 41223-754.601 C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 23 is hydrogen or C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a . In some embodiments of a compound of Formula (I) or (I-M), R 23 is C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a . In some embodiments of a compound of Formula (I) or (I-M), R 23 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (I-M), R 23 is hydrogen.
  • each R 15a is independently halogen, -CN, -OH, -OR a , or -NR c R d . In some embodiments of a compound of Formula (I), each R 15a is independently halogen.
  • R 25 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R 25a .
  • R 25 is C 1 -C 6 alkylene(cycloalkyl) or C 1 - C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R 25a .
  • each R 25a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 16a is independently halogen, -CN, -OH, -OR a , or -NR c R d . In some embodiments of a compound of Formula (I), each R 16a is independently halogen.
  • R 26 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkylene(cycloalkyl) or C 1 - C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R 26a .
  • R 16 is . In some embodiments of a compound of Formula (I), R 16 is . In some embodiments of a compound of Formula (I), R 16 is . In some embodiments of a compound of Formula (I), R 16 is not . In some embodiments of a compound of Formula (I), R 16 is not . In some embodiments of a compound of Formula (I), R 16 is not . In some embodiments of a compound of Formula (I), R 16 is not . In some embodiments of a compound of Formula (I-M), R 7 is hydrogen.
  • R 7 is a counterion. In some embodiments of a compound of Formula (I-M), R 7 is Na + . In some embodiments of a compound of Formula (I-M), R 7 is Li + . In some embodiments of a compound of Formula (I-M), R 7 is Mg 2+ . [0075] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (II); wherein: X is hydrogen or -CN; WSGR Docket No.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalky
  • the compound of Formula (II) gets metabolized in vivo.
  • the compound of Formula (II) gets metabolized in vivo to a compound of Formula (II-M).
  • R 22a taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;
  • R 13 is hydrogen or C 1 -C 6 alkyl;
  • R 14 is -OH or fluoro;
  • R 7 is hydrogen or a counterion;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl
  • WSGR Docket No. 41223-754.601 [0079] In some embodiments of a compound of Formula some embodiments of a compound of Formula some embodiments of a compound of Formula some embodiments of a compound of Formula [0080] In some embodiments of a compound of Formula (II) or (II-M), X is hydrogen. In some embodiments of a compound of Formula (II) or (II-M), X is -CN. [0081] In some embodiments of a compound of Formula (II) or (II-M), R 13 is hydrogen. In some embodiments of a compound of Formula (II) or (II-M), R 13 is C1-C6alkyl.
  • R 11 is hydrogen.
  • each R 11a is independently halogen, -CN, -OH, -OR a , or -NR c R d . In some embodiments of a compound of Formula (II) or (II-M), each R 11a is independently halogen.
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 21a .
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • each R 21a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl, WSGR Docket No. 41223-754.601 C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl). [0098] In some embodiments of a compound of Formula (II) or (II-M), R 22 is C 1 -C 6 alkyl or C 1 - C 6 alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a . In some embodiments of a compound of Formula (II) or (II-M), R 22 is C 1 -C 6 alkyl optionally substituted with one R 22a . In some embodiments of a compound of Formula (II) or (II-M), R 22 is C 1 -C 6 alkyl substituted with one R 22a . [0099] In some embodiments of a compound of Formula (II) or (II-M), R 22 is C 1 -C 6 heteroalkyl.
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl). [00101] In some embodiments of a compound of Formula (II) or (II-M), R 23 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen or C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a . In some embodiments of a compound of Formula (II) or (II-M), R 23 is C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a . In some embodiments of a compound of Formula (II) or (II-M), R 23 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (II-M), R 23 is hydrogen.
  • each R 22a is independently halogen, -OH, WSGR Docket No.
  • each R 22a is independently -OR a . In some embodiments of a compound of Formula (II) or (II-M), R 22a is -OR a . [00105] In some embodiments of a compound of Formula [00106] In some embodiments of a compound of Formula (II) or (II-M), R 12 is , , . , . embodiments of a compound of Formula (II) or (II-M), R 12 is .
  • each R 15a is independently halogen, - CN, -OH, -OR a , or -NR c R d . In some embodiments of a compound of Formula (II), each R 15a is independently halogen.
  • R 25 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 25a .
  • R 25 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R 25a .
  • R 25 is C 1 -C 6 alkylene(cycloalkyl) or C 1 - C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R 25a .
  • each R 25a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 15 is , or . In some embodiments of a compound of Formula (II), R 15 is . In some embodiments of a compound of Formula (II), R 15 is . In some embodiments of a compound of Formula (II), R 15 is . In some embodiments of a compound of Formula (II), R 15 is . In some embodiments of a compound of Formula (II), R 15 is . In some embodiments of a compound of Formula (II), R 15 is . In some embodiments of a compound of Formula (II), R 15 is . In some embodiments of a compound of Formula (II), R 15 is not . In some embodiments of a compound of Formula (II), R 15 is not .
  • R 15 is not .
  • R 26 is C 1 -C 6 alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independe ntly substituted with one or more R 26a .
  • R 26 is C 1 - C 6 alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 alkylene(5- to 6-membered cycloalkyl). [00116] In some embodiments of a compound of Formula (II), R 26 is C 1 -C 6 alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 26a . In some embodiments of a compound of Formula (II), R 26 is C 1 -C 6 alkylene(phenyl); wherein the alkylene and phenyl is optionally and independently substituted with one or more R 26a .
  • each R 26a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 15 is , WSGR Docket No. 41223-754.601
  • R 17 is , some embodiments of a compound of Formula some embodiments of a compound of Formula . , .
  • R 7 is hydrogen.
  • R 7 is a counterion. In some embodiments of a compound of Formula (II-M), R 7 is Na + . In some embodiments of a compound of Formula (II-M), R 7 is Li + . In some embodiments of a compound of Formula (II-M), R 7 is Mg 2+ . WSGR Docket No.
  • R 14 is -OH or fluoro;
  • R 7 is hydrogen or a counterion; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl,
  • G is some embodiments of a compound of Formula (IIa) or (IIa-M), G is WSGR Docket No. 41223-754.601 some embodiments of a compound of Formula (IIa) or (IIa-M), G is .
  • X is hydrogen.
  • X is -CN.
  • R 13 is hydrogen.
  • R 13 is C 1 -C 6 alkyl.
  • R 14 is -OH.
  • R 14 is fluoro.
  • each R 11a is independently halogen.
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 21a .
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl).
  • each R 21a is independently halogen, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 32 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; wherein the alkyl is optionally and independently substituted with one or more R.
  • R 32 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; wherein the alkyl is optionally and independently substituted with one or more R.
  • R 26 is C 1 -C 6 alkylene(cycloalkyl) or C 1 - C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 - C 6 alkylene(cycloalkyl) or C 1 -C 6 alkylene(aryl).
  • R 26 is C 1 -C 6 alkylene(cycloalkyl).
  • R 26 is C 1 - C 6 alkylene(aryl). In some embodiments of a compound of Formula (IIa), R 26 is C 1 - C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a . In some embodiments of a compound of Formula (IIa), R 26 is C 1 -C 6 alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkylene(4- to WSGR Docket No. 41223-754.601 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 alkylene(3- to 8-membered cycloalkyl).
  • R 26 is C 1 alkylene(4- to 7-membered cycloalkyl).
  • R 26 is C1alkylene(4- to 6-membered cycloalkyl).
  • R 26 is C 1 alkylene(5- to 6-membered cycloalkyl). [00140] In some embodiments of a compound of Formula (IIa), R 26 is C 1 -C 6 alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 26a . In some embodiments of a compound of Formula (IIa), R 26 is C 1 -C 6 alkylene(phenyl); wherein the alkylene and phenyl is optionally and independently substituted with one or more R 26a .
  • each R 26a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 16 is , , WSGR Docket No. 41223-754.601 . , . embodiments of a compound of Formula (IIa), R 16 is . In some embodiments of a compound . [00143] In some embodiments of a compound of Formula (IIa-M), R 17 is , . In some embodiments of a compound of Formula some embodiments of a compound of Formula WSGR Docket No. 41223-754.601 . In some embodiments of a compound of Formula (IIa-M), R 17 is [00144] In some embodiments of a compound of Formula (IIa-M), R 7 is hydrogen.
  • R 7 is a counterion. In some embodiments of a compound of Formula (IIa-M), R 7 is Na + . In some embodiments of a compound of Formula (IIa-M), R 7 is Li + . In some embodiments of a compound of Formula (IIa-M), R 7 is Mg 2+ .
  • the compound of Formula (III) gets metabolized in vivo. [00147] In some aspect, the compound of Formula (III) gets metabolized in vivo to a compound of Formula (II-M). [00148] In some embodiments of a compound of Formula some embodiments of a compound of Formula some embodiments of a [00149] In some embodiments of a compound of Formula (III), X is hydrogen. In some embodiments of a compound of Formula (III), X is -CN. [00150] In some embodiments of a compound of Formula (III), R 13 is hydrogen. In some embodiments of a compound of Formula (III), R 13 is C 1 -C 6 alkyl.
  • each R 11a is independently halogen.
  • R 21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 21a .
  • R 21 is C 1 -C 6 alkyl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R 21 is C 1 -C 6 alkyl, C 1 - C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • each R 21a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • R 22 is C 1 -C 6 alkyl or C 1 - C 6 alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, or C 1 - C 6 alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen or C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a .
  • R 23 is C1-C6alkyl optionally and independently substituted with one or more R 22a .
  • R 23 is C 1 -C 6 alkyl.
  • R 23 is hydrogen.
  • each R 22a is independently halogen, -OH, -OR a , - NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 25 is C 1 - C 6 alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 25a .
  • R 25 is C 1 -C 6 alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 25a .
  • each R 25a is independently halogen, -OH, -OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl.
  • each R 16a is independently halogen, - CN, -OH, -OR a , or -NR c R d . In some embodiments of a compound of Formula (III), each R 16a is independently halogen.
  • R 26 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkylene(cycloalkyl) or C 1 - C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R 26a .
  • each R 26a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 16 is not .
  • R 16 is not . In some embodiments of a compound of Formula (III), R 16 is not .
  • R 16 is not .
  • [00181] Also disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: WSGR Docket No.
  • the compound of Formula (IV) gets metabolized in vivo.
  • the compound of Formula (IV) gets metabolized in vivo to a compound of Formula (IV-M).
  • cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 21a on the same atom are taken together to form an oxo; or two R 21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalky
  • X is hydrogen. In some embodiments of a compound of Formula (IV) or (IV-M), X is -CN. In some embodiments of a compound of Formula (IV) or (IV-M), R 13 is hydrogen. In some embodiments of a compound of Formula (IV) or (IV-M), R 13 is C 1 -C 6 alkyl. [00187] In some embodiments of a compound of Formula (IV) or (IV-M), R 14 is -OH.
  • R 14 is fluoro.
  • R 11 is hydrogen.
  • each R 11a is independently halogen, -CN, -OH, -OR a , or -NR c R d . In some embodiments of a compound of Formula (IV) or (IV-M), each R 11a is independently halogen.
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 21a .
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C6alkylene(heteroaryl).
  • R 21 is C 1 -C 6 alkyl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • each R 21a is independently halogen, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - WSGR Docket No.
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • R 22 is C 1 -C 6 alkyl or C 1 - C 6 alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl). [00199] In some embodiments of a compound of Formula (IV) or (IV-M), R 23 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen or C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a . In some embodiments of a compound of Formula (IV) or (IV-M), R 23 is C1-C6alkyl optionally and independently substituted with one or more R 22a . In some embodiments of a compound of Formula (IV) or (IV-M), R 23 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV) or (IV-M), R 23 is hydrogen. WSGR Docket No.
  • each R 22a is independently halogen, - OH, -OR a , - NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 25 is C 1 -C 6 alkylene(cycloalkyl) or C 1 -C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R 25a .
  • R 25 is C 1 -C 6 alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 25a .
  • R 25 is C 1 -C 6 alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 25a .
  • each R 25a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 15 is , .
  • R 15 is .
  • R 15 is .
  • R 15 is .
  • R 15 is .
  • R 15 is not . In some embodiments of a compound of Formula (IV), R 15 is not . In some embodiments of a compound of Formula (IV), R 15 is not . In some embodiments of a compound of Formula (IV), R 15 is not . [00207] In some embodiments of a compound of Formula some embodiments of a compound of Formula some embodiments of a compound of Formula some embodiments of a compound of Formula (IV-M), R 17 is WSGR Docket No. 41223-754.601 . [00208] In some embodiments of a compound of Formula (IV-M), R 7 is hydrogen. In some embodiments of a compound of Formula (IV-M), R 7 is a counterion.
  • R 14 is -OH or fluoro;
  • R 25 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 - C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroary l is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C 1 -C 6 alkyl,
  • the compound of Formula (V) gets metabolized in vivo. [00211] In some aspect, the compound of Formula (V) gets metabolized in vivo to a compound of Formula (IV-M). [00212] In some embodiments of a compound of Formula some embodiments of a compound of Formula some embodiments of a [00213] In some embodiments of a compound of Formula (V), X is hydrogen. In some embodiments of a compound of Formula (V), X is -CN. WSGR Docket No. 41223-754.601 [00214] In some embodiments of a compound of Formula (V), R 13 is hydrogen.
  • R 13 is C 1 -C 6 alkyl.
  • R 14 is -OH.
  • R 14 is fluoro.
  • R 11 is hydrogen.
  • each R 11a is independently halogen, - CN, -OH, -OR a , or -NR c R d .
  • each R 11a is independently halogen.
  • R 21 is C 1 -C 6 alkyl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R 21 is C1-C6alkyl, C1- C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • each R 21a is independently halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 22 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • R 22 is C 1 -C 6 alkyl or C 1 - C 6 alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 22 is C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 - C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C 6 alkylene(heteroaryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • R 23 is hydrogen, C 1 -C 6 alkyl, or C 1 - C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R 22a .
  • R 23 is hydrogen or C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a .
  • R 23 is C1-C6alkyl optionally and independently substituted with one or more R 22a .
  • R 23 is C 1 -C 6 alkyl.
  • R 23 is hydrogen.
  • each R 22a is independently halogen, - OH, -OR a , - NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 25 is C 1 -C 6 alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R 25a .
  • R 25 is C 1 -C 6 alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 25a .
  • each R 25a is independently halogen, - OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 15 is , , , or . In some embodiments of a compound of Formula (V), R 15 is embodiments of a compound of Formula (V), R 15 is . In some embodiments of a compound of Formula (V), R 15 is . In some embodiments of a compound of Formula (V), R 15 is . In WSGR Docket No. 41223-754.601 some embodiments of a compound of Formula (V), R 15 is not . In some embodiments of a compound of Formula (V), R 15 is not . In some embodiments of a compound of Formula (V), R 15 is not . In some embodiments of a compound of Formula (V), R 15 is not .
  • R 26 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 26a .
  • R 26 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 - C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • R 26 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 - C6alkylene(heteroaryl).
  • R 26 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, aryl, C 1 -C 6 alkylene(cycloalkyl), or C 1 -C 6 alkylene(aryl).
  • R 26 is C 1 -C 6 alkyl or C 1 -C 6 aminoalkyl.
  • each R 26a is independently halogen, - OH, -OR a , - NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • WSGR Docket No. 41223-754.601 In some embodiments of a compound of Formula (V), R 16 is not . In some embodiments of a compound of Formula (V), R 16 is not .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl).
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen or C 1 -C 6 alkyl.
  • each R b is hydrogen. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently C 1 -C 6 alkyl.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkyl(heteroaryl).
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d are hydrogen. In some embodiments of a WSGR Docket No. 41223-754.601 compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R d are independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
  • Described herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a compound in Table 1. Table 1. Exemplary compounds.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or WSGR Docket No. 41223-754.601 interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • Labeled compounds [00257]
  • the compounds described herein exist in their isotopically -labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically -labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact 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 that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Pharmaceutically acceptable salts [00259]
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods WSGR Docket No.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof , or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Solvates [00265] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [00266] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
  • hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Tautomers [00267] In some situations, compounds exist as tautomers.
  • the compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond.
  • Prodrugs are meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug is typically inactive when administered to a subject, but is converted in vivo to an WSGR Docket No. 41223-754.601 active compound, for example, by hydrolysis.
  • prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam).
  • Prodrugs are delivered through any known methods described herein, including but not limited to orally, intravenously, intraperitoneal, or other method of administration known by those skilled in the art. [00269] A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs include any group bound to a heteroatom, such as the nitrogen of a pyridine which is cleaved in vivo to form the active compound or metabolite thereof.
  • examples of prodrugs include, but are not limited to, acetate, formate phosphate, and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
  • a prodrug is a salt.
  • a prodrug is a phosphate salt.
  • a prodrug is an alkyl phosphate salt.
  • a prodrug is an alkylated heteroaromatic salt.
  • a prodrug is a pyridinium salt. In some embodiments, a prodrug is a pyridinium alkylphosphate salt. In some embodiments, a prodrug is a pyridinium methylphosphate salt. In some embodiments, a prodrug comprises an alkyl phosphate bound to a heteroatom. In some embodiments, a prodrug comprises an alkyl phosphate bound to a heteroatom of a heterocycle.
  • a prodrug is any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each.
  • prodrugs are formed using groups attached to functionality, e.g., HO—, HS—, HOOC—, NHR—, associated with the drug or active compounds, that cleave in vivo.
  • prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol, and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
  • the groups illustrated above are exemplary, not exhaustive, and other varieties of prodrugs are possible. Such prodrugs of disclosed compounds fall within this scope.
  • prodrugs themselves and are converted into other forms, including the biologically active compound forms, when administered to a biological system.
  • prodrugs undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound.
  • the prodrug is biologically active, more, or less than the intended active drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, and/or pharmacodynamic half-life, etc.
  • Prodrug forms of compounds are utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.
  • Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992, Chapter 8: “Prodrugs and Drug delivery Systems” pp. 352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed. by E. B.
  • prodrugs comprise phosphorus moieties includ ing phosphates or derivatives thereof.
  • One such class of prodrugs is the aryl amidate (McGuigan) type.
  • McGuigan aryl amidate
  • the compounds of the present application comprise a prodrug moiety that is carbamate, thiocarbamate, or urea to mask an amino or hydroxy group on the active compound.
  • the prodrug moiety of carbamate, thiocarbamate, or urea is metabolized in vivo to afford the free amino or hydroxy moiety on the active compound.
  • the disclosure provides a method of treating, preventing and/or reducing the severity or extent of viral infections by administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the compound.
  • a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the compound.
  • the compounds described herein find use in a variety of applications for human and animal health.
  • the compounds described herein are inhibitors of coronavirus.
  • the efficacy of treatment is determined using quantification of viral load or other evidence of infection.
  • the compounds described herein reduce viral load in an individual suffering from a coronavirus infection.
  • administering refers to any route of introducing or delivering the composition or formulation to perform the intended function or treatment. Administration can be carried out by any route suitable for the delivery of composition or formulation. Thus, delivery routes can include intravenous, intramuscular, intraperitoneal, or subcutaneous delivery. Administration includes self-administration and the administration by another. [00281] As used herein, he terms “patient” “subject” “individual” and the like are used interchangeably, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject, or individual is a human.
  • the terms “prevent” and “prevention” refer to acting prior to overt disease or disorder onset, to prevent the disease or disorder from developing, or to minimize the extent of the disease or disorder, or to slow its course of development.
  • the term “cure” refers to heal, to make well, or to restore to good health or to allow a time without recurrence of disease so that the risk of recurrence is small.
  • a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the compound may experience as a result of the therapy a reduction of virus count or improvement of at least one symptom associated with the virus infection, including, for example, fever, coughing, fatigue, pain, etc.
  • the disclosure provides a method for treating, preventing and/or reducing the severity or extent of viral infection and associated disease from an RNA or DNA virus that includes but is not limited to coronaviruses, respiratory syncytial virus, influenza viruses, flaviviruses, hemorrhagic fever viruses, alphaviruses, polyomaviruses, herpesviruses, and poxviruses.
  • an RNA or DNA virus that includes but is not limited to coronaviruses, respiratory syncytial virus, influenza viruses, flaviviruses, hemorrhagic fever viruses, alphaviruses, polyomaviruses, herpesviruses, and poxviruses.
  • the disclosure provides a method for treating, preventing and/or reducing the severity or extent of viral infection, including, for example, a single-stranded positive sense RNA virus, coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), Zika, dengue, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, and Human immunodeficiency virus type 1.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • the disclosure provides a method for treating, preventing and/or reducing the severity or extent of viral infection, including, for example, a DNA virus, equine herpesvirus type 1, pseudorabies virus, BK polyomavirus, and porcine circovirus 2.
  • a DNA virus equine herpesvirus type 1, pseudorabies virus, BK polyomavirus, and porcine circovirus 2.
  • COVID-19 pandemic, SARS-CoV-2 is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV).
  • the disclosure provides a method for treating, preventing and/or reducing the severity or extent of viral infection and associated disease from an RNA or DNA virus that includes but is not limited to coronaviruses, respiratory syncytial virus, influenza viruses, flaviviruses, hemorrhagic fever viruses, alphaviruses, polyomaviruses, herpesviruses, and poxviruses.
  • RNA or DNA virus that includes but is not limited to coronaviruses, respiratory syncytial virus, influenza viruses, flaviviruses, hemorrhagic fever viruses, alphaviruses, polyomaviruses, herpesviruses, and poxviruses.
  • WSGR Docket No. 41223-754.601 Also disclosed herein is a method of treating an infection in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the infection is a viral infection.
  • the viral infection is caused by the SARS-CoV or SARS-CoV-2 virus.
  • the viral infection is COVID, or COVID-19.
  • the viral infection is caused by the Middle East respiratory syndrome coronavirus (MERS-CoV).
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • the viral infection is caused by a filovirus.
  • the viral infection is caused by the Ebola virus.
  • the viral infection is caused by the Marburg virus.
  • the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-CoV-2), Yellow Fever, Eastern Equine Encephalitis virus, Human Immunodeficiency virus (HIV), “African Swine Fever Viruses,” Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Bimaviridae, Bunyavirid ae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Ebolavirus, Deltaviridae, Filoviridae, Flaviviridae, Iridoviridae, Mononegavirus, Myoviridae, Papillomavirus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae,
  • the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-CoV-2), Adenoviridae, Arenaviridae, Arteriviridae, Astroviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae, Coronaviridae, Deltavirus, Filoviridae, Flaviviridae, Hepadnaviridae, Papovaviridae, Paramyxoviridae, Parvoviridae, Poxviridae, Reoviridae, Retroviridae, Rhabdoviridae, Togaviridae, and viruses which cause the common cold, and any combination thereof.
  • coronavirus disease 2019 SARS-CoV-2
  • Adenoviridae Arenaviridae
  • Arteriviridae Astroviridae
  • Birnaviridae Birnaviridae
  • Bunyaviridae Caliciviridae
  • Zaire ebolavirus is one of five known species (Bundibugyo ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, and Reston ebolavirus) within the genus Ebolavirus. With the exception of Reston ebolavirus, the other four known ebolaviruses can infect humans and cause a severe and often fatal hemorrhagic fever known as Ebola virus disease (EVD). In some embodiments the viral infection is caused by one ebolavirus.
  • compositions/Formulations [00295]
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds of this WSGR Docket No. 41223-754.601 invention may be administered to animals.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.
  • pharmaceutical compositions comprising a compound describe herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharm aceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular
  • intranasal e.g., buccal
  • topical e.g., buccal
  • rectal e.g., transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee -making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
  • Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee WSGR Docket No. 41223-754.601 cores.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • compositions for parental use are formulated as infusions or injections.
  • the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the pharmaceutical composition comprises a liquid carrier.
  • the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontox ic glyceryl esters, and any combinations thereof.
  • the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.
  • composition refers to a composition comprising a therapeutically effective compound and a pharmaceutically acceptable carrier and optionally, other materials, e.g., one or more inert components (for example, a detectable agent or label) or one or more active components.
  • the pharmaceutical composition facilitates administration of the therapeutically effective compound to a subject.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle in which the pharmaceutical composition is administered.
  • Pharmaceutically acceptable carriers may include one or more solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • Compositions can include components such as diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, or mixtures thereof.
  • pharmaceutically acceptable carriers include but are not limited to water, saline, phosphate buffered saline, aqueous dextrose solutions, glycerol solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, dextrose, gelatin, mannitol, cellulose malt, rice, flour, chalk, silica gel, sodium stearate, glycerol WSGR Docket No.
  • Carriers may also encompass a buffer or pH adjusting agent such as a salt prepared from an organic acid or base optionally mixed with a nontoxic surfactant.
  • buffers include but are not limited to organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, and phosphate buffers.
  • Additional carriers may include polymeric excipients or additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-.quadrature.- cyclodextrin), polyethylene glycols, flavoring agents such as cherry or wintergreen flavor, antimicrobial agents, sweeteners, antioxidants, antistatic agents.
  • the compositions may include a pharmaceutical carrier or excipient and a compound disclosed herein, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, binding agents etc.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • compositions can take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, solutions, suspensions, emulsion, aerosols, gels, implants, microneedles, tablets, pills, capsules, soft elastic or hard gelatin capsules, dermal patch, gummy bears, powders, suspensions, extended-release formulations, and the like, for example, in unit dosage forms suitable for simple administration of precise dosages.
  • the composition takes the forms of tablets, capsules, liquid caps, sublingual dissolving tablets, sublingual spray, nasal spray, gummy bear and/or dermal patch.
  • the composition is a liquid-based formulation including but not limited to an emulsion, suspension, solution, elixirs, or syrup in which the disclosed compound is dissolved and/or suspended, or in the form of a liquid-containing capsule in which the disclosed compound is dissolved and/or suspended in the liquid portion of the capsule core.
  • the composition may be a capsule filled with an effective therapeutic amount of the liquid pharmaceutical formulation.
  • the compound disclosed herein in combination with additional therapeutic agents useful for treating a coronavirus infection are administered simultaneously. In some embodiments, the compound disclosed herein in combination with additional therapeutic agents useful for treating a coronavirus infection are administered sequentially.
  • WSGR Docket No. 41223-754.601 the additional therapeutic agent is also active against Arenaviridae virus infections, particularly including Lassa and Junin virus, coronavirus infection and Junin virus infections.
  • Non-limiting examples of additional therapeutic agents include ribavirin, favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, and mixtures thereof.
  • the compounds and compositions of the present disclosure are also intended for use with general care provided to patients with Arenaviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen, corticosteroids, kinase inhibitors or monoclonal antibodies targeting cytokines and other immunomodulatory signaling or checkpoint ligands/receptors), pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including artemether and artesunate-lumefantrine combination therapy), typho
  • the additional therapeutic agent is an influenza antiviral agent (oseltamivir, zanamivir, baloxavir marboxil). In some embodiments, the additional therapeutic agent is an RSV antiviral agent (palivizumab). In some embodiments, the additional therapeutic agent is a monoclonal antibody cocktail. In some embodiments, the additional therapeutic agent is a monoclonal antibody cocktail for Ebolavirus disease (atoltivimab/maftivimab/odesivimab, Ebanga TM ). In some embodiments, the additional therapeutic agent is a steroid.
  • the additional therapeutic agent is a ribonucleic acid (RNA)-dependent RNA polymerase inhibitor, a checkpoint inhibitor or PD-1/PD-L1 inhibitor, a therapeutic vaccine, an RNA interference (RNAi) therapeutic, an antisense-based therapeutic, an coronavirus entry inhibitor, a TLR agonist, an RIG-I agonist, or an interferon.
  • RNA ribonucleic acid
  • RNAi RNA interference
  • antisense-based therapeutic an coronavirus entry inhibitor
  • TLR agonist a TLR agonist
  • RIG-I agonist RIG-I agonist
  • Co-administration of a compound of the disclosure with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the disclosure and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound WSGR Docket No. 41223-754.601 of the disclosure and one or more other active therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds of the disclosure before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the disclosure within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
  • a unit dose of a compound of the disclosure can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
  • a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the disclosure within seconds or minutes.
  • the combination therapy may provide “synergy” and “synergistic”, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co - formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • synergistic effect When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills, or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • a synergistic antiviral effect denotes an inhibitory activity that is greater than predicted additive activity of the individual compounds acting alone..
  • TLR Agonists TLR7, 8 and/or 9
  • TLR7, 8 and/or 9 TLR7, 8 and/or 9
  • the TLR agonist is RG7795, GS-9620, SM360320, or AZD 8848.
  • RIG-I agonists RIG-I agonists
  • the compound described herein is used in combination with a RIG-I agonist.
  • the RIG-I agonist is inarigivir.
  • Interferons [00323] In some embodiments, the compound described herein is used in combination with an interferon.
  • the interferon is interferon alpha (IFN-a), interferon alpha-2a, WSGR Docket No. 41223-754.601 recombinant interferon alpha-2a, peginterferon alpha-2a, interferon alpha-2b, recombinant interferon alpha- 2b, interferon alpha-2b XL, peginterferon alpha-2b, glycosylated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta- la, peginterferon beta- la, interferon delta, interferon lambda (IFN-l), peginterferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-g), interferon alfacon-l, interferon alpha-nl, interferon alpha-n3, albinterferon alpha-2b, BLX-8
  • the compound described herein is used in combination with an antiviral agent.
  • the antiviral agent is abacavir, acyclovir, adefovir, brivudine, cidofovir, didanosine, edoxudine, emtricitabine, entecavir, famciclovir, favipiravir, ganciclovir, idoxuridine, lamivudine, molnupiravir, nirmatrelvir, penciclovir, remdesivir, ribavirin, sofosbuvir, ST-193, stavudine, T-705 diphosphate,T-705 monophosphate, T-705 triphosphate, telbivudine, tenofovir alafenamide, tenofovir disoproxil, trifluridine, valaciclovir, valganciclovir,
  • the antiviral agent is molnupiravir. In some embodiments, the antiviral agent is nirmatrelvir/ritonavir.
  • Monoclonal antibodies [00325] In some embodiments, the compound described herein is used in combination with a monoclonal antibody. In some embodiments, the monoclonal antibody is bamlanivimab, REGEN-COV (casirivimab and imdevimab, administered together), bamlanivimab and etesevimab (administered together), sotrovimab, or tocilizumab.
  • the compound described herein is used in combination with a Guanosine Nucleotide Analog.
  • the Guanosine Nucleotide Analog is AT-527.
  • the compound described herein is used in combination with a protease inhibitor.
  • the protease inhibitor is nirmatrelvir, ritonavir, or a combination thereof.
  • contemplated drying agents include all those reported in the literature and known to one of skill, such as, but not limited to, magnesium sulfate, sodium sulfate, calcium sulfate, calcium chloride, potassium chloride, potassium hydroxide, sulfuric acid, quicklime, phosphorous pentoxide, potassium carbonate, sodium, silica gel, aluminum oxide, calcium hydride, lithium aluminum hydride (LAH), potassium hydroxide, and the like.
  • magnesium sulfate sodium sulfate, calcium sulfate, calcium chloride, potassium chloride, potassium hydroxide, sulfuric acid, quicklime, phosphorous pentoxide, potassium carbonate, sodium, silica gel, aluminum oxide, calcium hydride, lithium aluminum hydride (LAH), potassium hydroxide, and the like.
  • the amount of drying agent to add in each work up may be optimized by one of skill in the art and is not particularly limited. Further, although general guidance is provided for work-up of the intermediates in each step, it is generally understood by one of skill that other optional solvents and reagents may be equally substituted during the work-up steps. However, in some exceptional instances, it was found the very specific work-up conditions are required to maintain an unstable intermediate. Those instances are indicated below in the steps in which they occur. [00330] Many of the steps below indicate various work-ups following termination of the reaction. A work-up involves generally quenching of a reaction to terminate any remaining catalytic activity and starting reagents.
  • purification steps which may include, but is not limited to, flash column chromatography, filtration through various media and/or other preparative methods known in the art.
  • purification steps may include, but is not limited to, flash column chromatography, filtration through various media and/or other preparative methods known in the art.
  • organic co-solvents and quenching agents may be indicated in the steps described below, other equivalent organic solvents and quenching agents known to one of skill may be employed equally as well and are fully contemplated herein.
  • most of the work -ups in most steps may be further altered according to preference and desired end use or end product.
  • the number of extractions with organic solvent may be as many as one, two, three, four, five, or ten or more, depending on the desired result and scale of reaction. Except where specifically noted, the volume, amount of quenching agent, and volume of organic solvents used in WSGR Docket No. 41223-754.601 the work-up may be varied depending on specific reaction conditions and optimized to yield the best results. [00331] Additionally, where inert gas or noble gas is indicated, any inert gas commonly used in the art may be substituted for the indicated inert gas, such as argon, nitrogen, helium, neon, etc.
  • Step 3 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (1.4).
  • 2-methoxy-2-methylpropanoic acid 70.0 mg, 0.593 mmol
  • THF 40 mL
  • HATU 120 mg, 0.889 mmol
  • Step 1 Synthesis of (2R,3R,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((trimethylsilyl)oxy)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (3.1) [00340] To a solution of compound 1.3 (100 mg, 0.163 mmol) and pyridine (0.16 mL, 1.95 mmol) in DCM (1 mL) was added TMSCl (53.0 mg, 0.488 mmol) at 0 °C, the mixture was stirred at 20 °C for 1 h.
  • Step 2 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (3)
  • the title compound was prepared according to the procedure of Example 1, Step 4, using 3.1.
  • Step 1 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (4.1).
  • the title compound was prepared according to the procedure of Example 1, Step 3, using 1.3 and 2-ethoxy-2-methylpropanoic acid.
  • Step 2 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (4).
  • the title compound was prepared from compound 4.1. according to the procedure of Example 1, Step 4.
  • Step 1 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(3- isopropylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L- valinate (6.1).
  • Step 2 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(3- isopropylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (6).
  • the title compound was prepared from compound 6.1 according to the procedure of Example 1, Step 4.
  • Step 1 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-((R)-2- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L- valinate (9.1).
  • the title compound was prepared from compound 1.3 according to the procedure of Example 1, Step 3, using (R)-2-methylbutanoic acid.
  • Step 2 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-((R)-2- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (9).
  • the title compound was prepared from carbamate 9.1 according to the procedure of Example 1, Step 4.
  • Step 3 Synthesis of (6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-8-(4-pentanamidopyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-cyclohexylacetate (16.4).
  • Step 1 Synthesis of (6aR,8R,9R,9aR)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-8-cyano-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-methoxy-2- methylpropanoate (17.1). [00366] The title compound 17.1 was prepared from compound 16.2 according to the procedure of Example 16, Step 2, using 2-methoxy-2-methylpropanoic acid. MS (ESI): mass calcd.
  • Step 2 Synthesis of (6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-8-(4-pentanamidopyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-methoxy-2- methylpropanoate (17.2) [00367] The title compound 17.2 was prepared from compound 17.1 according to the procedure of Example 16, Step 3, using pentanoyl chloride. MS (ESI): mass calcd.
  • Step 3 Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-methoxy-2-methylpropanoate (17). [00368] The title compound 17 was prepared from compound 17.2 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C 22 H 29 N 5 O 7 , 475.21, found 476.10 [M+H] + .
  • Example 23 Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(3,3- diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (23).
  • Step 1 Synthesis of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (23.1).
  • Example 28 Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (28).
  • Step 1 Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (28.1).
  • Compound 34.1 was prepared according to the procedure of Example 1, Steps 1 and 2, using 2-cyclobutylacetyl chloride in place of cyclohexylacetyl chloride and using (tert-butoxycarbonyl)-D- valine in place of (tert-butoxycarbonyl)-L-valine.
  • Compound 34.1 was converted to the title compound 34.2 using the procedure of Example 1, Step 3.
  • Example 48 Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (48).
  • Example 49 Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(3- isopropylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (49).
  • reaction mixture was then lyophilized overnight to afford a residue which was purif ied by prep-HPLC (column: Gemini - C18150 ⁇ 21.2 mm, 5um; mobile phase: ACN in 20 mM TEAB; gradient: 0-15%) twice, and subsequently purified via ion column (column: HiPrepTM Q FF 16/10; mobile phase: water in 1M TEAB; gradient: 0-70%) to obtain the total compound 51 (13.81 mg, 0.0224 mmol, 18.7% yield, tris- triethylaminmonium salt) as a white solid.
  • Step 3 Synthesis of ((2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (54).
  • Compound 54 was prepared according to the procedure of Example 49, Step 2, using 54.2.- MS (ESI): mass calcd.
  • Tablet Formulation Ingredient Quantity per tablet (mg) compound 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 [00443] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Capsule Formulation Ingredient Quantity per capsule (mg) compound 200 lactose spray dried 148 magnesium stearate 2 EXAMPLE II: Evaluation of cellular permeability in Caco-2 cell monolayers. [00444] The bidirectional permeability of compounds across the Caco-2 cell monolayer was assessed. The Caco-2 model is a widely used in vitro model for small intestinal absorption and potential for efflux. [00445] Cell culture.
  • Caco-2 cells were grown in DMEM supplemented with 10% fetal bovine serum (FBS), 1% Penicillin-Streptomycin and 1% MEM NEAA. The cells were incubated at 37 °C, 5% CO 2 /95% air and saturated humidity. After reaching 80-90% confluency, the cells were gently detached with trypsin. Cells at passage 39 were seeded on the 24-well BD insert system at the density of 8 ⁇ 104 cells/cm 2 and cultured for 19 days with medium changed every 2-3 days. Measure the transepithelial electrical resistance (TEER) value of each well. The wells can be used only when their TEER values are greater than 600 Ohms/cm 2 . [00446] Transport assay.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin 1% MEM NEAA
  • the cells were rinsed with warm transport buffer.
  • Appropriate dosing and receiving solutions were applied to the donor and receiver chambers to initiate the transport assay in apical to basolateral (A to B) or basolateral to apical (B to A) directions (500 and 1300 ⁇ L for apical and basolateral wells, respectively).
  • Duplicate wells in each direction were used for the test compound and control compound.
  • the plate was incubated in CO 2 incubator at 37 °C, with 5% CO 2 /95% air and saturated humidity without shaking. The sample after 10-minute incubation was used as the T 0 sample, and the sample after 90-minute incubation was used as the T90 sample.
  • T0 and T90 samples were collected from the donor and receiver side of each well at the designed timepoint, mixed with the transport buffer and acetonitrile/MeOH (1:1, v/v) and the internal standard for LC/MS/MS analysis. All samples were vortexed and centrifuged at 4000 rpm at 4 °C for 15 minutes, diluted with pure water and stored at 4 °C before bioanalysis by LC/MS/MS. WSGR Docket No. 41223-754.601 [00447] Sample analysis. The concentrations of test compounds and control compounds in Caco-2 cells were quantitatively determined by LC/MS/MS method after protein precipitation. [00448] Calculations.
  • V R is the solution volume in the receiver chamber (0.4 mL on the apical side, 1.2 mL on the basolateral side); Area is the surface area for the insert membrane, i.e., 0.3 cm 2 for the area of the monolayer; Time is incubation time, expressed in seconds, i.e., 5400 s (90 min) for the current experiment; C 0 is the initial concentration of test compound or peak area ratio of control compounds in the donor chamber ( ⁇ M); V D is the volume in the donor chambers (0.4 mL on the apical side, 1.2 mL on the basolateral side); C D and C R are the final concentrations of test compounds or peak area ratio of control compounds in donor and receiver chambers, respectively.
  • Compounds are dosed as solutions or acceptable suspensions in vehicles generally-regarded as safe for in vivo studies. Groups of three rats per compound are utilized, and blood samples collected at 0.25, 0.5, 1, 2, 4, 8 and 24 h post-dose, stored on ice prior to plasma preparation by centrifugation at 4 °C at 6000 rpm for 5 min. Plasma samples are stored at -80 °C. Concentrations of Example Compounds and corresponding nucleosides resulting from metabolic processing are determined using ultra-high performance liquid chromatography-triple-quadrupole mass spectrometry, with an internal standard.
  • Pharmacokinetic parameters are derived from the resulting plasma concentration/time graphs, and include the following: plasma half-life (t 1/2 ), time to maximum plasma concentration (T max ), maximum plasma concentration (C max ), area under the curve of the plasma concentration/time graph (AUC last , through last timepoint obtained, and AUC Inf , including the extrapolated area), and mean residence time (MRT Inf ).
  • the resulting AUC Inf for the resulting nucleosides are compared with that resulting from intravenous bolus administration of the corresponding nucleosides in three rats, and an oral bioavailability (F, %) was be calculated as AUCinf, PO ⁇ ⁇ ⁇ ⁇ ( ⁇ ⁇ ) ⁇ ⁇ ( ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ) ⁇ ⁇ AUCinf, IV ⁇ ⁇ ⁇ ⁇ ( ⁇ ⁇ ) ⁇ ⁇ ( ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ) WSGR Docket No. 41223-754.601 [00451] Table 3 contains certain pharmacokinetic parameters obtained in rats for compounds of the invention.
  • the compounds were dosed by oral gavage (using 10% ethanol/90% propylene glycol as vehicle).
  • the compounds of the present invention provided higher plasma exposures of the parent nucleoside than via dosing of the nucleoside itself, demonstrating that the potential to deliver higher concentrations of the nucleoside using the prodrugs of the invention. Table 3.
  • EXAMPLE IV Evaluation of stability of example compounds in human fasted-state simulated gastric fluid, and fasted-state simulated intestinal fluid. [00452] The chemical stability of example compounds was determined using human fasted -state simulated gastric fluid, and fasted-state simulated intestinal fluid, prepared as follows.
  • FaSSGF • Weigh 1.0 g NaCl and dissolved it in 0.49 L water • Adjust pH value to 1.2, and adjust volume to 0.5 L in water • Filter the NaCl/HCl buffer through a 0.22 ⁇ m filter • Weigh 3.0 mg FaSSGF powder (Vendor: Biorelevant, catalog # FFF01), dissolve it in 50 mL NaCl/HCl buffer • Dissolve the FaSSGF powder in NaCl/HCl buffer and make up the volume to 50 mL • Store at 4 °C for future use.
  • FaSSIF • Weigh 0.695 g NaOH, 1.115 g maleic acid and 2.005 g NaCl, and dissolve in 0.49 L water WSGR Docket No.
  • test compounds were prepared as 50 ⁇ M working solutions in DMSO, and 2 ⁇ L test compound working solution was added to 98 ⁇ L of each buffer respectively in six tubes (for six timepoints, 0, 5, 15, 30, 60, and 120 min) and gently mixed.
  • EXAMPLE V Evaluation of SARS-CoV-2 RNA-dependent RNA polymerase inhibitory activity of nucleoside triphosphate derivatives.
  • the ability of selected amide-derivatized nucleoside triphosphates to inhibit the SARS-CoV-2 RNA-dependent RNA polymerase was assessed in a commercially-available biochemical assay (performed by BPS Bioscience Inc., 6405 Mira Mesa Blvd., Ste. 100, San Diego, CA 92121, USA). Enzymes and Substrates WSGR Docket No.
  • the RdRp reactions were conducted in duplicate at 37 °C for 60 min in a 10 ⁇ L mixture containing assay buffer, RNA duplex, ATP substrate and enzyme, and the test compound. These 10 ⁇ L reactions were carried out in wells of 384-well white plate (Nunc). Dilutions of the test compounds were prepared in assay buffer (5% DMSO concentration) and 2 ⁇ L of the dilution was added to a 6 ⁇ L of RdRp containing RNAse inhibitor for preincubation (30 minutes at room temperature with slow shaking). Reaction was started by addition of 2 ⁇ L of the substrate mix containing RNA duplex and ATP substrate.
  • the intensity (Ce) in each data set was defined as 100 % activity.
  • the intensity (C 0 ) in each data set was defined as 0 % activity.
  • the IC 50 value was determined as the concentration causing half-maximal percent activity.
  • Table 5 summarizes the results for select exemplary triphosphate analogs, plus negative control GS-441524 (parent nucleoside analog), and positive control compounds GS-443902 (Mackman, RL, et al, J Med Chem 2023, 66 (17), 11701-11717; DOI: 10.1021/acs.jmedchem.3c00750) and 6-chloropurine- ribose-5'-triphosphate.

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Abstract

L'invention concerne des analogues nucléosidiques biodisponibles par voie orale et des compositions pharmaceutiques contenant lesdits composés. Les composés et compositions de l'invention sont utiles pour le traitement d'infections à coronavirus, y compris une infection par le SARS-CoV-2.
PCT/US2023/084006 2022-12-14 2023-12-14 Analogues nucléosidiques biodisponibles par voie orale Ceased WO2024129963A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041203A2 (fr) * 2002-11-04 2004-05-21 Xenoport, Inc. Promedicaments de gemcitabine, leurs compositions pharmaceutiques et leurs utilisations
WO2021213288A1 (fr) * 2020-04-20 2021-10-28 中国科学院上海药物研究所 Utilisation pour application antivirale d'un analogue nucléosidique ou d'une formulation combinée contenant un analogue nucléosidique
WO2022142477A1 (fr) * 2020-12-30 2022-07-07 Southern University Of Science And Technology Méthodes et nucléosides modifiés pour le traitement d'infections à coronavirus
WO2023196458A1 (fr) * 2022-04-06 2023-10-12 VenatoRx Pharmaceuticals, Inc. Analogues nucléosidiques biodisponibles par voie orale

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041203A2 (fr) * 2002-11-04 2004-05-21 Xenoport, Inc. Promedicaments de gemcitabine, leurs compositions pharmaceutiques et leurs utilisations
WO2021213288A1 (fr) * 2020-04-20 2021-10-28 中国科学院上海药物研究所 Utilisation pour application antivirale d'un analogue nucléosidique ou d'une formulation combinée contenant un analogue nucléosidique
WO2022142477A1 (fr) * 2020-12-30 2022-07-07 Southern University Of Science And Technology Méthodes et nucléosides modifiés pour le traitement d'infections à coronavirus
WO2023196458A1 (fr) * 2022-04-06 2023-10-12 VenatoRx Pharmaceuticals, Inc. Analogues nucléosidiques biodisponibles par voie orale

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Title
ZHEN LE, DAI LIANG, WEN XIAOAN, YAO LAN, JIN XIAOLIANG, YANG XIAO-WEN, ZHAO WENFENG, YU SHENG-QI, YUAN HAOLIANG, WANG GUANGJI, SUN: "Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 60, no. 14, 27 July 2017 (2017-07-27), US , pages 6077 - 6088, XP093184946, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b00262 *

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