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WO2024102989A1 - Non-peptidic sars-cov-2 main protease inhibitors - Google Patents

Non-peptidic sars-cov-2 main protease inhibitors Download PDF

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Publication number
WO2024102989A1
WO2024102989A1 PCT/US2023/079356 US2023079356W WO2024102989A1 WO 2024102989 A1 WO2024102989 A1 WO 2024102989A1 US 2023079356 W US2023079356 W US 2023079356W WO 2024102989 A1 WO2024102989 A1 WO 2024102989A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkyl
optionally substituted
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PCT/US2023/079356
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French (fr)
Inventor
Wenshe Ray LIU
Shiqing Xu
Yugendar Reddy ALUGUBELLI
Veerabhardra Reddy VULUPALA
Sandeep Atla
Kaustav KHATUA
Zhi GENG
Lauren BLANKENSHIP
Peng-Hsun CHEN
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The Texas A&M University System
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Publication of WO2024102989A1 publication Critical patent/WO2024102989A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present disclosure relates to certain molecules, pharmaceutical compositions containing them, and methods of using them to treat viral infections.
  • Coronaviruses are a group of related RNA viruses that cause diseases in a wide range of vertebrates including humans and domestic animals.
  • CoVs coronviruses
  • HCoV-229E and HCoV-OC43 known as human pathogens.
  • SARS-CoV-1 a pathogen causing a severe respiratory infection.
  • SARS-CoV-1 a pathogen causing a severe respiratory infection.
  • SARS-CoV-NL63 and HCoV-HKUl Two additional human CoVs, HCoV-NL63 and HCoV-HKUl, that are mildly pathogenic.
  • MERS-CoV MERS-CoV that emerged in 2012 as a pathogen causing a severe respiratory infection.
  • SARS-CoV-1 and MERS-CoV are highly lethal pathogens, the public health, social, and economic damages that they have caused are diminutive in comparison to that from SARS-CoV- 2, a newly emerged human CoV pathogen that causes COVID-19. Rival only to the 1918 influenza pandemic, the COVID-19 pandemic has led to catastrophic impacts worldwide.
  • MPro SARS-CoV-2 main protease
  • nsps are essential for the virus to replicate its genome in host cells, evade the host immune system, and package new virions for the infection of new host cells.
  • Intervention of the proteolytic hydrolysis of ppla and pplab is a viable approach to stop SARS-CoV-2 infection.
  • MPro the other papain-like protease
  • MPro processes the majority of nsps. It is also more conserved than PLPro.
  • MPro genes in SARS-CoV and SARS-CoV-2 share 96% sequence identity.
  • Targeting MPro for drug discovery has been demonstrated as a successful route for the development of SARS-CoV-2 antivirals by the U.S. FDA approval of the use of Pfizer PAXLOVID for the treatment COVID-19. Therefore, small molecule medicines that inhibit SARS-CoV-2 M Pro (SC2M Pro ) are potentially effective treatment options for COVID-19.
  • SARS-CoV-2 M Pro small molecule medicines that inhibit SARS-CoV-2 M Pro
  • a series of new small molecules as potent SARS-CoV-2 MPro inhibitors were designed and synthesized.
  • these small molecules also showed promising antiviral activities against SARS-CoV-2, and many of the small molecules demonstrated superior antiviral activities in a head-to-head comparison with the FDA-approved COVID-19 drug PAXLOVID and nirmatrelvir. Although some treatment options are available, there is a continual need to develop small molecule medicines with improved efficacy and fewer side effects.
  • the disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein [008] Ar is C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein each hydrogen atom in C 6 -C 10 aryl or 5-10 membered heteroaryl is independently optionally substituted by an R a ; [009] X is H, deuterium, C 6 -C 10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C 1 -C 6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C 1 -C 6 alkyl-5-10 membered heteroaryl, -NR 1 C(O)R 2 , -OC(O)R 2 , -NR 1 C(O)C 1 -C 6 alkyl-R 2 , or -OC
  • the disclosure provides compounds of the formula [018] or a pharmaceutically acceptable salt thereof, wherein X, W, and R a are as defined herein, and n is 0, 1, 2, or 3.
  • the disclosure provides compounds of the formula [020] or a pharmaceutically acceptable salt thereof, wherein X and Ar are as defined herein.
  • X is H, deuterium, C 6 -C 10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C 1 -C 6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C 1 -C 6 alkyl-5-10 membered heteroaryl, -NR 1 C(O)R 2 , -OC(O)R 2 , -NR 1 C(O)C 1 -C 6 alkyl-R 2 , or -OC(O)C 1 -C 6 alkyl-R 2 , wherein each hydrogen atom in C
  • R 2 is C 1 -C 6 alkyl, 3-10 membered heterocyclyl, or C 6 -C 10 aryl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by an R 3 , and wherein each hydrogen atom in 3-10 membered heterocyclyl and C 6 -C 10 aryl is independently optionally substituted by an R b .
  • R 3 is independently optionally substituted by an R 3
  • R b is independently optionally substituted by an R b .
  • a pharmaceutical composition comprising at least one compound of any one of clauses 1-49, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • a method of treating disease, such as a viral infection comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1-49, or a pharmaceutically acceptable salt thereof.
  • alkyl includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms.
  • alkyl may be advantageously of limited length, including C 1 -C 12 , C 1 -C 10 , C 1 -C 9 , C 1 -C 8 , C 1 -C 7 , C 1 -C 6 , and C 1 -C 4 .
  • such particularly limited length alkyl groups including C 1 -C 8 , C 1 -C 7 , C 1 -C 6 , and C 1 -C 4 , and the like may be referred to as “lower alkyl.”
  • Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and
  • Alkyl may be substituted or unsubstituted.
  • alkyl may be combined with other groups, such as those provided above, to form a functionalized alkyl.
  • the combination of an “alkyl” group, as described herein, with a “carboxy” group may be referred to as a “carboxyalkyl” group.
  • Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.
  • alkenyl may be advantageously of limited length, including C 2 -C 12 , C 2 -C 9 , C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 .
  • alkenyl groups including C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 may be referred to as lower alkenyl.
  • Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • alkynyl includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e., C ⁇ C).
  • alkynyl may each be advantageously of limited length, including C 2 -C 12 , C 2 -C 9 , C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 .
  • such particularly limited length alkynyl groups including C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 may be referred to as lower alkynyl.
  • Alkynyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. It will be understood that in certain embodiments, aryl may be advantageously of limited size such as C 6 - C 10 aryl.
  • Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl and anthracenyl.
  • cycloalkyl refers to a 3 to 15 member all-carbon monocyclic ring, including an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group, or a carbocyclic ring that is fused to another group such as a heterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to 7- membered heterocyclic ring, where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system.
  • cycloalkyl may be advantageously of limited size such as C 3 -C 12 , C 3 -C 9 , C 3 -C 8 , C 3 -C 6 and C 4 -C 6 .
  • Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like.
  • cycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties: [086]
  • the terms “heterocycloalkyl”, “heterocyclyl”, or “heterocycle” refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms.
  • Heterocycloalkyl may optionally contain 1, 2, 3 or 4 heteroatoms.
  • a heterocycloalkyl group may be fused to another group such as another heterocycloalkyl, an aryl, or a heteroaryl group.
  • heterocycloalkyl may be advantageously of limited size such as 3- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or 6-membered heterocycloalkyl, and the like.
  • Heterocycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl, and the like.
  • heterocycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties: [087]
  • the heterocycyl group may be chromane, benzooxazinyl, or benzomorpholinyl.
  • Illustrative examples of heterocycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties: , , [089]
  • aryl refers to a monocyclic or fused ring group of 5 to 10 ring atoms, and also having a completely conjugated pi-electron system.
  • aryl may be advantageously of limited size such as 6- to 10-membered aryl and the like.
  • Aryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative aryl groups include, but are not limited to, phenyl and naphthyl.
  • heteroaryl refers to a monocyclic or fused ring group of 5 to 10 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system.
  • heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, 5- to 10-membered heteroaryl and the like.
  • Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • an atom exo to the heteroaryl ring atoms such as an amino or a hydroxyl group, may contribute to the pi-electron system.
  • tautomeric hydroxyl-pyrazole contains an -OH group, wherein the exo oxygen contributes to the pi-electron system, illustrated in the tautomeric pyrazolone configuration.
  • Illustrative heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benz
  • heteroaryl groups shown in graphical representations include the following entities, in the form of properly bonded moieties: [092]
  • the heteroaryl group may be [093]
  • “tautomer” refers each of two or more isomers of a compound which exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule.
  • a tautomer can be the isomers of pyrazolone and hydroxyl- pyrazole, such as [094]
  • “hydroxy” or “hydroxyl” refers to an -OH group.
  • alkoxy refers to both an -O-(alkyl) or an -O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • halo or “halogen” refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to a -CN group.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • a hydroxy substituted compound may exist as an oxo substituted tautomer, such as hydroxy-pyrazole and pyrazolone.
  • two substiutents may come together on the carbon to which they are attached to form an oxo.
  • a hydroxy-substituted pyrazole may be represented as an oxo tautomer, such as
  • a hydroxy-substituted quinoline may be represented as an oxo tautomer, such as .
  • “bond” refers to a covalent bond.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • substitution is meant to occur at any valency-allowed position on the system.
  • substituted means that the specified group or moiety bears one or more substituents. It will be understood that in certain embodiments, substitutions may be advantageously limited in number. In some embodiments, “substituted” means that the specified group or moiety bears one to five substituents.
  • substituted means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent. [0101] As used herein, “optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by C 1 -C 6 alkyl
  • an alkyl may be but need not be present on any of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or mono- or bicyclic heteroaryl by replacement of a hydrogen atom for each alkyl group, and the description includes situations where the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C
  • independently means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances.
  • the use of “independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different.
  • the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.
  • the phrase “taken together with the atoms to which they are attached” or “combine together with the atom to which they are attached” means that two substituents (e.g., two independent R b groups) attached to two separate atoms or attached to the same atom form the groups that are defined by the claim, such as .
  • the phrase “combine together with the atoms to which they are attached” means , for example, two independent R b groups on different ring atoms of such as carbon atom “1” and carbon atom “2” respectively as shown in the structure below form a ring with those ring atoms.
  • the phrase “or two R b taken together with the carbon atoms to which they are attached combine to form a fused C 6 -C 10 aryl ring, wherein each hydrogen atom in C 6 -C 10 aryl is independently optionally substituted with an R e ” used in connection with the embodiments described herein includes the compound represented as follows: .
  • the term “pharmaceutically acceptable salt” refers to those salts which counter ions which may be used in pharmaceuticals. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Such salts include: [0106] (1) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or [0107] (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N
  • compositions are well known to those skilled in the art, and any such pharmaceutically acceptable salt may be contemplated in connection with the embodiments described herein.
  • pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenz
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula I, and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula I).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject.
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula I, and uses of such metabolites in the methods of the disclosure.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula I, or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof.
  • any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • compounds depicted by a structural formula containing the symbol include both stereoisomers for the carbon atom to which the symbol is attached, specifically both the bonds are encompassed by the meaning of [0113]
  • Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • isotope-labeled compounds and salts can be used as medicaments.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • deuterium ( 2 H)-labeled compounds and salts may be therapeutically useful with potential therapeutic advantages over the non- 2 H-labeled compounds.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. [0114] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • compounds described herein comprise a moiety of the Formula I [0116] or a pharmaceutically acceptable salt thereof, wherein Ar, X, and W are as defined herein.
  • compounds described herein comprise the formula [0118] or a pharmaceutically acceptable salt thereof, wherein X, W, and R a are as defined herein, and n is 0, 1, 2, or 3.
  • the disclosure provides compounds of the formula [0120] or a pharmaceutically acceptable salt thereof, wherein X and Ar are as defined herein.
  • Ar is C 6 -C 10 aryl, wherein each hydrogen atom in C 6 -C 10 aryl is independently optionally substituted by an R a .
  • Ar is 5-10 membered heteroaryl, wherein each hydrogen atom 5-10 membered heteroaryl is independently optionally substituted by an R a .
  • Ar is a 5 membered heteroaryl. In some embodiments, Ar is a 6 membered heteroaryl. In some embodiments, Ar is a 7 membered heteroaryl. In some embodiments, Ar is an 8 membered heteroaryl. In some embodiments, Ar is a 9 membered heteroaryl. In some embodiments, Ar is a 10 membered heteroaryl. In some embodiments, Ar is pyridine, isoquinoline, quinoline, benzotriazole, benzoimidazole, or naphthyridine. In some embodiments, Ar is pyridine. In some embodiments, Ar is is isoquinoline. In some embodiments, Ar is benzotriazole.
  • Ar is selected from wherein n is 0, 1, or 2. In certain preferred embodiments, Ar is , wherein n is 0 or 1. [0123] In some embodiments, Ar is selected from wherein n is 0, 1, or 2. In some embodiments, Ar is selected from and wherein n is 0, 1, or 2. [0124] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In certain preferred embodiments, n is 0 or 1. [0125] In some embodiments, each R a , is independently deuterium, halo, -OH, -NR 5 R 6 , C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.
  • each R a when present, is independently halo. In some embodiments, each R a , when present, is independently -OH. For example, if R a is –OH on a heteroaryl, the —OH substituted heteroaryl may be represented as an oxo tautomer. In some embodiments, each R a , when present, is independently chloro.
  • R a is chloro and Ar is In some embodiments, R a is -OH and Ar is In some embodiments, Ar is selected from , , In some embodiments, Ar is selected from In certain preferred embodiments, Ar is [0127] In some embodiments, X is H, deuterium, C 6 -C 10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C 1 -C 6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C 1 -C 6 alkyl-5-10 membered heteroaryl, -NR 1 C(O)R 2 , -OC(O)R 2 , -NR 1 C(O)C 1 -C 6 alkyl-R 2 , or -OC(O)C 1 -C 6 alkyl-R 2 , wherein each hydrogen atom in C 1 -C
  • X is H, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -NR 1 C(O)R 2 , -OC(O)R 2 , or -NR 1 C(O)C 1 -C 6 alkyl-R 2 , wherein each hydrogen atom in C 1 -C 6 alkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted by an R 3 .
  • X is H.
  • X is 3-10 membered heterocyclyl, wherein each hydrogen atom in 3-10 membered heterocyclyl is independently optionally substituted by an R 3 .
  • X is 5-10 membered heteroaryl, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an R 3 .
  • X is -NR 1 C(O)R 2 .
  • X is -NR 1 C(O)C 1 -C 6 alkyl- R 2 , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by an R 3 .
  • X is -NR 1 C(O)CH 2 R 2 .
  • X is -OC(O)R 2 .
  • R 2 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl is independently optionally substituted by an R 3 , and wherein each hydrogen atom in 3-10 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl is independently optionally substituted by an R b .
  • R 2 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by an R 3 .
  • R 2 is C 3 -C 8 cycloalkyl, wherein each hydrogen atom in C 3 -C 8 cycloalkyl is independently optionally substituted by an R 3 .
  • R 2 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by an R 3 .
  • R 2 is methyl.
  • R 2 is ethyl.
  • R 2 is methyl, wherein each hydrogen atom in methyl is independently optionally substituted by an R 3 . In some embodiments, R 2 is methyl, wherein one hydrogen atom in methyl is optionally substituted by an R 3 . In some embodiments, R 2 is methyl, wherein two hydrogen atoms in methyl are independently optionally substituted by an R 3 . In some embodiments, R 2 is methyl, wherein three hydrogen atoms in methyl are independently optionally substituted by an R 3 .
  • R 3 is independently deuterium, halo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an R c .
  • R 3 is independently deuterium, halo, or C 1 -C 6 alkyl.
  • R 3 is independently halo.
  • R 3 is independently fluoro.
  • R 2 is trifluoromethyl.
  • R 2 is 3-10 membered heterocyclyl or C 6 -C 10 aryl, wherein each hydrogen atom in 3-10 membered heterocyclyl or C 6 -C 10 aryl is independently optionally substituted by an R b .
  • R 2 is a 3-10 membered heterocyclyl, wherein each hydrogen atom in the 3-10 membered heterocyclyl is independently optionally substituted by an R b .
  • R 2 is a 3-10 membered heterocyclyl, wherein R 2 is chromane, and wherein each hydrogen atom in chromane is independently optionally substituted by an R b .
  • R 2 is a 3-10 membered heterocyclyl, wherein R 2 is benzomorpholine, and wherein each hydrogen atom in benzomorpholine is independently optionally substituted by an R b .
  • R 2 is a 3-10 membered heterocyclyl, wherein R 2 is chromane, and wherein one hydrogen atom in chromane is substituted by an R b .
  • R 2 is a 3-10 membered heterocyclyl, wherein R 2 is benzomorpholine, and wherein one hydrogen atom in benzomorpholine is substituted by an R b .
  • R 2 is a C 6 -C 10 aryl, wherein R 2 is naphthalene, and wherein each hydrogen atom in naphthalene is independently optionally substituted by an R b .
  • R 2 is a C 6 -C 10 aryl, wherein R 2 is phenyl, and wherein each hydrogen atom in phenyl is independently optionally substituted by an R b .
  • R 2 is a C 6 -C 10 aryl, wherein R 2 is phenyl, and wherein one hydrogen atom in phenyl is substituted by an R b .
  • R 2 is a C 6 -C 10 aryl, wherein R 2 is naphthalene, and wherein one hydrogen atom in naphthalene is substituted by an R b .
  • R 2 is a C 6 -C 10 aryl, wherein R 2 is phenyl, and wherein two hydrogen atoms in phenyl are independently substituted by R b .
  • R 2 is a C 6 -C 10 aryl, wherein R 2 is naphthalene, and wherein two hydrogen atoms in naphthalene are independently substituted by R b .
  • R 2 is pyran, wherein each hydrogen atom in pyran is independently optionally substituted by an R b .
  • R 2 is morpholine, wherein each hydrogen atom in morpholine is independently optionally substituted by an R b .
  • two R b are taken together with the carbon atoms to which they are attached combine to form a fused C 6 -C 10 aryl ring, wherein each hydrogen atom in C 6 -C 10 aryl is independently optionally substituted with an R e .
  • two R b are taken together with the carbon atoms to which they are attached combine to form a fused phenyl ring, wherein each hydrogen atom in phenyl is independently optionally substituted with an R e .
  • two R b are taken together with the carbon atoms to which they are attached combine to form a fused phenyl ring, wherein 1 hydrogen atom in phenyl is substituted with an R e .
  • R b are taken together with the carbon atoms to which they are attached combine to form a fused phenyl ring, wherein 2 hydrogen atoms in phenyl is substituted with an R e .
  • each of R b when present, is independently deuterium, halo, -OH, -NR 5 R 6 , C 1 -C 6 alkoxy, or C 1 -C 6 alkyl, or two R b taken together with the carbon atoms to which they are attached combine to form a fused C 6 -C 10 aryl ring, wherein each hydrogen atom in C 6 - C 10 aryl is independently optionally substituted with an R e .
  • each of R b when present, is independently deuterium, halo, -OH, -NR 5 R 6 , C 1 -C 6 alkoxy, or C 1 -C 6 alkyl. In some embodiments, each of R b , when present, is independently deuterium, halo, or -OH. In some embodiments, each of R b , when present, is independently halo. In some embodiments, R b is independently chloro, fluoro, bromo, or iodo. In some embodiments, R b is chloro.
  • each of R e when present, is independently deuterium, halo, -OH, -NR 5 R 6 , C 1 -C 6 alkoxy, or C 1 -C 6 alkyl. In some embodiments, each of R e , when present, is independently deuterium, halo, or -OH. In some embodiments, each of R e , when present, is independently halo. In some embodiments, R e is independently chloro, fluoro, bromo, or iodo. In some embodiments, R e is chloro. [0140] In some embodiments, R 2 is selected from , wherein p is 0, 1, or 2. [0141] In some embodiments, p is 0.
  • p is 1. In some embodiments, p is 2. [0142] In some embodiments, R 2 is selected from wherein q is 0, 1, or 2. [0143] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. [0144] In some embodiments, each R b , when present, is independently halo. In some embodiments, R b is independently chloro, fluoro, bromo, or iodo. In some embodiments, R b is chloro. [0145] In some embodiments, R 2 is a selected from , wherein p is 0, 1, or 2. [0146] In some embodiments, p is 0. In some embodiments, p is 1.
  • R p is 2.
  • two R b are taken together with the carbon atoms to which they are attached combine to form a fused phenyl ring.
  • R 2 is a selected from , wherein t is 0, 1, or 2.
  • t is 0.
  • t is 1.
  • t is 2.
  • each R e when present, is independently halo.
  • R e is independently chloro, fluoro, bromo, or iodo. In some embodiments, R e is chloro.
  • R 2 is selected from In certain preferred embodiments, R 2 is [0152] In some embodiments, R 2 is a C 1 -C 6 alkyl, wherein each hydrogen atom in the C 1 -C 6 alkyl is independently optionally substituted by an R 3 . In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is methyl and each hydrogen atom in methyl is unsubstituted by an R 3 . In some embodiments, R 2 is methyl and each hydrogen atom in methyl is independently optionally substituted by R 3 . In some embodiments, R 2 is methyl and one hydrogen atom in methyl substituted by an R 3 .
  • each of R 3 is independently deuterium, halo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an R c .
  • R 3 is 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an R c .
  • R 3 is 3-10 membered heterocyclyl, wherein each hydrogen atom in 3-10 membered heterocyclyl is independently optionally substituted by an R c .
  • R 3 is 3-10 membered heterocyclyl, wherein one hydrogen atom in 3-10 membered heterocyclyl is substituted by an R c .
  • R 3 is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is unsubstituted. In some embodiments, R 3 is a 3-10 membered heterocyclyl, wherein R 3 is chromane, and wherein each hydrogen atom in chromane is independently optionally substituted by an R c . In some embodiments, R 3 is a 3-10 membered heterocyclyl, wherein R 3 is benzomorpholine, and wherein each hydrogen atom in benzomorpholine is independently optionally substituted by an R c .
  • each of R c when present, is independently deuterium, halo, -OH, -NR 5 R 6 , C 1 -C 6 alkoxy, or C 1 -C 6 alkyl. In some embodiments, each of R c , when present, is independently deuterium, halo, or -OH. In some embodiments, each of R c , when present, is independently halo. In some embodiments, R c is independently chloro, fluoro, bromo, or iodo. In some embodiments, R c is chloro. [0156] In some embodiments, R 3 is a selected from wherein s is 0, 1, or 2. [0157] n some embodiments, s is 0.
  • s is 1. In some embodiments, s is 2. [0158] In some embodiments, R 3 is [0159] In some embodiments, R 1 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 1 is H. [0160] In some embodiments X is selected from H, In certain preferred embodiments, X is [0161] In some embodiments, X is a 5-10 membered heteroaryl, wherein each hydrogen atom in the 5-10 membered heteroaryl is independently optionally substituted by an R 3 . In some embodiments, X is a 6 membered heteroaryl, wherein each hydrogen atom in the 6 membered heteroaryl is independently optionally substituted by an R 3 .
  • X is a 5 membered heteroaryl, wherein each hydrogen atom in the 5 membered heteroaryl is independently optionally substituted by an R 3 .
  • X is a triazole, wherein each hydrogen atom in triazole is independently optionally substituted by an R 3 .
  • X is an imidazole, wherein each hydrogen atom in imidazole is independently optionally substituted by an R 3 .
  • X is a pyrazolone, wherein each hydrogen atom in pyrazolone is independently optionally substituted by an R 3 .
  • X is a triazole, wherein one hydrogen atom in triazole is substituted by an R 3 .
  • X is an imidazole, wherein one hydrogen atom in imidazole is substituted by an R 3 .
  • X is an pyrazolone, wherein one hydrogen atom in pyrazolone is substituted by an R 3 .
  • each of R 3 is independently deuterium, halo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an R c .
  • R 3 is C 6 -C 10 aryl, wherein each hydrogen atom in C 6 -C 10 aryl is independently optionally substituted by an R c .
  • R 3 is phenyl, wherein each hydrogen atom in phenyl is independently optionally substituted by an R c .
  • R 3 is , wherein s is 0, 1, 2, or 3.
  • s is 1.
  • s is 2.
  • each of R c when present, is independently deuterium, halo, -OH, -NR 5 R 6 , C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.
  • each R c when present, is independently halo or C 1 -C 6 alkoxy. In some embodiments, R c is halo. In some embodiments, R c is chloro, fluoro, bromo, or iodo. In some embodiments, R c is chloro. In some embodiments, R c is C 1 -C 6 alkoxy. In some embodiments, R c is methoxy.
  • R 3 is selected from [0167]
  • X is selected from [0168]
  • X is selected from [0169]
  • W is H, deuterium, -C(O)H, -CN, C 1 -C 6 alkyl-R 4 , C 1 -C 6 alkyl- C(O)R 4 , C(O)R 4 , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium or halo.
  • W is -CN, C 1 -C 6 alkyl-R 4 , C(O)R 4 , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium or halo.
  • W is –CN.
  • W is C 1 -C 6 alkyl-R 4 , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium or halo.
  • W is C 1 -C 6 alkyl-R 4 , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by halo.
  • W is C 1 -C 6 alkyl-R 4 , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by chloro, fluoro, bromo, or iodo. In some embodiments, W is C 1 -C 6 alkyl-R 4 , wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by chloro. In some embodiments, W is C 1 -C 6 alkyl-R 4 , wherein C 1 -C 6 alkyl is methyl. In some embodiments, W is -CHCl-R 4 . [0172] In some embodiments, W is C(O)R 4 .
  • R 4 is independently H, deuterium, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an R d .
  • R 4 is a 5-10 membered heteroaryl, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an R d .
  • R 4 is a benzothiazole, wherein each hydrogen atom in benzothiazole is independently optionally substituted by an R d . In some embodiments, R 4 is a benzooxazole, wherein each hydrogen atom in benzooxazole is independently optionally substituted by an R d . In some embodiments, R 4 is a benzothiazole, wherein each hydrogen atom in benzothiazole is unsubstituted. In some embodiments, R 4 is a benzooxazole, wherein each hydrogen atom in benzooxazole is unsubstituted.
  • each R d when present, is independently deuterium, halo, -OH, - NR 5 R 6 , C 1 -C 6 alkoxy, or C 1 -C 6 alkyl. In some embodiments, each R d , when present, is independently halo. In some embodiments, each R d , when present, is independently -OH. In some embodiments, each R d , when present, is independently C 1 -C 6 alkoxy. [0175] In some embodiments, R 4 is selected from , wherein m is 0, 1, or 2. [0176] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
  • R 5 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 5 is H. [0178] In some embodiments, R 6 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 6 is H. [0179] In some embodiments, the compound is selected from the group consisting of: , , , , and In certain preferred embodiments, the compound is or [0180] In some embodiments, a pharmaceutical composition comprises at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • a method of treating disease comprises administering to a subject in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a method of treating disease comprises administering to a subject in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • X is H, deuterium, C 6 -C 10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C 1 -C 6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C 1 -C 6 alkyl-5-10 membered heteroaryl, -NR 1 C(O)R 2 , -OC(O)R 2 , -NR 1 C(O)C 1 -C 6 alkyl-R 2 , or -OC(O)C 1 -C 6 alkyl-R 2 , wherein each hydrogen atom in C
  • each R e when present, is independently halo.
  • 24 The compound or pharmaceutically acceptable salt of embodiment 22, wherein R e is chloro.
  • 25 The compound or pharmaceutically acceptable salt of any one of embodiments 16 to 24, wherein R 2 is selected from [0208] 26.
  • a pharmaceutical composition comprising at least one compound of embodiment 1, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • a method of treating disease comprising administering to a subject in need of such treatment an effective amount of a compound of embodiment 1, or a pharmaceutically acceptable salt thereof.
  • a method of treating disease comprising administering to a subject in need of such treatment an effective amount of a compound of embodiment 1, or a pharmaceutically acceptable salt thereof.
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient.
  • compositions according to the invention are sterile compositions.
  • Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art. [0239] Sterile compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl
  • the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 ⁇ g/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • the inventive compositions may be formulated for rectal administration as a suppository.
  • the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.
  • the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • Exemplary diseases include those caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Ebola virus, Paramyxoviruses, Bunyaviruses (Bunyavirales), Togaviruses, Filoviruses, Picornaviruses, Flaviviruses.
  • the disease is caused by SARS-CoV-2.
  • the compounds and pharmaceutical compositions of the invention specifically target SC2M Pro .
  • these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of this protease.
  • methods of treatment include treating viral infections.
  • methods are for treating viral infections caused by COVID-19.
  • an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein.
  • Additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease.
  • compositions and formulations of the invention can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.
  • additional such agents include, but are not limited to, remdesivir, favipiravir, ribavirin, monoclonal antibodies, dexamethasone, interferon, umifenovir, oseltamivir, lopinavir, and ritonavir.
  • the pharmaceutical compositions of the invention may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
  • a single colony grown on a LB plate containing 50 ⁇ g/mL kanamycin was picked and grown in 5 mL LB media supplemented with 50 ⁇ g/mL kanamycin overnight. This overnight culture was inoculated to 6 L 2YT media with 50 ⁇ g/mL kanamycin. Cells were grown to OD 600 as 0.8. At this point, 1 mM IPTG was added to induce the expression of His- SUMO-M Pro . Induced cells were let grown for 3 h and then harvested by centrifugation at 12,000 rpm, 4 °C for 30 min.
  • Cell pellets were resuspended in 150 mL lysis buffer (20 mM Tris-HCl, 100 mM NaCl, 10 mM imidazole, pH 8.0) and lysed the cells by sonication on ice. The lysate was clarified by centrifugation at 16,000 rpm, 4 °C for 30 min. The supernatant was decanted and mixed with Ni-NTA resins (GenScript). The resins were loaded to a column, washed the resins with 10 volumes of lysis buffer, and eluted the bound protein using elution buffer (20 mM Tris- HCl, 100 mM NaCl, 250 mM imidazole, pH 8.0).
  • Buffer of the elute was exchanged to another buffer (20 mM Tris-HCl, 100 mM NaCl, 10 mM imidazole, 1 mM DTT, pH 8.0) using a HiPrep 26/10 desalting column (Cytiva) and digested the elute using 10 units SUMO protease overnight at 4 °C.
  • the digested elute was subjected to Ni-NTA resins in a column to remove His-tagged SUMO protease, His-tagged SUMO tag, and undigested His-SUMO-M Pro .
  • the flow-through was loaded onto a Q-Sepharose column and purified M Pro using FPLC by running a linear gradient from 0 to 500 mM NaCl in a buffer (20 mM Tris-HCl, 1 mM DTT, pH 8.0). Fractions eluted from the Q-Sepharose column was concentrated and loaded onto a HiPrep 16/60 Sephacryl S-100 HR column and purified using a buffer containing 20 mM Tris-HCl, 100 mM NaCl, 1 mM DTT, and 1 mM EDTA at pH 7.8. The final purified was concentrated and stored in a -80 °C freezer. [0323] In Vitro M Pro Inhibition Potency Characterizations.
  • the assay is conducted using 20 nM M Pro and 10 ⁇ M Sub3.
  • 10 nM M Pro is used for synthesized compounds. All compounds are dissolved in DMSO as 10 mM stock solutions.
  • Sub3 is dissolved in DMSO as a 1 mM stock solution and is diluted 100 times in the final assay buffer containing 10 mM Na x H y PO 4 , 10 mM NaCl, 0.5 mM EDTA, and 1.25% DMSO at pH 7.6.
  • M Pro and the compounds are incubated in the final assay buffer for 30 min before adding the substrate to initiate the reaction catalyzed by M Pro .
  • HEK 293T/17 cells are grown in high-glucose DMEM with GlutaMAX supplement and 10% FBS in 10 cm culture plates under 37 °C and 5% CO2 to 80-90% confluency and then transfected cells with the pLVX-M Pro -eGFP-2 plasmid. 30 mg/mL polyethyleneimine and the total of 8 ⁇ g of the plasmid in 500 ⁇ L opti-MEM media are used for transfection. Transfected cells are incubated overnight.
  • cells are collected using 0.05% trypsin-EDTA to detach them from plates, resuspended collected cells in the original growth media, adjusted the cell density to 5x10 5 cells/mL, added 500 ⁇ L adjusted cells to each well of a 48-well plate, and then added 100 ⁇ L of a drug solution in DMEM.
  • Treated cells are incubated under 37 °C and 5% CO2 for 72 h. After 72 h incubation, cells are collected using trypsinization and centrifugation.
  • Collected cells are resuspended in 200 ⁇ L PBS and analyzed cells with fluorescence using a Cytoflex Research Flow Cytometer based on the size scatters (SSC-A and SSC-H) and forward scatter (FSC-A). Cells are gated based on SSC-A and FSC-A then with SSC-A and SSC-H. Fluorescence is detected with excitation at 488 nm and emission at 525 nm. All collected data are converted to csv files and analyzed using a self-prepared MATLAB script for massive data processing. The FITC-A column is sorted from lowest to highest. A 10 6 cutoff is set to separate the column to two groups with higher than 10 6 as positive and lower than 10 6 as negative.
  • CPE cytopathic effect
  • confluent african green monkey kidney cells (Vero E6) or human alveolar epithelial A549 cells stably expressing human ACE2 viral receptor, designated A549/hACE2, grown in 96-wells microtiter plates are pre-treated with serially 2-folds diluted individual drugs for two hours before infection with 100 or 500 infectious SARS-CoV-2 (USA-WA1/2020) particles in 100 ⁇ l EMEM supplemented with 2% FBS, respectively.
  • Cells pre-treated with parallelly diluted dimethyl sulfoxide (DMSO) with or without virus are included as positive and negative controls, respectively.
  • DMSO dimethyl sulfoxide

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Abstract

The present disclosure relates to certain molecules, pharmaceutical compositions containing them, and methods of using them to treat viral infections.

Description

NON-PEPTIDIC SARS-COV-2 MAIN PROTEASE INHIBITORS
RELATED APPLICATIONS
[001] This application claims the benefit of U.S. Provisional Application No. 63/424,294, filed November 10, 2022, the contents of each of which are fully incorporated by reference herein.
TECHNICAL FIELD
[002] The present disclosure relates to certain molecules, pharmaceutical compositions containing them, and methods of using them to treat viral infections.
BACKGROUND
[003] Coronaviruses (CoVs) are a group of related RNA viruses that cause diseases in a wide range of vertebrates including humans and domestic animals. Before 2003, there were only two CoVs, HCoV-229E and HCoV-OC43, known as human pathogens. The SARS pandemic in 2003 led to the revelation of SARS-CoV-1, a pathogen causing a severe respiratory infection. The subsequent surge in CoV research resulted in the discovery of two additional human CoVs, HCoV-NL63 and HCoV-HKUl, that are mildly pathogenic. One addition to this group was MERS-CoV that emerged in 2012 as a pathogen causing a severe respiratory infection. Although SARS-CoV-1 and MERS-CoV are highly lethal pathogens, the public health, social, and economic damages that they have caused are diminutive in comparison to that from SARS-CoV- 2, a newly emerged human CoV pathogen that causes COVID-19. Rival only to the 1918 influenza pandemic, the COVID-19 pandemic has led to catastrophic impacts worldwide.
[004] As of August 23, 2022, the total number of confirmed global COVID- 19 cases was over 597 million, of which 6.45 million succumbed to death (WHO data). To address this emergency, a large variety of drug repurposing research has been conducted to identify approved medications that might be potentially used as COVID-19 treatments. Significant part of this research has been targeting the SARS-CoV-2 main protease (MPro). MPro is a peptide fragment of two translation products ppla and pplab of the SARS-CoV-2 RNA genome after the virus infects human cells. Both ppla and pplab are very large polypeptides that need to undergo proteolytic hydrolysis to form 16 nonstructural proteins (nsps). These nsps are essential for the virus to replicate its genome in host cells, evade the host immune system, and package new virions for the infection of new host cells. Intervention of the proteolytic hydrolysis of ppla and pplab is a viable approach to stop SARS-CoV-2 infection. There are two internal peptide fragments from ppla and pplb that function as cysteine proteases to hydrolyze all nsps. One is MPro and the other papain-like protease (PLPro). As the major protease, MPro processes the majority of nsps. It is also more conserved than PLPro. MPro genes in SARS-CoV and SARS-CoV-2 share 96% sequence identity. [005] Targeting MPro for drug discovery has been demonstrated as a successful route for the development of SARS-CoV-2 antivirals by the U.S. FDA approval of the use of Pfizer PAXLOVID for the treatment COVID-19. Therefore, small molecule medicines that inhibit SARS-CoV-2 MPro (SC2MPro) are potentially effective treatment options for COVID-19. [006] In this disclosure, a series of new small molecules as potent SARS-CoV-2 MPro inhibitors were designed and synthesized. More importantly, these small molecules also showed promising antiviral activities against SARS-CoV-2, and many of the small molecules demonstrated superior antiviral activities in a head-to-head comparison with the FDA-approved COVID-19 drug PAXLOVID and nirmatrelvir. Although some treatment options are available, there is a continual need to develop small molecule medicines with improved efficacy and fewer side effects. SUMMARY [007] In one aspect, the disclosure relates to a compound of Formula I
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein [008] Ar is C6-C10 aryl or 5-10 membered heteroaryl, wherein each hydrogen atom in C6-C10 aryl or 5-10 membered heteroaryl is independently optionally substituted by an Ra; [009] X is H, deuterium, C6-C10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C1-C6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C1-C6 alkyl-5-10 membered heteroaryl, -NR1C(O)R2, -OC(O)R2, -NR1C(O)C1-C6 alkyl-R2, or -OC(O)C1-C6 alkyl-R2, wherein each hydrogen atom in C1-C6 alkyl, C6-C10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl is independently optionally substituted by an R3; [010] W is H, deuterium, -CHO, -CN, C1-C6 alkyl-R4, C1-C6 alkyl-C(O)R4, or C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo; [011] each of R1, R5, and R6 is independently H, deuterium, or C1-C6 alkyl; [012] R2 is C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl and C3-C8 cycloalkyl is independently optionally substituted by an R3, and wherein each hydrogen atom in 3-10 membered heterocyclyl, C6-C10 aryl and 5-10 membered heteroaryl is independently optionally substituted by an Rb; [013] each of R3 is independently deuterium, halo, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rc; [014] R4 is independently H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rd; and [015] each of Ra, Rc, Rd, and Re, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl; and [016] each of Rb, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl, or two Rb taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re. [017] In another aspect, the disclosure provides compounds of the formula
Figure imgf000004_0001
[018] or a pharmaceutically acceptable salt thereof, wherein X, W, and Ra are as defined herein, and n is 0, 1, 2, or 3. [019] In another aspect, the disclosure provides compounds of the formula
Figure imgf000004_0002
[020] or a pharmaceutically acceptable salt thereof, wherein X and Ar are as defined herein. [021] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another. [022] 1. A compound of formula
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein Ar is C6-C10 aryl or 5-10 membered heteroaryl, wherein each hydrogen atom in C6-C10 aryl or 5-10 membered heteroaryl is independently optionally substituted by an Ra; X is H, deuterium, C6-C10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C1-C6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C1-C6 alkyl-5-10 membered heteroaryl, -NR1C(O)R2, -OC(O)R2, -NR1C(O)C1-C6 alkyl-R2, or -OC(O)C1-C6 alkyl-R2, wherein each hydrogen atom in C1-C6 alkyl, C6-C10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl is independently optionally substituted by an R3; W is H, deuterium, -C(O)H, -CN, C1-C6 alkyl-R4, C1-C6 alkyl-C(O)R4, or C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo; each of R1, R5, and R6 is independently H, deuterium, or C1-C6 alkyl; R2 is C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl and C3-C8 cycloalkyl is independently optionally substituted by an R3, and wherein each hydrogen atom in 3-10 membered heterocyclyl, C6-C10 aryl and 5-10 membered heteroaryl is independently optionally substituted by an Rb; each of R3 is independently deuterium, halo, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rc; R4 is independently H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rd; and each of Ra, Rc, Rd, and Re, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl; and each of Rb, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl, or two Rb taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re. [023] 2. The compound or pharmaceutically acceptable salt of clause 1, wherein Ar is 5-10 membered heteroaryl, wherein each hydrogen atom 5-10 membered heteroaryl is independently optionally substituted by an Ra. [024] 3. The compound or pharmaceutically acceptable salt of clause 1 or 2, wherein Ar is selected from
Figure imgf000006_0002
and
Figure imgf000006_0003
wherein n is 0, 1, or 2. [025] 4. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein each Ra, when present, is independently halo. [026] 5. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein each Ra, when present, is independently chloro. [027] 6. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein Ar is selected from
Figure imgf000006_0001
[028] 7. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein X is H, 5-10 membered heteroaryl, -N(R1)C(O)R2, -OC(O)R2, or -N(R1)C(O)C1-C6 alkyl-R2, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an R3. [029] 8. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein X is H. [030] 9. The compound or pharmaceutically acceptable salt of any one of clauses 1-7, wherein X is -NR1C(O)R2. [031] 10. The compound or pharmaceutically acceptable salt of any one of clauses 1-7, wherein X is -NR1C(O)C1-C6 alkyl-R2. [032] 11. The compound or pharmaceutically acceptable salt of any one of clauses 1-7 and 10, wherein X is -NR1C(O)CH2R2. [033] 12. The compound or pharmaceutically acceptable salt of any one of clauses 1-7, wherein X is -OC(O)R2. [034] 13. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein R2 is C1-C6 alkyl, 3-10 membered heterocyclyl, or C6-C10 aryl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by an R3, and wherein each hydrogen atom in 3-10 membered heterocyclyl and C6-C10 aryl is independently optionally substituted by an Rb. [035] 14. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein R2 is a C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally substituted by an R3. [036] 15. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein R2 is methyl or trifluoromethyl. [037] 16. The compound or pharmaceutically acceptable salt of any one of clauses 1-13, wherein R2 is a 3-10 membered heterocyclyl, wherein each hydrogen atom in the 3-10 membered heterocyclyl is independently optionally substituted by an Rb. [038] 17. The compound or pharmaceutically acceptable salt of any one of clauses 1-13 and 16, wherein R2 is selected from
Figure imgf000007_0001
wherein p is 0, 1, or 2. [039] 18. The compound or pharmaceutically acceptable salt of clause 17, wherein p is 1. [040] 19. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein each Rb, when present, is independently halo. [041] 20. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein Rb is chloro. [042] 21. The compound or pharmaceutically acceptable salt of clause 16, wherein R2 is pyran or morpholine, wherein each hydrogen atom in pyran or morpholine is independently optionally substituted by an Rb. [043] 22. The compound or pharmaceutically acceptable salt of any one of clauses 16 and 21, wherein two Rb are taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re. [044] 23. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein each Re, when present, is independently halo. [045] 24. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein Re is chloro. [046] 25. The compound or pharmaceutically acceptable salt of any one of clauses 1-13 and 16 to 24, wherein R2 is selected from
Figure imgf000008_0001
. [047] 26. The compound or pharmaceutically acceptable salt of any one of clauses 1-13, wherein R2 is a C6-C10 aryl, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted by an Rb. [048] 27. The compound or pharmaceutically acceptable salt of any one of clauses 1-13 and 26, wherein R2 is naphthalene or phenyl, wherein naphthalene or phenyl is independently optionally substituted by (Rb)q, wherein q is 0, 1, or 2. [049] 28. The compound or pharmaceutically acceptable salt of clause 27, wherein q is 1 or 2. [050] 29. The compound or pharmaceutically acceptable salt of any one of clauses 1-21 and 26- 27, wherein each Rb, when present, is independently halo. [051] 30. The compound or pharmaceutically acceptable salt of any one of clauses 1-21 and 26- 29, wherein Rb is chloro. [052] 31. The compound or pharmaceutically acceptable salt of any one of clauses 1-13 and 26 to 30, wherein R2 is selected from
Figure imgf000008_0002
[053] 32. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein R1 is H. [054] 33. The compound or pharmaceutically acceptable salt of any one of clauses 1-7, wherein X is a 5-10 membered heteroaryl, wherein each hydrogen atom in the 5-10 membered heteroaryl is independently optionally substituted by an R3. [055] 34. The compound or pharmaceutically acceptable salt of any one of clauses 1-7 and 33, wherein X is a triazole, imidazole, or pyrazolone, wherein each hydrogen atom in triazole, imidazole, or pyrazolone is independently optionally substituted by an R3. [056] 35. The compound or pharmaceutically acceptable salt of any one of clauses 1-7 and 33- 34, wherein R3 is phenyl, wherein phenyl is independently optionally substituted by (Rc)s, wherein s is 0, 1, 2, or 3. [057] 36. The compound or pharmaceutically acceptable salt of any one of clauses 1-7 and 33- 35, wherein R3 is
Figure imgf000009_0001
. [058] 37. The compound or pharmaceutically acceptable salt of any one of clauses 1-7 and 35- 36, wherein each Rc, when present, is independently halo or C1-C6 alkoxy. [059] 38. The compound or pharmaceutically acceptable salt of any one of clauses 1-7 and 37, wherein Rc is chloro or methoxy. [060] 39. The compound or pharmaceutically acceptable salt of any one of clauses 1-7 and 33- 38, wherein R3 is selected from
Figure imgf000009_0003
[061] 40. The compound or pharmaceutically acceptable salt of any one of clauses 1-7 and 33- 39, wherein X is selected from ,
Figure imgf000009_0002
[062] 41. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein W is -CN, C1-C6 alkyl-R4, C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo. [063] 42. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein W is –CN. [064] 43. The compound or pharmaceutically acceptable salt of any one of clauses 1-41, wherein W is C1-C6 alkyl-R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo. [065] 44. The compound or pharmaceutically acceptable salt of any one of clauses 1-41 and 43, wherein W is -CHCl-R4. [066] 45. The compound or pharmaceutically acceptable salt of any one of clauses 1-41, wherein W is C(O)R4. [067] 46. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein R4 is a 5-10 membered heteroaryl, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an Rd. [068] 47. The compound or pharmaceutically acceptable salt of any one of the preceding clauses, wherein R4 is selected from
Figure imgf000010_0001
, wherein m is 0, 1, or 2. [069] 48. The compound or pharmaceutically acceptable salt of clause 47, wherein m is 0. [070] 49. The compound or pharmaceutically acceptable salt of clause 1, wherein the compound is selected from the group consisting of:
Figure imgf000010_0002
Figure imgf000011_0001
. [071] 50. A pharmaceutical composition comprising at least one compound of any one of clauses 1-49, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. [072] 51. A method of treating disease, such as a viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1-49, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION [073] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. [074] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference. [075] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. [076] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense. [077] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently. [078] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001. [079] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer). [080] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. DEFINITIONS [081] As used herein, the term “alkyl” includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C1-C12, C1-C10, C1-C9, C1-C8, C1-C7, C1-C6, and C1-C4, Illustratively, such particularly limited length alkyl groups, including C1-C8, C1-C7, C1-C6, and C1-C4, and the like may be referred to as “lower alkyl.” Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo (=O), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, -NO2, and amino, or as described in the various embodiments provided herein. It will be understood that “alkyl” may be combined with other groups, such as those provided above, to form a functionalized alkyl. By way of example, the combination of an “alkyl” group, as described herein, with a “carboxy” group may be referred to as a “carboxyalkyl” group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like. [082] As used herein, the term “alkenyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon double bond (i.e., C=C). It will be understood that in certain embodiments, alkenyl may be advantageously of limited length, including C2-C12, C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Illustratively, such particularly limited length alkenyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4 may be referred to as lower alkenyl. Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. [083] As used herein, the term “alkynyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e., C≡C). It will be understood that in certain embodiments, alkynyl may each be advantageously of limited length, including C2-C12, C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Illustratively, such particularly limited length alkynyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4 may be referred to as lower alkynyl. Alkynyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. [084] As used herein, the term “aryl” refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. It will be understood that in certain embodiments, aryl may be advantageously of limited size such as C6- C10 aryl. Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. [085] As used herein, the term “cycloalkyl” refers to a 3 to 15 member all-carbon monocyclic ring, including an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group, or a carbocyclic ring that is fused to another group such as a heterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to 7- membered heterocyclic ring, where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, cycloalkyl may be advantageously of limited size such as C3-C12, C3-C9, C3-C8, C3-C6 and C4-C6. Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like. Illustrative examples of cycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties:
Figure imgf000014_0001
[086] As used herein, the terms “heterocycloalkyl”, “heterocyclyl”, or “heterocycle” refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms. Heterocycloalkyl may optionally contain 1, 2, 3 or 4 heteroatoms. A heterocycloalkyl group may be fused to another group such as another heterocycloalkyl, an aryl, or a heteroaryl group. Heterocycloalkyl may also have one of more double bonds, including double bonds to nitrogen (e.g., C=N or N=N) but does not contain a completely conjugated pi- electron system. It will be understood that in certain embodiments, heterocycloalkyl may be advantageously of limited size such as 3- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or 6-membered heterocycloalkyl, and the like. Heterocycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl, and the like. Illustrative examples of heterocycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties:
Figure imgf000015_0001
[087] In a particular embodiment, the heterocycyl group may be chromane, benzooxazinyl, or benzomorpholinyl. [088] Illustrative examples of heterocycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties:
Figure imgf000016_0001
, , [089] As used herein, the term “aryl” refers to a monocyclic or fused ring group of 5 to 10 ring atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, aryl may be advantageously of limited size such as 6- to 10-membered aryl and the like. Aryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative aryl groups include, but are not limited to, phenyl and naphthyl. [090] As used herein, the term “heteroaryl” refers to a monocyclic or fused ring group of 5 to 10 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, 5- to 10-membered heteroaryl and the like. Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. In some embodiments, it will be understood that an atom exo to the heteroaryl ring atoms, such as an amino or a hydroxyl group, may contribute to the pi-electron system. For example, tautomeric hydroxyl-pyrazole contains an -OH group, wherein the exo oxygen contributes to the pi-electron system, illustrated in the tautomeric pyrazolone configuration. [091] Illustrative heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl, and the like. Illustrative examples of heteroaryl groups shown in graphical representations, include the following entities, in the form of properly bonded moieties:
Figure imgf000016_0002
Figure imgf000017_0001
[092] In a particular embodiment, the heteroaryl group may be
Figure imgf000017_0002
[093] As used herein, “tautomer” refers each of two or more isomers of a compound which exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule. In a particular embodiment, a tautomer can be the isomers of pyrazolone and hydroxyl- pyrazole, such as
Figure imgf000017_0003
[094] As used herein, “hydroxy” or “hydroxyl” refers to an -OH group. [095] As used herein, “alkoxy” refers to both an -O-(alkyl) or an -O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. [096] As used herein, “halo” or “halogen” refers to fluorine, chlorine, bromine or iodine. [097] As used herein, “cyano” refers to a -CN group. [098] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone. In another example, a hydroxy substituted compound may exist as an oxo substituted tautomer, such as hydroxy-pyrazole and pyrazolone. In another example, two substiutents may come together on the carbon to which they are attached to form an oxo. In a particular embodiment, a hydroxy-substituted pyrazole may be represented as an oxo tautomer, such as
Figure imgf000018_0002
In some embodiments, a hydroxy-substituted quinoline may be represented as an oxo tautomer, such as
Figure imgf000018_0001
. [099] As used herein, “bond” refers to a covalent bond. [0100] The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one or more substituents. It will be understood that in certain embodiments, substitutions may be advantageously limited in number. In some embodiments, “substituted” means that the specified group or moiety bears one to five substituents. In other embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent. [0101] As used herein, “optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by C1-C6 alkyl” means that an alkyl may be but need not be present on any of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl by replacement of a hydrogen atom for each alkyl group, and the description includes situations where the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is substituted with an alkyl group and situations where the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is not substituted with the alkyl group. [0102] As used herein, “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances. For example, in a circumstance where several equivalent hydrogen groups are optionally substituted by another group described in the circumstance, the use of “independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different. Or for example, where multiple groups exist all of which can be selected from a set of possibilities, the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different. [0103] As used herein, the phrase “taken together with the atoms to which they are attached” or “combine together with the atom to which they are attached” means that two substituents (e.g., two independent Rb groups) attached to two separate atoms or attached to the same atom form the groups that are defined by the claim, such as
Figure imgf000019_0001
. In particular, the phrase “combine together with the atoms to which they are attached” means , for example, two independent Rb groups on different ring atoms of
Figure imgf000019_0003
such as carbon atom “1” and carbon atom “2” respectively as shown in the structure below form a ring with those ring atoms.
Figure imgf000019_0004
[0104] For example, the phrase “or two Rb taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re” used in connection with the embodiments described herein includes the compound represented as follows:
Figure imgf000019_0002
. [0105] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which counter ions which may be used in pharmaceuticals. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Such salts include: [0106] (1) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or [0107] (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like. [0108] Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharmaceutically acceptable salt may be contemplated in connection with the embodiments described herein. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985. [0109] For a compound of Formula I that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. [0110] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula I, and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula I). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. [0111] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula I, and uses of such metabolites in the methods of the disclosure. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula I, or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem.1997, 40, 2011-2016; Shan et al., J. Pharm. Sci.1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res.1995, 34, 220-230; Bodor, Adv. Drug Res.1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991). [0112] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. For example, it will be appreciated that compounds depicted by a structural formula containing the symbol
Figure imgf000021_0001
include both stereoisomers for the carbon atom to which the symbol
Figure imgf000021_0002
is attached, specifically both the bonds
Figure imgf000021_0003
are encompassed by the meaning of
Figure imgf000021_0004
[0113] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 36Cl, and 125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. For example, isotope-labeled compounds and salts can be used as medicaments. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. For example, deuterium (2H)-labeled compounds and salts may be therapeutically useful with potential therapeutic advantages over the non-2H-labeled compounds. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. [0114] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent –A-B-, where A ≠ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member. REPRESENTATIVE EMBODIMENTS [0115] In some embodiments, compounds described herein comprise a moiety of the Formula I
Figure imgf000022_0001
[0116] or a pharmaceutically acceptable salt thereof, wherein Ar, X, and W are as defined herein. [0117] In some embodiments, compounds described herein comprise the formula
Figure imgf000022_0002
[0118] or a pharmaceutically acceptable salt thereof, wherein X, W, and Ra are as defined herein, and n is 0, 1, 2, or 3. [0119] In another aspect, the disclosure provides compounds of the formula
Figure imgf000023_0001
[0120] or a pharmaceutically acceptable salt thereof, wherein X and Ar are as defined herein. [0121] In some embodiments, Ar is C6-C10 aryl, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted by an Ra. In some embodiments, Ar is 5-10 membered heteroaryl, wherein each hydrogen atom 5-10 membered heteroaryl is independently optionally substituted by an Ra. In some embodiments, Ar is a 5 membered heteroaryl. In some embodiments, Ar is a 6 membered heteroaryl. In some embodiments, Ar is a 7 membered heteroaryl. In some embodiments, Ar is an 8 membered heteroaryl. In some embodiments, Ar is a 9 membered heteroaryl. In some embodiments, Ar is a 10 membered heteroaryl. In some embodiments, Ar is pyridine, isoquinoline, quinoline, benzotriazole, benzoimidazole, or naphthyridine. In some embodiments, Ar is pyridine. In some embodiments, Ar is isoquinoline. In some embodiments, Ar is benzotriazole. [0122] In some embodiments, Ar is selected from
Figure imgf000023_0004
wherein n is 0, 1, or 2. In certain preferred embodiments, Ar is
Figure imgf000023_0002
, wherein n is 0 or 1. [0123] In some embodiments, Ar is selected from
Figure imgf000023_0003
wherein n is 0, 1, or 2. In some embodiments, Ar is selected from
Figure imgf000023_0005
and wherein n is 0, 1, or 2.
Figure imgf000023_0006
[0124] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In certain preferred embodiments, n is 0 or 1. [0125] In some embodiments, each Ra, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl. In some embodiments, each Ra, when present, is independently halo. In some embodiments, each Ra, when present, is independently -OH. For example, if Ra is –OH on a heteroaryl, the –OH substituted heteroaryl may be represented as an oxo tautomer. In some embodiments, each Ra, when present, is independently chloro. [0126] In some embodiments, Ra is chloro and Ar is
Figure imgf000024_0001
In some embodiments, Ra is -OH and Ar is
Figure imgf000024_0002
In some embodiments, Ar is selected from
Figure imgf000024_0003
, , In some embodiments, Ar is selected from
Figure imgf000024_0004
In certain preferred embodiments, Ar is
Figure imgf000024_0005
[0127] In some embodiments, X is H, deuterium, C6-C10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C1-C6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C1-C6 alkyl-5-10 membered heteroaryl, -NR1C(O)R2, -OC(O)R2, -NR1C(O)C1-C6 alkyl-R2, or -OC(O)C1-C6 alkyl-R2, wherein each hydrogen atom in C1-C6 alkyl, C6-C10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl is independently optionally substituted by an R3. [0128] In some embodiments, X is H, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -NR1C(O)R2, -OC(O)R2, or -NR1C(O)C1-C6 alkyl-R2, wherein each hydrogen atom in C1-C6 alkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is independently optionally substituted by an R3. In some embodiments, X is H. In some embodiments, X is 3-10 membered heterocyclyl, wherein each hydrogen atom in 3-10 membered heterocyclyl is independently optionally substituted by an R3. In some embodiments, X is 5-10 membered heteroaryl, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an R3. In some embodiments, X is -NR1C(O)R2. In some embodiments, X is -NR1C(O)C1-C6 alkyl- R2, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by an R3. In some embodiments, X is -NR1C(O)CH2R2. In some embodiments, X is -OC(O)R2. [0129] In some embodiments, R2 is C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl and C3-C8 cycloalkyl is independently optionally substituted by an R3, and wherein each hydrogen atom in 3-10 membered heterocyclyl, C6-C10 aryl and 5-10 membered heteroaryl is independently optionally substituted by an Rb. In some embodiments, R2 is C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by an R3. In some embodiments, R2 is C3-C8 cycloalkyl, wherein each hydrogen atom in C3-C8 cycloalkyl is independently optionally substituted by an R3. [0130] In some embodiments, R2 is C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by an R3. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is methyl, wherein each hydrogen atom in methyl is independently optionally substituted by an R3. In some embodiments, R2 is methyl, wherein one hydrogen atom in methyl is optionally substituted by an R3. In some embodiments, R2 is methyl, wherein two hydrogen atoms in methyl are independently optionally substituted by an R3. In some embodiments, R2 is methyl, wherein three hydrogen atoms in methyl are independently optionally substituted by an R3. [0131] In some embodiments, R3 is independently deuterium, halo, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rc. In some embodiments, R3 is independently deuterium, halo, or C1-C6 alkyl. In some embodiments, R3 is independently halo. In some embodiments, R3 is independently fluoro. [0132] In some embodiments, R2 is trifluoromethyl. [0133] In some embodiments, R2 is 3-10 membered heterocyclyl or C6-C10 aryl, wherein each hydrogen atom in 3-10 membered heterocyclyl or C6-C10 aryl is independently optionally substituted by an Rb. In some embodiments, R2 is a 3-10 membered heterocyclyl, wherein each hydrogen atom in the 3-10 membered heterocyclyl is independently optionally substituted by an Rb. [0134] In some embodiments, R2 is a 3-10 membered heterocyclyl, wherein R2 is chromane, and wherein each hydrogen atom in chromane is independently optionally substituted by an Rb. In some embodiments, R2 is a 3-10 membered heterocyclyl, wherein R2 is benzomorpholine, and wherein each hydrogen atom in benzomorpholine is independently optionally substituted by an Rb. [0135] In some embodiments, R2 is a 3-10 membered heterocyclyl, wherein R2 is chromane, and wherein one hydrogen atom in chromane is substituted by an Rb. In some embodiments, R2 is a 3-10 membered heterocyclyl, wherein R2 is benzomorpholine, and wherein one hydrogen atom in benzomorpholine is substituted by an Rb. [0136] In some embodiments, R2 is a C6-C10 aryl, wherein R2 is naphthalene, and wherein each hydrogen atom in naphthalene is independently optionally substituted by an Rb. In some embodiments, R2 is a C6-C10 aryl, wherein R2 is phenyl, and wherein each hydrogen atom in phenyl is independently optionally substituted by an Rb. In some embodiments, R2 is a C6-C10 aryl, wherein R2 is phenyl, and wherein one hydrogen atom in phenyl is substituted by an Rb. In some embodiments, R2 is a C6-C10 aryl, wherein R2 is naphthalene, and wherein one hydrogen atom in naphthalene is substituted by an Rb. In some embodiments, R2 is a C6-C10 aryl, wherein R2 is phenyl, and wherein two hydrogen atoms in phenyl are independently substituted by Rb. In some embodiments, R2 is a C6-C10 aryl, wherein R2 is naphthalene, and wherein two hydrogen atoms in naphthalene are independently substituted by Rb. [0137] In some embodiments, R2 is pyran, wherein each hydrogen atom in pyran is independently optionally substituted by an Rb. In some embodiments, R2 is morpholine, wherein each hydrogen atom in morpholine is independently optionally substituted by an Rb. In some embodiments, two Rb are taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re. In some embodiments, two Rb are taken together with the carbon atoms to which they are attached combine to form a fused phenyl ring, wherein each hydrogen atom in phenyl is independently optionally substituted with an Re. In some embodiments, two Rb are taken together with the carbon atoms to which they are attached combine to form a fused phenyl ring, wherein 1 hydrogen atom in phenyl is substituted with an Re. In some embodiments, two Rb are taken together with the carbon atoms to which they are attached combine to form a fused phenyl ring, wherein 2 hydrogen atoms in phenyl is substituted with an Re. [0138] In some embodiments, each of Rb, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl, or two Rb taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6- C10 aryl is independently optionally substituted with an Re. In some embodiments, each of Rb, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl. In some embodiments, each of Rb, when present, is independently deuterium, halo, or -OH. In some embodiments, each of Rb, when present, is independently halo. In some embodiments, Rb is independently chloro, fluoro, bromo, or iodo. In some embodiments, Rb is chloro. [0139] In some embodiments, each of Re, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl. In some embodiments, each of Re, when present, is independently deuterium, halo, or -OH. In some embodiments, each of Re, when present, is independently halo. In some embodiments, Re is independently chloro, fluoro, bromo, or iodo. In some embodiments, Re is chloro. [0140] In some embodiments, R2 is selected from
Figure imgf000027_0001
, wherein p is 0, 1, or 2. [0141] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. [0142] In some embodiments, R2 is selected from
Figure imgf000027_0004
wherein q is 0, 1, or 2. [0143] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. [0144] In some embodiments, each Rb, when present, is independently halo. In some embodiments, Rb is independently chloro, fluoro, bromo, or iodo. In some embodiments, Rb is chloro. [0145] In some embodiments, R2 is a selected from
Figure imgf000027_0002
, wherein p is 0, 1, or 2. [0146] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. [0147] In some embodiments, two Rb are taken together with the carbon atoms to which they are attached combine to form a fused phenyl ring. [0148] In some embodiments, R2 is a selected from
Figure imgf000027_0003
, wherein t is 0, 1, or 2. [0149] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. [0150] In some embodiments, each Re, when present, is independently halo. In some embodiments, Re is independently chloro, fluoro, bromo, or iodo. In some embodiments, Re is chloro. [0151] In some embodiments, R2 is selected from
Figure imgf000028_0001
In certain preferred embodiments, R2 is
Figure imgf000028_0002
[0152] In some embodiments, R2 is a C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally substituted by an R3. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is methyl and each hydrogen atom in methyl is unsubstituted by an R3. In some embodiments, R2 is methyl and each hydrogen atom in methyl is independently optionally substituted by R3. In some embodiments, R2 is methyl and one hydrogen atom in methyl substituted by an R3. [0153] In some embodiments, each of R3 is independently deuterium, halo, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rc. In some embodiments, R3 is 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rc. [0154] In some embodiments, R3 is 3-10 membered heterocyclyl, wherein each hydrogen atom in 3-10 membered heterocyclyl is independently optionally substituted by an Rc. In some embodiments, R3 is 3-10 membered heterocyclyl, wherein one hydrogen atom in 3-10 membered heterocyclyl is substituted by an Rc. In some embodiments, R3 is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is unsubstituted. In some embodiments, R3 is a 3-10 membered heterocyclyl, wherein R3 is chromane, and wherein each hydrogen atom in chromane is independently optionally substituted by an Rc. In some embodiments, R3 is a 3-10 membered heterocyclyl, wherein R3 is benzomorpholine, and wherein each hydrogen atom in benzomorpholine is independently optionally substituted by an Rc. [0155] In some embodiments, each of Rc, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl. In some embodiments, each of Rc, when present, is independently deuterium, halo, or -OH. In some embodiments, each of Rc, when present, is independently halo. In some embodiments, Rc is independently chloro, fluoro, bromo, or iodo. In some embodiments, Rc is chloro. [0156] In some embodiments, R3 is a selected from
Figure imgf000029_0001
wherein s is 0, 1, or 2. [0157] n some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. [0158] In some embodiments, R3 is
Figure imgf000029_0002
[0159] In some embodiments, R1 is H, deuterium, or C1-C6 alkyl. In some embodiments, R1 is H. [0160] In some embodiments X is selected from H,
Figure imgf000029_0003
Figure imgf000029_0004
In certain preferred embodiments, X is
Figure imgf000029_0005
[0161] In some embodiments, X is a 5-10 membered heteroaryl, wherein each hydrogen atom in the 5-10 membered heteroaryl is independently optionally substituted by an R3. In some embodiments, X is a 6 membered heteroaryl, wherein each hydrogen atom in the 6 membered heteroaryl is independently optionally substituted by an R3. In some embodiments, X is a 5 membered heteroaryl, wherein each hydrogen atom in the 5 membered heteroaryl is independently optionally substituted by an R3. In some embodiments, X is a triazole, wherein each hydrogen atom in triazole is independently optionally substituted by an R3. In some embodiments, X is an imidazole, wherein each hydrogen atom in imidazole is independently optionally substituted by an R3. In some embodiments, X is a pyrazolone, wherein each hydrogen atom in pyrazolone is independently optionally substituted by an R3. In some embodiments, X is a triazole, wherein one hydrogen atom in triazole is substituted by an R3. In some embodiments, X is an imidazole, wherein one hydrogen atom in imidazole is substituted by an R3. In some embodiments, X is an pyrazolone, wherein one hydrogen atom in pyrazolone is substituted by an R3. [0162] In some embodiments, each of R3 is independently deuterium, halo, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rc. In some embodiments, R3 is C6-C10 aryl, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted by an Rc. In some embodiments, R3 is phenyl, wherein each hydrogen atom in phenyl is independently optionally substituted by an Rc. [0163] In some embodiments, R3 is
Figure imgf000030_0003
, wherein s is 0, 1, 2, or 3. [0164] In some embodiments, s is 1. In some embodiments, s is 2. [0165] In some embodiments, each of Rc, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl. In some embodiments, each Rc, when present, is independently halo or C1-C6 alkoxy. In some embodiments, Rc is halo. In some embodiments, Rc is chloro, fluoro, bromo, or iodo. In some embodiments, Rc is chloro. In some embodiments, Rc is C1-C6 alkoxy. In some embodiments, Rc is methoxy. [0166] In some embodiments, R3 is selected from
Figure imgf000030_0001
[0167] In some embodiments, X is selected from
Figure imgf000030_0002
[0168] In some embodiments, X is selected from
Figure imgf000031_0001
[0169] In some embodiments, W is H, deuterium, -C(O)H, -CN, C1-C6 alkyl-R4, C1-C6 alkyl- C(O)R4, C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo. In some embodiments, W is -CN, C1-C6 alkyl-R4, C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo. [0170] In certain preferred embodiments, W is –CN. [0171] In some embodiments, W is C1-C6 alkyl-R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo. In some embodiments, W is C1-C6 alkyl-R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by halo. In some embodiments, W is C1-C6 alkyl-R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by chloro, fluoro, bromo, or iodo. In some embodiments, W is C1-C6 alkyl-R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by chloro. In some embodiments, W is C1-C6 alkyl-R4, wherein C1-C6 alkyl is methyl. In some embodiments, W is -CHCl-R4. [0172] In some embodiments, W is C(O)R4. [0173] In some embodiments, R4 is independently H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rd. In some embodiments, R4 is a 5-10 membered heteroaryl, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an Rd. In some embodiments, R4 is a benzothiazole, wherein each hydrogen atom in benzothiazole is independently optionally substituted by an Rd. In some embodiments, R4 is a benzooxazole, wherein each hydrogen atom in benzooxazole is independently optionally substituted by an Rd. In some embodiments, R4 is a benzothiazole, wherein each hydrogen atom in benzothiazole is unsubstituted. In some embodiments, R4 is a benzooxazole, wherein each hydrogen atom in benzooxazole is unsubstituted. [0174] In some embodiments, each Rd, when present, is independently deuterium, halo, -OH, - NR5R6, C1-C6 alkoxy, or C1-C6 alkyl. In some embodiments, each Rd, when present, is independently halo. In some embodiments, each Rd, when present, is independently -OH. In some embodiments, each Rd, when present, is independently C1-C6 alkoxy. [0175] In some embodiments, R4 is selected from
Figure imgf000032_0002
, wherein m is 0, 1, or 2. [0176] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0177] In some embodiments, R5 is H, deuterium, or C1-C6 alkyl. In some embodiments, R5 is H. [0178] In some embodiments, R6 is H, deuterium, or C1-C6 alkyl. In some embodiments, R6 is H. [0179] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000032_0001
Figure imgf000033_0002
, , , , and In certain preferred embodiments, the compound is
Figure imgf000033_0004
or
Figure imgf000033_0003
[0180] In some embodiments, a pharmaceutical composition comprises at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. [0181] In some embodiments, a method of treating disease, such as a viral infection, comprises administering to a subject in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. [0182] ALTERNATIVE EMBODIMENTS [0183] 1. A compound of formula
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein Ar is C6-C10 aryl or 5-10 membered heteroaryl, wherein each hydrogen atom in C6-C10 aryl or 5- 10 membered heteroaryl is independently optionally substituted by an Ra; X is H, deuterium, C6-C10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C1-C6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C1-C6 alkyl-5-10 membered heteroaryl, -NR1C(O)R2, -OC(O)R2, -NR1C(O)C1-C6 alkyl-R2, or -OC(O)C1-C6 alkyl-R2, wherein each hydrogen atom in C1-C6 alkyl, C6-C10 aryl, 3- 10 membered heterocyclyl, and 5-10 membered heteroaryl is independently optionally substituted by an R3; W is H, deuterium, -C(O)H, -CN, C1-C6 alkyl-R4, C1-C6 alkyl-C(O)R4, C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo; each of R1, R5, and R6 is independently H, deuterium, or C1-C6 alkyl; R2 is C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl and C3-C8 cycloalkyl is independently optionally substituted by an R3, and wherein each hydrogen atom in 3-10 membered heterocyclyl, C6-C10 aryl and 5-10 membered heteroaryl is independently optionally substituted by an Rb; each of R3 is independently deuterium, halo, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rc; R4 is independently H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rd; and each of Ra, Rc, Rd, and Re, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl; and each of Rb, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1- C6 alkyl, or two Rb taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re. [0184] 2. The compound or pharmaceutically acceptable salt of embodiment 1, wherein Ar is 5- 10 membered heteroaryl, wherein each hydrogen atom 5-10 membered heteroaryl is independently optionally substituted by an Ra. [0185] 3. The compound or pharmaceutically acceptable salt of embodiment 1 or 2, wherein Ar is selected from
Figure imgf000034_0001
wherein n is 0, 1, or 2. [0186] 4. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein each Ra, when present, is independently halo. [0187] 5. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein each Ra, when present, is independently chloro. [0188] 6. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein Ar is selected from
Figure imgf000035_0001
[0189] 7. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein X is H, 5-10 membered heteroaryl, -N(R1)C(O)R2, -OC(O)R2, or -N(R1)C(O)C1-C6 alkyl-R2, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an R3. [0190] 8. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein X is H. [0191] 9. The compound or pharmaceutically acceptable salt of embodiment 7, wherein X is -NR1C(O)R2. [0192] 10. The compound or pharmaceutically acceptable salt of embodiment 7, wherein X is -NR1C(O)C1-C6 alkyl-R2. [0193] 11. The compound or pharmaceutically acceptable salt of embodiment 10, wherein X is -NR1C(O)CH2R2. [0194] 12. The compound or pharmaceutically acceptable salt of embodiment 7, wherein X is -OC(O)R2. [0195] 13. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein R2 is C1-C6 alkyl, 3-10 membered heterocyclyl, or C6-C10 aryl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by an R3, and wherein each hydrogen atom in 3-10 membered heterocyclyl and C6-C10 aryl is independently optionally substituted by an Rb. [0196] 14. The compound or pharmaceutically acceptable salt of embodiment 13, wherein R2 is a C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally substituted by an R3. [0197] 15. The compound or pharmaceutically acceptable salt of embodiment 14, wherein R2 is methyl or trifluoromethyl. [0198] 16. The compound or pharmaceutically acceptable salt of embodiment 13, wherein R2 is a 3-10 membered heterocyclyl, wherein each hydrogen atom in the 3-10 membered heterocyclyl is independently optionally substituted by an Rb. [0199] 17. The compound or pharmaceutically acceptable salt of embodiment 16, wherein R2 is selected from
Figure imgf000036_0002
wherein p is 0, 1, or 2. [0200] 18. The compound or pharmaceutically acceptable salt of embodiment 17, wherein p is 1. [0201] 19. The compound or pharmaceutically acceptable salt of embodiment 17, wherein each Rb, when present, is independently halo. [0202] 20. The compound or pharmaceutically acceptable salt of embodiment 19, wherein Rb is chloro. [0203] 21. The compound or pharmaceutically acceptable salt of embodiment 16, wherein R2 is pyran or morpholine, wherein each hydrogen atom in pyran or morpholine is independently optionally substituted by an Rb. [0204] 22. The compound or pharmaceutically acceptable salt of embodiment 21, wherein two Rb are taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re. [0205] 23. The compound or pharmaceutically acceptable salt of embodiment 22, wherein each Re, when present, is independently halo. [0206] 24. The compound or pharmaceutically acceptable salt of embodiment 22, wherein Re is chloro. [0207] 25. The compound or pharmaceutically acceptable salt of any one of embodiments 16 to 24, wherein R2 is selected from
Figure imgf000036_0001
[0208] 26. The compound or pharmaceutically acceptable salt of embodiment 13, wherein R2 is a C6-C10 aryl, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted by an Rb. [0209] 27. The compound or pharmaceutically acceptable salt of embodiment 26, wherein R2 is naphthalene or phenyl, wherein naphthalene or phenyl is independently optionally substituted by (Rb)q, wherein q is 0, 1, or 2. [0210] 28. The compound or pharmaceutically acceptable salt of embodiment 27, wherein q is 1 or 2. [0211] 29. The compound or pharmaceutically acceptable salt of embodiment 27, wherein each Rb, when present, is independently halo. [0212] 30. The compound or pharmaceutically acceptable salt of embodiment 29, wherein Rb is chloro. [0213] 31. The compound or pharmaceutically acceptable salt of any one of embodiments 26 to 30, wherein R2 is selected from
Figure imgf000037_0001
[0214] 32. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein R1 is H. [0215] 33. The compound or pharmaceutically acceptable salt of embodiment 7, wherein X is a 5-10 membered heteroaryl, wherein each hydrogen atom in the 5-10 membered heteroaryl is independently optionally substituted by an R3. [0216] 34. The compound or pharmaceutically acceptable salt of embodiment 33, wherein X is a triazole, imidazole, or pyrazolone, wherein each hydrogen atom in triazole, imidazole, or pyrazolone is independently optionally substituted by an R3. [0217] 35. The compound or pharmaceutically acceptable salt of embodiment 33, wherein R3 is phenyl, wherein phenyl is independently optionally substituted by (Rc)s, wherein s is 0, 1, 2, or 3. [0218] 36. The compound or pharmaceutically acceptable salt of embodiment 33, wherein R3 is
Figure imgf000037_0002
. [0219] 37. The compound or pharmaceutically acceptable salt of embodiment 35, wherein each Rc, when present, is independently halo or C1-C6 alkoxy. [0220] 38. The compound or pharmaceutically acceptable salt of embodiment 37, wherein C1-C6 alkoxy is methoxy. [0221] 39. The compound or pharmaceutically acceptable salt of embodiment 33, wherein R3 is selected from
Figure imgf000037_0003
[0222] 40. The compound or pharmaceutically acceptable salt of any one of embodiments 33 to 39, wherein X is selected from
Figure imgf000038_0001
[0223] 41. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein W is -CN, C1-C6 alkyl-R4, C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo. [0224] 42. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein W is –CN. [0225] 43. The compound or pharmaceutically acceptable salt of embodiment 41, wherein W is C1-C6 alkyl-R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo. [0226] 44. The compound or pharmaceutically acceptable salt of embodiment 43, wherein W is -CHCl-R4. [0227] 45. The compound or pharmaceutically acceptable salt of embodiment 41, wherein W is C(O)R4. [0228] 46. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein R4 is a 5-10 membered heteroaryl, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an Rd. [0229] 47. The compound or pharmaceutically acceptable salt of any one of the preceding embodiments, wherein R4 is selected from
Figure imgf000038_0002
, wherein m is 0, 1, or 2. [0230] 48. The compound or pharmaceutically acceptable salt of embodiment 47, wherein m is 0. [0231] 49. A compound selected from the group consisting of:
Figure imgf000039_0001
[0232] 50. A pharmaceutical composition comprising at least one compound of embodiment 1, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
[0233] 51. A method of treating disease, such as a viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound of embodiment 1, or a pharmaceutically acceptable salt thereof. [0234] The following represent illustrative embodiments of compounds of the Formula I:
[0235] Table A:
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
[0236] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected. [0237] Pharmaceutical Compositions [0238] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti- oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art. [0239] Sterile compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions. [0240] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration. [0241] For oral administration, the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. [0242] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. [0243] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents. [0244] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. [0245] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository. [0246] For topical applications, the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery. [0247] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. [0248] The term “subject” refers to a mammalian patient in need of such treatment, such as a human. [0249] Exemplary diseases include those caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Ebola virus, Paramyxoviruses, Bunyaviruses (Bunyavirales), Togaviruses, Filoviruses, Picornaviruses, Flaviviruses. In some example, the disease is caused by SARS-CoV-2. [0250] In one aspect, the compounds and pharmaceutical compositions of the invention specifically target SC2MPro. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of this protease. In preferred embodiments, methods of treatment include treating viral infections. In other embodiments, methods are for treating viral infections caused by COVID-19. [0251] In the inhibitory methods of the invention, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. [0252] In treatment methods according to the invention, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID). [0253] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. [0254] Drug Combinations [0255] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention. [0256] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the invention, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For viral infections, additional such agents include, but are not limited to, remdesivir, favipiravir, ribavirin, monoclonal antibodies, dexamethasone, interferon, umifenovir, oseltamivir, lopinavir, and ritonavir. The pharmaceutical compositions of the invention may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents. [0257] Chemical Synthesis
[0258] Exemplary chemical entities useful in methods of the description will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups.
[0259] Abbreviations
[0260] The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:
Figure imgf000048_0001
Figure imgf000049_0002
[0261] Representative Synthetic Procedure I
Figure imgf000049_0001
[0262] Scheme S1. The synthesis of compounds 6 and 7. Reaction conditions: (a) TMS-CN, AcOH, THF; (b) Et3N, Ac2O; (c) NH4Cl, NH3; (d) Et3N, Ac2O.
Figure imgf000050_0001
[0263] Compound 6 [0264] (5-chloropyridin-3-yl)(cyano)methyl acetate: [0265] To a stirred solution of 2-(5-chloropyridin-3-yl)-2-hydroxyacetonitrile (50 mg, 0.29 mmol) in DCM (5 mL) at 0 °C was added Et3N (62 µL, 0.44 mmol). After 15 min, acetic anhydride (33.7 µL, 0.35 mmol) was added, and the mixture was stirred at rt for 3 h. The reaction was quenched with water (5 mL), and the mixture was concentrated in a vacuum. The residue was partitioned between DCM (10 mL) and H2O (5 mL). The aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in a vacuum. The residue was then purified with flash chromatography (0-70% EtOAc in Hexanes as the eluent) to afford Compound 6 as a white solid (40 mg, 64%). [0266] 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 2.3 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.81 (t, J = 2.1 Hz, 1H), 6.38 (s, 1H), 2.14 (s, 3H).13C NMR (101 MHz, CDCl3) δ 168.55, 150.73, 146.65, 135.16, 132.66, 129.05, 114.88, 60.05, 20.33.
Figure imgf000050_0002
[0267] Compound 7 [0268] N-((5-chloropyridin-3-yl)(cyano)methyl)acetamide: [0269] To a stirred solution of 2-amino-2-(5-chloropyridin-3-yl)acetonitrile (50 mg, 0.29 mmol) in DCM (5 mL) at 0 °C was added Et3N (63 µL, 44.9 mmol). After 15 min, acetic anhydride (34 µL, 0.35 mmol) was added, and the mixture was stirred at rt for 3 h. The reaction was quenched with water (5 mL), and the mixture was concentrated in a vacuum. The residue was partitioned between DCM (10 mL) and H2O (5 mL). The aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in a vacuum. The residue was then purified with flash chromatography (0-70% EtOAc in Hexanes as the eluent) to afford Compound 7 as a white solid (41 mg, 66%). [0270] 1H NMR (400 MHz, DMSO) δ 9.24 (d, J = 7.6 Hz, 1H), 8.68 (dd, J = 25.0, 2.1 Hz, 2H), 8.01 (t, J = 1.9 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 1.95 (s, 3H). [0271] Representative Synthetic Procedure II
Figure imgf000051_0001
[0272] Scheme S2. The synthesis of compound 8. Reaction conditions: Et3N, Ac2O. [0273] Compound 8 [0274] N-(cyano(isoquinolin-4-yl)methyl)acetamide: [0275] To a stirred solution of 2-amino-2-(isoquinolin-4-yl)acetonitrile (50 mg, 0.27 mmol) in DCM (5 mL) at 0 °C was added Et3N (57 µL, 0.40 mmol). After 15 min, acetic anhydride (31 µL, 0.32 mmol) was added, and the mixture was stirred at rt for 3 h. The reaction was quenched with water (5 mL), and the mixture was concentrated in a vacuum. The residue was partitioned between DCM (10 mL) and H2O (5 mL). The aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in a vacuum. The residue was then purified with flash chromatography (0-70% EtOAc in Hexanes as the eluent) to afford Compound 8 as a white solid (30 mg, 49%). [0276] 1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 9.33 (d, J = 7.5 Hz, 1H), 8.77 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.99 (ddd, J = 8.5, 6.8, 1.3 Hz, 1H), 7.86 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 1.98 (s, 3H).
[0277] Representative Synthetic Procedure III
Figure imgf000052_0002
[0278] Scheme S3. The synthesis of compounds 3, 4, and 5. Reaction conditions: HATU, DIPEA, DCM.
Figure imgf000052_0001
[0279] Compound 3
[0280] 6-chloro-2V-((5-chloropyridin-3-yl)(cyano)methyl)chromane-4-carboxamide:
[0281] 6-chlorochromane-4-carboxylic acid (100 mg, 0.47 mmol) and 2-amino-2-(5- chloropyridin-3-yl)acetonitrile (94 mg, 0.56mmol) were dissolved in DCM (6.0 ml) and HATU (268 mg, 0.70 mmol) was added. The reaction mixture was stirred at room temperature for 5 min and Hunig’s base (0.12 mL 0.70 mmol) was added. The solution was stirred for 2 hours. The mixture was poured onto an aqueous sodium hydrogen carbonate (saturated, 20 ml) and water (20 ml). The mixture was stirred in an Erlenmeyer flask for 10 min. The aqueous layer was extracted with DCM. The organic layer was washed with brine, dried on MgSO4. It was concentrated under reduced pressure. The crude product was purified by flash (eluted with 20:80 to 55:45 EtOAc/ hexanes) to give the title Compound 3 as a colorless solid (72 mg, 42%). [0282] 1H NMR (400 MHz, DMSO) δ 9.54 (dd, J = 14.0, 7.5 Hz, 1H), 8.73 – 8.48 (m, 2H), 7.97- 7.94 (m, 1H), 7.15 – 6.99 (m, 2H), 6.75 (dd, J = 8.7, 4.8 Hz, 1H), 6.26 (t, J = 7.5 Hz, 1H), 4.27 – 4.03 (m, 2H), 3.72 (td, J = 5.8, 3.3 Hz, 1H), 2.07 – 1.93 (m, 2H).13C NMR (101 MHz, DMSO) δ 173.12, 153.92, 149.27, 146.98, 135.15, 132.35, 131.69, 129.19, 128.59, 124.01, 122.17, 119.10, 117.81, 64.02, 41.92, 25.16.
Figure imgf000053_0001
[0283] Compound 4 [0284] 2-(6-chloro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-((5-chloropyridin-3- yl)(cyano)methyl)acetamide: [0285] 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J = 8.1, 2.2 Hz, 2H), 7.76 – 7.64 (m, 2H), 6.68 – 6.58 (m, 2H), 6.32 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 8.8 Hz, 1H), 4.26 – 4.15 (m, 2H), 3.83 (s, 2H), 3.40 – 3.29 (m, 2H).
Figure imgf000053_0002
[0286] Compound 5 [0287] 7-chloro-N-((5-chloropyridin-3-yl)(cyano)methyl)-1-naphthamide: [0288] 1H NMR (400 MHz, DMSO) δ 9.99 (d, J = 7.4 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.20 – 8.13 (m, 2H), 8.09 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 7.1, 1.3 Hz, 1H), 7.64 (ddd, J = 7.2, 4.4, 2.2 Hz, 2H), 6.59 (d, J = 7.3 Hz, 1H).
[0289] Representative Synthetic Procedure IV
Figure imgf000054_0002
[0290] Scheme S4. The synthesis of compounds 9 and 10. Reaction conditions: (a) ethyl benzo[d]thiazole-2-carboxylate, LDA, THF, -78 °C; (b) NaBH4, MeOH, 0 °C to rt; (c) SOCl2, DCM.
Figure imgf000054_0001
[0291] Compound 10 [0292] 1-(benzo[d]thiazol-2-yl)-2-(5-chloropyridin-3-yl)ethan-1-one: [0293] A solution of compound 3-chloro-5-methylpyridine (200 mg, 1.57 mmol) in anhydrous THF (6 mL) was treated at −78 °C with freshly made LDA (3.14 mL, 3.14 mmol). After 45 min stirring, a solution of compound ethyl benzo[d]thiazole-2-carboxylate (390 mg, 1.88 mmol) in THF (2.5 mL) was added dropwise. The resulting mixture was then stirred for 15 min at −78 °C and quenched at this temperature by the addition of saturated NH4Cl (15 mL). Upon warming to room temperature, the reaction was diluted with EtOAc (10 mL), and brine (8 mL), and dried over MgSO4. Concentration under reduced pressure, followed by flash chromatography (silica gel, 0–20 % EtOAc/hexane gradient) afforded compound Compound 10 as a colorless solid (340 mg, 76 %). [0294] 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 10.2, 2.1 Hz, 2H), 8.24 – 8.06 (m, 1H), 7.93 (dt, J = 7.9, 0.9 Hz, 1H), 7.69 (t, J = 2.1 Hz, 1H), 7.58-7.45 (m, 2H), 4.53 (s, 2H).13C NMR (101 MHz, CDCl3) δ 190.98, 165.08, 153.43, 148.73, 147.59, 137.62, 137.25, 131.98, 130.50, 128.17, 127.31, 125.70, 122.55, 41.51.
Figure imgf000054_0003
[0295] Compound 9 [0296] 2-(1-chloro-2-(5-chloropyridin-3-yl)ethyl)benzo[d]thiazole: [0297] 1-(benzo[d]thiazol-2-yl)-2-(5-chloropyridin-3-yl)ethan-1-one Compound 10 (200 mg, 0.69 mmol) is dissolved in methanol (10 mL) and cooled to 0 °C. To this Sodium borohydride (40 mg, 1.04 mmol) is added and stirred for 30 min. After 30 min, the reaction is quenched with water, volatiles is concentrated, and crude was extracted with DCM. The combined organic layers are dried (MgS04), filtered, and concentrated and the crude is used immediately after drying. To a solution of the crude intermediate (140 mg, 0.48 mmol) in DCM was slowly added SOCl2 (0.07 mL, 0.96 mmol) at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was quenched with ice/H2O and neutralized with saturated NaHCO3 solution. The organic phase was collected and washed with brine three times, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by flash chromatography (silica gel, 0–20 % EtOAc/hexane gradient) afforded compound Compound 9 as a colorless solid (100 mg, 67 %). [0298] 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.72 – 7.65 (m, 1H), 7.58 (t, J = 2.1 Hz, 1H), 7.53 – 7.46 (m, 1H), 7.39 – 7.27 (m, 2H), 5.18 (dd, J = 8.3, 6.5 Hz, 1H), 3.68 (dd, J = 14.5, 6.5 Hz, 1H), 3.49 (dd, J = 14.5, 8.3 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 162.16, 150.82, 148.43, 147.89, 140.49, 136.77, 132.83, 131.98, 126.25, 125.04, 120.73, 111.00, 52.81, 38.65. [0299] Representative Synthetic Procedure V
Figure imgf000055_0001
[0300] Scheme S5. The synthesis of compound 11. Reaction conditions: (a) CuBr2, EtOAc, 80 °C; (b) 1H-benzo[d][1,2,3]triazole, TBAF, THF.
Figure imgf000055_0002
[0301] 1-(benzo[d]thiazol-2-yl)-2-bromoethan-1-one: [0302] A mixture of anhydrous cuprous bromide (1 g, 7.5 mmol) and 1-(benzo[d]thiazol-2- yl)ethan-1-one (0.88 g, 5 mmol) in ethyl acetate (10 mL) was refluxed for 24 h. After cooling, the precipitate was filtered and washed with ethyl acetate (3 x 5 mL). The solvent was removed by distillation from the combined solutions and the crude product was purified by flash column chromatography. [0303] 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.7 Hz, 1H), 7.97 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 4.80 (s, 1H).
Figure imgf000056_0001
[0304] Compound 11 [0305] 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-(benzo[d]thiazol-2-yl)ethan-1-one: [0306] Compounds 1-(benzo[d]thiazol-2-yl)-2-bromoethan-1-one and 1H- benzo[d][1,2,3]triazole were added in a roundbottom flask and TBAF was added. Reaction was stirred for 30 min. Reaction product was purified by flash column chromatography. [0307] 1H NMR (400 MHz, CDCl3) δ 8.25 – 8.18 (m, 1H), 8.07 (dt, J = 8.4, 0.9 Hz, 1H), 8.01 – 7.94 (m, 1H), 7.65 – 7.51 (m, 2H), 7.50 – 7.31 (m, 3H), 6.37 (s, 2H). [0308] Representative Synthetic Procedure VI
Figure imgf000056_0002
[0309] Scheme S6. The synthesis of compound 12. Reaction conditions: COMU, DCM, NMM, 0 °C. [0310] Compound 12 [0311] 3,4-dichloro-N-(cyano(isoquinolin-4-yl)methyl)benzamide [0312] To a solution of 3,4-dichlorobenzoic acid (104 mg, 0.546 mmol) and 2-amino-2- (isoquinolin-4-yl)acetonitrile (100 mg, 0.546 mmol) in anhydrous DCM was added NMM (0.22 mL, 2.185 mmol) and was cooled to 0 °C. COMU (278 mg, 0.655 mmol) was added to the solution under 0 °C and then stirred at the same room temperature for 3 h. The reaction mixture was then washed with saturated NaHCO3 solution (2 X 30 mL), and saturated brine solution (2 X 10 mL) sequentially. The organic layer was dried over anhydrous Na2SO4 and then concentrated on vacuum. The residue was then purified with flash chromatography (10-40% EtOAc in hexanes as the eluent) to afford Compound 12 as half-white solid. [0313] 1H NMR (400 MHz, DMSO) δ 9.99 (d, J = 7.3 Hz, 1H), 9.45 (s, 1H), 8.81 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.96 – 7.84 (m, 2H), 7.80 (dd, J = 8.3, 5.4 Hz, 2H), 7.07 (d, J = 7.2 Hz, 1H). [0314] Representative Synthetic Procedure VII
Figure imgf000057_0001
[0315] Scheme S7. The synthesis of compound 19. Reaction conditions: (a) TMS-CN, AcOH:H2O; (b) NH4Cl, Aq. NH3; (c) Et3N, TFAA. [0316] Compound 19 [0317] N-(cyano(isoquinolin-4-yl) methyl)-2,2,2-trifluoroacetamide: [0318] To a stirred solution of 2-amino-2-(isoquinolin-4-yl)acetonitrile (70 mg, 0.38 mmol) in DCM (5 mL) at 0 °C was added Et3N (78 µL, 0.57 mmol). After 15 min, trifluoroacetic anhydride (TFAA) (64 µL, 0.46 mmol) was added, and the mixture was stirred at rt for 3 h. The reaction was quenched with water (5 mL), and the mixture was concentrated on vacuum. The residue was partitioned between DCM (10 mL) and H2O (5 mL). The aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in a vacuum. The residue was then purified with flash chromatography (0-70% EtOAc in Hexanes as the eluent) to afford Compound 19 as a white solid (45 mg, 42%). [0319] 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 9.00 (d, J = 8.2 Hz, 1H), 8.40 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.77 – 7.71 (m, 1H), 6.72 (d, J = 8.5 Hz, 1H). [0320] Biological Examples [0321] MPro Expression and Purification. [0322] The expression plasmid pET28a-His-SUMO-MPro was constructed and used to transform E. coli BL21(DE3) cells. A single colony grown on a LB plate containing 50 µg/mL kanamycin was picked and grown in 5 mL LB media supplemented with 50 µg/mL kanamycin overnight. This overnight culture was inoculated to 6 L 2YT media with 50 µg/mL kanamycin. Cells were grown to OD600 as 0.8. At this point, 1 mM IPTG was added to induce the expression of His- SUMO-MPro. Induced cells were let grown for 3 h and then harvested by centrifugation at 12,000 rpm, 4 °C for 30 min. Cell pellets were resuspended in 150 mL lysis buffer (20 mM Tris-HCl, 100 mM NaCl, 10 mM imidazole, pH 8.0) and lysed the cells by sonication on ice. The lysate was clarified by centrifugation at 16,000 rpm, 4 °C for 30 min. The supernatant was decanted and mixed with Ni-NTA resins (GenScript). The resins were loaded to a column, washed the resins with 10 volumes of lysis buffer, and eluted the bound protein using elution buffer (20 mM Tris- HCl, 100 mM NaCl, 250 mM imidazole, pH 8.0). Buffer of the elute was exchanged to another buffer (20 mM Tris-HCl, 100 mM NaCl, 10 mM imidazole, 1 mM DTT, pH 8.0) using a HiPrep 26/10 desalting column (Cytiva) and digested the elute using 10 units SUMO protease overnight at 4 °C. The digested elute was subjected to Ni-NTA resins in a column to remove His-tagged SUMO protease, His-tagged SUMO tag, and undigested His-SUMO-MPro. The flow-through was loaded onto a Q-Sepharose column and purified MPro using FPLC by running a linear gradient from 0 to 500 mM NaCl in a buffer (20 mM Tris-HCl, 1 mM DTT, pH 8.0). Fractions eluted from the Q-Sepharose column was concentrated and loaded onto a HiPrep 16/60 Sephacryl S-100 HR column and purified using a buffer containing 20 mM Tris-HCl, 100 mM NaCl, 1 mM DTT, and 1 mM EDTA at pH 7.8. The final purified was concentrated and stored in a -80 °C freezer. [0323] In Vitro MPro Inhibition Potency Characterizations. [0324] The assay is conducted using 20 nM MPro and 10 µM Sub3. For synthesized compounds, 10 nM MPro is used. All compounds are dissolved in DMSO as 10 mM stock solutions. Sub3 is dissolved in DMSO as a 1 mM stock solution and is diluted 100 times in the final assay buffer containing 10 mM NaxHyPO4, 10 mM NaCl, 0.5 mM EDTA, and 1.25% DMSO at pH 7.6. MPro and the compounds are incubated in the final assay buffer for 30 min before adding the substrate to initiate the reaction catalyzed by MPro. The production format is monitored in a fluorescence plate reader with excitation at 336 nm and emission at 455 nm. [0325] In cellulo MPro Inhibition Potency Characterizations. [0326] HEK 293T/17 cells are grown in high-glucose DMEM with GlutaMAX supplement and 10% FBS in 10 cm culture plates under 37 °C and 5% CO2 to 80-90% confluency and then transfected cells with the pLVX-MPro-eGFP-2 plasmid. 30 mg/mL polyethyleneimine and the total of 8 µg of the plasmid in 500 µL opti-MEM media are used for transfection. Transfected cells are incubated overnight. On the second day, cells are collected using 0.05% trypsin-EDTA to detach them from plates, resuspended collected cells in the original growth media, adjusted the cell density to 5x105 cells/mL, added 500 µL adjusted cells to each well of a 48-well plate, and then added 100 µL of a drug solution in DMEM. Treated cells are incubated under 37 °C and 5% CO2 for 72 h. After 72 h incubation, cells are collected using trypsinization and centrifugation. Collected cells are resuspended in 200 µL PBS and analyzed cells with fluorescence using a Cytoflex Research Flow Cytometer based on the size scatters (SSC-A and SSC-H) and forward scatter (FSC-A). Cells are gated based on SSC-A and FSC-A then with SSC-A and SSC-H. Fluorescence is detected with excitation at 488 nm and emission at 525 nm. All collected data are converted to csv files and analyzed using a self-prepared MATLAB script for massive data processing. The FITC-A column is sorted from lowest to highest. A 106 cutoff is set to separate the column to two groups with higher than 106 as positive and lower than 106 as negative. The positive group is integrated and divided the total integrated fluorescence intensity by the total cell positive cell counts. The standard deviation of positive fluorescence is calculated. All processed data are plotted and fitted to a four-parameter Hill equation in GraphPad 9.0 to obtain determined EC50 values. [0327] Cell-based Assay for SARS-CoV-2 Inhibition Potency Characterizations. [0328] A slightly modified cytopathic effect (CPE)-based microneutralization assay is used to evaluate the drug efficacy against SARS-CoV-2 infection. Briefly, confluent african green monkey kidney cells (Vero E6) or human alveolar epithelial A549 cells stably expressing human ACE2 viral receptor, designated A549/hACE2, grown in 96-wells microtiter plates are pre-treated with serially 2-folds diluted individual drugs for two hours before infection with 100 or 500 infectious SARS-CoV-2 (USA-WA1/2020) particles in 100 μl EMEM supplemented with 2% FBS, respectively. Cells pre-treated with parallelly diluted dimethyl sulfoxide (DMSO) with or without virus are included as positive and negative controls, respectively. After cultivation at 37 °C for 3 days, individual wells are observed under the microcopy for the status of virus-induced formation of CPE. The efficacy of individual drugs is calculated and expressed as the lowest concentration capable of completely preventing virus-induced CPE in 100% (EC100) or 50% (EC50) of the wells. All compounds are dissolved in 100% DMSO as 10 mM stock solutions before subjecting to dilutions with culture media. [0329] The following represent biological data of compounds of the Formula I: [0330] Table B:
Figure imgf000059_0001
Figure imgf000060_0001

Claims

WHAT IS CLAIMED IS: 1. A compound of formula
Figure imgf000061_0001
or a pharmaceutically acceptable salt thereof, wherein Ar is C6-C10 aryl or 5-10 membered heteroaryl, wherein each hydrogen atom in C6-C10 aryl or 5-10 membered heteroaryl is independently optionally substituted by an Ra; X is H, deuterium, C6-C10 aryl, 3-10 membered heterocyclyl, -C(O)-3-10 membered heterocyclyl, C1-C6 alkyl-3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, C1-C6 alkyl-5-10 membered heteroaryl, -NR1C(O)R2, -OC(O)R2, -NR1C(O)C1-C6 alkyl-R2, or -OC(O)C1-C6 alkyl-R2, wherein each hydrogen atom in C1-C6 alkyl, C6-C10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl is independently optionally substituted by an R3; W is H, deuterium, -C(O)H, -CN, C1-C6 alkyl-R4, C1-C6 alkyl-C(O)R4, C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo; each of R1, R5, and R6 is independently H, deuterium, or C1-C6 alkyl; R2 is C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl and C3-C8 cycloalkyl is independently optionally substituted by an R3, and wherein each hydrogen atom in 3-10 membered heterocyclyl, C6-C10 aryl and 5-10 membered heteroaryl is independently optionally substituted by an Rb; each of R3 is independently deuterium, halo, -OH, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rc; R4 is independently H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl is independently optionally substituted by an Rd; each of Ra, Rc, Rd, and Re, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl; and each of Rb, when present, is independently deuterium, halo, -OH, -NR5R6, C1-C6 alkoxy, or C1-C6 alkyl, or two Rb taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re.
2. The compound or pharmaceutically acceptable salt of claim 1, wherein Ar is 5-10 membered heteroaryl, wherein each hydrogen atom 5-10 membered heteroaryl is independently optionally substituted by an Ra.
3. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein Ar is selected from
Figure imgf000062_0002
and
Figure imgf000062_0003
wherein n is 0, 1, or 2.
4. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein each Ra, when present, is independently halo.
5. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein each Ra, when present, is independently chloro.
6. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein Ar is selected from
Figure imgf000062_0001
7. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein X is H, 5-10 membered heteroaryl, -N(R1)C(O)R2, -OC(O)R2, or -N(R1)C(O)C1- C6 alkyl-R2, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an R3.
8. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein X is H.
9. The compound or pharmaceutically acceptable salt of any one of claims 1-7, wherein X is -NR1C(O)R2.
10. The compound or pharmaceutically acceptable salt of any one of claims 1-7, wherein X is -NR1C(O)C1-C6 alkyl-R2.
11. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 10, wherein X is -NR1C(O)CH2R2.
12. The compound or pharmaceutically acceptable salt of any one of claims 1-7, wherein X is -OC(O)R2.
13. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein R2 is C1-C6 alkyl, 3-10 membered heterocyclyl, or C6-C10 aryl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by an R3, and wherein each hydrogen atom in 3-10 membered heterocyclyl and C6-C10 aryl is independently optionally substituted by an Rb.
14. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein R2 is a C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally substituted by an R3.
15. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein R2 is methyl or trifluoromethyl.
16. The compound or pharmaceutically acceptable salt of any one of claims 1-13, wherein R2 is a 3-10 membered heterocyclyl, wherein each hydrogen atom in the 3-10 membered heterocyclyl is independently optionally substituted by an Rb.
17. The compound or pharmaceutically acceptable salt of any one of claims 1-13 and 16, wherein R2 is selected from
Figure imgf000063_0001
wherein p is 0, 1, or 2.
18. The compound or pharmaceutically acceptable salt of claim 17, wherein p is 1.
19. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein each Rb, when present, is independently halo.
20. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein Rb is chloro.
21. The compound or pharmaceutically acceptable salt of claim 16, wherein R2 is pyran or morpholine, wherein each hydrogen atom in pyran or morpholine is independently optionally substituted by an Rb.
22. The compound or pharmaceutically acceptable salt of any one of claims 16 and 21, wherein two Rb are taken together with the carbon atoms to which they are attached combine to form a fused C6-C10 aryl ring, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted with an Re.
23. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein each Re, when present, is independently halo.
24. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein Re is chloro.
25. The compound or pharmaceutically acceptable salt of any one of claims 1-13 and 16 to 24, wherein R2 is selected from
Figure imgf000064_0001
26. The compound or pharmaceutically acceptable salt of any one of claims 1-13, wherein R2 is a C6-C10 aryl, wherein each hydrogen atom in C6-C10 aryl is independently optionally substituted by an Rb.
27. The compound or pharmaceutically acceptable salt of any one of claims 1-13 and 26, wherein R2 is naphthalene or phenyl, wherein naphthalene or phenyl is independently optionally substituted by (Rb)q, wherein q is 0, 1, or 2.
28. The compound or pharmaceutically acceptable salt of claim 27, wherein q is 1 or 2.
29. The compound or pharmaceutically acceptable salt of any one of claims 1-21 and 26-27, wherein each Rb, when present, is independently halo.
30. The compound or pharmaceutically acceptable salt of any one of claims 1-21 and 26-29, wherein Rb is chloro.
31. The compound or pharmaceutically acceptable salt of any one of claims 1-13 and 26 to 30, wherein R2 is selected from
Figure imgf000064_0002
32. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein R1 is H.
33. The compound or pharmaceutically acceptable salt of any one of claims 1-7, wherein X is a 5-10 membered heteroaryl, wherein each hydrogen atom in the 5-10 membered heteroaryl is independently optionally substituted by an R3.
34. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 33, wherein X is a triazole, imidazole, or pyrazolone, wherein each hydrogen atom in triazole, imidazole, or pyrazolone is independently optionally substituted by an R3.
35. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 33-34, wherein R3 is phenyl, wherein phenyl is independently optionally substituted by (Rc)s, wherein s is 0, 1, 2, or 3.
36. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 33-35, wherein R3 is
Figure imgf000065_0001
.
37. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 35-36, wherein each Rc, when present, is independently halo or C1-C6 alkoxy.
38. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 37, wherein Rc is chloro or methoxy.
39. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 33-38, wherein R3 is selected from
Figure imgf000065_0002
.
40. The compound or pharmaceutically acceptable salt of any one of claims 1-7 and 33-39, wherein X is selected from ,
Figure imgf000065_0003
41. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein W is -CN, C1-C6 alkyl-R4, C(O)R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo.
42. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein W is –CN.
43. The compound or pharmaceutically acceptable salt of any one of claims 1-41, wherein W is C1-C6 alkyl-R4, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium or halo.
44. The compound or pharmaceutically acceptable salt of any one of claims 1-41 and 43, wherein W is -CHCl-R4.
45. The compound or pharmaceutically acceptable salt of any one of claims 1-41, wherein W is C(O)R4.
46. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein R4 is a 5-10 membered heteroaryl, wherein each hydrogen atom in 5-10 membered heteroaryl is independently optionally substituted by an Rd.
47. The compound or pharmaceutically acceptable salt of any one of the preceding claims, wherein R4 is
Figure imgf000066_0001
, wherein m is 0, 1, or 2.
48. The compound or pharmaceutically acceptable salt of claim 47, wherein m is 0.
49. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is selected from the group consisting of:
Figure imgf000066_0002
Figure imgf000067_0001
50. A pharmaceutical composition comprising at least one compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
51. A method of treating disease, such as a viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1- 49, or a pharmaceutically acceptable salt thereof.
PCT/US2023/079356 2022-11-10 2023-11-10 Non-peptidic sars-cov-2 main protease inhibitors WO2024102989A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010129816A2 (en) * 2009-05-07 2010-11-11 Intellikine, Inc. Heterocyclic compounds and uses thereof
WO2022047054A2 (en) * 2020-08-27 2022-03-03 The Texas A&M University System Inhibitors of sars cov-2 infection and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010129816A2 (en) * 2009-05-07 2010-11-11 Intellikine, Inc. Heterocyclic compounds and uses thereof
WO2022047054A2 (en) * 2020-08-27 2022-03-03 The Texas A&M University System Inhibitors of sars cov-2 infection and uses thereof

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