WO2022072975A1 - Compositions et méthodes de traitement du sras-cov-2 par inhibition de protéase à papaïne - Google Patents

Compositions et méthodes de traitement du sras-cov-2 par inhibition de protéase à papaïne Download PDF

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WO2022072975A1
WO2022072975A1 PCT/US2021/071439 US2021071439W WO2022072975A1 WO 2022072975 A1 WO2022072975 A1 WO 2022072975A1 US 2021071439 W US2021071439 W US 2021071439W WO 2022072975 A1 WO2022072975 A1 WO 2022072975A1
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compound
substituted
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compounds
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Scott Pegan
Ian DURIE
Brendan FREITAS
Ralph Tripp
Brian Cummings
David Crich
Daniil AHIADORME
Yagya SUBEDI
Emmanuel ONOBUN
Jarvis Hill
Kapil UPADHYAYA
Mike PIRRONE
Rahul Bagul
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University Of Georgia Research Foundation, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • sequence identifier numbers (SEQ ID NO).
  • SEQ ID NOs correspond numerically to the sequence identifiers ⁇ 400>1 , ⁇ 400>2, etc.
  • the Sequence Listing in written computer readable format (CRF), is incorporated by reference in its entirety.
  • betacoronaviruses have spilled over from animals to cause disease outbreaks in humans on multiple occasions with often deleterious outcomes. Coronaviruses can be divided into four branches, and betacoronaviruses can be further broken down into four subgroups, 2a-2d. In 2015, it was found that subgroup 2b contained not only the 2003 pandemic causing SARS-CoV-1 but a cluster of 15 SARS-like coronaviruses. Many of these SARS-like viruses are prevalent among Chinese horseshoe bats but also have been shown to infect a range of diverse hosts. Additionally, these viruses were found to be similar enough that merely replacing their spike protein with that of SARS-CoV-1 enabled them to productively infect primary human airway cells.
  • betacoronaviruses upon infection translate two polypeptides pp1a and pplab, which are cleaved into 16 nonstructural proteins (Nsp1 to Nsp16).
  • Nsp1-16 form the virus's membrane bound replicase complex, which is necessary to transcribe the viral RNA genome prior to translation.
  • CoVs encode two proteases that process the polyproteins into their functional units.
  • the 3C-like protease also known as the main protease, cleaves Nsp4-Nsp16.
  • the papain-like protease (PLpro) cleaves Nsp1-3.
  • the genomes of coronaviruses can contain up to two PLPs. However, the genomes of group 2b viruses mirror that of Middle East respiratory syndrome (MERS) CoV, a subgroup 2c virus by encoding only one PLpro.
  • MERS Middle East respiratory syndrome
  • PLpros as well as papain-like protease 2 (PLP2) in two papain-like proteases, have demonstrated immunosuppressive effects on host organisms by reversing post-translational modification by ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15).
  • Ub post-translational modification
  • ISG15 interferon-stimulated gene product 15
  • Post- translational modification with Ub and ISG15 has a profound impact on host type-l IFN and NFKB inflammatory responses, as well as upregulating the production of cytokines, chemokines, and other ISGs.
  • Ub-like protein (Ubl) modifiers have been shown to facilitate inhibition, sequestration, or proteasomal degradation of marked proteins.
  • Ubl Ub-like protein
  • viral encoded PLpros can allow critical viral proteins to remain intact, active, and suppress an anti-viral immune state until the virus is able to replicate.
  • BtSCoV-Rf1 BtSCoV-Rf1.2004 is a group 2b virus isolated from greater horseshoe bats, and of the currently identified 2b viruses it is the most distantly related to SARS- CoV-1 other than SARS-CoV-2 (FIGs. 1A-1B).
  • the effective inhibitors can be categorized into two sets: series I compounds, which typically utilize an amide backbone, and series II compounds such as 6577871 , which commonly have a piperidine scaffold. Both categories have proven effective in inhibiting PLpros from SARS-CoV-1 and SARS-CoV-2 but are not fully optimized in backbone structure or arene ring decoration. Additionally, it remains unknown whether these inhibitors would be effective against a wider array of coronavirus group 2b PLpros.
  • Protease inhibitors have a long history of being used as a basis for antiviral therapy, the most salient examples being HIV and Hepatitis C. Within coronaviruses themselves, main protease inhibitors have been shown to reverse the progression of fatal coronavirus infection. With no therapeutics available for the treatment of those infected by SARS-CoV-2, and with virus variants emerging against which existing vaccines may not be fully effective, there is an overwhelming need to identify lead compounds that are effective against proposed viral drug targets with SARS-CoV-2. The lead compounds would ideally have low cellular toxicity in multiple cell lines and be metabolically stable. These needs and other needs are satisfied by the present disclosure.
  • the disclosure in one aspect, relates to viral papain protease inhibitors, methods of making the same, pharmaceutical compositions comprising the same, and methods of treating and/or preventing COVID-19 and other coronavirus diseases using the same.
  • the papain protease inhibitors have a core or linker structure featuring at least one nitrogen atom and substituted or unsubstituted cycloalkyl, aromatic, or heteroaromatic groups on either side of the core structure.
  • the papain protease inhibitors are capable of ablating viral deubiquitination and/or delSGase activity.
  • FIGs. 1A-1B show a sequence alignment of PLPs from SARS family coronaviruses including conserved structural features. Sequences shown are for BtSCoV-Rf1 .2004 (SEQ ID NO. 1), SARS-CoV-2 (accession number SEQ ID NO. 2), SARS-CoV-1 SEQ ID NO. 3), SZ16 (SEQ ID NO. 4), HKU3.2 (SEQ ID NO. 5), Rm1.2004 (SEQ ID NO. 6), MERS-CoV (SEQ ID NO. 7), and NL63 (SEQ ID NO. 8). The secondary structure shown is the predicted by DSSP for BtSCoV-Rf 1.2004 PLpro. Similarity and alignment calculations were performed using ClustalW.
  • Residue positions that are fully conserved are marked in gray with white text, with those being highly conserved marked in gray with black text.
  • Residues that form the zinc finger motif are marked with stars at positions 191 and 194, while other residues forming the catalytic triad are marked with black stars at other positions.
  • Residues forming interactions between the Ubl domain and thumb domain of PLpros are marked in light gray stars.
  • the BL2 loop is boxed in gray (final row of FIG. 1B).
  • FIG. 2A shows a surface rendering of a SARS-CoV-2 PLpro homology model highlighting its differences with SARS-CoV-1 PLpro.
  • the SARS-CoV-2 PLpro is shown in gray, with the proximal ubiquitin binding site in dark gray (left front region) and the distal ubiquitin binding site in dark gray (top center region near “thumb domain” label). Amino acid sites where PLpro differs between SARS-CoV-2 and SARS-CoV are labeled.
  • FIG. 2B shows the opposite face of the model.
  • FIG. 3A shows activity of BtSCoV-Rf1 .2004 PLpro for different linkages of poly-Ub.
  • FIG. 3A At 37 °C, 10 ⁇ M each of M1 , K6, K11 , K27, K29, K33, K48, and K63 linked di-Ub were incubated with 20 nM BtSCoV-Rf1 .2004 PLpro. Samples were taken from the reaction tube at indicated time points.
  • FIG. 3B Under similar reaction conditions 13.65 ⁇ M each of K48 and K63 linked tetra-Ub was incubated with 23 nM PLpro for 3 hours with samples taken at given time points.
  • FIG. 4 shows activity of BtSCoV-Rf 1.2004 PLpro for prolSG15 from multiple species.
  • BtSCoV-Rf 1.2004 PLpro was evaluated for the cleavage of prolSG15s from the following species (NCBI accession numbers following species names): human (Homo sapiens, AAH09507.1), cow (Bos taurus; NP_776791.1), vesper bat (Myotis davidir, ELK23605.1), Egyptian fruit bat (Rousettus aegyptiacus ⁇ XP_015999857.1), pig (Sus scrota, ACB87600.1), hedgehog (Erinaceus europaeus: XP_007525810.2), mouse (Mus musculus: AAB02697.1), dromedary camel (Camelus dromedarius: XP_010997700.1), sheep (Ovis aries: AF152103.1), northern
  • each ISG15 was incubated with 20 nM of SARS-CoV-2 PLpro for at least 1 hr with samples taken at the time points indicated.
  • the summary of the prolSG15 cleavage assays for BtSCoV-Rf1 .2004 PLpro is presented as a heat map where a lower number of squares indicates low or no cleavage and a higher number of squares indicates relatively robust cleavage.
  • FIGs. 5A-5C show tertiary Structure of group 2b PLpros
  • FIG. 5A Cartoon representation of BtSCoV-Rf1 .2004 PLpro secondary structure with helix and sheet labels corresponding to FIG. 1 dssp calculations
  • FIG. 5B Overlaid cartoon representations of BtSCoV-Rf1 .2004 PLpro, SARS- CoV-1 PLpro (PDB 3E9S), and SARS-CoV-2 PLpro (PDB 7JIR). The four PLpro domains are labeled and boxed with gray shaded regions, from left to right as pictured: Fingers, Palm, Thumb, Ubl.
  • FIG. 5C Overlaid cartoon representations of BtSCoV-Rf1.2004 PLpro, MERS-CoV PLpro (PDB 5W8T), and MHV PLP (5WFI) with their Ubl domains represented by ribbons.
  • FIGs. 6A-6C show inhibitor binding pocket of three group 2b viruses.
  • FIG. 6A A Fo-Fc electron density map is shown contoured at 1o (mesh), with GRL0617 shown in light gray and BtSCoV-Rf1 PLpro shown in dark gray.
  • FIG. 6B Stereoview of GRL0617 (stick structure) bound to BtSCoV-Rf1 PLpro overlaid with SARS-CoV-2 (white surface and dark areas) showing a possible path to active site for future inhibitors.
  • FIG. 6C Stereoview overlay of GRL0167 bound to three different SARS-CoV PLpros: BtSCoV-Rf1 , SARS-CoV-1 , and SARS-CoV-2.
  • FIG. 7 shows crystal contacts affecting PLpro conformation Zinc finger loops of the two domains differ due to a crystal contact being made by chain B.
  • GRL0617 of chain B is shifted in the binding pocket due to a crystal contact with chain B V226.
  • FIGs. 8A-8B show BtSCoV-Rf1 PLpro in complex with DC12.
  • FIG. 8A A 2Fo-Fc electron density map is shown contoured at 1o (mesh) with DC12 and BtSCoV-Rf1 PLpro.
  • FIG. 8B Overlay of DC37 (dark gray stick structures) bound to SARS-CoV-2 PLpro (light gray stick structures).
  • FIG. 9A shows key hydrophobic and hydrogen bonding interactions of series I inhibitor GRL0617.
  • FIG. 9B shows ley hydrophobic and hydrogen bonding interactions of a series II inhibitor.
  • papain protease inhibitors useful for the treatment of SARS-CoV-2 and other human and animal coronaviruses.
  • the papain protease inhibitors have a structure of Formula I:
  • L forms a scaffold, linker, or central core of the compounds
  • V, W, and R 1 form a “Western” element as referred to elsewhere herein
  • X, Y, Z, and R 2 form an “Eastern” element as referred to elsewhere herein.
  • V can be selected from an aryl group, a fused aryl group, a cycloalkyl group, or a fused cycloalkyl group.
  • exemplary substituents in this position include, but are not limited to, the following:
  • W can be N or CH.
  • R 1 can be hydrogen or a substituted or unsubstituted alkyl group such as, for example, methyl or aminomethyl.
  • L can be selected from the following:
  • R 3 is hydrogen.
  • Y can be CH or N or can be absent.
  • R 2 can be selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, -CH 2 OH, -CH 2 NH 2 , -CH 2 CHOHCH 2 OH, -CH 2 CHOHCH 2 NH 2 , -CH 2 CHNH 2 CH 2 OH, -CH 2 CH 2 OH, and -CH 2 CH 2 NH 2 .
  • R 2 is hydrogen.
  • Z can be a substituted or unsubstituted aryl or heteroaryl group.
  • the substituted or unsubstituted aryl group can include one or more of a C1-C4 alkyl substituent, an amino substituent, a C1-C4 alkoxy substituent, a substituted or unsubstituted amide substituent, a nitro group, a halogen such as, for example, -Cl, -Br, -F, or -I, a dioxolane fused to the aryl or heteroaryl group, or any combination thereof.
  • Z can be selected from the following:
  • Z when Y is absent, Z can be covalently bonded to X. In a further aspect, when X and Y are both absent, Z can be covalently bonded to L.
  • V is selected from a fused aryl group having 3 or 4 rings, a fused cycloalkane, a bridged cycloalkane, or a polycyclic alkane
  • W, R 1 , X, Y, R 2 , and Z are defined as described above, and L can be selected from
  • V can be selected from
  • the papain protease inhibitor has Formula II, Formula III, Formula IV, Formula V, or Formula VI:
  • the papain protease inhibitors disclosed herein can have one or more stereocenters.
  • the stereocenters can have an R configuration, an S configuration, a scalemic mixture of R and S configurations, and/or a racemic mixture of R and S configurations.
  • the papain protease inhibitors can be synthesized from enantiomerically or diastereomerically pure starting materials and retain the absolute configuration of the starting materials in the final product.
  • chirality can be introduced during synthesis of the papain protease inhibitors. Further in this aspect, an enantiomeric excess of R or S compound can be synthesized based on reaction conditions, or a racemic mixture can result.
  • stereoisomers such as, for example, column chromatography with a chiral stationary phase, can be employed to separate a desired enantiomer or diastereomer from the mixed-stereochemistry reaction product.
  • stereoisomers are not separated.
  • reagents for step (i) can include, but are not limited to, acetic acid, and sodium cyanoborohydride in methanol solvent.
  • step (i) can be conducted at about room temperature for from 12 to 48 hours.
  • reagents for step (ii) can include, but are not limited to, lithium hydroxide monohydrate in tetra hydrofuran and water (5:1 THF:H 2 O, V/V). Further in this aspect, step (ii) can be conducted at about room temperature for from about 30 min to about 3 h.
  • reagents for step (iii) can include, but are not limited to, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC, or EDCI), hydroxybenzotriazole (HOBT), and N,N-diisopropylethylamine (DIEA or DIPEA) in dimethylformamide (DMF).
  • step (iii) can be conducted at about room temperature for from about 6 h to about 24 h.
  • m and n can independently be 1 , 2, or 3.
  • V, Z, and R 1 can be defined as above.
  • the cyclic amine starting material can be a spiro, bridged, or fused compound or include a spiro, bridged, or fused element such as, for example, a substituted 2- azaspiro[3.3]heptane.
  • further modifications known in the art can be used to change, add, or remove functional groups (e.g. catalytic hydrogenation to convert a nitro group to a primary amine, or protection/deprotection of a reactive group).
  • functional groups e.g. catalytic hydrogenation to convert a nitro group to a primary amine, or protection/deprotection of a reactive group.
  • Other exemplary synthetic schemes are provided in the Examples.
  • ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.
  • a further aspect includes from the one particular value and/or to the other particular value.
  • ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x' to ‘y' as well as the range greater than ‘x' and less than ‘y'.
  • the range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less' and should be interpreted to include the specific ranges of ‘about x', ‘about y', and ‘about z' as well as the ranges of ‘less than x', less than y', and ‘less than z'.
  • the phrase ‘about x, y, z, or greater' should be interpreted to include the specific ranges of ‘about x', ‘about y', and ‘about z' as well as the ranges of ‘greater than x', greater than y', and ‘greater than z'.
  • the phrase “about ‘x' to ‘y'”, where ‘x' and ‘y' are numerical values, includes “about ‘x' to about ‘y'”.
  • a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1 %, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1 %; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.
  • the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined.
  • an “effective amount” refers to an amount that is sufficient to achieve the desired modification of a physical property of the composition or material.
  • an “effective amount” of a filler in a pharmaceutical composition refers to an amount that is sufficient to achieve the desired improvement in the property modulated by the formulation component, e.g. achieving the desired size or volume for a pharmaceutical dosage form.
  • the specific level in terms of wt% in a composition required as an effective amount will depend upon a variety of factors including the active ingredient, dosage, presence of other therapeutic agents in the dosage form, and intended method of administration of the pharmaceutical composition.
  • temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).
  • Described herein are coronavirus papain protease inhibitors that have therapeutic or clinical utility. Also described herein are methods of synthesizing the papain protease inhibitors. Also described herein are methods of administering the papain protease inhibitors to a subject in need thereof. In some aspects, the subject can have COVID-19 or another coronavirus-related disease.
  • Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure.
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more -OCH 2 CH 2 O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more - CO(CH 2 ) 8 CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (/.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can be cyclic or acyclic.
  • the alkyl group can be branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
  • alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
  • polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
  • hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like.
  • the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkanediyl refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • the groups, — CH 2 — (methylene), — CH 2 CH 2 — , — CH 2 C(CH3)2CH 2 — , and — CH 2 CH 2 CH 2 — are non-limiting examples of alkanediyl groups.
  • Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA 1 — OA 2 or — OA 1 — (OA 2 ) a — OA 3 , where “a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described here
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • heterocycloalkynyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized TT electrons above and below the plane of the molecule, where the TT clouds contain (4n+2) TT electrons.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasing is a specific type of aryl group and is included in the definition of “aryl.”
  • the aryl group can be a single ring structure or can contain multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond.
  • biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • amine or “amino” as used herein are represented by the formula — NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is -NH 2 .
  • alkylamino as used herein is represented by the formula — NH(-alkyl) and — N(-alkyl) 2 , where alkyl is a described herein.
  • Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino
  • esters as used herein is represented by the formula — OC(O)A 1 or — C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polyester as used herein is represented by the formula — (A 1 O(O)C-A 2 -C(O)O) a — or — (A 1 O(O)C-A 2 -OC(O)) a — , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula — (A 1 O-A 2 O) a — , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halo halogen
  • halide halogen or halide
  • pseudohalide pseudohalogen or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides.
  • Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
  • heteroalkyl refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted.
  • the heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[c/]oxazolyl, benzo[c/]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1 ,2-b]pyridazinyl, imidazo[1 ,2-a]pyrazinyl, benzo[c][1 ,2,5]thiadiazolyl, benzo[c][1 ,2,5]oxadiazolyl, and pyrido[2,3- b] pyrazinyl.
  • heterocycle or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
  • Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1 ,2,3-oxadiazole, 1 ,2,5-oxadiazole and 1 ,3,4-oxadiazole, thiadiazole, including, 1 ,2,3-thiadiazole, 1 ,2,5-thiadiazole, and 1 ,3,4-thiadiazole, triazole, including, 1 ,2,3-triazole, 1 ,3,4-triazole, tetrazole, including 1 ,2,3,4-tetrazole and 1 ,2,4,5-tetrazole, pyr
  • heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
  • a C2 heterocyclyl includes a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocyclyl includes a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.
  • bicyclic heterocycle or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
  • Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
  • Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1 , 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1 , 2 or 3 ring heteroatoms.
  • Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1 ,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, 2,3-dihydro- 1 ,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1 H-pyrazolo[4,3-c]pyridin-3-yl; 1 H-pyrrolo[3,2- b]pyridin-3-yl; and 1 H-pyrazolo[3,2-b]pyridin-3-yl.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
  • the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetra hydrofury I.
  • hydroxyl or “hydroxy” as used herein is represented by the formula — OH.
  • ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • nitro as used herein is represented by the formula — NO 2 .
  • nitrile or “cyano” as used herein is represented by the formula — CN.
  • sil as used herein is represented by the formula — SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo is represented by the formulas — S(O)A 1 , — S(O) 2 A 1 , — OS(O) 2 A 1 , or — OS(O) 2 OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula — S(O) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfone as used herein is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • thiol as used herein is represented by the formula — SH.
  • R 1 ,” “R 2 ,” “R 3 ,”... “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (/.e., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • the disclosed compounds can contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 - iPh, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0-2 R ⁇ , -(haloR ⁇ ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR ⁇ , -(CH 2 ) 0-2 CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), -CN, -N 3 , -(CH 2 ) 0 _ 2 C(O)R ⁇ , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR ⁇ , -(CH 2 ) 0-2 SR ⁇ , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , - (CH 2 ) 0-2 NHR ⁇ ,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR* 2 ) 2-3 O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R* include halogen, -R e , -(haloR ⁇ ), -OH, - OR ⁇ , -O(haloR’), -ON, -C(O)OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NR ⁇ 2 , or -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rt, -NR ⁇ , -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH 2 C(O)Rt - S(O) 2 Rt, -S(O) 2 NRT 2I -C(S)NRt 2 , -C(NH)NRt 2 , or -N(R t )S(O) 2 R t ; wherein each R* is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R t , taken together with their intervening atom(s) form
  • Suitable substituents on the aliphatic group of R 1- are independently halogen, - R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , -O(haloR’), -ON, -C(O)OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NR ⁇ 2 , or - NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci ⁇ aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • leaving group refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
  • hydrolysable group and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
  • hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-lnterscience, 1999).
  • organic residue defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
  • Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
  • Organic residues can preferably include 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • an organic residue can include 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.
  • a very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
  • a 2,4- thiazolidinedione radical in a particular compound has the structure: regardless of whether thiazolidinedione is used to prepare the compound.
  • the radical for example an alkyl
  • the number of atoms in a given radical is not critical to the presently disclosed compounds unless it is indicated to the contrary elsewhere herein.
  • Organic radicals contain one or more carbon atoms.
  • An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
  • an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
  • Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
  • an organic radical that includes no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono- substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • Inorganic radicals contain no carbon atoms and therefore include only atoms other than carbon.
  • Inorganic radicals include bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations.
  • Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together.
  • inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
  • the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
  • Inorganic radicals do not include metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
  • the present disclosure includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included.
  • the products of such procedures can be a mixture of stereoisomers.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-lngold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • Compounds described herein include atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically-labeled or isotopically- substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, and 36 CI, respectively.
  • Compounds further include prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
  • Certain isotopically-labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the disclosed compounds can be present as solvates.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the disclosure to form solvates and hydrates. Unless stated to the contrary, the disclosure includes all such possible solvates.
  • co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction.
  • One or more components of this molecular complex provide a stable framework in the crystalline lattice.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004.
  • Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.
  • ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.
  • amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the disclosure includes all such possible tautomers.
  • polymorphic forms or modifications It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the disclosure can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the disclosure includes all such possible polymorphic forms.
  • a structure of a compound can be represented by a formula:
  • n is typically an integer. That is, R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , and R n(e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) is halogen, then R n(b) is not necessarily halogen in that instance.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • compositions of the disclosure Disclosed are the components to be used to prepare the compositions of the disclosure as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary.
  • compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.
  • the disclosed compounds can possess at least one center of asymmetry, they can be present in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers. The stereoisomers can be present in the mixtures in any arbitrary proportions. In some aspects, provided this is possible, the disclosed compounds can be present in the form of the tautomers.
  • the disclosed compounds can be used in the form of salts derived from inorganic or organic acids.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds.
  • Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts, which may be similarly prepared by reacting the drug compound with a suitable pharmaceutically acceptable base.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure; or following final isolation by reacting a free base function, such as a secondary or tertiary amine, of a disclosed compound with a suitable inorganic or organic acid; or reacting a free acid function, such as a carboxylic acid, of a disclosed compound with a suitable inorganic or organic base.
  • a free base function such as a secondary or tertiary amine
  • a free acid function such as a carboxylic acid
  • Acidic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting moieties comprising one or more nitrogen groups with a suitable acid.
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • salts further include, but are not limited, to the following: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (iseth)
  • basic nitrogen- containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl
  • Basic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine.
  • Pharmaceutical acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • bases which may be used in the preparation of pharmaceutically acceptable salts include the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H- imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
  • IC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process.
  • IC 50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.
  • EC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process, or component of a process.
  • an EC 50 for a disclosed compound can be determined in an in vitro or cell-based assay system.
  • Such in vitro assay systems frequently utilize a cell line that either expresses endogenously a target of interest, or has been infected with a coronavirus, or has been transfected with a suitable expression vector that directs expression of a recombinant form of the target such as the SARS-CoV-2 papain protease.
  • administering can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravitreal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g.
  • a composition the perivascular space and adventitia can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells.
  • parenteral can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • therapeutic agent can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and/or physiologic effect on a subject to which it is administered to by local and/or systemic action.
  • a therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed.
  • a therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • attachment can refer to covalent or non-covalent interaction between two or more molecules.
  • Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Walls forces, dipole-dipole interactions, dipole-induced-dipole interactions, London dispersion forces, hydrogen bonding, halogen bonding, electromagnetic interactions, TT-TT interactions, cation-n interactions, anion-n interactions, polar n-interactions, and hydrophobic effects.
  • subject can refer to a vertebrate organism, such as a mammal (e.g. human). “Subject” can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof.
  • the terms “treating” and “treatment” can refer generally to obtaining a desired pharmacological and/or physiological effect.
  • the effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as COVID-19, SARS, and/or another coronavirus.
  • the effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition.
  • treatment can include any treatment of COVID-19 and/or another coronavirus in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions.
  • treatment as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment.
  • Those in need of treatment can include those already with the disorder and/or those in which the disorder is to be prevented.
  • the term "treating" can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • dose can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.
  • terapéutica can refer to treating, healing, and/or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.
  • an effective amount can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human.
  • An effective amount can be administered in one or more administrations, applications, or dosages.
  • the term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.
  • the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts.
  • the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease.
  • the desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.
  • the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
  • a response to a therapeutically effective dose of a disclosed compound and/or pharmaceutical composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent.
  • Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response.
  • the amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and/or pharmaceutical composition, by changing the disclosed compound and/or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • prophylactically effective amount refers to an amount effective for preventing onset or initiation of a disease or condition.
  • prevent refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • pharmaceutically acceptable salts means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate
  • esters of compounds of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • examples of pharmaceutically acceptable, non- toxic esters of the present disclosure include C 1 -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C 1 -to-C 4 alkyl esters are preferred.
  • Esters of disclosed compounds can be prepared according to conventional methods.
  • esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid.
  • the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.
  • amide refers to non-toxic amides of the present disclosure derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6- membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to-C 2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods.
  • Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide.
  • the pharmaceutically acceptable amides are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, and piperidine.
  • compositions can contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug.
  • prodrug represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
  • the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • contacting refers to bringing a disclosed compound or pharmaceutical composition in proximity to a cell, a target protein, or other biological entity together in such a manner that the disclosed compound or pharmaceutical composition can affect the activity of the a cell, target protein, or other biological entity, either directly; i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent.
  • the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof.
  • pharmaceutically-acceptable carriers means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants.
  • the disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences.
  • the disclosed pharmaceutical compositions include a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant.
  • the disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially and intratumorally.
  • aerosol delivery forms for the disclosed pharmaceutical compositions.
  • higher and/or repeated doses of the pharmaceutical compositions may be needed for severe cases of COVID-19 and/or other coronaviruses.
  • by delivering the pharmaceutical compositions directly to the lungs any systemic effects from large doses of the drug can be avoided.
  • pharmaceutical compositions delivered directly to the lungs can exert an immediate and specific effect on symptoms in the airways and/or pulmonary blood vessels.
  • the pharmaceutical formulations including the disclosed compounds can be prepared as inhaled forms.
  • the pharmaceutical formulations can be dispensed by metered-dose inhalers with or without adapter chambers, dry powder inhalers, nebulizers used with or without masks, or soft mist inhalers.
  • the pharmaceutical formulations when they are inhaled, they can include excipients especially useful for inhaled drugs including, but not limited to, sugars including lactose monohydrate or anhydrous lactose, lipids including oleic acid, amino acids, surfactants including lecithin, polymers, absorption enhancers, propellants, solvents, and the like.
  • the pharmaceutical formulations can be micronized or spray dried or processed by another means prior to loading into dispensing devices.
  • those skilled in the art will be able to select excipients to achieve the desired particle size, delivered dose, flowability, and other properties.
  • delivered dosages from aerosol or inhaled forms of the pharmaceutical compositions disclosed herein can be approximately the same as dosages for other forms (e.g., oral, intramuscular injection).
  • delivered dosages from aerosol or inhaled forms of the pharmaceutical compositions disclosed herein can be higher than dosages for other forms, due to lack of mobility to other organs and systems.
  • aerosol and/or inhaled forms of the pharmaceutical compositions can be as high as 30-35 mg/kg of subject body weight or greater.
  • dosages for aerosol and/or inhaled forms of the pharmaceutical compositions can be less than 30 mg/kg of subject body weight.
  • the aerosol and/or inhaled forms of the pharmaceutical compositions disclosed herein can be used once per day, or twice per day, or as needed as symptoms dictate. In a further aspect, the aerosol and/or inhaled forms of the pharmaceutical compositions disclosed herein can be used as single treatments or on a consistent basis until symptoms subside.
  • parenteral administration includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof.
  • a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.
  • salts can be prepared from pharmaceutically acceptable non-toxic bases or acids.
  • salts of the disclosed compounds are those wherein the counter ion is pharmaceutically acceptable.
  • salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are contemplated by the present disclosure.
  • Pharmaceutically acceptable acid and base addition salts are meant to include the therapeutically active non-toxic acid and base addition salt forms which the disclosed compounds are able to form.
  • a disclosed compound comprising an acidic group or moiety e.g., a carboxylic acid group
  • a pharmaceutically acceptable salt can be used to prepare a pharmaceutically acceptable salt.
  • such a disclosed compound may include an isolation step comprising treatment with a suitable inorganic or organic base.
  • base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • Bases which can be used to prepare the pharmaceutically acceptable base-addition salts of the base compounds are those which can form non-toxic base-addition salts, i.e., salts containing pharmacologically acceptable cations such as, alkali metal cations (e.g., lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine-(meglumine), lower alkanolammonium and other such bases of organic amines.
  • pharmacologically acceptable cations such as, alkali metal cations (e.g., lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine-(meglumine), lower alkanolammonium and other such bases of organic amines.
  • derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • such pharmaceutically acceptable organic non-toxic bases include, but are not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any of the four butylamine isomers, betaine, caffeine, choline, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, N,N'- dibenzylethylenediamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, tromethamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinuclidine, pyridine, quinoline and
  • a disclosed compound comprising a protonatable group or moiety can be used to prepare a pharmaceutically acceptable salt.
  • a disclosed compound may include an isolation step comprising treatment with a suitable inorganic or organic acid.
  • acid addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding basic compounds with an aqueous solution containing the desired pharmacologically acceptable anions and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.
  • Acids that can be used to prepare the pharmaceutically acceptable acid-addition salts of the base compounds are those which can form non-toxic acid-addition salts, i.e. , salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids.
  • non-toxic acid-addition salts i.e. , salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids.
  • inorganic acids include hydrochloric hydrobromic, sulfuric, nitric, phosphoric and the like.
  • organic acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like.
  • the acid-addition salt contains an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the present disclosure, and/or pharmaceutically acceptable salt(s) thereof can also be administered by controlled release means and/or delivery devices.
  • the compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. That is, a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages.
  • unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vials for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers; and segregated multiples thereof.
  • This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
  • the pharmaceutical compositions disclosed herein include a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents.
  • the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • a disclosed compound, or pharmaceutically acceptable salt thereof can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, extenders, or carriers suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration.
  • Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used.
  • the compounds may be administered as a dosage that has a known quantity of the compound.
  • oral administration can be a preferred dosage form, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • other dosage forms may be suitable depending upon clinical population (e.g., age and severity of clinical condition), solubility properties of the specific disclosed compound used, and the like.
  • the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • any convenient pharmaceutical media can be employed.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques.
  • compositions in an oral dosage form can include one or more pharmaceutical excipient and/or additive.
  • suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated, aliphatic oxyalcohols, for example methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12 to 22 carbon
  • auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose.
  • Conventional coating substances may also be used to produce the oral dosage form.
  • Plasticizing agents that may be considered as coating substances in the disclosed oral dosage forms are: citric and tartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl- phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxye
  • suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents may be included as carriers.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • a disintegrator can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • an oral dosage form such as a solid dosage form
  • Suitable biodegradable polymers useful in achieving controlled release of a drug include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a tablet containing a disclosed compound can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • a solid oral dosage form such as a tablet
  • enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid- methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.
  • enteric coating materials may be selected on the basis of testing to achieve an enteric coated dosage form designed ab initio to have a preferable combination of dissolution time, coating thicknesses and diametral crushing strength (e.g., see S. C. Porter et al. “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol. 22:42p (1970)).
  • the enteric coating may contain hydroxypropyl-methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.
  • an oral dosage form can be a solid dispersion with a water soluble or a water insoluble carrier.
  • water soluble or water insoluble carrier include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, or hydroxypropylmethylcellulose, ethyl cellulose, or stearic acid.
  • an oral dosage form can be in a liquid dosage form, including those that are ingested, or alternatively, administered as a mouth wash or gargle.
  • a liquid dosage form can include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
  • the pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
  • water particularly sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1 ,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulfoxide, triglycerides and the like.
  • alcohols ethanol, propanol, isopropanol, 1 ,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol
  • oils for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil
  • paraffins dimethyl sulfoxide, triglycerides and the like.
  • a liquid dosage form such as a drinkable solutions
  • the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- and multivalent alcohols with 2- 4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols with molecular weights between 200-600 (for example 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1 ,2-propylene glycol, organic amides, for example amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary or tertiary C1-C4-amines or C1-C4-hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide, N,N-dimethyl acetamide, lower aliphatic amines and diamines with 2-6 carbon atoms, such
  • solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1- methyl-3-(2-hydroxyethyl)imidazolidone-(2).
  • solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides
  • polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20.
  • Polyoxyethylated substances of this kind may for example be obtained by reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 Mol ethylene oxide per 1 Mol glyceride).
  • hydroxyl group-containing compounds for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals
  • ethylene oxide for example 40 Mol ethylene oxide per 1 Mol glyceride.
  • oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil. See also Dr. H. P.
  • a liquid dosage form can further contain preservatives, stabilizers, buffer substances, flavor correcting agents, sweeteners, colorants, antioxidants and complex formers and the like.
  • Complex formers which may be for example be considered are: chelate formers such as ethylene diamine retrascetic acid, nitrilotriacetic acid, diethylene triamine pentacetic acid and their salts.
  • a liquid dosage form with physiologically acceptable bases or buffers may optionally be necessary to stabilize a liquid dosage form with physiologically acceptable bases or buffers to a pH range of approximately 6 to 9. Preference may be given to as neutral or weakly basic a pH value as possible (up to pH 8).
  • ⁇ -, ⁇ - or y-cyclodextrins or their derivatives in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-p-cyclodextrin or sulfobutyl- ⁇ -cyclodextrin.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the present disclosure in pharmaceutical compositions.
  • a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form can further include liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • compositions of the present disclosure suitable injection, such as parenteral administration, such as intravenous, intramuscular, or subcutaneous administration.
  • Pharmaceutical compositions for injection can be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present disclosure suitable for parenteral administration can include sterile aqueous or oleaginous solutions, suspensions, or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some aspects, the final injectable form is sterile and must be effectively fluid for use in a syringe.
  • the pharmaceutical compositions should be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • Injectable solutions can be prepared in which the carrier can be saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • a disclosed parenteral formulation can include about 0.01-0.1 M, e.g. about 0.05 M, phosphate buffer. In a further aspect, a disclosed parenteral formulation can include about 0.9% saline.
  • a disclosed parenteral pharmaceutical composition can include pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions, and emulsions.
  • pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include but not limited to water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • a disclosed parenteral pharmaceutical composition may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives.
  • Also contemplated for injectable pharmaceutical compositions are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the subject or patient.
  • the disclosed compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials e.g., as an emulsion in an acceptable oil
  • ion exchange resins e.g., as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
  • Pharmaceutical compositions of the present disclosure can be in a form suitable for topical administration.
  • topical application means administration onto a biological surface, whereby the biological surface includes, for example, a skin area (e.g., hands, forearms, elbows, legs, face, nails, anus and genital areas) or a mucosal membrane.
  • a topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch.
  • compositions can be in a form suitable for use in transdermal devices.
  • These formulations can be prepared, utilizing a compound of the present disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods.
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • the carrier optionally includes a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives.
  • the specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emollience).
  • an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp.
  • ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
  • Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
  • Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
  • Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
  • W/O water-in-oil
  • O/W oil-in-water
  • Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.
  • Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids, and oftentimes include a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like.
  • Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil.
  • Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also called the “internal” phase, generally contains petrolatum and/or a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information.
  • Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel.
  • the base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like.
  • the pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information.
  • Gel formulations are semisolid, suspension-type systems.
  • Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil.
  • Preferred organic macromolecules, i.e. , gelling agents are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark CarbopolTM.
  • hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; modified cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.
  • Sprays generally provide the active agent in an aqueous and/or alcoholic solution which can be misted onto the skin for delivery.
  • Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved.
  • the carrier evaporates, leaving concentrated active agent at the site of administration.
  • Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application.
  • Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique.
  • Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system.
  • Foams can be water-based or aqueous alkanolic, but are typically formulated with high alcohol content which, upon application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment.
  • Skin patches typically include a backing, to which a reservoir containing the active agent is attached.
  • the reservoir can be, for example, a pad in which the active agent or composition is dispersed or soaked, or a liquid reservoir.
  • Patches typically further include a frontal water permeable adhesive, which adheres and secures the device to the treated region. Silicone rubbers with self-adhesiveness can alternatively be used. In both cases, a protective permeable layer can be used to protect the adhesive side of the patch prior to its use.
  • Skin patches may further include a removable cover, which serves for protecting it upon storage.
  • Examples of patch configuration which can be utilized with the present invention include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive.
  • the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film.
  • a membrane is disposed between two distinct drug-in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film.
  • Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g., emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition.
  • suitable carriers according to the present invention therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions.
  • suitable carriers include, without limitation, alcohols, such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.
  • alcohols such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannito
  • Topical compositions of the present disclosure can, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the dispenser device may, for example, include a tube.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration.
  • Such notice for example, may include labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • Compositions comprising the topical composition of the invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Another patch system configuration which can be used by the present invention is a reservoir transdermal system design which is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi- permeable membrane and adhesive.
  • the adhesive component of this patch system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane.
  • Yet another patch system configuration which can be utilized by the present invention is a matrix system design which is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner.
  • the component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.
  • compositions of the present disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • compositions containing a compound of the present disclosure, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.
  • the pharmaceutical composition may be packaged in a variety of ways.
  • an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form.
  • Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like.
  • the container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package.
  • the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions.
  • the disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example include metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Pharmaceutical compositions comprising a disclosed compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the present disclosure.
  • the pharmaceutical composition will contain from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • an appropriate dosage level will generally be about 0.01 to 1000 mg per kg patient body weight per day and can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 500 mg/kg per day, about 0.1 to 250 mg/kg per day, or about 0.5 to 100 mg/kg per day.
  • a suitable dosage level can be about 0.01 to 1000 mg/kg per day, about 0.01 to 500 mg/kg per day, about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1 .0 to 1000 mg of the active ingredient, particularly 1 .0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated.
  • the compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.
  • Such unit doses as described hereinabove and hereinafter can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day.
  • such unit doses can be administered 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration.
  • dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
  • a typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
  • the time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • the present disclosure is further directed to a method for the manufacture of a medicament for modulating viral PLpro or PLP2 activity (e.g., treatment of one or more viral diseases or symptoms associated with PLpro or PLP2 activity) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent.
  • the present disclosure further relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.
  • compositions can further include other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological or clinical conditions.
  • compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for a disclosed compound or the other drugs may have utility as well as to the use of such a composition for the manufacture of a medicament.
  • the present disclosure also relates to a combination of disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a PLP2 and/or PLpro inhibitor.
  • the present disclosure also relates to such a combination for use as a medicine.
  • the present disclosure also relates to a product comprising (a) disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and (b) an additional coronavirus therapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the modulatory effect of the disclosed compound and the additional therapeutic agent.
  • the different drugs of such a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.
  • compositions Containing the Disclosed Papain Protease Inhibitors
  • compositions including the disclosed papain protease inhibitors.
  • the pharmaceutical compositions further include at least one excipient.
  • the pharmaceutical composition can be administered to a subject orally, by inhalation, by intravenous administration, or by any other disclosed method.
  • the pharmaceutical compositions include one or more additional therapeutic agents for COVID-19 or another coronavirus disease.
  • the additional therapeutic agent can be selected from an interleukin-6 inhibitor such as, for example, sarilumab, siltuximab, tocilizumab, or a combination thereof; an H2 blocker such as, for example, cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, or a combination thereof; an anticoagulant such as, for example, heparin, warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, enoxaparin, fondaparinux, another anticoagulant, or a combination thereof; an antitussive such as, for example, dextromethorphan, benzonatate, or a combination thereof; an antibiotic such as, for example, azithromycin, clar
  • a method for reducing the severity of at least one symptom of a coronavirus in a subject including the step of administering to the subject a therapeutically effective amount of at least one papain protease inhibitor disclosed herein or at least one pharmaceutical composition as described herein.
  • the subject can be a mammal or a bird.
  • the mammal can be a human, bat, pangolin, mouse, rat, pig, dog, cat, camel, cow, raccoon dog, palm civet, or another mammal.
  • the bird can be a chicken, turkey, or another poultry bird or a pet bird.
  • the at least one symptom can be selected from fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle aches, headache, loss of sense of taste, loss of sense of smell, sore throat, congestion, runny nose, nausea, vomiting, diarrhea, confusion, chest pressure, blood clots, a rash, discoloration of fingers or toes, delirium, dizziness, muscle weakness, hypoxia, multisystem inflammatory syndrome in children, or any combination thereof.
  • a method for preventing infection of a subject by a coronavirus including administering to the subject a therapeutically effective amount of at least one papain protease inhibitor disclosed herein or at least one pharmaceutical composition as described herein.
  • the coronavirus can be SARS-CoV-2, SARS-CoV-1 , MERS, another coronavirus, or any combination thereof.
  • the compound or pharmaceutical composition can have an IC 50 of less than 100 ⁇ M, or of less than 50 ⁇ M.
  • a method for reducing at least one process related to coronavirus pathogenesis in a plurality of cells including contacting the cells with at least one papain protease inhibitor or pharmaceutical composition as disclosed herein.
  • the process related to coronavirus pathogenesis can be selected from reduction of viral RNA replication, ablation of viral deubiquitination, ablation of delSGase activity, cleavage of a viral polypeptide, suppression of a host innate immune response, or a combination thereof.
  • CoV-2 PLpro preferentially processes ISG15 and K48 polyubiquitin.
  • CoV-2 PLpro has now been enzymatically characterized to the point needed for an in-depth drug discovery endeavor.
  • SARS-CoV-2 PLpro homology models were generated using the MODELLER software suite, version 9.19. For all models, the PLpro from SARS-CoV-2 (accession number MN908947.3) was used as the unknown.
  • the homology model of SARS-CoV-2 PLpro in its holo open form used PDB entry 5E6J as a template, while PDB entry 3E9S was used as a template for the SARS- CoV-2 PLpro homology model used in the docking of GRL0617. Structural differences between SARS CoV and SARS-CoV-2 are shown in FIGs. 2A-2B, while active site residues including Loop BL2 are shown in FIG. 7.
  • one of these sites in SARS-CoV-2 PLpro, K232 is equivalent to Q233 in SARS-CoV PLpro.
  • a mutation Q233E notably diminished the deubiquitinase activity of that PLpro in favor of more robust delSGylase activity. This further suggests that the enzymatic activities of SARS-CoV-2 PLpro may indeed differ from those of the SARS-CoV PLpro.
  • DC12 and DC28 show a great deal of promise.
  • a spiroazetidine replaces the piperidine ring of in the compound scaffold.
  • DC12 shows little signs of cytotoxicity at doses up to at least 50 ⁇ M in epithelial cells (data not shown) and has IC 50 S of 5.4 ⁇ M and 7.4 ⁇ M for CoV-2 PLpro and SARSL- Rf1-CoV PLpro respectively.
  • DC28 has near 1 ⁇ M IC 50 S for both PLpros and has been co- crystallized with the SARSL-Rf1-CoV protease.
  • the culture was centrifuged at 12,000 g for 10min, and the pellet was collected and stored in a -80 °C freezer.
  • the lysate was centrifuged at 30,000 g for 30min to remove all insoluble products.
  • the supernatant was then filtered and placed onto Ni-nitrilotriacetic agarose resin (Qiagen). The resin was washed using five column volumes of lysis buffer containing 10 mM imidazole.
  • ISG15-AMC concentrations of substrate ranged from 625 nM to 20 ⁇ M, and Ub-AMC ranged from 235 nM to 30 ⁇ M.
  • Protease concentrations used for the Ub-AMC and ISG15-AMC assays were 5 and 1 nM, respectively.
  • v V max /(1 + (KM/[S]))
  • k cat V max /[E]
  • Example 6 BtS CoV-Rf1.2004 PLpro Poly-Ub Cleavage Assays
  • Lys6, Lys11 , Lys29, Lys33, Lys48, Lys63, and linear linked di-Ub obtained from Boston Biochem were incubated at 10 ⁇ M with 20 nM BtSCoV-Rf1 .2004 PLpro. Reactions were performed in AMC buffer at a volume of 45 pL and a temperature of 37 °C. 10 ⁇ L samples were taken at the indicated time points and heat-shocked at 98 °C for 5 min. Lys48 and Lys63 linked tetra-Ub obtained from Boston Biochem were incubated at 13.67 ⁇ M with 23 nM BtSCoV- Rf1.2004 PLpro.
  • Reactions were performed in AMC buffer at a volume of 70 pL and a temperature of 37 °C. 8 pL samples were taken at the indicated time points and heat-shocked at 98 °C for 5 min. SDS-PAGE analysis was performed using Mini-PROTEAN TGX and Coomassie blue.
  • Hits from the screen were scaled up to hanging-drop 24-well plates containing a 500 mL reservoir of the crystallization solution and were optimized using varying salt, precipitant, pH, additive and protein concentration gradients.
  • the final crystallization condition for the optimized BtSCoV-Rf1.2004 PLpro-GRL0617 co-crystal was 0.2 M ammonium acetate, 20% PEG 1000.
  • DC12 in 100% DMSO was added to the protein sample at a 5:1 molar ratio and a final DMSO concentration of 0.5%.
  • a crystal screen was set up for the sample against a suite of 768 commercially available conditions (Qiagen) in 96-well hanging-drop plates using a Mosquito robot (TTP Labtech).
  • Phases for the BtSCoV-Rf1 .2004 PLpro-GRL0617 and DC12 co-crystal structures were solved by molecular replacement in Phaser.
  • a homology model of BtSCoV-Rf1 .2004 PLpro based on a SARS-CoV-1 PLpro-GRL0617 co-crystal structure (PDB 3E9S) was used as a reference for the GRL0617 complex, while the BtSCoV-Rf1 .2004 PLpro-GRL0617 structure was used as the model for the DC12 complex.
  • the finger, thumb, and palm domains of the PLpro were used as a search model, placing 2 copies in the asymmetric unit of the GRL0617 complex and 1 in the asymmetric unit of the DC12 complex. Afterwards the Ubl domains were built in manually. The phased models were modified through alternating rounds of manual building and refinement in Coot and Phenix. The final models were validated in MolProbity.
  • a set of preclinically vetted non-covalent therapeutic candidates for IND that target PLpro of CoV-2 has been designed. Candidates having low toxicity and that are metabolically stable in vivo with low nanomolar affinities for PLpro and low micromolar EC 50 for CoV-2 have been identified and synthesized. Regarding potency, this requires a 1-2 order of magnitude improvement in enzyme affinity and a 2-3 order magnitude increase in potency towards the virus. This magnitude of improvements has been routinely seen in SBDD optimization of lead compounds including those of preclinical antiviral candidates.
  • Y269 interacts with the amino group in the eastern arene of one disclosed compound, but with the amide carbonyl of the latter set of compounds compound.
  • the eastern arene itself has been subjected to the usual variations in the aromatic substitution pattern including changes in substitution level, type and position.
  • aromatic substitution pattern including changes in substitution level, type and position.
  • Each round of iteration has taken full advantage of the quantitative structure-activity relationship (QSAR), ADMET, and virtual screening capabilities discussed previously to prioritize lists of compounds and minimize time-consuming and unnecessary work at the laboratory bench.
  • QSAR quantitative structure-activity relationship
  • ADMET virtual screening capabilities
  • Azetidines and spiroazetidines and other small bicyclic moieties and their connection to the eastern arene by amide, thioamide, sulfonimide, squaramide, urea, thiourea, and related linkages have been explored (Table 1).
  • IC 50 assays were performed using methods similar methods to peptide-AMC, Ub-AMC, and ISG15-AMC cleavage experiments and those described previously. Viral samples were run at 100 nM against 50 ⁇ M Peptide-AMC in 98% AMC buffer 2% DMSO. Reactions were performed in duplicate with inhibitor concentrations ranging from 1.25 ⁇ M to 20 ⁇ M, or 100 ⁇ M depending on compound tested. BtSCoV-Rf 1.2004 PLpro was run at 1 ⁇ M against 50 ⁇ M peptide-AMC in 98% AMC buffer/2% DMSO. Reactions were performed in triplicate with inhibitor concentrations ranging from 195nM to 100 ⁇ M, depending on compound tested. IC 50 calculations were performed using Prism8 from GraphPad. IC 50 values of the disclosed compounds and percentage inhibition against multiple coronaviruses are shown in Table 1.
  • Candidates synthesized were initially evaluated for their potency at 200 ⁇ M towards SARS-CoV-2 PLpro using the RLRGG-AMC (Arg-Leu-Arg-Gly-Gly-7-amido-4-methylcoumarin) substrate in an identical manner to that used in the preliminary data and previously against SARS- CoV PLpro.
  • Compounds with potency of at least 40% have undergone dose-response testing to determine their IC 50 S with and without Triton X-100 to screen out promiscuous inhibitors. If no candidates in a round showed 40% inhibition, then the top 10 underwent dose-response testing with RLRGG-AMC. The top 5 hits of each round had a mode of action determined.
  • This group included not only PLpros from MERS-CoV, and SARS-CoV-1 , but also from betacoronavirus subgroup 2b members like SARSL- Rf1-CoV. To ensure rigor, all enzymatic assays were performed in triplicate.
  • the last step in each optimization round was cytotoxicity and antiviral analysis using a variety of medium throughput toxicity assays, including MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium), neutral red uptake, and lactate dehydrogenase (LDH).
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium
  • LDH lactate dehydrogenase
  • SI selectivity indexes
  • SARS-CoV-2 (2019-nCoV/USA-WA1/2020; MN985325.1) was received from BEI resources and propagated in Vero clone E6, Vero E6, CRL-1586. Infections were done at a multiplicity of infection (MOI) of 0.1 in serum-free in Dulbecco's minimal essential medium (DMEM) for 1 h after which the virus-containing media was decanted and replaced with DMEM supplemented with 1 % heat-inactivated fetal bovine serum. The virus was propagated for 72 hours before it was harvested and the titer determined by plaque assay on Vero E6 cells (PM ID: 22684013).
  • MOI multiplicity of infection
  • DMEM Dulbecco's minimal essential medium
  • the viral plaques were counted and the titer was determined as PFU/ml.
  • the Vero cells were plated at 3 x 10 5 cells/well in a 6-well plate and incubated overnight at 37 °C. The following day the compounds were prepared into the following concentrations/well in a separate plate; 80 ⁇ M, 65 ⁇ M, 45 ⁇ M, 30 ⁇ M, and 15 ⁇ M.
  • the cells were washed once with PBS 1 x and then infected at a multiplicity of infection (MOI) of 0.1 for 1 h after which the virus containing media was removed and the compounds concentrations were added to the cells and incubated for 72 hours at 37 °C at 5% CO 2 . The cells were then fixed and stained with crystal violet to determine plaque numbers. These were all done in duplicate and the calculations were performed using Prism8 from GraphPad.
  • MOI multiplicity of infection
  • necrosis was demonstrated to be the primary mechanism of cell death, the role of the inflammasome was determined by treating cells with NLRP3 inhibitors. These experiments determined the mechanisms by which these compounds exert their non-selective toxicity, which was key to understanding their molecular mechanisms of action. Such data aids in the ability to predict toxicity in vivo.
  • Serum shift assays were conducted to determine the effect of their plasma protein binding on toxicity. These assays were conducted as described above for BEAS-2B cells; except studies were conducted at the CC 50 as opposed to the EC 50 . These studies were necessary since the higher concentrations of compounds at the CC 50 may result in greater protein binding. While serum shifts assays are inexpensive and relatively quick and do not require an LC-MS assays or radiolabel, they are limited in that they do not allow for the determination of kinetic constants, which are often critical for dose modeling in human patients.
  • B max (B max x C)/(Kd + C)
  • B max is the maximum number of binding sites expressed as nanomoles bound per gram of protein
  • C is the compound concentration
  • Kd is the equilibrium dissociation constant.
  • Kd is the inverse of the binding affinity (Ka).
  • Non-targeted toxicity was assessed in numerous diverse cell lines, including Renal Proximal Tubular Epithelial Cells (RPTECs, ATCC CRL-4031), BEAS-2B bronchial epithelial cells (ATCC CRL-9609), A549 adenocarcinomic alveolar basal epithelial cells (ATCC, CCL-185), and SH-SY5Y neuroblastoma cells (ATCC, CRL-2266).
  • RPTECs Renal Proximal Tubular Epithelial Cells
  • ATCC CRL-9609 BEAS-2B bronchial epithelial cells
  • A549 adenocarcinomic alveolar basal epithelial cells ATCC, CCL-185
  • SH-SY5Y neuroblastoma cells ATCC, CRL-2266.
  • RPTECs were grown in DMEM/F12 (ATCC, 30-2006) supplemented with hTERT Immortalized RPTEC Growth Kit (ATCC, ACS-4007); A549 and SH-SY5Y cells were grown in DMEM (ATCC, 30-2002) supplemented with 10% Fetal Bovine Serum (VWR, 97068-085) and 1 % penicillin-streptomycin solution (ATCC, 30-2300).
  • BEAS-2B cells were grown using the BEGM BulletKit (Lonza, CC-3170) and flasks were coated with 0.03 mg/mL bovine collagen (Fisher, CB-40231) and 0.01 mg/mL human fibronectin (Fisher, CB- 40008A). All cells were maintained at 37 °C in a 5% CO 2 incubator.
  • Cytotoxicity was assessed using MTT staining and cell morphology.
  • Cells were seeded in 48-well tissue culture plates at densities between 25 - 50,000 (A549, BEAS-2B), 100,000 (RPTEC), and 50 - 150,000 (SH-SY5Y) cells per well depending on growth rate and experimental conditions. Cells were maintained at 37 °C in a 5% CO 2 incubator for a minimum of 24 hr and were at least 80% confluent prior to dosing. Inhibitors were dissolved in DMSO and diluted in different culture media to their final concentrations.
  • DMSO DMSO alone
  • GRL0617 a GRL0617
  • cells were treated with 175, 250, 500, 750, or 1000 ⁇ M concentrations.
  • inhibitors and DMSO controls
  • DMEM DMEM containing 10% (v/v) Fetal Bovine Serum and 1 % penicillin-streptomycin for 5 minutes prior to cell exposure. Stability was assessed by incubation of inhibitors for 24 hr at 37 °C in media. Alterations in cytotoxicity as compared to un-incubated controls were indicative of serum binding or inhibitor instability.
  • MTT (Sigma, M2128-1G) was added after 48 hr treatment at a final concentration of 0.1 mg/mL, and plates were incubated for 2 hr at 37 °C. After media aspiration, the remaining MTT formazan crystals were dissolved in DMSO and absorbance was determined for each well at 490 nm using a BMG CLARIOstar plate reader. Experiments were performed in triplicate per passage in at least 3 distinct passages of cells. The concentration of protease inhibitor that resulted in 50% growth inhibition (CC 50 ) as compared to DMSO control was estimated from a non-linear regression curve as calculated in GraphPad Prism 7.
  • Example 15 In vitro Studies to Determine Mutagenicity and Viral Resistance
  • the 5 compounds with the highest SI were assessed for mutagenicity using high throughput Ames Testing.
  • the testing was performed by the Center for Drug Discovery (CDD) at the University of Georgia as previously described.
  • Compounds were examined using a 384 well microplate format (MPFTM), using a Salmonella typhimurium tester strain TA98, in the presence (10% (vol/vol)) and absence of a phenobarbital/ ⁇ -naphthoflavone- induced rat liver S9 metabolic activation system Compounds were dissolved in solvent control from the lowest EC 50 to the highest CC 50 .
  • 2-Aminoanthracene (2-AA) and 2-nitrofluorene (2-NF) were used as positive controls with or without metabolic activation, respectfully.
  • Test wells were compared to control wells for their revertant total count.
  • Compounds chosen for further in vitro PK screening were those whose basal rate of reverse mutations did not exceed background at the SI (typically 6-8% for the bacterial strains studied).
  • Example 16 Determination of In vitro Stability, Clearance, and Drug Metabolism Profiles
  • Stability assays were performed as previously described. Compounds were incubated in human plasma and their stability determined at 1 , 5, 10, 30 and 60 minutes, as well 24 hours. Stability was determined by assessing the loss of the parent compound using LC-MS/MS. Human plasma was purchased from AlternativeTM Research (Novi, Ml).
  • CYP inhibition was determined using P450-GloTM Assays (Promega, Madison, Wl). These assays use luminescence as indicators of CYP activity provided that an enzyme source is added and are amicable to purified proteins or subcellular fractions, can be used to identify the role contribution of specific CYP isozymes by changing out the luciferin bound substrate, and can be used to screen for CYP inhibitors. They can also be used to estimate K m when recombinant CYP are used.
  • Example 17 In vivo Efficacy of PLpro Inhibitors as Prophylaxis and to Treat SARS-CoV-2 Infection
  • the MTD in hamsters was determined after exposure using a dose range of 0, 0.2, 2, 20 mg/kg of each compound administered daily for 7 days. At each time point, animals were assessed for weight change and clinical signs of toxicity (behavior, respiratory patterns, cardiovascular, motor activities, changes in fur). Dose schedule was altered in a stepwise manner (either decreased or staggered) based on the above clinical signs of morbidity/mortality. Four to seven days are selected to align with the antiviral studies also described herein. Animals were euthanized following the last dose and necropsied to assess tissue pathology and well as chemical markers of injury in blood and urine. Another set of animals were assessed 2 weeks post dosing and then sacrificed to assess potential pathologies. Since COVID-19 may affect multiple organs, gross pathology was examined in the lung, brain, liver, heart, kidney, pancreas, adrenals, sex organs, and thyroid.
  • Euthanasia was performed with pentobarbitol sodium (390 mg/mL; 1 mL/10 kg of body weight) after initial sedation with ketamine/xylazine/acepromazine, as per the guidelines of the IACUC of the Center for Biologies Evaluation and Research, US FDA, and in accordance with the guidelines of the NIH Animal Care and Use Committee.
  • Hamsters were monitored for clinical symptoms (body temperature, activity, respiratory signs, and weight loss) daily and were sacrificed and the lungs collected for virologic and histopathological analyses.
  • lungs were inflated with 10% buffered formalin, then immersed in formalin. Following fixation and inactivation of SARSCoV-2, lungs were moved to BSL2 and embedded in paraffin and four-micron sections stained with hematoxylin and eosin (HE).
  • HE hematoxylin and eosin
  • PLpro inhibitors reduce SARS-CoV-2 shedding and inflammatory cytokines expression in BAL fluid.
  • Hamsters were either treated with inhibitors prior to infection (prophylaxis) or at day 2 pi (treatment).
  • Hamsters were infected with 10 3 pfu of SARS- CoV-2.
  • Hamsters were i.p. treated with 0.2, 2 or 20 mg/kg inhibitor either at day 0 prior to infection or at day 2 pi.
  • BAL fluids from hamsters were collected and virus titers evaluated.
  • Quantitative PCR was performed using hamster IFNa, IFNp, IFNy, IL1a, IL1p, IL2, IL4, IL6, IL8, IL10, IL12p40, IL17, granzyme A, MCP1 , TNFa, and GAPDH gene specific primers.
  • Ct values were normalized to hamster GAPDH and their expressions relative to basal samples were calculated using 2(- AACt) formula. The doses used above can be altered depending on the outcome of the MTD studies.
  • Example 18 Determination of PK and Toxicity of PLpro Inhibitors
  • Biochemical parameters were measured and included glucose, total cholesterol, triglycerides, total protein, albumin, serum glutamic oxaloacetic transaminase serum glutamic pyruvic transaminase, lactate dehydrogenase, alkaline phosphatase, y-glutamyl transpeptidase, bilirubin, creatinine, and blood urine nitrogen using diagnostic kits in a semi-automatic biochemical analyzer. Histopathological assessment included H&E of the above tissues, scored by a pathologist. Tissue and blood were isolated from any animal demonstrating morbidity or mortality and prepared for analysis, as described. The doses used may be lowered or staggered depending on signs of morbidity. Mean differences between the control and treatment groups were analyzed by an ANOVA followed by Tukey's multiple comparison as the posthoc test.
  • N--(2-Methyl-5-nitrophenyl)-2-(naphthalen-1-yl)acetamide (100 mg, 0.31 mmol) was dissolved in 1 ,4-dioxane (6 mL) and Pd/C (10% wt) (19.9 mg, 0.037 mmol) was added. The reaction mixture then was stirred for 4h under H 2 (balloon) at 20 °C. After completion of the reaction, detected by LCMS, the reaction mixture was filtered on CELITE® and the filter cake was washed with Et 2 O (3x20 mL).
  • tert-Butyl (R)-3-[(1 '-(Naphthalen-T-yl)ethyl]carbamoyl)azetidine-1-carboxylate was synthesized via modification of a literature procedure.
  • Isopropyl piperidine-4-carboxylate hydrochloride 114 (2.07 g, 10 mmol) was added into the solution of acetonaphthone (1.70 g, 10 mmol) in anhydrous tetrahydrofuran (THF) (300 mL) under argon atmosphere. Then titanium (IV) isopropoxide (3.55 g, 12.5 mmol) was added into the reaction mixture. The reaction mixture was stirred for 12 h at room temperature, cooled down to -78 °C, and sodium cyanoborohydride (1 .35 g, 20 mmol) was added. The temperature was slowly raised to room temperature, and the reaction mixture was stirred for another 24 h.
  • THF tetrahydrofuran
  • the suspension was stirred for 5 min at room temperature and cooled to 0 °C before it was treated dropwise with a mixture of 2-methoxypyrdin-4-yl methylamine (7 mg, 0.057 mmol) and diisopropylethylamine (0.037 g, 0.28 mmol) in DCM (1 mL) over (5 mins).
  • the reaction mixture was then allowed to warm at room temperature and stirred for (12 h) before it was quenched with water (5 mL) and extracted with DCM (2 x 5 mL).
  • Reagents and conditions (a) RNH 2 , carbonyl diimidazole, THF, rt to reflux
  • Benzophenone N--methyl-(1-naphthyl)hydrazone Reagents and conditions: (a) NaH, Mel, MeOH, DMF, 20 °C, 3.5 h.
  • the reaction mixture was cooled to 0 °C before it was quenched with water (20 mL) and extracted with ethyl acetate (3x20 mL), and the combined organic phase washed with 1 N HCI (30 mL), saturated aqueous NaHCO 3 (30 mL), and brine (30 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was subjected to flash chromatography (0 to 10% ethyl acetate/hexane) to give the product (1.8 g, 87%) as a light orange solid.
  • Reagents and conditions (a) HCI, THF, 20 °C, 12 h.
  • Reagents and conditions (a) NaOH, H 3 O + , rt, 12 h (b) (2-Methoxypyridin-4-yl)methanamine, GDI, THF, rt to 70 °C, 2.5 h.
  • the crude mixture was dissolved in dry THF (1.6 mL) and treated with 1 ,1 '-carbonyl diimidazole (30.5 mg, 0.19 mmol) in two portions. The resulting mixture was stirred at 20 °C for 2 h, then was treated with (2-methoxypyridin-4-yl)methylamine (16.2 ⁇ L, 0.13 mmol) and the temperature increased to 70 °C for 0.5 h.
  • reaction mixture then was stirred for 10 min at 0 °C and then refluxed for 3 h. After completion, detected by LCMS, the reaction mixture was quenched with sat. aq. NaHCO 3 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO 4 and concentrated to dryness. The crude product was purified by flash column chromatography over silica gel (eluent: hexanes : EtOAc (EtOAc, 0 — > 30 %)) to give the title compound as white solid 260 mg (70 %).
  • N-Methyl-N--(1-naphthyl)hydrazine (90 mg, 0.52 mmol) and 3-ethoxy-4-((2-methyl-5- nitrophenyl)amino)cyclobut-3-ene-1 , 2-dione (173 mg, 0.63 mmol) were taken up in ethanol (1.7 mL) and stirred at 20 °C for 16 h.
  • the reaction mixture was concentrated and purified by silica gel column chromatography (20 - 60% ethyl acetate/hexane) to yield the product (63.1 mg, 30%) as a dark brown syrup.
  • Reagents and conditions (a) Pd/C, H 2 , 1 ,4-dioxane, AcOH, 20 °C, 5 h.
  • reaction mixture was stirred at 20 °C for 3 h before it was washed with 1 N HCI (2x2 mL), saturated aqueous NaHCO 3 (2x 2 mL), brine (2 mL), dried over Na 2 SO 4 , filtered, concentrated and then purified by flash chromatography (0 to 50% ethyl acetate/hexane) to give the product (0.1 g, 84%) as a white solid.
  • Reagents and conditions (a) Pd/C, H 2 , 1 ,4-dioxane, 20 °C, 5 h.
  • Reagents and conditions (a) NaH, CH 3 I, DMF, 20 °C, 3.5 h.
  • Reagents and conditions (a) HCI, THF, 20 °C, 12 h.
  • reaction mixture was stirred at 20 °C for 4 h before it was washed with 1 N HCI (2x2 mL), saturated aqueous NaHCO 3 (2x2 mL), brine (2 mL), dried over Na 2 SO 4 , filtered, concentrated and then subjected to flash column chromatographic purification (0 to 50% ethyl acetate/hexane) to give the product (0.2 g, 80%) as a white solid.
  • PLpros are Highly conserveed among SARS-like Coronaviruses
  • group 2b Prior to SARS-CoV-2, group 2b consisted of fifteen SARS-like viruses originating from several species of old-world bats, primarily horseshoe bats. Sequence analysis of these viruses along with that of SARS-CoV-2 revealed that each encoded one of six unique PLpro sequences (FIGs. 1A-1B). The recent A146D mutation in the SARS-CoV-2 strain originating from the United Kingdom brings the total to seven. Both the genomes and PLpros of group 2b viruses share sequence identity greater than 80 percent. PLpros and PLP2 have been shown to vary in terms of substrate preference and activity.
  • BtSCoV-Rf 1.2004 was isolated from the greater horseshoe bat (R. ferrumequinum) in Yichang, China, just 320 km from the location of the initial outbreak of the SARS-CoV-2 pandemic.
  • BtSCoV-Rf1 .2004 was chosen because at 93.9% conservation it is the most distantly related group 2b virus from SARS-CoV-1 other than SARS-CoV-2.
  • the kinetic parameters of SARS-CoV-2 PLpro are from Freitas et al.
  • the kinetic parameters of SARS-CoV PLpro (ppl ab 1541-1855; 1-315) and MERS-CoV PLpro (ppl ab 1484-1802; 3-322) are from Baez-Santos et al.
  • the kinetic parameters of MHV PLP are from Chen et al.
  • BtSCoV-Rf1 .2004 PLpro for Ub-AMC is 1.0 ⁇ 0.0 ⁇ M -1 min -1 with K M and k ca t values of 14.3 ⁇ 0.9 and 13.9 ⁇ 0.4, respectively.
  • BtSCoV-Rf1 .2004 PLpro demonstrated a clear preference for ISG15 over Ub.
  • saturation could not be reached to determine K M and kcat values.
  • using first-order kinetics the enzymatic efficiency was found to be 56.6 ⁇ 5.3 ⁇ M -1 min -1 .
  • the difficulty in saturating the PLpro appears to be due to its robust delSGylase activity, which is twice as efficient as any other SARS-CoV PLpro.
  • a rate of 595 min -1 was observed at 20 ⁇ M.
  • the calculated maximum turnover for ISG15-AMC by SARS-CoV-1 is 436 min -1 , making BtSCoV-Rf1 .2004 PLpro the most robust delSGylase among coronavirus PLpros by a considerable margin.
  • BtSCoV-Rf1 .2004 PLpro's enzymatic efficiency for peptide-AMC is 0.1 ⁇ 0.007 ⁇ M -1 min -1 , which is within the range of other group 2b PLpros.
  • PLpros have often shown greater ability to process poly-Ub chains than those of mono- Ub conjugates. To determine if this is the case with BtSCoV-Rf1 .2004, PLpro cleavage activity was tested against the eight different linkage types of di-Ub M1 , K6, K1 1 , K27, K29, K33, K48, and K63. Utilizing similar experimental conditions to those used to evaluate other PLpros24, 31 , 10 ⁇ M of each di-Ub was incubated with 20 nM PLpro from BtSCoV-Rf1 .2004. BtSCoV-Rf 1.2004 demonstrated little ability to cleave di-Ub of any linkage type.
  • DelSGylases have been shown to be selective for ISG15s from species which they have been found to productively infect. Unlike Ub that is almost completely conserved between species, ISG15 can vary with sequence similarity as low as 60% within class Mammalia. In vivo, ISG15 is translated as a pro-form that consists of the mature ISG15 with several amino acids following the LRLRGG cleavage site (prolSG15). Given BtSCoV-Rf1.2004 PLpro's similarity with other subgroup 2b PLpros in substrate preference for ISG15 over mono-Ub, molecular weight shift experiments using prolSG15s from various species were used to assess ISG15 species preference among a collection of fourteen species. The experimental parameters that were employed were consistent with previous studies focusing on other PLpros incubating 20 nM PLpro with 10 ⁇ M prolSG15 originating from the various species (FIGs. 3A-3B).
  • an x-ray crystal structure of the BtSCoV-Rf1 .2004 PLpro was obtained for comparison to structures of SARS-CoV-1 and SARS- CoV-2 PLpros.
  • the structure was determined to a resolution of 3.16A in space group P21212.
  • a homology model of BtSCoV-Rf1 .2004 PLpro based on a SARS-CoV-1 PLpro (PDB 3E9S) catalytic core was used as a search model.
  • the Ubl domain for the monomers was subsequently located using the Ubl of 3E9S as a search model.
  • the BtSCoV-Rf1 .2004 PLpro resembles other group 2b PLpros in secondary and tertiary structure (FIGs. 5A-5C). It consists of a catalytic core made up of a palm, thumb, and zinc finger domain. The core was found in a holo, open conformation. Additionally, the PLpros contain an N-terminal Ubl domain. The Ubl domain of BtSCoV-Rf1 .2004 is shifted approximately 90 degrees from previously seen elongated forms and is tucked against the catalytic domain when compared to the typical extended conformation.
  • This contact is also responsible for a shift in the zinc finger loop.
  • the zinc finger loop appears to be the most variable region within the catalytic core of the PLpro (FIG. 6B). Similar shifts in both the zinc finger loop and the western naphthyl group of GRL0617 are seen in the structures of SARS-CoV-1 (FIG. 6B) and SARS-CoV-2 (FIG. 6C) respectively, and also appear to be caused by crystal contacts.
  • the similar variation between the A chain and B chain monomers and variation between PLpros indicates that artifacts of the crystal lattice may be equally or more influential to ligand binding than residue differences between enzymes.
  • the naphthalene-based inhibitors can be categorized into two groups by their backbone structure.
  • the series I and II hits share a common binding site for their western hydrophobic moieties.
  • the two series differ in the eastern arene moieties, which occupy proximal but different binding pockets, and by the central core - a simple amide unit in series I and a piperidine ring in series II. This suggested that there exists considerable scope for innovation in the central core, in terms of both the spacing it provides between the eastern and western arenes and the basic structure employed.
  • DC-PHRM-13 was first prepared based on the azetidine core by standard means.
  • spirodiazetidine coupled to nicotinic acid DC-PHRM- 34 was synthesized (Scheme 6).
  • the BtSCoV-Rf1.2004 PLpro-GRL0617 complex structure was used as a search model for phasing the catalytic core. Upon finding a single monomer in the asymmetric unit, the Ubl domain was added. As with the GRL0167 co-crystal structure, the Ubl domain of this structure was in a tucked conformation.
  • the naphthyl group of DC-PHRM-12 is situated approximately 0.9A further away from the two prolines (FIG. 8B).
  • the difference in naphthyl group location could be due to a shift of the BL2 loop caused by the bulky 1 ,3-dioxolane ring.
  • the eastern arene groups of both DC-PHRM-12 and DC-PHRM-37 cause a shift in the BL2 loop that is similar to the conformation it adopts to accommodate Ubl substrates. However this shift is more pronounced in the DC-PHRM-37 co-crystal structure, even causing Q270 to flip away from the arene rings in order to avoid a steric clash.
  • the preliminary toxicity of these inhibitors was determined by assessing their ability to decrease the reductive capability of numerous cells using the MTT assay and determining CC 50 values. These values were compared to that determined for GRL0617 as well as Mesecar 15g, both of which have been previously assessed for cytotoxicity. As previously reported, GRL0617 and Mesecar 15g has the lower cytotoxicity as determined by CC 50 in multiple cells, including human renal proximal tubule cells (RPTEC), Beas-2B, A549 and Sh-SH5Y cells. DC-PHRM-12 did not reduce MTT staining below 50% in A549 of Sh-SY5Y cells at concentrations as high as 100 mM, which as similar to GRL6017.
  • DC-PHRM- 12 displayed the lowest CC 50 values in comparison to DC-PHRM-28 and DC-PHRM-16.
  • the CC 50 reported in these cells is folds-higher than the IC 50 reported for inhibition of PLpro degradation, as determined above.
  • alteration of the east moiety appeared to alter the CC 50 , as compared to the west moiety or the central rings.
  • the addition of the central ring decreased the CC 50 as compared to GRL0617, as shown by comparison of DC compounds and Mesecar 15g.
  • the effect of these compounds on MTT staining was validated using cell morphology, which demonstrated morphological characteristics of cell death in combination with reduced cell number.
  • DC-PHRM-12 Incubation of DC-PHRM-12 in media containing serum further decreased the toxicity of this compounds, suggesting chemical instability, enhanced protein binding, or both. In contrast, the toxicity of DC-PHRM-16, DC-PHRM-28, and DC-PHRM-37 was not altered by the presence of FBS in the media, or by incubation in media and serum overnight. This suggests that serum binding to these compounds does not alter their toxicity, and further suggest that these chemicals are relatively stable in media and serum for at least 24 hours.
  • the residues lining the active site, BL2 loop, P3 site, and P4 site are identical among all seven unique PLpros.
  • the BL2 loop, P3 site, and P4 site are responsible for binding naphthalene inhibitors as well as the leucine and arginine of the C-terminal RLRGG amino acid sequence of Ubl substrates.
  • the active site facilitates hydrolysis of the Ubl substrate peptide bond.
  • the UIM which is known to accommodate both Ub and ISG15 binding, is fully conserved between BtSCoV-Rf1 .2004 and SARS-CoV-1 .
  • SARS-CoV-2 PLpro has six differences at the UIM, T171 (S), H172(Y), K196(Q), L217(F), V226(T), and Q233(K). Of the six points of difference in SARS-CoV-2, five are identical across the other group 2b PLpros and the sixth, V226(l) of BtSCoV-Rm 1.2004, is likely to be inconsequential due to the similarity between Valine and Isoleucine. The conservation of Q233 is noteworthy because experiments have shown Q233(E) SARS-CoV-1 mutants notably diminished DUB activity but increased delSGylase activity.
  • viral PLpros have distinct substrate preferences even between Ubls.
  • the substrate(s) that a protease is particular efficient at processing can provide clues to which pathways are most critical to inhibit for viral replication. Trends in these substrate preferences can be useful in predicting howto treat related diseases that may arise in the future, however activities can vary widely between viruses.
  • group 2a murine hepatitis virus (MHV) PLP2 has a strong preference for Ub over ISG15
  • group 2b and 2c PLpros appears to favor ISG15.
  • the kinetic profile of SARS-CoV-2 PLpro is more similar to that of MERS-CoV than SARS-CoV-1.
  • Interspecies variation in ISG15 has been shown to limit the zoonotic range of influenza B.
  • the similarity in species specificity between group 2b viruses indicates that these viruses probably infect many of the same host species. Humans, palm civets, pangolins, minks, and several bats have all been identified as host species for group 2b viruses, and some have been shown to host multiple 2b viruses.
  • the largely conserved species preferences of group 2b viruses may also enable them to productively infect new species that already serve as reservoirs for other 2b viruses with relatively few mutations.
  • BtSCoV-Rf1 .2004 PLpro may be able to serve as a useful tool in determining residues that affect interspecies differences between SARS-CoV-1 and SARS-CoV-2.
  • the delSGylase activities of these PLpros differ against ISG15s from sheep, camel, northern tree shrew, and jackknife fish.
  • the PLpro of BtSCoV-Rf1.2004 matches the activity of SARS-CoV-2 against sheep, camel, and jackknife fish, but matches that of SARS-CoV-1 against northern tree shrew.
  • SARS-CoV-1 While mammalian respiratory viruses would not naturally infect fish, SARS-CoV-1 , MERS-CoV, and mouse hepatitis virus (MHV) PLpros all demonstrate some off-target activity towards jackknife fish ISG15.
  • SARS-CoV-2 was the first betacoronavirus to show no appreciable activity towards fish ISG15, but the lack of activity demonstrated by BtSCoV-Rf1 .2004 PLpro, which is more closely related to SARS-CoV-1 , could help discern which differences are responsible.
  • BtSCoV-Rf 1.2004 and SARS-CoV-1 PLpros sharing a conserved UIM that is not shared by SARS-CoV-2 PLpro it is surprising that BtSCoV-Rf1 .2004 has a kinetic profile towards mono-Ub-AMC that is more similar to that of SARS-CoV-2 than SARS-CoV-1. While all three PLpros are similarly efficient at processing mono-Ub, SARS-CoV-1 has a substantially higher maximum turnover rate. Di-Ub cleavage assays data supports the results of the mono-Ub-AMC assays.
  • BtSCoV-Rf1 .2004 PLpro processed a small amount of K48 d-Ub into mono-Ub after 1 hr (FIGs. 3A-3B), while previous studies show SARS-CoV-1 having some modest activity towards several linkage types of di-UB and SARS-CoV-2 having no ability to cleave di-Ub of any kind.
  • DUB activity may be a determining factor in viral pathogenicity, as well as a critical part of the survival strategy of individual viruses.
  • the group 2a betacoronavirus MHV has one of the few PLpros that is a more robust DUB than delSGylase, and recent studies show that loss of DUB activity reduces MHV pathogenicity. Similar effects have been observed when DUB activity is ablated in the ovarian tumor domain protease of Crimean Congo hemorrhagic fever virus (CCHFV).
  • CCHFV Crimean Congo hemorrhagic fever virus
  • SARS-CoV-1 which is far more pathogenic than SARS-CoV-2, also has more robust DUB activity. If the relationship between DUB activity and pathogenicity proves to be causal then viruses with higher DUB activity would warrant extensive monitoring. However, exceedingly deadly spillover events are often self- limiting as hosts die before they are able to transmit the disease.
  • MHV which relies more heavily on DUB than delSGylase activity, has high activity against K11 , K48, and K63 di-Ub.
  • K11 and K48 linked Ub are proteasomal degradation signals. By cleaving these Ub linkage types viruses keep their proteins functional in the cytosol longer.
  • K63 linked Ub is involved in regulating RLR signaling and IFN production. By suppressing those signals a virus can keep its host's innate immune system in a passive rather than anti-viral state for a longer period post-infection.
  • the group 2b PLpros prefer long chain Ub over di-Ub.
  • SARS-CoV-2 which has little DUB activity at all, is still capable of cleaving K48 tetra-Ub into di-Ub, but can't process di-Ub into mono- Ub regardless of linkage form.
  • SARS-CoV-1 is slightly more active against several forms of di- Ub, but cleaves long chains more quickly.
  • BtSCoV-Rf1.2004 PLpro which has similar activity towards mono-Ub-AMC as SARS-CoV-2 PLpro, demonstrated little observable activity towards di-Ub.
  • Naphthalene-Based Inhibitors are Broadly Effective Group 2b Therapeutics
  • Baez-Santos, Y. M. et al X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases. J Med Chem 2014, 57, 2393-2412. DOI: 10.1021/jm401712t. 13. Baez-Santos, Y. M. et al, Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus. J Virol 2014, 88, 12511-12527. DOI: 10.1128/JVI.01294-14.
  • Kilianski, A.; et al Cell-based antiviral screening against coronaviruses: developing virus- specific and broad-spectrum inhibitors. Antiviral Res 2014, 101 , 105-12.
  • Li, W. et al, Bats are natural reservoirs of SARS-like coronaviruses. Science 2005, 310 (5748), 676-9. DOI: 10.1126/science.1118391 .
  • Ratia, K. et al Structural Basis for the Ubiquitin-Linkage Specificity and delSGylating Activity of SARS-CoV Papain-Like Protease. PLoS Pathog 2014, 10, e1004113. DOI: 10.1371/journal.ppat.1004113.

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Abstract

Selon un aspect, l'invention concerne des inhibiteurs de protéase à papaïne virale, leurs procédés de fabrication, des compositions pharmaceutiques les comprenant, et des méthodes de traitement et/ou de prévention de la COVID-19 et autres maladies à coronavirus en ayant recours à ceux-ci. Selon un aspect, les inhibiteurs de protéase à papaïne ont une structure de noyau ou de lieur caractérisant au moins un atome d'azote et des groupes cycloalkyle, aromatiques ou hétéroaromatiques substitués ou non substitués de chaque côté de la structure de noyau. Selon un autre aspect, les inhibiteurs de protéase à papaïne sont capables d'effectuer l'ablation de la désubiquitination virale et/ou de l'activité de la déISGase. Le présent abrégé est destiné à servir d'outil d'exploration à des fins de recherche dans ce domaine technique particulier et ne se limite pas à la présente invention.
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WO2023114379A1 (fr) * 2021-12-16 2023-06-22 Huahai Us Inc. Inhibiteurs de plpro
WO2024033479A1 (fr) * 2022-08-11 2024-02-15 Remynd N.V. Dérivés d'(aza)spiroheptane pour le traitement de troubles neurodégénératifs

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US20100087442A1 (en) * 2002-04-25 2010-04-08 Ono Pharmaceutical Co., Ltd Diketohydrazine derivative compounds and drugs containing the compounds as the active ingredient
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023114379A1 (fr) * 2021-12-16 2023-06-22 Huahai Us Inc. Inhibiteurs de plpro
WO2024033479A1 (fr) * 2022-08-11 2024-02-15 Remynd N.V. Dérivés d'(aza)spiroheptane pour le traitement de troubles neurodégénératifs

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