Heterocyclic antiviral agents
Inventors
Panarese, Joseph D. • Rafferty, Sean • Thielman, Jonathan • Kenton, Nathaniel T. • Bartlett, Samuel • Or, Yat Sun
Assignees
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Publication Number
US-12145941-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts, thereof: which inhibit coronavirus replication activity. The invention further relates to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and methods of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to compounds represented by Formula (I), or pharmaceutically acceptable salts thereof, and defines a core scaffold with variables A, B, R1 through R4, R3, R13, and R14. A is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclic, and B is optionally substituted aryl or optionally substituted heteroaryl. The compounds include stereochemical variants and isoindolinone/spiro-ring type compounds, with examples and analytical characterization provided.
The disclosed compound scope uses structural formulae referenced as Formula (IX), Formula (IX-A), Formula (X), and Formula (VI), including X-1 to X-4 and X-1a to X-4a, for defining aspects of Formula (I). The description provides extensive definition language for substituents and ring/side-chain components, including selection sets for R10 and options for aryl, heteroaryl, cycloalkyl, and heterocycloalkyl characterizations.
The patent places the compounds in a therapeutic context for treating, preventing, or otherwise inhibiting coronavirus infection, notably SARS-CoV-2, and for respiratory disorders. The stated target activity is inhibition of viral 3C or 3C-like protease, and the document includes references to related coronaviruses, pharmaceutically acceptable salts, pharmaceutical compositions, administration, and dosing considerations.
Claims Coverage
The claim coverage centers on one independent Formula (I) compound claim with extensive structural variable definitions and dependent claims that specify particular compounds and medical use. The inventive features also include method coverage for inhibiting viral 3C/3CL protease in a subject and for treating or preventing coronavirus infection.
Formula (I) compound framework with defined substituent sets
A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclic; B is optionally substituted aryl or optionally substituted heteroaryl; R1, R2, and R4 are each independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; alternatively R1 and R2 are taken together with the carbon atom to form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; R3 is selected from —CN, —C(O)R15, —CH(OH)SO3R16, —C(O)NR13R14, —C(O)C(O)NR13R14, or optionally substituted C2-C8 alkynyl; and R13 and R14 are independently defined by hydrogen or the same substituent classes, with an alternative ring-forming option.
Protease-inhibition substituent group selection for R3 and ring-forming amine substituents
R3 is selected from —CN, —C(O)R15, —CH(OH)SO3R16, —C(O)NR13R14, —C(O)C(O)NR13R14, or optionally substituted C2-C8 alkynyl; R13 and R14 are each independently selected from hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, with an alternative where R13 and R14 together with the nitrogen atom form an optionally substituted 3- to 8-membered heterocyclic ring.
Formula-based refinements and explicit compound sets
The compound is further specified as defined by one of the additional formula references, including Formula (VI), and/or as a compound selected from a set of compounds that includes multiple depicted structures and corresponding chemical files.
Inhibition of viral 3C/3CL protease by administration
A method for inhibiting a viral 3C/3CL protease in a subject by administering an effective amount of a compound according to claim 1.
Treating or preventing coronavirus infection
A method for treating or preventing coronavirus infection by administering therapeutically effective amounts of the Formula (I) compounds or pharmaceutically acceptable salts thereof.
Overall, the claim set centers on a Formula (I) compound definition with explicitly defined substituent and ring-forming options, together with method coverage directed to viral 3C/3CL protease inhibition and treatment or prevention of coronavirus infection.
Stated Advantages
Inhibits viral 3C/3CL protease in a subject when administered as an effective amount.
Inhibits coronavirus replication by targeting the coronavirus 3C-like protease (3CLpro/Mpro).
Provides pharmaceutical compositions and methods for treating or preventing coronavirus infection.
Documented Applications
Evaluation in a SARS-CoV-2 3CL protease FRET assay with IC50 classification ranges A<0.1 μM, B 0.1–1 μM, and C>1 μM.
Use as an antiviral 3C/3CL protease inhibitor in a subject via administration of an effective amount.
Treating or preventing coronavirus infection by administering a therapeutically effective amount of a Formula (I) compound or pharmaceutically acceptable salt.
Method for inhibiting a viral 3C/3CL protease in a subject by administering an effective amount of a compound represented by Formula (I).
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