Antiviral heteroaryl ketone derivatives
Inventors
Owen, Dafydd Rhys • Pettersson, Martin Youngjin • Reese, Matthew Richard • Sammons, Matthew Forrest • Tuttle, Jamison Bryce • YANG, Qingyi
Assignees
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Publication Number
US-12577240-B2
Publication Date
2026-03-17
Expiration Date
Abstract
The invention relates to compounds of Formula I wherein R1, R2, p, m, A, Z1, Z2, Z3 and Z4 are as defined herein, pharmaceutical compositions comprising the compounds, methods of treating COVID-19 in a patient by administering therapeutically effective amounts of the compounds, and methods of inhibiting or preventing replication of SARS-CoV-2 with the compounds.
Core Innovation
The disclosure relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, where A is S or O and Z1, Z2, Z3 and Z4 are each independently CR3 or N. The compound is defined by a set of variable substituents including R1, R1a, R1b, R2, R2a, R3, and indices m, n and p, with detailed options for alkyl, alkoxy, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituent structures.
The core structure is further constrained by selections for fused or spiro cycloalkyl formations for the R2 substituent options, including ring structures that may be optionally substituted with R2a. The R3 substituent includes hydrogen, halo, cyano, C1–C6 alkyl optionally substituted with fluoro, C1–C6 alkoxy optionally substituted with fluoro, and (C1–C6 alkyl)-SO2—, establishing a defined chemical space for Formula I compounds with specific heteroatom-containing moieties and substitution ranges.
The disclosure provides synthetic examples and characterization for benzothiazole-containing and related analogs, including HCl salts, intermediates, trifluoroacetylation, deprotection, and final amide couplings. It also includes SARS-CoV-2 antiviral evaluation assay descriptions and reports assay results in a table with Ki and EC50 values for Examples 1–20, tied to SARS-CoV-2 antiviral activity and 3CLpro inhibition using a FRET-based assay format.
Claims Coverage
The consolidated claim coverage includes one broad compound claim to Formula I (plus pharmaceutically acceptable salts) and a treatment method scope for COVID-19. The main inventive features are the defined Formula I framework with multiple variable positions and the therapeutic use of those compounds.
Formula I compound structural definition with variable substituents
A compound of Formula I or a pharmaceutically acceptable salt thereof wherein A is S or O; Z1, Z2, Z3 and Z4 are each independently CR3 or N; and wherein the compound is defined by the substituent framework including R1, R1a, R1b, R2, R2a, R3, and indices m, n and p with specified options for the chemical classes of those substituents and substitution patterns.
COVID-19 treatment using a compound of claim 1
A method for treating COVID-19 in a patient by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
Across the identified independent coverage, the inventive aspects focus on the defined Formula I chemical space with detailed variable substituent definitions (A, Z1–Z4, and the R-group and index parameters) and therapeutic use for treating COVID-19 by administering a therapeutically effective amount of a compound of claim 1 (or a pharmaceutically acceptable salt).
Stated Advantages
The compounds act as SARS-CoV-2 3CL protease inhibitors.
The disclosure motivates targeting the 3CL protease in view of coronavirus infection and SARS-CoV-2/COVID-19.
Documented Applications
Treating COVID-19 by administering therapeutically effective amounts of a compound of Formula I or a pharmaceutically acceptable salt thereof.
Inhibiting or preventing SARS-CoV-2 replication as described in the disclosure [procedural detail omitted for safety].
Mechanistic and gene-profiling applications/uses associated with SARS-CoV-2 3CL protease inhibitor use [procedural detail omitted for safety].
Prophylactic use statements are described in the disclosure [procedural detail omitted for safety].
SARS-CoV-2 antiviral evaluation, including a SARS-CoV-2 3CLpro FRET assay reporting Ki and EC50 values for Examples 1–20.
SARS-CoV-2 antiviral assay using VeroE6/hACE2 with a CellTiter-Glo ATP readout.
P-glycoprotein efflux assessment using CP-100356.
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