Protease Inhibitors for Treating or Preventing Coronavirus Infection

Abstract

Provided herein are novel compounds as protease inhibitors, pharmaceutical compositions, use of such compounds in treating or preventing coronavirus infection, and processes for preparing such compounds.

Important Compound Classes

Title

Protease Inhibitors for Treating or Preventing Coronavirus Infection

Patent Publication Number

WO 2023/133174 A1

URL: https://patents.google.com/patent/WO2023133174A1/en

Publication Date

July 13, 2023

Priority Applications

US 63/297,391 and US 63/430,444

Priority Dates

January 7, 2022 and December 6, 2022

Inventors

Campbell, B. T.; Chang, W.; Hartingh, T. J.; Hurzy, D. M.; Kelly, M. J., III; Klinger, F.-M.; Layton, M. E.; McCauley, J. A.; Nawrat, C. C.; Parish, C. A.; Perkins, J. J.; Roecker, A. J.; De Lera Ruiz, M.; Schreier, J. D.; Shurtleff, V. W.; Su, J.; Truong, Q. T.

Assignee Company

Merck Sharp & Dohme LLC, USA

Disease Area

Coronavirus infection

Biological Target

Protease

Summary

Coronaviruses (CoVs) are large, enveloped, positive-stranded RNA viruses that comprise of the Coronovirinae subfamily in the Norovirales order. CoVs are further classified into four genera: alpha coronavirus, beta coronavirus, gamma coronavirus, and delta coronavirus. Alpha and beta CoVs infect humans and other mammals, whereas the gamma and delta CoVs infect only animals (e.g., birds, sea mammals, pigs). CoV infection can result in a wide range of acute or chronic diseases of the respiratory, enteric, and central nervous systems.

To date, seven different coronaviruses that cause disease in humans have been identified: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and most recently SARS-CoV-2.

SARS-CoV-2 is a pandemic of CoV. The CoV particles consist of a cell-derived lipid membrane containing structural proteins spike (S), membrane (M), envelop (E), and nucleocapsid (N). The virion contains a large (25–32 kb) non-segmented positive-sense single-strand viral RNA genome.

The present application describes a series of novel compounds as protease inhibitors for treating or preventing coronavirus infection. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

R₁ = C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ fluoroalkyl, -(CH₂)_p-R_1c, H;

R₂ = F, OH, C₁–C₃ alkyl, C₁–C₃ fluoroalkyl, -O-C₁–C₃ alkyl, -O-C₁–C₃ fluoroalkyl, or ring R_2cy;

R_3a = C₁–C₆ alkyl, C₁–C₆ methoxy, C₁–C₆ fluoroalkyl, -CH₂O-(C₁–C₆ alkyl), , -(CH₂)_t-Y_3c;

M = -O-, or -N(H)-;

R_3b = C₁–C₆ alkyl, or -(CH₂)_u-Y_3b;

m = 0, 1, 2, or 3; and n = 1 or 2.

Biological Assay

The SARS2 coronavirus 3CL protease assay was performed. The compounds described in this application were tested for their ability to inhibit protease. The protease IC₅₀ values (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for protease inhibition and the biological data obtained from testing representative examples.

Key Structures

Claims

Total claims: 22

Compound claims: 13

Pharmaceutical composition claims: 3

Method of treatment claims: 4

Use of compound claims: 2

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.