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US-20260125392-A1 - URACIL DERIVATIVES HAVING VIRUS REPLICATION INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

US20260125392A1US 20260125392 A1US20260125392 A1US 20260125392A1US-20260125392-A1

Abstract

A compound exhibiting coronavirus 3CL protease inhibitory activity or a pharmaceutically acceptable salt thereof, represented by Formula (I) wherein Ring A is a ring represented by: wherein X is a single bond or the like, R 2 is substituted or unsubstituted aromatic carbocyclyl or the like, R 3c is substituted or unsubstituted aromatic carbocyclyl or the like, R 3 is substituted or unsubstituted aromatic carbocyclyl or the like, R 3a is a hydrogen atom or the like, R 3b is a hydrogen atom, R 8a is substituted or unsubstituted aromatic carbocyclyl or the like, and R 8b is a hydrogen atom or the like, R 1 is a substituted or unsubstituted aromatic heterocyclyl, m is 0 or the like, R 5a is each independently a hydrogen atom or the like, R 5b is each independently a hydrogen atom or the like, R 6 is cyano or the like, and R 7a and R 7b are each independently a hydrogen atom or the like.

Inventors

  • Jun Sato
  • Hiromitsu SHIBAYAMA
  • Keiichiro HIRAI
  • YUTO UNOH
  • Shota UEHARA
  • Shuji Yonezawa
  • Kana Kurahashi
  • Eiichi Kojima

Assignees

  • SHIONOGI & CO., LTD.

Dates

Publication Date
20260507
Application Date
20260106
Priority Date
20220408

Claims (19)

  1. 1 . A compound represented by Formula (I): wherein Ring A is a ring represented by: wherein X is a single bond, —CR 4a R 4b —, —C(═O)—, —O—, or —S—; R 4a and R 4b are each independently a hydrogen atom, or substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or substituted or unsubstituted alkyl; R 3c is a hydrogen atom, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, or substituted or unsubstituted alkyloxy; R 3 is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, or substituted or unsubstituted alkyloxy; R 3a is a hydrogen atom, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkyloxy; R 3b is a hydrogen atom; R 8a is substituted or unsubstituted aromatic carbocyclyl or substituted or unsubstituted aromatic heterocyclyl; and R 8b is a hydrogen atom, or substituted or unsubstituted alkyl; or, R 8a and R 8b may be taken together with a carbon atom to which R 8a and R 8b are bonded to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle; R 1 is substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino or cyano; m is 0, 1, or 2; R 5a is each independently a hydrogen atom, or substituted or unsubstituted alkyl; R 5b is each independently a hydrogen atom, or substituted or unsubstituted alkyl; R 6 is cyano, halogen, or substituted or unsubstituted alkynyl; R 7a and R 7b are each independently a hydrogen atom, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxycarbonyl, or, R 7a and R 7b may be taken together with a carbon atom to which R 7a and R 7b are bonded to form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle, or a pharmaceutically acceptable salt thereof.
  2. 2 . The compound according to claim 1 , wherein Ring A is a ring represented by: wherein R 3c , R 3 , X, and R 2 have the same meanings as those in claim 1 , or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound according to claim 1 , wherein Ring A is a ring represented by: wherein R 3c , X, and R 2 are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
  4. 4 . The compound according to claim 1 , wherein R 1 is substituted or unsubstituted aromatic heterocyclyl or substituted or unsubstituted non-aromatic heterocyclyl, or a pharmaceutically acceptable salt thereof.
  5. 5 . The compound according to claim 1 , wherein X is a single bond or —CH 2 —, or a pharmaceutically acceptable salt thereof.
  6. 6 . The compound according to claim 1 , wherein R 2 is substituted or unsubstituted aromatic carbocyclyl, or a pharmaceutically acceptable salt thereof.
  7. 7 . The compound according to claim 1 , wherein R 3c and R 3 are each independently substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or a pharmaceutically acceptable salt thereof.
  8. 8 . The compound according to claim 1 , wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof.
  9. 9 . The compound according to claim 1 , wherein R 5a is each independently a hydrogen atom, and R 5b is each independently a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  10. 10 . The compound according to claim 1 , wherein R 6 is cyano, or a pharmaceutically acceptable salt thereof.
  11. 11 . The compound according to claim 1 , wherein R 7a and R 7b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof.
  12. 12 . The compound according to claim 1 , wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  13. 13 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  14. 14 . A coronavirus 3CL protease inhibitor comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
  15. 15 . A coronavirus replication inhibitor comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
  16. 16 . The coronavirus replication inhibitor according to claim 15 , wherein the coronavirus is an alphacoronavirus and/or betacoronavirus.
  17. 17 . The coronavirus replication inhibitor according to claim 15 , wherein the coronavirus is SARS-CoV-2.
  18. 18 . A method for treating and/or preventing a disease associated with coronavirus 3CL proteases, the method comprising administering a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a human in need thereof.
  19. 19 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof for use in treating and/or preventing a disease associated with coronavirus 3CL proteases.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. application Ser. No. 18/554,130 filed Oct. 5, 2023, which is a national stage application entered under 35 U.S.C. § 371 of international application no. PCT/JP2023/014316 filed Apr. 7, 2023, which claims priority to Japan Patent Application No. 2022-207187 filed Dec. 23, 2022, Japan Patent Application No. 2022-094627 filed Jun. 10, 2022, and Japan Patent Application No. 2022-064593 filed Apr. 8, 2022, each of which is incorporated by reference herein in its entirety. SEQUENCE LISTING A sequence listing in electronic (XML file) format is filed with this application and incorporated herein by reference. The name of the XML file is “ATTACHF_Sequence_Listing-1660.xml”; the file was created on Jan. 5, 2026; the size of the file is 3,574 bytes. TECHNICAL FIELD The present invention relates to a compound exhibiting coronavirus 3CL protease inhibitory activity and a pharmaceutical composition comprising a compound exhibiting coronavirus 3CL protease inhibitory activity. BACKGROUND ART Coronaviruses, which belong to the order Nidovirales, family Coronaviridae, and the subfamily Coronavirinae, are positive-sense single-stranded RNA viruses that have a genome size of about 30 kilobases and are the largest among the known RNA viruses. Coronaviruses are classified into four genera, namely, the genus Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, and a total of seven types of coronaviruses, including two kinds in the genus Alphacoronavirus (HCoV-229E and HCoV-NL63) and five kinds in the genus Betacoronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2), are known as coronaviruses that infect humans. Among these, four kinds (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens of common cold, while the other three kinds are severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), and a novel coronavirus (SARS-CoV-2), all of which cause severe pneumonia. Novel coronavirus infections (COVID-19) that occurred in December 2019, rapidly spread to the international community, and the pandemic was announced by the WHO on Mar. 11, 2020. The number of infected people confirmed as of Mar. 10, 2023, was more than 670 million, and the number of deaths reached more than 6.88 million (Non-patent Document 1). Droplet infection, contact infection, and aerosol infection have been reported as main routes of infection of SARS-CoV-2, and it has been confirmed that SARS-CoV-2 continues to drift in air together with aerosols and maintains infectivity for about 3 hours (Non-patent Document 2). The incubation period is about 2 to 14 days, and cold-like symptoms such as fever (87.9%), dry cough (67.7%), malaise (38.1%), and phlegm (33.4%) are typical (Non-patent Document 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, and the like occurs. Furthermore, multiple organ failure such as renal failure and hepatic failure has also been reported. In Japan, as a result of drug repositioning of existing drugs, remdesivir, which is an antiviral drug, dexamethasone, which is an anti-inflammatory drug, and baricitinib, which is an antirheumatic drug, have been approved as therapeutic agents against COVID-19, and in January 2022, tocilizumab, which is an anti-IL-6 receptor antibody, have been received additional approval. Furthermore, in July 2021, ronapreve(casirivimab/imdevimab), which is an antibody cocktail therapy, was approved as special case approval, in September 2021, sotrovimab was approved as special case approval, and in December 2021, molnupiravir was approved as special case approval. Sufficient evidence has not been obtained on the efficacy and safety of these drugs. Accordingly, it is imperative to create therapeutic agents against COVID-19. Upon infection of cells, coronaviruses synthesize two polyproteins. In these two polyproteins, replication complexes producing viral genomes, and two proteases are included. Proteases play an indispensable role for cleaving the polyproteins synthesized by viruses and causing each of the proteins to function. Between these two proteases, 3CL protease (main protease) bears most of the cleavage of the polyproteins (Non-patent Document 4). Regarding COVID-19 therapeutic agents targeting 3CL proteases, it was published in ClinicalTrials.gov that Phase 1b trials for Lufotrelvir (PF-07304814), which is a prodrug of PF-00835231, have completed by Pfizer Inc (NCT04535167). Furthermore, in March 2021, Pfizer Inc. announced that Phase 1 trials for PF-07321332, a therapeutic agent against novel coronavirus infections, will be initiated. The structural formulae of PF-00835231, Lufotrelvir and PF-07321332 are as shown below, and these agents are different from the compound of the present invention in chemical structure (Non-pate