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US-20260125365-A1 - TRIAZINE DERIVATIVES HAVING VIRUS REPLICATION INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

US20260125365A1US 20260125365 A1US20260125365 A1US 20260125365A1US-20260125365-A1

Abstract

The present invention provides a compound exhibiting coronavirus 3CL protease inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same. Furthermore, the present invention provides a crystalline form useful as an active pharmaceutical ingredient, and a pharmaceutical composition comprising the same. A compound represented by Formula (I): wherein Y is N or the like; R 1 is substituted or unsubstituted aromatic heterocyclyl or the like; R 2 is substituted or unsubstituted aromatic carbocyclyl or the like; R 3 is substituted or unsubstituted aromatic heterocyclyl or the like; —X— is —NH— or the like; m is 1 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; n is 1 or the like; R 4a is each independently a hydrogen atom or the like; and R 4b is each independently a hydrogen atom or the like, or a pharmaceutically acceptable salt thereof.

Inventors

  • Yuki Tachibana
  • Takahiro SUTO
  • Michihito SASAKI
  • Shota UEHARA
  • YUTO UNOH
  • Kenji Nakahara
  • Yoshiyuki Taoda
  • Koji KASAMATSU
  • Yukiko YAMATSU
  • Shigeru Ando
  • Atsuhiro IMURO

Assignees

  • SHIONOGI & CO., LTD.
  • NATIONAL UNIVERSITY CORPORATION HOKKAIDO UNIVERSITY

Dates

Publication Date
20260507
Application Date
20260107
Priority Date
20210414

Claims (20)

  1. 1 . A compound represented by Formula (I): wherein Y is N, or CR 7 ; R 7 is a hydrogen atom, or substituted or unsubstituted alkyl; R 1 is substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted amino; R 2 is substituted or unsubstituted aromatic carbocyclyl (provided that para-monofluorophenyl, para-monochlorophenyl, and para-monomethylphenyl are excluded), substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl; R 3 is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic hetero cyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or substituted or unsubstituted alkyl; —X— is —NR 6 —, —CR 6 R 6′ —, —O—, —S—, or a single bond; R 6 and R 6′ are each independently a hydrogen atom, or substituted or unsubstituted alkyl; 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; n is 0, 1, or 2; R 4a is each independently a hydrogen atom, or substituted or unsubstituted alkyl; R 4b is each independently a hydrogen atom, or substituted or unsubstituted alkyl; provided that the following compounds are excluded: or a pharmaceutically acceptable salt thereof.
  2. 2 . The compound according to claim 1 , wherein Y is N, or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound according to claim 1 , wherein —X— is —NH—, or a pharmaceutically acceptable salt thereof.
  4. 4 . The compound according to claim 1 , wherein R 2 is substituted or unsubstituted 6 to 14 membered aromatic carbocyclyl, substituted or unsubstituted 5 to 10 membered non-aromatic carbocyclyl, substituted or unsubstituted 5 to 10 membered aromatic heterocyclyl, or substituted or unsubstituted 5 to 10 membered non-aromatic heterocyclyl, or a pharmaceutically acceptable salt thereof.
  5. 5 . The compound according to claim 1 , wherein R 2 is 6 membered aromatic carbocyclyl substituted with one halogen or one cyano, and further substituted with 1, 2, 3 or 4 substituent(s) selected from substituent group G, or 6 membered aromatic heterocyclyl substituted with one halogen or one cyano, and further substituted with 1 or 2 substituent(s) selected from substituent group G; wherein the substituent group G is the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy, or a pharmaceutically acceptable salt thereof.
  6. 6 . The compound according to claim 1 , wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof.
  7. 7 . The compound according to claim 1 , wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.
  8. 8 . The compound according to claim 1 , wherein R 4a is each independently a hydrogen atom or unsubstituted alkyl, and R 4b is each independently a hydrogen atom, 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 1 is substituted or unsubstituted aromatic heterocyclyl, or a pharmaceutically acceptable salt thereof.
  11. 11 . The compound according to claim 1 , wherein R 1 is substituted or unsubstituted aromatic heterocyclyl, m is 1, R 5a is a hydrogen atom, and R 5b is a hydrogen atom, or pharmaceutically acceptable salt thereof.
  12. 12 . The compound according to claim 1 , wherein R 1 is substituted or unsubstituted aromatic heterocyclyl, and m is 0, or a pharmaceutically acceptable salt thereof.
  13. 13 . The compound according to claim 1 , wherein R 3 is substituted or unsubstituted 6 membered aromatic carbocyclyl, substituted or unsubstituted 3 to 10 membered non-aromatic carbocyclyl, substituted or unsubstituted 5 to 6 membered aromatic heterocyclyl, substituted or unsubstituted 9 to 10 membered aromatic heterocyclyl, substituted or unsubstituted 13 to 15 membered aromatic heterocyclyl, or substituted or unsubstituted 3 to 20 membered non-aromatic heterocyclyl, or a pharmaceutically acceptable salt thereof.
  14. 14 . The compound according to claim 1 , wherein R 3 is substituted or unsubstituted 6 membered aromatic carbocyclyl, substituted or unsubstituted 9 to 10 membered aromatic heterocyclyl, or substituted or unsubstituted 9 to 13 membered non-aromatic heterocyclyl, or a pharmaceutically acceptable salt thereof.
  15. 15 . The compound according to claim 1 , wherein Formula (T) is Formula (I′): wherein R 1′ isa group represented by Formula: R 2′ is a group represented by Formula: R 3′ is a group represented by Formula: or a pharmaceutically acceptable salt thereof.
  16. 16 . The compound according to claim 1 , wherein Formula (I) is Formula (I′): wherein R 1′ is a group represented by Formula: R 2′ is a group represented by Formula: R 3′ is a group represented by Formula: or a pharmaceutically acceptable salt thereof.
  17. 17 . The compound according to claim 1 , wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  18. 18 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
  19. 19 . A coronavirus 3CL protease inhibitor comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
  20. 20 . A coronavirus replication inhibitor comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. application Ser. No. 17/790,358 filed Jun. 30, 2022, which is a U.S. national stage application of international application No. PCT/JP2022/006495 filed Feb. 17, 2022, which claims priority to Japan Patent Application No. 2021-153819 filed Sep. 22, 2021, Japan Patent Application No. 2021-105802 filed Jun. 25, 2021, and Japan Patent Application No. 2021-068672 filed Apr. 14, 2021, 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 “AttachE_SEQUENCE_LISTING_1712.xml”; the file was created on Dec. 31, 2025; the size of the file is 2,822 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. Furthermore, the present invention relates to a crystal and a cocrystal of a compound or a pharmaceutically acceptable salt thereof, exhibiting 3CL protease inhibitory activity or a pharmaceutical composition comprising the same. 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, the genus 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 Wuhan, China, 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 Jan. 28, 2022, was more than 360 million, and the number of deaths reached more than 5.63 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, structural proteins for producing new viral particles, 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 tri