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CN-122003236-A - 3 CL-protease inhibitors for the treatment or prevention of coronavirus infections in animals

CN122003236ACN 122003236 ACN122003236 ACN 122003236ACN-122003236-A

Abstract

Provided herein are methods for treating or preventing diseases caused by veterinary coronaviruses in non-human animals suffering from coronavirus infections, particularly feline coronavirus infections.

Inventors

  • SUN DEHENG
  • PENG JINGJING
  • ZHANG MAN
  • DING XIAO
  • REN FENG

Assignees

  • 英矽智能科技知识产权有限公司

Dates

Publication Date
20260508
Application Date
20240925
Priority Date
20230925

Claims (20)

  1. 1. A method of treating or preventing a disease caused by a zoocoronavirus in a non-human animal having a coronavirus infection, the method comprising administering to the non-human animal an effective amount of a compound having the formula (I): (I) or a veterinarily acceptable salt or stereoisomer thereof, Wherein the method comprises the steps of R 1 is halogen; r 2 is halogen; ring a is aryl or heteroaryl; Each R 3 is independently halogen, -CN, -NO 2 、-OH、-OR a 、-SH、-SR a 、-SF 5 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R 3a ; Each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein each alkyl is independently and optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, -NH 2 、C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; Each R 3a is independently halogen, -CN, -NO 2 、-OH、-OR a 、-SR a 、C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; L is- (CR 4 R 4 ) p -; Each R 4 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl; ring B is a 6-membered aryl or 5-or 6-membered heteroaryl; each R 6 is independently halogen, -CN, -NO 2 、-OH、C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl; ring C is cycloalkyl or heterocycloalkyl; Each R 8 is independently halogen, -CN, -NO 2 、-OH、-OR a 、-SH、-SR a 、C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; m is 0,1 or 2; n is 0,1, 2, 3 or 4; p is 0,1, 2, 3 or 4, and Q is 0,1 or 2.
  2. 2. The method of claim 1, wherein ring B is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms.
  3. 3. The method of claim 1, wherein ring C is a 6-membered cycloalkyl or a 6-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms.
  4. 4. The method of claim 3, wherein ring C is 6-membered cycloalkyl.
  5. 5. The method of claim 3, wherein ring C is a 6-membered heterocycloalkyl containing 1 heteroatom.
  6. 6. The method of any one of claims 1-5, wherein the compound has formula (Ia): (Ia), Wherein the method comprises the steps of R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 , m, n, q, L and Ring A are as defined above; x and Y are each independently N, O, S or C, and Z is O, N, S or C.
  7. 7. The method of claim 6, wherein the compound has formula (Ib): (Ib), wherein R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 , m, n, q, L, X, Y, Z and ring A are as defined above.
  8. 8. The method of any one of claims 1-7, wherein p is 0.
  9. 9. The method of any one of claims 1-8, wherein ring a is a 5-or 6-membered heteroaryl.
  10. 10. The method of any one of claims 1-8, wherein ring a is phenyl.
  11. 11. The method of any one of claims 6-9, wherein X and Y are independently N or CH.
  12. 12. The method of claim 11, wherein X and Y are both N.
  13. 13. The method of any one of claims 6-12, wherein Z is-O-.
  14. 14. The method of claim 1 OR claim 2, wherein n is 1 and R 3 is-OR a 、-SR a OR heteroaryl.
  15. 15. The method of claim 14, wherein R a is C 1 -C 6 haloalkyl.
  16. 16. The method of claim 14, wherein R 3 is-OR a .
  17. 17. The method of claim 16, wherein R 3 is-OR a and R a is C 1 -C 6 haloalkyl comprising 1-6 halogens.
  18. 18. The method of claim 17, wherein R 3 is-OR a and R a is methyl substituted with 1-3 halogens OR ethyl substituted with 1-5 halogens.
  19. 19. The method of claim 17 or 18, wherein R 3 is-OCF 2 Cl、-OCF 3 or-OCF 2 CF 3 .
  20. 20. The method of claim 14, wherein R 3 is-SR a .

Description

3 CL-protease inhibitors for the treatment or prevention of coronavirus infections in animals Cross reference This patent application claims the benefit of International application No. PCT/CN2023/121194 filed on 25 th 9 of 2023, which is incorporated herein by reference in its entirety. Background Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. Since the 30s of the 20 th century, they have been considered pathogenic conditions in the veterinary field. They infect a wide variety of animals including pigs, cattle, horses, camels, domestic pets (e.g., cats, dogs, etc.), ferrets, rodents, birds, and bats. Most animal-related coronaviruses infect the gut and spread through the faecal route. There are two forms of feline coronavirus, both of which belong to members of the genus coronavirus type 1. Although feline enterocoronavirus is a less clinically important pathogen, spontaneous mutation of the virus can lead to Feline Infectious Peritonitis (FIP), a high mortality disease. There are two different coronaviruses that infect dogs, canine coronavirus (CCoV), which belongs to a member of the genus coronavirus type 1, which causes mild gastrointestinal disease. Canine respiratory coronavirus (CRCoV) is a member of the genus βcoronavirus type 1 and is associated with HCoV-OC43, which can cause respiratory disease. Similarly, there are two coronaviruses that infect ferrets. Ferret enterocoronaviruses cause a gastrointestinal syndrome known as Epidemic Catarrhal Enteritis (ECE) in animals, and a systemic form of more deadly virus (e.g., FIP in cats), known as Ferret Systemic Coronavirus (FSC). There remains a need for new methods of treating or preventing diseases caused by coronaviruses (VETERINARY CORONAVIRUS) in non-human animals, particularly infectious peritonitis in cats. SUMMARY The present disclosure provides a method of treating or preventing a disease caused by a veterinary coronavirus in a non-human animal having a coronavirus infection, the method comprising administering to the non-human animal an effective amount of a compound as described herein having formula (I): (I) or a veterinarily acceptable salt or stereoisomer thereof. In another aspect, the present disclosure provides a method of treating or preventing a feline coronavirus infection in a non-human animal in need thereof, the method comprising administering to the non-human animal an effective amount of a compound disclosed herein or a veterinarily acceptable salt thereof. In another aspect, the present disclosure provides a method of treating or preventing infectious peritonitis in a cat in a non-human animal in need thereof, the method comprising administering to the non-human animal an effective amount of a compound disclosed herein or a veterinarily acceptable salt thereof. In a further aspect, the present disclosure provides the use of a compound disclosed herein, or a veterinarily acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease caused by a veterinary coronavirus in a non-human animal suffering from a coronavirus infection. In another aspect, the present disclosure provides the use of a compound disclosed herein, or a veterinarily acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of feline coronavirus infection in a non-human animal in need thereof. In another aspect, the present disclosure provides the use of a compound disclosed herein, or a veterinarily acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of infectious peritonitis in a cat of a non-human animal in need thereof. In another aspect, the present disclosure provides a compound disclosed herein, or a veterinarily acceptable salt thereof, for use in treating or preventing a disease caused by a veterinary coronavirus in a non-human animal having a coronavirus infection. In another aspect, the present disclosure provides a compound disclosed herein, or a veterinarily acceptable salt thereof, for use in treating or preventing feline coronavirus infection in a non-human animal in need thereof. In another aspect, the present disclosure provides a compound disclosed herein, or a veterinarily acceptable salt thereof, for use in treating or preventing feline infectious peritonitis in a non-human animal in need thereof. Incorporated by reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Brief Description of Drawings The features of the invention are set forth in detail in the appended claims. The features of the present invention will be better understood by reference to the following detailed description of exemplary embodiments that make use of the principles of the inve