3CL-protease inhibitors for treatment or prevention of veterinary coronavirus infections

Abstract

Provided herein are methods for treating or preventing a disease caused by an veterinary coronavirus in a non-human animal suffering from a coronavirus infection, in particular a feline coronavirus infection.

Description

[0001] Cross-references

[0002] This patent application claims the benefit of International Application No. PCT / CN2023 / 121194, filed on September 25, 2023, which is incorporated herein by reference in its entirety.

[0003] background

[0004] Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. They have been recognized as pathogenic conditions in veterinary medicine since the 1930s. They infect animals including pigs, cattle, horses, camels, and domestic pets. example like A wide variety of animals, including cats, dogs, ferrets, rodents, birds, and bats, are susceptible to coronaviruses. Most animal-associated coronaviruses infect the gut and are transmitted via the fecal-oral route.

[0005] There are two forms of feline coronaviruses, both members of the genus *Alphacoronavirus* 1. While feline enteric coronavirus is a pathogen of less clinical importance, spontaneous mutations of this virus can lead to feline infectious peritonitis (FIP), a highly fatal disease. There are two different coronaviruses that infect dogs: canine coronavirus (cCoV), a member of the genus *Alphacoronavirus* 1, which causes mild gastrointestinal illness; and canine respiratory coronavirus (CRCoV), a member of the genus *βcoronavirus* 1 and associated with HCoV-OC43, which causes respiratory illness. Similarly, there are two coronaviruses that infect ferrets. Ferret enteric coronavirus causes a gastrointestinal syndrome called animal epidemic catarrhal enteritis (ECE), and a more deadly systemic form of the virus (such as feline FIP) called ferret systemic coronavirus (FSC).

[0006] New treatments or preventative measures are still needed for diseases caused by veterinary coronaviruses in nonhuman animals, particularly feline infectious peritonitis.

[0007] Overview

[0008] This disclosure provides a method for treating or preventing disease caused by a veterinary coronavirus in non-human animals suffering from coronavirus infection, the method comprising administering to the non-human animal an effective amount of a compound having formula (I) as described herein:

[0009] (I)

[0010] Or its veterinary-acceptable salts or stereoisomers.

[0011] In another aspect, this disclosure provides a method for treating or preventing feline coronavirus infection in non-human animals in need, the method comprising administering to the non-human animal an effective amount of the compound disclosed herein or a veterinarily acceptable salt thereof.

[0012] In another aspect, this disclosure provides a method for treating or preventing feline infectious peritonitis in non-human animals in need, the method comprising administering to the non-human animal an effective amount of the compound disclosed herein or a veterinarily acceptable salt thereof.

[0013] In another aspect, this disclosure provides the use of the compounds disclosed herein or veterinary acceptable salts thereof in the preparation of medicaments for the treatment or prevention of diseases caused by veterinary coronaviruses in nonhuman animals suffering from coronavirus infection.

[0014] In another aspect, this disclosure provides for the use of the compounds disclosed herein or veterinary acceptable salts thereof in the preparation of medicaments for the treatment or prevention of feline coronavirus infection in nonhuman animals in need of such treatment.

[0015] In another aspect, this disclosure provides the use of the compounds disclosed herein or veterinary acceptable salts thereof in the preparation of medicaments for the treatment or prevention of feline infectious peritonitis in nonhuman animals in need of such treatment.

[0016] In another aspect, this disclosure provides the compounds disclosed herein or their veterinary acceptable salts for the treatment or prevention of diseases caused by veterinary coronaviruses in non-human animals suffering from coronavirus infection.

[0017] In another aspect, this disclosure provides the compounds disclosed herein or their veterinary acceptable salts for the treatment or prevention of feline coronavirus infection in nonhuman animals in need of such treatment.

[0018] In another aspect, this disclosure provides the compounds disclosed herein or their veterinary acceptable salts for the treatment or prevention of feline infectious peritonitis in nonhuman animals in need of such treatment.

[0019] By incorporating references

[0020] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference. Brief description of the attached diagram

[0022] The features of the invention are set forth in detail in the appended claims. The features of the invention will be better understood by referring to the following detailed description and accompanying drawings of exemplary embodiments utilizing the principles of the invention, wherein:

[0023] Figure 1This study demonstrates the in vitro cellular antiviral effect of compound 7 against PEDV in Vero cells.

[0024] Detailed description

[0025] definition

[0026] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, the word "comprising" and its variations, such as "including" and "containing," in the following specification and claims should be interpreted in an open, inclusive sense, i.e., "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0027] Throughout this specification, references to "some embodiments" or "one embodiment" mean that a particular feature, structure, or characteristic associated with that embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in a particular embodiment" appearing in different places throughout this specification do not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be incorporated in one or more embodiments in any suitable manner. Additionally, as used in this specification and the appended claims, unless expressly stated otherwise, the singular forms "a," "an," and "the" include plural references. It should also be noted that the term "or" is generally used to include "and / or" unless expressly stated otherwise.

[0028] Unless otherwise indicated, the following terms have the following meanings as used herein:

[0029] "Oxytochemical" refers to the compound oxygen (O).

[0030] "Cyano" refers to -CN.

[0031] "alkyl" refers to a straight-chain or branched monovalent group of a saturated hydrocarbon having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-ethyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, etc. Whenever it appears in this article, the numerical range, such as "C1-C6 alkyl" or "C 1-6 "alkyl" indicates that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the term "alkyl" when no numerical range is specified. In some embodiments, the alkyl group is C10. 1-10 Alkyl group. In some embodiments, the alkyl group is C10. 1-6 Alkyl group. In some embodiments, the alkyl group is C10. 1-5 Alkyl group. In some embodiments, the alkyl group is C10. 1-4 Alkyl group. In some embodiments, the alkyl group is C10. 1-3 Alkyl groups. Unless otherwise specified in this specification, alkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with halogen.

[0032] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6-30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused (when fused with cycloalkyl or heterocyclic alkyl groups, the aryl group is bonded through aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is 6- to 10-membered aryl. In some embodiments, the aryl group is 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems of anthracene, naphthalene, phenanthrene, anthracene, azulene, benzene, chrysene, fluorene, asymmetric indole, symmetric indole, indene, naphthalene, phenatene, pleiadene, pyrene, and benzo[a]phenanthrene. Unless otherwise specified in this specification, the aryl group may optionally be substituted with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, -COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the aryl group is optionally substituted with halogens.

[0033] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl group is bonded by non-aromatic ring atoms), spirocyclic, or bridged ring systems. In some embodiments, the cycloalkyl group is fully saturated. Representative cycloalkyl groups include, but are not limited to, those having 3-15 carbon atoms (C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), 3-10 carbon atoms (C3-C) 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyl groups are 3- to 10-membered fully saturated cycloalkyl groups or 3- to 6-membered cycloalkyl groups. In some embodiments, the cycloalkyl group is a 3- to 6-membered fully saturated cycloalkyl group or 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethylbicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in this specification, cycloalkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0034] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine.

[0035] "Halogenated alkyl" refers to an alkyl group as defined above, which is substituted by one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0036] "Hydroxyalkyl" refers to an alkyl group as defined above, which is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0037] "Aminoalkyl" refers to an alkyl group as defined above, which is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0038] "Heteroalkyl" means an alkyl group in which one or more alkyl skeleton atoms are selected from atoms other than carbon, such as alkyl groups of oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the carbon atom of the heteroalkyl group to the rest of the molecule. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the carbon atom of the heteroalkyl group to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified in this specification, heteroalkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl groups are optionally substituted with halogens.

[0039] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2-23 carbon atoms and 1-8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises 1-3 nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises 1 nitrogen atom. In some embodiments, the heterocyclic alkyl comprises 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified in this specification, heterocyclic alkyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic systems, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl group is bonded through non-aromatic ring atoms), spirocyclic, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, those having 2-15 carbon atoms (C2-C4). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups), 2-10 carbon atoms (C2-C4) 10 Fully saturated heterocyclic alkyl or C2-C 10Heterocyclic alkyl groups with 2-8 carbon atoms (C2-C8 fully saturated heterocyclic alkyl groups or C2-C8 heterocyclic alkyl groups), 2-7 carbon atoms (C2-C7 fully saturated heterocyclic alkyl groups or C2-C7 heterocyclic alkyl groups), 2-6 carbon atoms (C2-C6 fully saturated heterocyclic alkyl groups or C2-C6 heterocyclic alkyl groups), 2-5 carbon atoms (C2-C5 fully saturated heterocyclic alkyl groups or C2-C5 heterocyclic alkyl groups), or 2-4 carbon atoms (C2-C4 fully saturated heterocyclic alkyl groups or C2-C4 heterocyclic alkyl groups). Examples of these heterocyclic alkyl groups include, but are not limited to, aziridinyl, aziridine, oxadiazinyl, dioxopentyl, thienyl[1,3]m-dithiohexane, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, and pyrroleyl. Pyrazolyl, quininecycloyl, thiazoyl, tetrahydrofuranyl, trithiohexacyclohexyl, tetrahydropyranyl, thiomorpholinyl, thio-morpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl, and 2-oxo-1,3-m-dioxacyclopenten-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl has 2-10 carbons on the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is not necessarily the same as the total number of atoms (including heteroatoms) constituting the heterocycloalkyl group (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise specified in this specification, heterocyclic alkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc., as described below.In some embodiments, the heterocyclic alkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0040] "Heteroaryl" refers to a 5- to 14-membered cyclic group comprising 1-13 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl comprises 1-3 nitrogen atoms. In some embodiments, the heteroaryl comprises 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl comprises 1 nitrogen atom. The heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl is bonded through aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms on the heteroaryl may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, acrylonitrile, acrylonitrile, benzimidazolyl, benzothiazolyl, benzoindolyl, benzo-m-dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxa-achexenyl, 1,4-benzodioxylalkyl, benzonaphthuronyl, benzooxazolyl, benzo-m-dioxacyclopentenyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophene, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzothiophene, furanyl, furanoneyl, isothiazolyl The following groups are listed: imidazole, indazole, indolyl, indazole, isoindolyl, dihydroindolyl, isodihydroindolyl, isoquinolinyl, inazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoachenginyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiopheneyl. Unless otherwise specified in this specification, heteroaryl groups may optionally be substituted with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, heteroaryl groups may optionally be substituted with halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups.In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0041] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation will occur and the possibility that it will not occur. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between full and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is spatially impractical and / or synthetically infeasible. Therefore, any substituents mentioned should generally be understood to have a maximum molecular weight of about 1,000 Daltons and more typically at most about 500 Daltons.

[0042] The term "animal" or "non-human animal" includes warm-blooded animals (excluding humans) and fish. For example, an animal can be a feline, bovine, bird, canine, mustelid, equine, suidae, lagomorph, or fish. Non-human mammals are preferred. For example Cattle, sheep, pigs, camels, deer, horses, poultry, rabbits, goats, dogs and cats, buffalo, donkeys, elk and reindeer, as well as fur-bearing animals such as mink, chinchillas and raccoons, birds such as hens, geese, turkeys and ducks, and fish such as freshwater and saltwater fish, such as trout, carp and eels. Domesticated animals, such as dogs or cats, are particularly preferred.

[0043] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound, whether administered to a non-human animal or as part of a series of doses, that effectively produces the desired therapeutic effect.

[0044] "Treatment" of nonhuman animals or cells refers to any type of intervention intended to alter the natural processes of a nonhuman animal or cell. In some implementations, treatment includes administering a veterinary composition after the onset of a pathological event or exposure to a pathogen, including stabilizing the condition (e.g., preventing the condition from worsening) or alleviating the condition.

[0045] Unless otherwise indicated, the term "veterinary acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the preparation, other ingredients contained in the composition, and / or non-human animals receiving the treatment. The term "pharmaceutical acceptable" has the same or similar meaning as "veterinary acceptable".

[0046] Linking substituents are described in various locations within this disclosure. If the structure explicitly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl," then "alkyl" should be understood to represent an alkylene linking group.

[0047] When the bonds connecting to substituents are shown to cross the bonds of two atoms within the ring, these substituents can bond to any atom in the ring. When substituents are listed without specifying which atom they bond to the rest of the compound in a given structure, these substituents can bond to any atom in the structure. Combinations of multiple substituents and / or multiple variables are permitted, provided that such combinations produce stable compounds.

[0048] When any variable (e.g., R) i When a group appears more than once in any composition or structural formula of a compound, its definition for each occurrence is independent of its definition for each subsequent occurrence. Therefore, for example, if a group is shown as being surrounded by 0-2 R... i In the case of partial substitution, the group can optionally be replaced by up to two R groups. i Partial replacement, and R i Each time it appears, it is independently selected from R. i The definition of . Similarly, combinations of multiple substituents and / or multiple variables are allowed, as long as such combinations produce stable compounds.

[0049] As used in this article, the term "C" i -C j "C" represents a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C1-C6 represents 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some implementations, the term "C" is used to indicate the number of carbon atoms. 1-12 "Indicates 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3, or especially 1 to 2 carbon atoms.

[0050] As used herein, the term “heteroatom” refers to nitrogen (N), oxygen (O), sulfur (S), or phosphorus (P), and includes any oxidized form of nitrogen, sulfur, or phosphorus and quaternized forms of basic nitrogen (including N-oxides).

[0051] As used herein, the term “substituted”, whether or not preceded by the term “optionally”, means that one or more hydrogen atoms of the specified moiety are replaced by suitable substituents. It should be understood that “substituted” or “substituted” includes the implicit condition that such substitution conforms to the permissible valence of the substituted atom and that such substitution produces a stable or chemically viable compound, for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise indicated, an “optionally substituted” group may have suitable substituents at each substituted position of the group, and when more than one position on any specified structure can be substituted by more than one substituent selected from the specified group, the substituents may be the same or different at each position. Those skilled in the art will understand that the substituent itself may be substituted, if appropriate. Unless specifically noted as “unsubstituted,” the chemical portions referred to herein should be understood to include substituted variants. For example, the “aryl” group or portion implicitly includes both substituted and unsubstituted variants.

[0052] Treatment

[0053] This disclosure provides a method for treating or preventing disease caused by animal coronaviruses in non-human animals suffering from coronavirus infection, the method comprising administering to the non-human animal an effective amount of a compound having formula (I):

[0054] (I)

[0055] Or a veterinary-acceptable salt or stereoisomer.

[0056] in

[0057] R 1 It is a halogen;

[0058] R 2 It is a halogen;

[0059] Ring A is aryl or heteroaryl;

[0060] Each R 3 Independently halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -SF5, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently influenced by one or more R 3a replace;

[0061] Each R a It is independently a C1-C6 alkyl or a C1-C6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more R;

[0062] Each R is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl;

[0063] Each R 3a Independently halogen, -CN, -NO2, -OH, -OR a -SR a C1-C6 alkyl or C1-C6 haloalkyl;

[0064] L is -(CR) 4 R 4 ) p -;

[0065] Each R 4 It is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0066] R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0067] Ring B is a 6-membered aryl or a 5- or 6-membered heteroaryl;

[0068] Each R 6 It can be independently a halogen, -CN, -NO2, -OH, C1-C6 alkyl, or C1-C6 haloalkyl;

[0069] R 7 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0070] The ring C is a cycloalkyl or heterocycloalkyl group;

[0071] Each R 8 Independently halogen, -CN, -NO2, -OH, -OR a -SH, -SR a C1-C6 alkyl or C1-C6 haloalkyl;

[0072] m is 0, 1, or 2;

[0073] n can be 0, 1, 2, 3, or 4;

[0074] p is 0, 1, 2, 3, or 4; and

[0075] q can be 0, 1, or 2.

[0076] In some embodiments, ring A is aryl. In some embodiments, ring A is 5- to 10-membered ( ). For example 5-, 6-, 7-, 8-, 9-, or 10-aryl. In some embodiments, ring A is 6- to 8-aryl. For example 6-, 7-, or 8-membered aryl. In some embodiments, ring A is 6-membered aryl. In some embodiments, ring A is phenyl.

[0077] In some embodiments, ring A is a heteroaryl group. In some embodiments, ring A is 5- to 10-membered ( ). For example 5-, 6-, 7-, 8-, 9-, or 10-membered) heteroaryl. In some embodiments, ring A is a 5- or 6-membered heteroaryl. In some embodiments, ring A is a 5- to 10-membered ( ) heteroaryl containing 1, 2, or 3 heteroatoms. For example 5-, 6-, 7-, 8-, 9-, or 10-membered) heteroaryl groups. In some embodiments, ring A is a 6- to 8-membered (heteroaryl) group containing 1, 2, or 3 heteroatoms. For example 6-, 7-, or 8-membered heteroaryl. In some embodiments, ring A is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms.

[0078] In some embodiments, ring B is 6-aryl. In some embodiments, ring B is phenyl.

[0079] In some embodiments, ring B is a 5- to 6-membered heteroaryl group. In some embodiments, ring B is a 6-membered heteroaryl group. In some embodiments, ring B comprises 1, 2, or 3 heteroatoms. For example 5- or 6-membered heteroaryl groups (containing oxygen, sulfur, nitrogen, phosphorus, etc.). In some embodiments, ring B is composed of 1, 2, or 3 heteroatoms (…). For example A 6-membered heteroaryl group (containing oxygen, sulfur, nitrogen, phosphorus, etc.). In some embodiments, ring B is a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from oxygen and nitrogen. In some embodiments, ring B is a 6-membered heteroaryl group containing 1 nitrogen atom. In some embodiments, ring B is a 6-membered heteroaryl group containing 2 nitrogen atoms. In some embodiments, ring B is a 6-membered heteroaryl group containing 3 nitrogen atoms. In some embodiments, ring B is pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, ring B is pyridyl or pyrimidinyl. In some embodiments, ring B is pyridyl. In some embodiments, ring B is pyrimidinyl. In some embodiments, ring B is... .

[0080] In some embodiments, the cyclic C is a cycloalkyl group. In some embodiments, the cyclic C is 3- to 10-membered (C-C). For example3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered) cycloalkyl. The ring C is 5- to 8-membered (e.g., 5-, 6-, 7-, or 8-membered) cycloalkyl. In some embodiments, the ring C is a 6-membered cycloalkyl. In some embodiments, the ring C is a 6-membered fully saturated cycloalkyl. In some embodiments, the ring C is cyclohexyl.

[0081] In some embodiments, the ring C is a heterocyclic alkyl group. In some embodiments, the ring C is 3- to 10-membered (HCO3-). For example 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic alkyl groups. In some embodiments, the ring C is composed of 1, 2, or 3 heteroatoms. For example Oxygen, sulfur, nitrogen, phosphorus, etc.) 3 to 10-yuan ( For example 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic alkyl groups. In some embodiments, the ring C is composed of 1, 2, or 3 heteroatoms. For example 5- to 8-element (oxygen, sulfur, nitrogen, phosphorus) For example 5-, 6-, 7-, or 8-membered) heterocyclic alkyl groups. In some embodiments, the ring C is composed of 1, 2, or 3 heteroatoms ( For example A 6-membered heterocyclic alkyl group containing oxygen, sulfur, nitrogen, phosphorus, etc. In some embodiments, the ring C is a heteroatom containing one heteroatom (…). For example A 6-membered heterocyclic alkyl group containing oxygen, sulfur, nitrogen, phosphorus, etc. In some embodiments, ring C is a 6-membered heterocyclic alkyl group containing 1, 2, or 3 heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, ring C is a 6-membered heterocyclic alkyl group containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, ring C is a 6-membered heterocyclic alkyl group containing 1 heteroatom selected from oxygen, nitrogen, and sulfur. In some embodiments, ring C is a 6-membered heterocyclic alkyl group containing 1 oxygen atom. In some embodiments, ring C is a 6-membered heterocyclic alkyl group containing 1 nitrogen atom. In some embodiments, ring C is a 6-membered heterocyclic alkyl group containing 1 sulfur atom. In some embodiments, ring C is tetrahydropyran. In some embodiments, ring C is... .

[0082] In some implementation schemes, R 1 and R 2 Each is independently fluorine, chlorine, bromine, or iodine. In some implementations, R 1 It is fluorine or chlorine. In some implementations, R 2 It is fluorine or chlorine. In some embodiments, R 1 It is fluorine, and R 2 It is chlorine. In some implementations, R 1 It is chlorine, and R 2 It is fluorine.

[0083] In some implementations, each R 3 Independently -OH, -OR a -SH, -SR a -SF5 or heteroaryl. In some embodiments, each R 3 Independently for -OR a -SR a Or heteroaryl. In some embodiments, each R 3 Independently -OH. In some implementations, each R 3 Independently for -OR a .

[0084] In some implementations, each R 3 Independently for -OR a , where R a C1-C6 alkyl ( For example Methyl, ethyl, propyl, isopropyl, n-butyl, different- Butyl, Zhong- Butyl, Uncle - Butyl, just- (Amyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.)

[0085] In some implementations, each R 3 Independently for -OR a , where R a C1-C6 haloalkyl ( For example Trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). In some embodiments, each R 3 Independently for -OR a , where R a For containing 1-6 (e.g., 1, 2, 3, 4, 5, or 6) halogens ( For example C1-C6 haloalkyl groups (bromine, chlorine, fluorine, or iodine). In some embodiments, each R 3 Independently for -OR a , where R a It is a C1-C6 haloalkyl group containing one, two, or three fluorine atoms. In some embodiments, each R... 3 Independently for -OR a , where Ra It is a C1-C6 haloalkyl group containing three fluorine atoms. In some embodiments, each R 3 Independently for -OR a , where R a It is a C1-C6 haloalkyl group containing 1, 2, or 3 chlorine atoms. In some embodiments, each R 3 Independently for -OR a , where R a It is a C1-C6 haloalkyl group containing chlorine and fluorine. In some embodiments, each R 3 Independently for -OR a , where R a It is a C1-C6 haloalkyl group comprising one chlorine and one fluorine moiety. In some embodiments, each R 3 Independently for -OR a , where R a It is a C1-C6 haloalkyl group containing one chlorine and two fluorine atoms.

[0086] In some implementations, each R 3 Independently for -OR a , where R a For being 1, 2 or 3 halogens ( For example A methyl group substituted with bromine, chlorine, fluorine, or iodine. In some embodiments, each R... 3 Independently for -OR a , where R a The methyl group is substituted with one, two, or three fluorine atoms. In some embodiments, each R... 3 Independently for -OR a , where R a The methyl group is substituted with three fluorine atoms. In some embodiments, each R... 3 Independently for -OR a , where R a The methyl group is substituted with one, two, or three chlorine atoms. In some embodiments, each R... 3 Independently for -OR a , where R a The methyl group is substituted with three chlorine atoms. In some embodiments, each R... 3 Independently for -OR a , where R a The methyl group is substituted with chlorine and fluorine. In some embodiments, each R 3 Independently for -OR a , where R a The methyl group is substituted with one chlorine and one fluorine molecule. In some embodiments, each R... 3 Independently for -OR a , where R aThe methyl group is substituted with one chlorine and two fluorine groups. In some embodiments, each R... 3 Independently -OCF2Cl or -OCF3. In some implementations, n is 1, and R 3 It is either -OCF2Cl or -OCF3.

[0087] In some implementations, each R 3 Independently for -OR a , where R a For use with 1, 2, 3, 4 or 5 halogens ( For example Ethyl groups substituted with bromine, chlorine, fluorine, or iodine. In some embodiments, each R... 3 Independently for -OR a , where R a Ethyl groups substituted with 1, 2, 3, 4, or 5 fluorine atoms. In some embodiments, each R... 3 Independently for -OR a , where R a It is an ethyl group substituted with 5 fluorine atoms. In some embodiments, each R 3 Independently for -OR a , where R a Ethyl groups substituted with 1, 2, 3, 4, or 5 chlorine atoms. In some embodiments, each R... 3 Independently for -OR a , where R a For ethyl groups substituted with 5 chlorine atoms. In some embodiments, each R 3 Independently for -OR a , where R a Ethyl groups substituted with chlorine and fluorine. In some embodiments, each R... 3 Independently, it is -OCF2CF3. In some implementations, n is 1, and R 3 It is -OCF2CF3.

[0088] In some implementations, each R 3 Independently -SH, -SR a Or -SF5. In some implementations, each R 3 Independently for -SR a .

[0089] In some implementations, each R 3 Independently for -SR a , where R a C1-C6 alkyl ( For example Methyl, ethyl, propyl, isopropyl, n-butyl, different- Butyl, Zhong- Butyl, Uncle - Butyl, just- (Amyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.)

[0090] In some implementations, each R 3 Independently for -SR a , where R a C1-C6 haloalkyl ( For example Trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). In some embodiments, each R 3 Independently for -SR a , where R a For containing 1-6 (e.g., 1, 2, 3, 4, 5, or 6) halogens ( For example C1-C6 haloalkyl groups (bromine, chlorine, fluorine, or iodine). In some embodiments, each R 3 Independently for -SR a , where R a It is a C1-C6 haloalkyl group containing one, two, or three fluorine atoms. In some embodiments, each R... 3 Independently for -SR a , where R a It is a C1-C6 haloalkyl group containing three fluorine atoms. In some embodiments, each R 3 Independently for -SR a , where R a It is a C1-C6 haloalkyl group containing 1, 2, or 3 chlorine atoms. In some embodiments, each R 3 Independently for -SR a , where R a It is a C1-C6 haloalkyl group containing chlorine and fluorine. In some embodiments, each R 3 Independently for -SR a , where R a It is a C1-C6 haloalkyl group comprising one chlorine and one fluorine moiety. In some embodiments, each R 3 Independently for -SR a , where R a It is a C1-C6 haloalkyl group containing one chlorine and two fluorine atoms.

[0091] In some implementations, each R 3 Independently for -SRa , where R a For being 1, 2 or 3 halogens ( For example A methyl group substituted with bromine, chlorine, fluorine, or iodine. In some embodiments, each R... 3 Independently for -SR a , where R a The methyl group is substituted with one, two, or three fluorine atoms. In some embodiments, each R... 3 Independently for -SR a , where R a The methyl group is substituted with three fluorine atoms. In some embodiments, each R... 3 Independently for -SR a , where R a The methyl group is substituted with one, two, or three chlorine atoms. In some embodiments, each R... 3 Independently for -SR a , where R a The methyl group is substituted with three chlorine atoms. In some embodiments, each R... 3 Independently for -SR a , where R a The methyl group is substituted with chlorine and fluorine. In some embodiments, each R 3 Independently for -SR a , where R a The methyl group is substituted with one chlorine and one fluorine molecule. In some embodiments, each R... 3 Independently for -SR a , where R a The methyl group is substituted with one chlorine and two fluorine groups. In some embodiments, each R... 3 Independently -SCF3. In some implementations, n is 1, and R 3 It is -SCF3.

[0092] In some implementations, each R 3 Independently, it is a heteroaryl group. In some embodiments, R 3 It is 5 to 10 yuan. For example 5-, 6-, 7-, 8-, 9-, or 10-aryl) heteroaryl groups. In some embodiments, R 3 It is a 5- or 6-membered heteroaryl group. In some embodiments, R 3 It is a 5-membered heteroaryl group.

[0093] In some implementations, each R 3 Independently, it is a 5- to 10-membered heteroatom containing 1, 2, or 3 heteroatoms. For example 5-, 6-, 7-, 8-, 9-, or 10-aryl) heteroaryl groups. In some embodiments, each R 3Independently, it is a 5- to 8-membered heteroatom containing 1, 2, or 3 heteroatoms. For example 5-, 6-, 7-, or 8-aryl) heteroaryl groups. In some embodiments, each R 3 Independently, it is a 5-membered heteroaryl group containing 1, 2, or 3 heteroatoms. In some embodiments, each R 3 It is independently a 5-membered heteroaryl group containing 2 heteroatoms.

[0094] In some implementations, each R 3 Each is independently a 5-membered heteroaryl group comprising 1, 2, or 3 heteroatoms, wherein each heteroatom is independently an O, N, or S atom. In some embodiments, each R 3 Each is independently a 5-membered heteroaryl group comprising 1, 2, or 3 heteroatoms, wherein each heteroatom is independently an N or S atom. In some embodiments, each R 3 Each is independently a 5-membered heteroaryl group comprising two heteroatoms, wherein each heteroatom is independently an N or S atom. In some embodiments, each R 3 Independently, it is a 5-membered heteroaryl group comprising one N atom and one S atom. In some embodiments, each R 3 Independently In some implementations, each R 3 Independently In some implementations, n is 1, and R 3 for In some implementations, n is 1, and R 3 for .

[0095] In some implementations, each R 3 Independently halogenated. In some implementations, each R... 3 Independently for -CN. In some implementations, each R 3 Independently, it is -NO2.

[0096] In some implementations, each R 3 Independently C1-C6 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, different- Butyl, Zhong- Butyl, Uncle - Butyl, just- Pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0097] In some implementations, each R 3 Independently C1-C6 haloalkyl ( For example Trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). In some embodiments, each R 3 Independently, it comprises 1-6 (e.g., 1, 2, 3, 4, 5, or 6) halogens. For example C1-C6 haloalkyl groups (bromine, chlorine, fluorine or iodine).

[0098] In some implementations, each R 3 Independently cycloalkyl. In some embodiments, each R 3 Independently, it is a cycloalkyl group comprising 3-15 cyclic carbon atoms, 3-12 cyclic carbon atoms, 3-10 cyclic carbon atoms, 3-9 cyclic carbon atoms, 3-8 cyclic carbon atoms, 3-7 cyclic carbon atoms, 3-6 cyclic carbon atoms, 3-5 cyclic carbon atoms, 4-15 cyclic carbon atoms, 4-12 cyclic carbon atoms, 4-10 cyclic carbon atoms, 4-9 cyclic carbon atoms, 4-8 cyclic carbon atoms, 4-7 cyclic carbon atoms, 4-6 cyclic carbon atoms, or 4-5 cyclic carbon atoms.

[0099] In some implementations, each R 3 Independently, it is a heterocyclic alkyl group. In some embodiments, each R... 3 Independently for containing 3-15 ( For example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) cyclic carbon atoms and 1 to 8 heterocyclic alkyl groups (e.g., 1, 2, 3, 4, 5, 6, 7 or 8) selected from nitrogen, oxygen, phosphorus, silicon and sulfur.

[0100] In some implementations, each R 3 Independently aryl. In some implementations, each R 3 Independently priced at 5 to 10 yuan ( For example 5-, 6-, 7-, 8-, 9-, or 10-aryl. In some embodiments, each R 3 Independently priced at 6- to 8- yuan ( For example 6-, 7-, or 8-aryl. In some embodiments, each R 3 Independently 6-aryl. In some embodiments, each R 3 It is independently phenyl.

[0101] In some implementations, L is -(CR) 4 R 4) p -. In some implementations, L is -(CR 4 R 4 ) p - and p is 0. In some implementations, L is -(CR 4 R 4 ) p - and p is 1. In some implementations, L is -(CR 4 R 4 ) p - and p is 2. In some implementations, L is -(CR 4 R 4 ) p - and p is 3. In some implementations, L is -(CR 4 R 4 ) p - and p is 4.

[0102] In some implementations, each R 4 Independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 4 Independently hydrogen. In some implementations, each R 4 Halogens are independent of each other.

[0103] In some implementations, each R 4 Independently C1-C6 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, different- Butyl, Zhong- Butyl, Uncle - Butyl, just- Pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0104] In some implementations, each R 4 Independently C1-C6 haloalkyl ( For example Trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). In some embodiments, each R 4 Independently, it comprises 1-6 (e.g., 1, 2, 3, 4, 5, or 6) halogens. For example C1-C6 haloalkyl groups (bromine, chlorine, fluorine or iodine).

[0105] In some implementation schemes, R 5 It is a C1-C6 alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, etc. different- Butyl, Zhong- Butyl, Uncle - Butyl, just- Pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc. In some embodiments, R 5 It is a C1-C5 alkyl group. In some embodiments, R 5 It is a C1-C4 alkyl group. In some embodiments, R 5 It is a C1-C3 alkyl group. In some embodiments, R 5 It is methyl or ethyl. In some embodiments, R 5 It is a methyl group.

[0106] In some implementation schemes, R 5 C1-C6 haloalkyl ( For example Trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). In some embodiments, R 5 For containing 1-6 (e.g., 1, 2, 3, 4, 5, or 6) halogens ( For example C1-C6 haloalkyl groups (bromine, chlorine, fluorine or iodine).

[0107] In some implementation schemes, R 5 It is a C1-C6 hydroxyalkyl group. In some embodiments, R 5 It is a C1-C5 hydroxyalkyl group. In some embodiments, R 5 It is a C1-C4 hydroxyalkyl group. In some embodiments, R 5 It is a C1-C3 hydroxyalkyl group. In some embodiments, R 5 The methyl group is substituted with a hydroxyl group. In some embodiments, R 5 It is an ethyl group that has been substituted with a hydroxyl group.

[0108] In some implementation schemes, R 5 It is a C1-C6 aminoalkyl group. In some embodiments, R 5 It is a C1-C5 aminoalkyl group. In some embodiments, R 5It is a C1-C4 aminoalkyl group. In some embodiments, R 5 It is a C1-C3 aminoalkyl group. In some embodiments, R 5 The methyl group is replaced by an amino group. In some embodiments, R 5 It is an ethyl group that has been substituted with an amino group.

[0109] In some implementation schemes, R 5 It is a C1-C6 heteroalkyl group. In some embodiments, R 5 It is a C1-C5 heteroalkyl group. In some embodiments, R 5 It is a C1-C4 heteroalkyl group. In some embodiments, R 5 It is a C1-C3 heteroalkyl group.

[0110] In some implementations, each R 6 Independently, it is a halogen, -CN, -NO2, -OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 6 Independently halogenated, -CN, -NO2, or -OH. In some embodiments, each R... 6 Halogens are independent of each other.

[0111] In some implementations, each R 6 Independently C1-C6 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, different- Butyl, Zhong- Butyl, Uncle - Butyl, just- Pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc. In some embodiments, each R 6 Independently C1-C5 alkyl. In some embodiments, each R 6 Independently C1-C4 alkyl. In some embodiments, each R 6 Independently, each R is a C1-C3 alkyl group. In some embodiments, each R 6 Independently methyl or ethyl. In some embodiments, each R 6 Independently, it is methyl.

[0112] In some implementations, each R 6 Independently C1-C6 haloalkyl ( For exampleTrifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). In some embodiments, each R 6 Independently, it comprises 1-6 (e.g., 1, 2, 3, 4, 5, or 6) halogens. For example C1-C6 haloalkyl groups (bromine, chlorine, fluorine or iodine).

[0113] In some implementation schemes, R 7 It is hydrogen.

[0114] In some implementation schemes, R 7 It is a C1-C6 alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, etc. different- Butyl, Zhong- Butyl, Uncle - Butyl, just- Pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc. In some embodiments, R 7 It is a C1-C5 alkyl group. In some embodiments, R 7 It is a C1-C4 alkyl group. In some embodiments, R 7 It is a C1-C3 alkyl group. In some embodiments, R 7 It is methyl or ethyl. In some embodiments, R 7 It is a methyl group.

[0115] In some implementation schemes, R 7 C1-C6 haloalkyl ( For example Trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). In some embodiments, R 7 For containing 1-6 (e.g., 1, 2, 3, 4, 5, or 6) halogens ( For example C1-C6 haloalkyl groups (bromine, chlorine, fluorine or iodine).

[0116] In some implementation schemes, R 7 It is a C1-C6 hydroxyalkyl group. In some embodiments, R 7 It is a C1-C5 hydroxyalkyl group. In some embodiments, R 7 It is a C1-C4 hydroxyalkyl group. In some embodiments, R 7It is a C1-C3 hydroxyalkyl group. In some embodiments, R 7 The methyl group is substituted with a hydroxyl group. In some embodiments, R 7 It is an ethyl group that has been substituted with a hydroxyl group.

[0117] In some implementation schemes, R 7 It is a C1-C6 aminoalkyl group. In some embodiments, R 7 It is a C1-C5 aminoalkyl group. In some embodiments, R 7 It is a C1-C4 aminoalkyl group. In some embodiments, R 7 It is a C1-C3 aminoalkyl group. In some embodiments, R 7 The methyl group is replaced by an amino group. In some embodiments, R 7 It is an ethyl group that has been substituted with an amino group.

[0118] In some implementation schemes, R 7 It is a C1-C6 heteroalkyl group. In some embodiments, R 7 It is a C1-C5 heteroalkyl group. In some embodiments, R 7 It is a C1-C4 heteroalkyl group. In some embodiments, R 7 It is a C1-C3 heteroalkyl group.

[0119] In some implementations, each R 8 Halogens independently ( For example (bromine, chlorine, fluorine, or iodine). In some implementations, each R 8 Independently fluorine or chlorine. In some embodiments, each R 8 Independently for fluorine. In some implementations, q is 2, and each R 8 It is fluorine.

[0120] In some implementations, each R 8 Independently -CN, -NO2, -OH, -OR a -SH or -SR a In some implementations, each R 8 Independently -CN, -NO2, -OH, or -SH. In some implementations, each R... 8 Independently for -OR a or -SR a , where R a As defined above.

[0121] In some implementations, each R 8 Independently C1-C6 alkyl, For example Methyl, ethyl, propyl, isopropyl, n-butyl, different- Butyl, Zhong-Butyl, Uncle - Butyl, just- Pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc. In some embodiments, each R 8 Independently C1-C5 alkyl. In some embodiments, each R 8 Independently C1-C4 alkyl. In some embodiments, each R 8 Independently, each R is a C1-C3 alkyl group. In some embodiments, each R 8 Independently methyl or ethyl. In some embodiments, each R 8 Independently, it is methyl.

[0122] In some implementations, each R 8 Independently C1-C6 haloalkyl ( For example Trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). In some embodiments, each R 8 Independently, it comprises 1-6 (e.g., 1, 2, 3, 4, 5, or 6) halogens. For example C1-C6 haloalkyl groups (bromine, chlorine, fluorine or iodine).

[0123] In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2.

[0124] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0125] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4.

[0126] In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2.

[0127] In some implementations, m is 0, n is 1, p is 0, and q is 0 or 2.

[0128] In some embodiments, the compound has formula (Ia):

[0129] (Ia)

[0130] in

[0131] R 1 R 2 R 3 R 5 R 6 R 7 R 8 , m, n, q, L and ring A are as defined in this paper;

[0132] X and Y are each independently N, O, S, or C; and

[0133] Z can be O, N, S, or C.

[0134] In some embodiments, the compound has formula (Ib):

[0135] (Ib)

[0136] Where 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 in this paper.

[0137] In some embodiments, X and Y are independently N or CH. In some embodiments, one of X and Y is N, and the other is N or CH. In some embodiments, X is N and Y is CH. In some embodiments, X is CH and Y is N. In some embodiments, both X and Y are N.

[0138] In some implementations, Z is -O-. In some implementations, Z is -S-. In some implementations, Z is -N-. In some implementations, Z is -C-.

[0139] In some implementation schemes, for , or .

[0140] In some embodiments, the compound has the formula (Ic):

[0141] (Ic),

[0142] Where R 1 R 2 R3 R 5 R 6 R 7 R 8 Z, m, and q are as defined in this paper.

[0143] In some embodiments, the compound has the formula (Id):

[0144] (Id),

[0145] Where R 1 R 2 R 3 R 5 R 6 R 7 R 8 Z, m, and q are as defined in this paper.

[0146] In some embodiments, the compound has the formula (Ie):

[0147] (Ie),

[0148] Where R 1 R 2 R 3 R 5 R 6 R 7 R 8 Z, m, and q are as defined in this paper.

[0149] In some implementations, one or more hydrogen atoms on ring A, ring B, or ring C are replaced by one or more deuterium atoms.

[0150] In some implementation schemes, R, R 3 R 3a R 4 R 5 R 6 R 7 R 8 and / or R a One or more of the groups contain deuterium in a percentage higher than the natural abundance of deuterium.

[0151] In some embodiments of the compounds disclosed herein, one or more hydrogen atoms in one or more of the following groups are replaced by one or more deuterium atoms: R, R 3 R 3a R 4 R 5 R 6 R 7 R 8 and / or R a .

[0152] In some embodiments of the compounds disclosed herein, R, R 3 R 3a R 4 R 5 R 6 R 7 R 8 and / or R a The deuterium abundance of each of them is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium.

[0153] This document covers any combination of the groups described above for various variables. Throughout the specification, those skilled in the art will select the groups and their substituents to provide stable moieties and compounds.

[0154] In some implementations, the compound is one of the compounds in Table 1.

[0155] Table 1

[0156]

[0157] Stereochemistry is arbitrarily specified, except outside.

[0158] In some embodiments, the non-human animal is selected from the families Felidae, Bovidae, birds, Canidae, Mustelidae, Equidae, Suidae, and Leporidae. In some embodiments, the Felidae animal is a cat. In some embodiments, the Bovidae animal is a cattle, yak, bison, buffalo, antelope, sheep, or goat. In some embodiments, the birds are chickens, guinea fowl, pheasants, or turkeys. In some embodiments, the Canidae animal is a domestic dog, wolf, coyote, fox, or jackal. In some embodiments, the Mustelidae animal is a weasel, ferret, badger, otter, mink, or wolverine. In some embodiments, the Equidae animal is a horse, donkey, or zebra. In some embodiments, the Suidae animal is a domestic pig. In some embodiments, the Suidae animal is a miniature pig. In some embodiments, the Leporidae animal is a rabbit.

[0159] In some implementations, the animal coronavirus is feline coronavirus, bovine coronavirus (BCoV), avian coronavirus (AvCoV), canine coronavirus (CCoV), canine respiratory coronavirus (CRCoV), ferret coronavirus (FRCoV), guinea fowl coronavirus (GfCoV), equine coronavirus (ECoV), pheasant coronavirus (PhCoV), transmissible gastroenteritis coronavirus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine respiratory coronavirus (PRCoV), porcine hemagglutination encephalomyelitis virus (PHEV), porcine delta coronavirus (PDCoV), porcine acute diarrhea coronavirus (SADS-CoV), rabbit coronavirus (RbCoV), turkey coronavirus (TCoV), or African antelope coronavirus (BuCoV).

[0160] In some implementations, feline coronavirus is referred to as feline enterocoronavirus (FECV) or feline infectious peritonitis virus (FIPV).

[0161] In some implementations, AvCoV is infectious bronchitis virus (IBV).

[0162] In some implementations, the disease is feline infectious peritonitis.

[0163] In another aspect, this disclosure provides a method for treating or preventing feline coronavirus infection in non-human animals in need, the method comprising administering to the non-human animal an effective amount of the compound provided herein or a veterinarily acceptable salt thereof.

[0164] In another aspect, this disclosure provides a method for treating or preventing feline coronavirus infection in non-human animals in need, the method comprising administering to the non-human animal an effective amount of a compound selected from Table 1 or a veterinarily acceptable salt thereof.

[0165] In another aspect, this disclosure provides a method for treating or preventing feline infectious peritonitis in non-human animals in need, the method comprising administering to the non-human animal an effective amount of the compound provided herein or a veterinarily acceptable salt thereof.

[0166] In another aspect, this disclosure provides a method for treating or preventing feline infectious peritonitis in non-human animals in need, the method comprising administering to the non-human animal an effective amount of a compound selected from Table 1 or a veterinarily acceptable salt thereof.

[0167] In another aspect, this disclosure provides for the use of the compounds provided herein or veterinary-acceptable salts thereof in the preparation of medicaments for the treatment or prevention of diseases caused by veterinary coronaviruses in non-human animals suffering from coronavirus infection.

[0168] In another aspect, this disclosure provides the use of compounds selected from Table 1 or veterinary-acceptable salts thereof in the preparation of medicaments for the treatment or prevention of diseases caused by veterinary coronaviruses in non-human animals suffering from coronavirus infection.

[0169] In another aspect, this disclosure provides for the use of the compounds provided herein or veterinary-acceptable salts thereof in the preparation of medicaments for the treatment or prevention of feline coronavirus infection in nonhuman animals in need of such treatment.

[0170] In another aspect, this disclosure provides the use of compounds selected from Table 1 or veterinary acceptable salts thereof in the preparation of medicaments for the treatment or prevention of feline coronavirus infection in nonhuman animals in need of such treatment.

[0171] In another aspect, this disclosure provides for the use of the compounds provided herein or veterinary acceptable salts thereof in the preparation of medicaments for the treatment or prevention of feline infectious peritonitis in nonhuman animals in need of such treatment.

[0172] In another aspect, this disclosure provides the use of compounds selected from Table 1 or veterinary-acceptable salts thereof in the preparation of medicaments for the treatment or prevention of feline infectious peritonitis in nonhuman animals in need of such treatment.

[0173] In another aspect, this disclosure provides for the use of compounds provided herein or veterinary-acceptable salts thereof for the treatment or prevention of disease caused by veterinary coronaviruses in non-human animals suffering from coronavirus infection.

[0174] In another aspect, this disclosure provides compounds selected from Table 1 or veterinary-acceptable salts thereof for the treatment or prevention of diseases caused by veterinary coronaviruses in non-human animals suffering from coronavirus infection.

[0175] In another respect, this disclosure provides for the use of the compounds provided herein or their veterinary-acceptable salts for the treatment or prevention of feline coronavirus infection in non-human animals in need of such treatment.

[0176] In another aspect, this disclosure provides compounds selected from Table 1 or veterinary-acceptable salts thereof for the treatment or prevention of feline coronavirus infection in non-human animals in need of such treatment.

[0177] In another aspect, this disclosure provides the compounds provided herein or their veterinary-acceptable salts for the treatment or prevention of feline infectious peritonitis in nonhuman animals in need of such treatment.

[0178] In another aspect, this disclosure provides compounds selected from Table 1 or veterinary-acceptable salts thereof for the treatment or prevention of feline infectious peritonitis in nonhuman animals in need of such treatment.

[0179] Isomers / stereoisomers

[0180] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis, syn, zusammen (Z)), trans (trans, anti, entgegen (E)) isomers and corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, and each center exists in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, and corresponding mixtures thereof. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as a single stereoisomer by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, a dissociable complex is preferred. In some embodiments, diastereomers possess different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized to separate the diastereomers. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by a separation / resolution technique based on solubility differences. In some embodiments, optically pure enantiomers are recovered along with the resolving agent using any practical method that does not lead to racemization.

[0181] Labeled compounds

[0182] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering these isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering these isotopically labeled compounds as a veterinary composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are equivalent to the compounds described herein, but in fact, one or more atoms are replaced by atoms having atomic weights or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example: 2 H (D), 3 H, 13 C 14 C l5 N、18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds described herein containing the aforementioned isotopes and / or other atomic isotopes, and their veterinary-acceptable salts or stereoisomers, are within the scope of this disclosure. Certain isotope-labeled compounds, such as those doped with radioactive isotopes, are also included. 3 H and 14 Compounds of C can be used for drug and / or substrate tissue distribution assays. Tritium substitution, i.e. 3 H and carbon-14 14 C isotopes are particularly preferred due to their ease of preparation and detectability.

[0183] In some embodiments, the deuterium abundance in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium. In some embodiments, one or more of the substituents disclosed herein contain deuterium in a percentage higher than the natural deuterium abundance. In some embodiments, one or more hydrogen atoms in one or more of the substituents disclosed herein are replaced by one or more deuterium atoms.

[0184] In some embodiments, the compounds described herein are labeled in other ways, including, but not limited to, using chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0185] Veterinary acceptable salt

[0186] In some embodiments, the compounds described herein are present as veterinary acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering these veterinary acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering these veterinary acceptable salts as a veterinary composition.

[0187] In some embodiments, the compounds described herein have acidic or basic groups, and thus react with a variety of inorganic or organic bases and any one of inorganic and organic acids to form veterinary-acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their stereoisomers, or by reacting the purified compounds in their free form alone with a suitable acid or base and isolating the resulting salts.

[0188] Examples of veterinary-acceptable salts include those prepared by reacting the compounds described herein with inorganic, organic acids, or inorganic bases. These salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, disglucurons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-2-phosphates, glycerophosphates, glycolates, hemisulfates, heptahydrates, hexyn-1,6-dicitates, hydroxybenzoates, and gamma-hydroxybutyrates. Salts, hydrochlorides, hydrobromides, hydroiodates, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malonates, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmitates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, pyrosulfates, pyrophosphates, propynates, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, octanoates, sebacic acid salts, sulfonates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and xylenesulfonates.

[0189] Furthermore, the compounds described herein can be prepared into veterinary-acceptable salts by reacting the compounds in their free base form with veterinary-acceptable inorganic or organic acids, including but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, etc. Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids, such as oxalic acid, although not veterinary acceptable on their own, can be used to prepare salts that can be used as intermediates in obtaining the compounds disclosed herein or their stereoisomers and their veterinary acceptable acid addition salts.

[0190] In some embodiments, the compounds described herein containing free acid groups react with a suitable base, such as, veterinary-acceptable hydroxides, carbonates, bicarbonates, sulfates of metal cations; ammonia; or veterinary-acceptable primary, secondary, tertiary, or quaternary amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2O. + (C 1-4 Alkyl)4, etc.

[0191] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternary ammonium compounds containing any basic nitrogen-containing group. In some embodiments, such quaternization yields products that are soluble or dispersed in water or oil.

[0192] solvates

[0193] In some embodiments, the compounds described herein are present in the form of solvates. This disclosure provides methods for treating diseases by administering these solvates. This disclosure also provides methods for treating diseases by administering these solvates in the form of veterinary compositions.

[0194] The solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed by a crystallization process using veterinary-acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. Solvates of the compounds described herein can be conveniently prepared or formed by the methods described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents such as dioxane, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein can exist in both solvated and non-solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated and non-solvated forms are considered equivalent.

[0195] tautomer

[0196] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers of the structures described herein. Tautomers are compounds that can interconvert through hydrogen atom migration, accompanied by the conversion of single bonds and adjacent double bonds. In the bond arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomer forms of the compounds disclosed herein are considered. The exact proportions of tautomers depend on a variety of factors, including temperature, solvent, and pH.

[0197] Veterinary preparations

[0198] According to standard veterinary practice, the compounds described herein, alone or in combination with veterinarily acceptable carriers, excipients, or diluents, are administered to non-human animals in need as a veterinary composition. In one embodiment, the compounds disclosed herein may be administered to cats. These compounds may be administered orally or parenterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and local routes.

[0199] On the other hand, this document provides veterinary compositions comprising the compounds described herein or veterinary-acceptable salts, solvates, or stereoisomers thereof, and at least one veterinary-acceptable excipient. The veterinary compositions are formulated in a conventional manner using one or more veterinary-acceptable excipients that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. Appropriate formulations depend on the chosen route of administration. These veterinary compositions and methods of their preparation can be found, for example, in the following publications: 'Remington's Veterinary Sciences', 19th edition (Mack Publishing Company, 1995; and "Veterinary Dosage Forms: Tablets, Vol. 1", H. Lieberman and L. Lachman, Marcel Dekker, NY, 1980 (ISBN 0-8247-6918-X), which are incorporated herein by reference.

[0200] In some implementations, veterinary-acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combination thereof.

[0201] The veterinary compositions described herein may be administered to non-human animals via appropriate routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. The veterinary formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-melt formulations, tablets, capsules, pills, powders, lozenges, effervescent formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-granule formulations, and mixed immediate-release and controlled-release formulations. In some embodiments, the veterinary compositions may also be mixed with non-human animal feed.

[0202] Veterinary compositions comprising the compounds described herein or their veterinary-acceptable salts, solvates or stereoisomers thereof are prepared in a conventional manner, for example by way of example only, through conventional mixing, dissolving, granulating, ingot making, grinding, emulsifying, encapsulating, embedding or pressing methods.

[0203] The veterinary composition for oral use is obtained by the following steps: mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture (if desired) after adding suitable excipients to obtain tablets or cores. Suitable excipients include, for example, fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, a disintegrant is added, such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate. In some embodiments, dyes or pigments are added to the coating of the tablet or core for identifying or characterizing different combinations of active compound dosages.

[0204] Veterinary compositions administered orally include push-fit capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Push-fit capsules contain an active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate) and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0205] Veterinary compositions intended for parenteral use are formulated as infusion or injection solutions. In some embodiments, veterinary compositions suitable for injection or infusion comprise sterile aqueous solutions, dispersions, or sterile powders containing the compounds described herein or their veterinarily acceptable salts, solvates, or stereoisomers. In some embodiments, the veterinary composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and any combination thereof. In some embodiments, the veterinary composition also comprises a preservative to prevent microbial growth.

[0206] This disclosure also provides veterinary compositions comprising at least one active ingredient as defined above and its veterinary carrier.

[0207] Veterinary carriers are materials that can be used for the purpose of administering the composition, and they can be solid, liquid, or gaseous materials that are inert or acceptable in the veterinary field and are compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or via any other desired route.

[0208] Application route

[0209] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and local administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0210] Example

[0211] The synthesis of compounds 1-8 is described in detail in Examples 92a, 90a, 33a, 1a, 34a, 5a, 94a and 4a of WO2023078231 (which is incorporated herein by reference in its entirety).

[0212] Example A: Compound on FIPV M pro Evaluation of in vitro inhibitory activity

[0213] Cloning FIPV M pro (WSU-79 / 1146, AAY32595.1), in Escherichia coli ( E. coli The substrate for Dabcyl-KTSAVLQSGFRKM-E (Edans) was expressed and purified. The assay buffer contained 20 mM Tris-HCl (pH 7.3), 100 mM NaCl, 1 mM EDTA, 5 mM TCEP, and 0.1% BSA. pro In enzyme assays, FIPV M pro The final concentrations of protein and substrate were 25 nM and 12.5 μM, respectively. For the 100% inhibition control (HPE, 100% effect), 10 μM GC376 was added. For the no-inhibition control (ZPE, zero inhibition effect), no compound was added and DMSO was used instead. Each activity assay site had a relevant background control to normalize fluorescence interference from the compound. After incubation at 30 °C for 60 min, fluorescence signals (RFU) were detected at Ex / Em = 340 nm / 490 nm using a microplate reader M2e (SpectraMax). The IC50 of the compound was calculated using a nonlinear regression model of logarithm (inhibitor) versus response with a variable slope (4 parameters) in GraphPad Prism software. 50 value.

[0214] Representative biochemical data are shown in Table 2 below.

[0215] Table 2

[0216]

[0217]

[0218] IC 50 (μM): 0 <A≤0.06; 0.06<B≤0.15; 0.15<C≤10; D> 10

[0219] Example B: PK Study

[0220] Cats (n=3 / group) received a single oral dose of the test product via oral gavage. Following administration, the gavage tube was flushed with approximately 10 mL of water. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Plasma was obtained within 1 hour of blood collection by centrifugation at 3500 g for 5 minutes at 4°C. At least 200 µL of plasma was collected and transferred to a 2 mL tube, which was temporarily stored upright on dry ice. Sample analysis was performed by bioanalysts at Frontage Laboratories (China). The concentration of the analyte in plasma was determined using fragment ion-based multiple reaction monitoring (MRM) LC-MS / MS for pharmacokinetic studies in cats.

[0221] Miniature pigs (n=2 / group) received a single oral dose of the test product via oral gavage. Following administration, the gavage tube was flushed with approximately 10 mL of water. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Plasma was obtained within 1 hour of blood collection by centrifugation at 3500 g for 5 minutes at 4°C. At least 200 µL of plasma was collected and transferred to a 2 mL tube, which was temporarily stored upright on dry ice. Sample analysis was performed by bioanalysts at Frontage Laboratories (China). The concentration of the analyte in plasma was determined using fragment ion-based multiple reaction monitoring (MRM) LC-MS / MS for pharmacokinetic studies in cats. Samples were analyzed according to Tier 2 as per SOP BIO-427-R0 developed by Suzhou Frontage New Drug Development Co., Ltd. Tier 2 assays consisted of two separate standard curves, one placed at the beginning of the analytical run and the other at the end of the sample analysis. Three levels of QC (low, medium, and high) were used to ensure the reliability of the assay. The concentration of the analyte in plasma was determined using a standard calibration curve. Pharmacokinetic parameters were calculated using non-compartmental analysis with Phoenix® WinNonlin® software (version 8.3, Certara, Princeton, NJ).

[0222] The cat and mini pig PK data for compound 7 are shown in Table 3 below.

[0223] Table 3

[0224]

[0225] Compounds, such as compound 7, showed good oral exposure in cats and miniature pigs.

[0226] Example C: In vitro cellular antiviral activity against PEDV

[0227] The compound was diluted to final concentrations of 2.44 nM, 9.77 nM, 39.06 nM, 156.25 nM, 0.625 μM, 2.5 μM, and 10 μM using DMEM (FBS-free). Once the cells (Vero cells) in the 6-well plates reached confluence, the culture medium was discarded, and the wells were washed three times with PBS buffer. At specified time points, cells were treated by replacing the maintenance solution with DMEM (FBS-free) containing the specified concentration of the compound, with three replicates per group. Viral fluid was collected and subjected to freeze-thaw cycles. The samples were then centrifuged at 8000 g for 15 min, and the supernatant was collected for serial dilution. After the cells in the 96-well plates reached complete confluence, diluted supernatant was added, and the cells were cultured for another 48 h. The number of wells showing cytopathic effect (CPE) was observed and recorded. TCID was calculated using the Reed-Muench method as a reference. 50 and EC 50 Compound 7's in vitro cellular antiviral activity against PEDV is as follows: Figure 1 As shown, only the positive control (PC) and DMSO were tested at 0h. Figure 1 As shown, compound 7 exhibits low TCID at concentrations of 156.25 nM or higher. 50 Values ​​(not shown at concentrations of 10 μM, 2.5 μM, and 0.625 μM TCID) 50 The values ​​(because they were below the detection limit) indicate that a good in vitro antiviral effect was achieved.

[0228] Compounds, such as compound 7, showed good in vitro antiviral activity against PEDV in cell assays.

[0229] Example D: in vivo FIPV efficacy model

[0230] Nine cats were purchased from a laboratory animal company. Rectal swabs were collected, and RNA was extracted using a kit. Reverse transcription was performed to obtain cDNA, and PCR detection using FIPV-specific primers showed negative results. Six cats were selected for FIPV infection, while one cat was retained as a negative control. Throughout the experiment, the cats had free access to water and food. To ensure the accuracy of this experiment, care was taken to avoid cross-contamination during feeding and daily management.

[0231] Viral titers were determined using a plaque assay. FIPV virus solutions were serially diluted and used to infect CRFK cells. After virus adsorption, a layer of molten semi-solid nutrient agar was added to provide limited virus diffusion in the monolayer cell culture. At a dilution of 10^-7, eight plaques were observed, indicating a viral titer of 8 × 10^7 PFU / mL.

[0232] The challenged cats were divided into two groups of three cats each (two males and one female). One group received 2 mL of viral solution orally, while the other group received 1 mL of viral solution intraperitoneally. The remaining three cats were kept in reserve.

[0233] Starting from day 2 post-attack, body temperature, weight, and visual symptoms were monitored daily. Additionally, rectal swabs were collected daily for reverse transcription PCR testing.

[0234] On day 15 post-attack, imaging studies and a complete blood count were performed. Imaging techniques such as ultrasound and digital radiography (DR) were used to focus on pleural and peritoneal effusions and lymph node status. Hematological examinations, including biochemical and blood cell analyses, focused on changes in neutrophil and lymphocyte levels.

[0235] An autopsy is performed to observe pathological changes in different organs.

Claims

1. A method for treating or preventing disease caused by a veterinary coronavirus in non-human animals suffering from coronavirus infection, the method comprising administering to the non-human animal an effective amount of a compound having formula (I): (I) Or its veterinary-acceptable salts or stereoisomers, in R 1 It is a halogen; R 2 It is a halogen; Ring A is aryl or heteroaryl; Each R 3 Independently halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -SF5, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently influenced by one or more R 3a replace; Each R a It is independently a C1-C6 alkyl or a C1-C6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more R; Each R is independently a halogen, -CN, -OH, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 3a Independently halogen, -CN, -NO2, -OH, -OR a -SR a C1-C6 alkyl or C1-C6 haloalkyl; L is -(CR) 4 R 4 ) p -; Each R 4 It is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R 5 It is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; Ring B is a 6-membered aryl or a 5- or 6-membered heteroaryl; Each R 6 It can be independently a halogen, -CN, -NO2, -OH, C1-C6 alkyl, or C1-C6 haloalkyl; R 7 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; The ring C is a cycloalkyl or heterocycloalkyl group; Each R 8 Independently halogen, -CN, -NO2, -OH, -OR a -SH, -SR a C1-C6 alkyl or C1-C6 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 can be 0, 1, or 2.

2. The method of claim 1, wherein ring B is a 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms.

3. The method of claim 1, wherein the ring C is a 6-membered cycloalkyl or a 6-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms.

4. The method of claim 3, wherein the cyclic C is a 6-membered cycloalkyl group.

5. The method of claim 3, wherein ring C is a 6-membered heterocyclic alkyl group containing one heteroatom.

6. The method of any one of claims 1-5, wherein the compound has formula (Ia): (I), in 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 can be O, N, S, or C.

7. The method of claim 6, wherein the compound has the formula (Ib): (One), Where 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. The method of any one of claims 1-7, wherein p is 0.

9. The method of any one of claims 1-8, wherein ring A is a 5- or 6-membered heteroaryl group.

10. The method of any one of claims 1-8, wherein ring A is phenyl.

11. The method of any one of claims 6-9, wherein X and Y are independently N or CH.

12. The method of claim 11, wherein both X and Y are N.

13. The method of any one of claims 6-12, wherein Z is -O-.

14. The method of claim 1 or claim 2, wherein n is 1, and R 3 For -OR a -SR a Or mixed aryl groups.

15. The method of claim 14, wherein R a It is a C1-C6 haloalkyl group.

16. The method of claim 14, wherein R 3 For -OR a .

17. The method of claim 16, wherein R 3 For -OR a And R a It is a C1-C6 haloalkyl group containing 1-6 halogens.

18. The method of claim 17, wherein R 3 For -OR a And R a It is a methyl group substituted with 1-3 halogens or an ethyl group substituted with 1-5 halogens.

19. The method of claim 17 or 18, wherein R 3 It can be -OCF2Cl, -OCF3, or -OCF2CF3.

20. The method of claim 14, wherein R 3 For -SR a .

21. The method of claim 20, wherein R 3 For -SR a And R a It is a C1-C6 haloalkyl group containing 1-6 halogens.

22. The method of claim 21, wherein R 3 For -SR a And R a The methyl group is replaced by 1-3 halogens.

23. The method of claim 22, wherein R 3 It is -SCF3.

24. The method of claim 14, wherein R 3 It is a heteroaryl group.

25. The method of claim 24, wherein R 3 It is a 5-membered heteroaryl group.

26. The method of claim 25, wherein R 3 It is a 5-membered heteroaryl group containing 1 or 2 heteroatoms.

27. The method of claim 26, wherein the heteroatom is an N or S atom.

28. The method of claim 26 or 27, wherein R 3 It is a 5-membered heteroaryl group containing one N atom and one S atom.

29. The method of claim 28, wherein R 3 for .

30. The method of claim 29, wherein R 3 for .

31. The method of any one of claims 1-29, wherein R 5 It is a C1-C6 alkyl group.

32. The method of claim 31, wherein R 5 It is a methyl group.

33. The method of any one of claims 1-32, wherein R 7 It is hydrogen.

34. The method of any one of claims 1-33, wherein R 8 It is a halogen.

35. The method of claim 34, wherein R 8 It is F.

36. The method of any one of claims 1-35, wherein m is 0, n is 1, p is 0, and q is 0 or 2.

37. The method of any one of claims 5-36, wherein for , or .

38. The method of claim 6, wherein the compound has the formula (Ic): (Ic), Where R 1 R 2 R 3 R 5 R 6 R 7 R 8 Z, m, and q are as defined above.

39. The method of claim 38, wherein the compound has the formula (Id): (Id)。 40. The method of claim 39, wherein the compound has the formula (Ie): (Ie)。 41. The method of any one of claims 1-40, wherein the compound is selected from: , , , , , , and .

42. The method of any one of claims 1-41, wherein the non-human animal is selected from the families Felidae, Bovidae, birds, Canidae, Mustelidae, Equidae, Suidae and Leporidae.

43. The method of claim 42, wherein the feline is a cat.

44. The method of claim 42, wherein the bovine animal is a cattle, yak, bison, buffalo, antelope, sheep, or goat.

45. The method of claim 42, wherein the bird is a chicken, guinea fowl, pheasant, or turkey.

46. ​​The method of claim 42, wherein the canid is a domestic dog, wolf, coyote, fox, or jackal.

47. The method of claim 42, wherein the mustelid is a weasel, ferret, badger, otter, mink, or wolverine.

48. The method of claim 42, wherein the equine is a horse, a donkey, or a zebra.

49. The method of claim 42, wherein the pig family is domestic pig or miniature pig.

50. The method of claim 42, wherein the rabbit is a rabbit.

51. The method of any one of claims 1-50, wherein the animal coronavirus is feline coronavirus, bovine coronavirus (BCoV), avian coronavirus (AvCoV), canine coronavirus (CCoV), canine respiratory coronavirus (CRCoV), ferret coronavirus (FRCoV), guinea fowl coronavirus (GfCoV), equine coronavirus (ECoV), pheasant coronavirus (PhCoV), transmissible gastroenteritis coronavirus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine respiratory coronavirus (PRCoV), porcine hemagglutination encephalomyelitis virus (PHEV), porcine delta coronavirus (PDCoV), porcine acute diarrhea coronavirus (SADS-CoV), rabbit coronavirus (RbCoV), turkey coronavirus (TCoV), or African antelope coronavirus (BuCoV).

52. The method of claim 51, wherein the feline coronavirus is feline enterocoronavirus (FECV), porcine epidemic diarrhea virus (PEDV), or feline infectious peritonitis virus (FIPV).

53. The method of claim 51, wherein AvCoV is infectious bronchitis virus (IBV).

54. The method of claim 51, wherein the disease is feline infectious peritonitis.

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