Method for treating feline coronavirus or calicivirus infection

Abstract

The present invention relates to the use of a compound represented by Formula I in feline coronavirus or calicivirus infection. The compound represented by Formula I can efficiently inhibit the replication of feline coronavirus or calicivirus, has low toxicity and side effects, high oral bioavailability, good drug discovery potential, and can be used for the treatment of diseases caused by feline coronavirus or calicivirus infection. JPEG2025523557000048.jpg33170

Description

Technical Field

[0001] <Cross - reference to Related Applications> This application claims the priority of Chinese Patent Applications with the previously filed application numbers 202310030217.6 and 202210744698.2, the entire content and disclosure of which are incorporated herein by reference.

[0002] The present invention relates to the field of veterinary medicine, and specifically, to the use of nucleoside - based compounds and their combined preparations in the treatment of feline coronavirus or calicivirus infection.

Background Art

[0003] Feline coronavirus (FCoV) belongs to the family Coronaviridae, is a group of enveloped positive-strand RNA viruses, and is commonly found in cats. In nature, FCoV exists as two different biotypes, namely feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV), and the latter is a mutated form of FECV. FECV infection is widespread in cats, and it is estimated that 40-80% of cats worldwide transmit the virus. FECV infects the gastrointestinal epithelial cells of cats for a long time and is usually transmitted through the fecal route. Most FECV infections in cats are asymptomatic, and some cats experience diarrhea, vomiting, loss of appetite, and fever. The FIPV biotype appears after a single nucleotide polymorphism or deletion (inactivating the viral 3c protease gene in FECV), and is also related to mutations in the viral spike protein. Inactivation of the 3c protease changes cell tropism, allows the virus to replicate within macrophages, and promotes systemic spread of FIPV and the development of feline infectious peritonitis (FIP). FIP is a progressive immune-related disease in cats. FIP disease may be divided into the "wet" or "dry" FIP forms. Wet FIP is correlated with inflammation of the visceral serosa and retina, resulting in fluid exudation into the abdomen and / or chest cavity. The characteristics of dry FIP are granulomatous lesions in parenchymal organs such as the liver, central nervous system, or eyes. The progression of either the wet or dry form of FIP is always fatal. FIP is a major problem in environments with a high density of cats (e.g., multi-cat families, catteries, shelters, cat rescue facilities). The disease is most common in relatively young cats (<3 years old), especially kittens, because the FECV replication level is relatively high, increasing the likelihood of mutation to the FIPV biotype and reducing resistance to viruses with these mutations. FIP is the main cause of death in cats under 2 years old, and the worldwide cat mortality rate is estimated to be 0.3%-1%.

[0004] Feline calicivirus is a single-stranded RNA virus with a non-enveloped spherical capsid, has high infectivity, can cause moderate self-limiting acute oral problems and upper respiratory tract diseases, and is one of the most common causative agents of feline infectious upper respiratory tract diseases. Currently, there is still no targeted drug for feline stomatitis caused by feline calicivirus. Generally, supportive treatment with hormones or antibiotics is carried out, which is prone to recurrence. In severe cases, it is treated by total tooth extraction surgery, causing great pain to the cat.

[0005] Currently, there is no approved vaccine or effective antiviral therapy for the treatment of FIP or feline stomatitis. Therefore, there is a great need for the development of effective drugs, especially orally administered drugs, for treating related diseases caused by feline coronavirus or calicivirus infection.

Summary of the Invention

Problems to be Solved by the Invention

[0006] To solve the above problems, the present invention provides a drug for treating related diseases caused by feline coronavirus or calicivirus infection. The drug has significant anti-feline coronavirus (FIPV) activity, high oral bioavailability, and can be used for preventing or treating feline infectious peritonitis and feline stomatitis.

Means for Solving the Problems

[0007] The present invention provides the use of a compound represented by Formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts in the manufacture of an inhibitor that inhibits the replication of feline coronavirus or calicivirus, and / or the use of a compound represented by Formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts in the manufacture of a drug for the treatment, prevention, and / or alleviation of related diseases caused by feline coronavirus or calicivirus infection, JPEG2025523557000002.jpg33170Of these, R1 is hydrogen, substituted or unsubstituted C 1-20 Alkanoyl group, C 3-10 cycloalkylformyl groups, each of which is substituted with one or more Q1; R2 is hydrogen, substituted or unsubstituted C 1-20 Alkanoyl group, C 3-10 cycloalkylformyl groups, each of which is substituted with one or more Q groups; JPEG2025523557000003.jpg12170R3 is hydrogen, substituted or unsubstituted C 1-20 Alkanoyl group, C 3-10 cycloalkylformyl groups, wherein the substitutions are substituted with one or more Q3; Q1, Q2, and Q3 are each independently selected from hydrogen, a cyano group, an amino group, a hydroxyl group, and a halogen; R4 is selected from hydrogen, deuterium, a cyano group, an amino group, a hydroxy group, and a halogen.

[0008] The present invention relates to the use of a composition containing a compound represented by formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, or pharma- ceutically acceptable salt thereof in the manufacture of an inhibitor for inhibiting the replication of feline coronavirus or calicivirus; and / or the use of a composition containing a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention, alleviation of related diseases caused by feline coronavirus or calicivirus infection; JPEG2025523557000004.jpg33170Of these, R1 is hydrogen, substituted or unsubstituted C 1-20 Alkanoyl group, C 3-10 cycloalkylformyl groups, each of which is substituted with one or more Q1; R2 is hydrogen, substituted or unsubstituted C 1-20 Alkanoyl group, C 3-10Selected from cycloalkylformyl groups, the above substitution is substituted with one or more Q2, JPEG2025523557000005.jpg12170R3 is hydrogen, substituted or unsubstituted C 1-20 alkanoyl group, C 3-10 Selected from cycloalkylformyl groups, the above substitution is substituted with one or more Q3, Q1, Q2, and Q3 are each independently selected from hydrogen, a cyano group, an amino group, a hydroxy group, and a halogen, R4 is selected from hydrogen, deuterium, a cyano group, an amino group, a hydroxy group, and a halogen.

Advantages of the Invention

[0009] (a) The compound of formula I described in the present invention can efficiently inhibit the replication of feline coronavirus or calicivirus and has little toxic effect on normal feline cells. (b) The compound of formula I described in the present invention has high in vivo inhibitory activity against feline infectious peritonitis virus. (c) The compound of formula I described in the present invention has low toxicity and side effects in feline in vivo, high oral bioavailability, stable metabolism, and good drug discovery potential. This suggests that the active compound of the present invention has excellent medicinal prospects in the field of treating feline coronavirus or calicivirus infection.

Modes for Carrying Out the Invention

[0010] In order to more clearly and understandably clarify the technical solution and beneficial effects of the present invention, specific embodiments will be given below for detailed description. Unless otherwise defined, the technical and scientific terms used in this specification have the same meaning as those in the technical and scientific fields to which this application belongs.

[0011] According to one aspect, the present invention provides the use of a compound represented by formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof in the manufacture of an inhibitor that inhibits the replication of feline coronavirus or calicivirus, JPEG2025523557000006.jpg32170Among them, R1 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q1s, R2 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q2s, JPEG2025523557000007.jpg12170R3 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q3s, Q1, Q2, Q3 are each independently selected from hydrogen, a cyano group, an amino group, a hydroxy group, and a halogen, R4 is selected from hydrogen, deuterium, a cyano group, an amino group, a hydroxy group, and a halogen.

[0012] In certain embodiments, R1 in the above formula I is selected from hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, a C 3-7 cycloalkylformyl group.

[0013] In certain embodiments, R1 in the above formula I is selected from hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, a C 3-6 cycloalkylformyl group.

[0014] In certain embodiments, R1 in the above formula I is hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, a C 14 alkanoyl group, a C 16 alkanoyl group, a C 18It is selected from an alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group and a cyclohexylformyl group.

[0015] In certain embodiments, Q1 above is selected from hydrogen, an amino group, a hydroxy group and a halogen.

[0016] In certain embodiments, Q1 above is selected from hydrogen, an amino group and a halogen.

[0017] In certain embodiments, Q1 above is selected from hydrogen and an amino group.

[0018] In certain embodiments, R2 in formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 selected from cycloalkylformyl groups.

[0019] In certain embodiments, R2 in formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-6 selected from cycloalkylformyl groups.

[0020] In certain embodiments, R2 in formula I above is hydrogen, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, 2-ethylbutyryl group, 3,3-dimethylbutyryl group, heptanoyl group, octanoyl group, 2-propylvaleryl group, nonanoyl group, decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C 18 alkanoyl group, selected from a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group and a cyclohexylformyl group.

[0021] In certain embodiments, Q2 above is selected from hydrogen, an amino group, a hydroxy group and a halogen.

[0022] In certain embodiments, Q2 is selected from hydrogen, an amino group, and a halogen.

[0023] In certain embodiments, Q2 is selected from hydrogen and an amino group.

[0024] In certain embodiments, R1 and R2 in Formula I are not simultaneously hydrogen.

[0025] JPEG2025523557000008.jpg12170

[0026] In certain embodiments, R3 in Formula I is hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 selected from cycloalkylformyl groups.

[0027] In certain embodiments, R3 in Formula I is hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, C 3-6 selected from cycloalkylformyl groups.

[0028] In certain embodiments, R3 in Formula I is hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C 18 selected from alkanoyl groups, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group.

[0029] In certain embodiments, Q3 is selected from hydrogen, an amino group, a hydroxy group, and a halogen.

[0030] In certain embodiments, Q3 is selected from hydrogen, an amino group, and a halogen.

[0031] In one embodiment, the above Q3 is selected from hydrogen and an amino group.

[0032] In one embodiment, R4 in the above formula I is selected from hydrogen, deuterium, and halogen.

[0033] In one embodiment, R4 in the above formula I is selected from hydrogen, deuterium, fluorine, chlorine, and iodine.

[0034] In one embodiment, the compound represented by the above formula I is JPEG2025523557000009.jpg87170JPEG2025523557000010.jpg254170

[0035] According to another aspect, the present invention provides the use of a compound represented by formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts in the manufacture of a drug for the treatment and / or prevention and alleviation of related diseases caused by feline coronavirus or calicivirus infection. JPEG2025523557000011.jpg32170Among them, R1 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q1s. R2 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q2s. JPEG2025523557000012.jpg12170R3 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q3s. Q1, Q2, and Q3 are each independently selected from hydrogen, a cyano group, an amino group, a hydroxy group, and a halogen. R4 is selected from hydrogen, deuterium, a cyano group, an amino group, a hydroxy group, and a halogen.

[0036] In certain embodiments, R1 in Formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 selected from cycloalkylformyl groups.

[0037] In certain embodiments, R1 in Formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-6 selected from cycloalkylformyl groups.

[0038] In certain embodiments, R1 in Formula I above is hydrogen, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, 2-ethylbutyryl group, 3,3-dimethylbutyryl group, heptanoyl group, octanoyl group, 2-propylvaleryl group, nonanoyl group, decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C 18 alkanoyl group, cyclopropylformyl group, cyclobutylformyl group, cyclopentylformyl group, and cyclohexylformyl group.

[0039] In certain embodiments, Q1 above is selected from hydrogen, an amino group, a hydroxy group, and a halogen.

[0040] In certain embodiments, Q1 above is selected from hydrogen, an amino group, and a halogen.

[0041] In certain embodiments, Q1 above is selected from hydrogen and an amino group.

[0042] In certain embodiments, R2 in Formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 selected from cycloalkylformyl groups.

[0043] In one embodiment, R2 in Formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-6 selected from cycloalkylformyl groups.

[0044] In one embodiment, R2 in Formula I above is hydrogen, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, 2-ethylbutyryl group, 3,3-dimethylbutyryl group, heptanoyl group, octanoyl group, 2-propylvaleryl group, nonanoyl group, decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C 18 alkanoyl group, cyclopropylformyl group, cyclobutylformyl group, cyclopentylformyl group and cyclohexylformyl group.

[0045] In one embodiment, Q2 above is selected from hydrogen, amino group, hydroxy group and halogen.

[0046] In one embodiment, Q2 above is selected from hydrogen, amino group and halogen.

[0047] In one embodiment, Q2 above is selected from hydrogen and amino group.

[0048] In one embodiment, R1 and R2 in Formula I above are not hydrogen at the same time.

[0049] JPEG2025523557000013.jpg12170

[0050] In one embodiment, R3 in Formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 selected from cycloalkylformyl groups.

[0051] In one embodiment, R3 in Formula I above is hydrogen, substituted or unsubstituted C 1-18An alkanoyl group, C 3-6 selected from a cycloalkylformyl group.

[0052] In certain embodiments, R3 in Formula I above is hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, C 14 an alkanoyl group, C 16 an alkanoyl group, C 18 selected from an alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group.

[0053] In certain embodiments, Q3 above is selected from hydrogen, an amino group, a hydroxy group, and a halogen.

[0054] In certain embodiments, Q3 above is selected from hydrogen, an amino group, and a halogen.

[0055] In certain embodiments, Q3 above is selected from hydrogen and an amino group.

[0056] In certain embodiments, R4 in Formula I above is selected from hydrogen, deuterium, and a halogen.

[0057] In certain embodiments, R4 in Formula I above is selected from hydrogen, deuterium, fluorine, chlorine, and iodine.

[0058] In certain embodiments, the compound represented by Formula I above is JPEG2025523557000014.jpg245170JPEG2025523557000015.jpg98170

[0059] In certain embodiments, the related diseases caused by the above feline coronavirus or calicivirus infection are selected from feline infectious peritonitis and feline stomatitis.

[0060] According to another aspect, the present invention provides the use of a compound represented by formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof in the manufacture of an inhibitor that inhibits the replication of feline coronavirus or calicivirus, JPEG2025523557000016.jpg32170Among them, R1 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q1s, R2 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q2s, JPEG2025523557000017.jpg12170R3 is selected from hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, a C 3-10 cycloalkylformyl group, and the above substitution is substituted with one or more Q3s, Q1, Q2, and Q3 are each independently selected from hydrogen, a cyano group, an amino group, a hydroxy group, and a halogen, R4 is selected from hydrogen, deuterium, a cyano group, an amino group, a hydroxy group, and a halogen.

[0061] In certain embodiments, R1 in formula I above is selected from hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, a C 3-7 cycloalkylformyl group.

[0062] In certain embodiments, R1 in formula I above is selected from hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, a C 3-6 cycloalkylformyl group.

[0063] In one embodiment, R1 in the above formula I is hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C 18 alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group.

[0064] In one embodiment, Q1 above is selected from hydrogen, an amino group, a hydroxy group, and a halogen.

[0065] In one embodiment, Q1 above is selected from hydrogen, an amino group, and a halogen.

[0066] In one embodiment, Q1 above is selected from hydrogen and an amino group.

[0067] In one embodiment, R2 in the above formula I is hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 cycloalkylformyl group.

[0068] In one embodiment, R2 in the above formula I is hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, C 3-6 cycloalkylformyl group.

[0069] In one embodiment, R2 in the above formula I is hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C18 It is selected from an alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group.

[0070] In certain embodiments, Q2 is selected from hydrogen, an amino group, a hydroxy group, and a halogen.

[0071] In certain embodiments, Q2 is selected from hydrogen, an amino group, and a halogen.

[0072] In certain embodiments, Q2 is selected from hydrogen and an amino group.

[0073] In certain embodiments, R1 and R2 in formula I are not both hydrogen at the same time.

[0074] JPEG2025523557000018.jpg12170

[0075] In certain embodiments, R3 in formula I is hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 selected from cycloalkylformyl groups.

[0076] In certain embodiments, R3 in formula I is hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, C 3-6 selected from cycloalkylformyl groups.

[0077] In certain embodiments, R3 in formula I is hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C 18It is selected from an alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group.

[0078] In certain embodiments, Q3 is selected from hydrogen, an amino group, a hydroxy group, and a halogen.

[0079] In certain embodiments, Q3 is selected from hydrogen, an amino group, and a halogen.

[0080] In certain embodiments, Q3 is selected from hydrogen and an amino group.

[0081] In certain embodiments, R4 in Formula I is selected from hydrogen, deuterium, and a halogen.

[0082] In certain embodiments, R4 in Formula I is selected from hydrogen, deuterium, fluorine, chlorine, and iodine.

[0083] In certain embodiments, the compound represented by Formula I is JPEG2025523557000019.jpg112170JPEG2025523557000020.jpg231170

[0084] According to another aspect, the present invention provides the use of a compound represented by Formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof in the manufacture of a drug for the treatment and / or prevention and alleviation of related diseases caused by feline coronavirus or calicivirus infection, JPEG2025523557000021.jpg33170wherein, R1 is hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, C 3-10 selected from a cycloalkylformyl group, the above substitution is substituted with one or more Q1, R2 is hydrogen, a substituted or unsubstituted C 1-20 alkanoyl group, C 3-10Selected from cycloalkylformyl groups, the above substitution is substituted with one or more Q2s, JPEG2025523557000022.jpg12170R3 is hydrogen, substituted or unsubstituted C 1-20 alkanoyl group, C 3-10 Selected from cycloalkylformyl groups, the above substitution is substituted with one or more Q3s, Q1, Q2, and Q3 are each independently selected from hydrogen, a cyano group, an amino group, a hydroxy group, and a halogen, R4 is selected from hydrogen, deuterium, a cyano group, an amino group, a hydroxy group, and a halogen.

[0085] In certain embodiments, R1 in Formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 selected from cycloalkylformyl groups.

[0086] In certain embodiments, R1 in Formula I above is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-6 selected from cycloalkylformyl groups.

[0087] In certain embodiments, R1 in Formula I above is hydrogen, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, 2-ethylbutyryl group, 3,3-dimethylbutyryl group, heptanoyl group, octanoyl group, 2-propylvaleryl group, nonanoyl group, decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C 18 alkanoyl group, cyclopropylformyl group, cyclobutylformyl group, cyclopentylformyl group, and cyclohexylformyl group.

[0088] In certain embodiments, Q1 above is selected from hydrogen, an amino group, a hydroxy group, and a halogen.

[0089] In one embodiment, Q1 is selected from hydrogen, an amino group, and a halogen.

[0090] In one embodiment, Q1 is selected from hydrogen and an amino group.

[0091] In one embodiment, R2 in Formula I is hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, a C 3-7 cycloalkylformyl group.

[0092] In one embodiment, R2 in Formula I is hydrogen, a substituted or unsubstituted C 1-18 alkanoyl group, a C 3-6 cycloalkylformyl group.

[0093] In one embodiment, R2 in Formula I is hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, a C 14 alkanoyl group, a C 16 alkanoyl group, a C 18 alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group.

[0094] In one embodiment, Q2 is selected from hydrogen, an amino group, a hydroxy group, and a halogen.

[0095] In one embodiment, Q2 is selected from hydrogen, an amino group, and a halogen.

[0096] In one embodiment, Q2 is selected from hydrogen and an amino group.

[0097] In one embodiment, R1 and R2 in Formula I are not both hydrogen at the same time.

[0098] JPEG2025523557000023.jpg12170

[0099] In one embodiment, R3 in the above formula I is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-7 selected from cycloalkylformyl groups.

[0100] In one embodiment, R3 in the above formula I is hydrogen, substituted or unsubstituted C 1-18 alkanoyl group, C 3-6 selected from cycloalkylformyl groups.

[0101] In one embodiment, R3 in the above formula I is hydrogen, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, 2-ethylbutyryl group, 3,3-dimethylbutyryl group, heptanoyl group, octanoyl group, 2-propylvaleryl group, nonanoyl group, decanoyl group, C 14 alkanoyl group, C 16 alkanoyl group, C 18 alkanoyl group, cyclopropylformyl group, cyclobutylformyl group, cyclopentylformyl group and cyclohexylformyl group.

[0102] In one embodiment, the above Q3 is selected from hydrogen, amino group, hydroxy group and halogen.

[0103] In one embodiment, the above Q3 is selected from hydrogen, amino group and halogen.

[0104] In one embodiment, the above Q3 is selected from hydrogen and amino group.

[0105] In one embodiment, R4 in the above formula I is selected from hydrogen, deuterium and halogen.

[0106] In certain embodiments, R4 in formula I above is selected from hydrogen, deuterium, fluorine, chlorine, and iodine.

[0107] In certain embodiments, the compound represented by formula I above is JPEG2025523557000024.jpg244170JPEG2025523557000025.jpg98170

[0108] In certain embodiments, the related diseases caused by the above feline coronavirus or calicivirus infection are selected from feline infectious peritonitis and feline stomatitis.

[0109] In certain embodiments, the pharmaceutical composition comprises at least one of the above compounds or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts, as well as pharmaceutically acceptable carriers, diluents, or excipients.

[0110] In certain embodiments, the pharmaceutical composition also comprises PF-07321332 (Nirmatrelvir), S-217622 (Ensitrelvir), FHPI (4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1,3-dihydro-imidazol-2-ylidene]cyclohex-2,5-dien-1-one), Aloxistatin, Conivaptan, favipiravir, Galidesivir, NHC (EIDD-1931), EIDD-2801, GC-376, Lopinavir, Ritonavir, Nelfinavir, Chloroquine, hydroxychloroquine, cyclosporine, Carrimycin, baicalin, baicalein, forsythoside, chlorogenic acid, emodin, mycophenolic acid, Mycophenolate mofetil, Naphthoquine, Ciclesonide, Ribavirin, Penciclovir, Leflunomide, Teriflunomide, nafamostat, nitazoxanide, Darunavir, Arbidol, Camostat, Niclosamide, baricitinib, Ruxolitinib, Dasatinib, Saquinavir, Beclabuvir, Simeprevir, Palivizumab, Motavizumab, RSV-IGIV MEDI557, A-60444 (RSV-604), MDT-637, BMS-433771, or other antiviral agents selected from the group consisting of pharmaceutically acceptable salts thereof, or combinations thereof.,

[0111] In one embodiment, the pharmaceutical composition also comprises another antiviral drug selected from the group consisting of PF-07321332 (Nirmatrelvir), S-217622 (Ensitrelvir), FHPI (4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1,3-dihydro-imidazol-2-ylidene] cyclohex-2,5-dien-1-one), aloxistatin, conivaptan, favipiravir, NHC (EIDD-1931), EIDD-2801, baicalin, baicalein, forsythoside, chlorogenic acid, emodin, glycyrrhizic acid, chloroquine, hydroxychloroquine, nelfinavir.

[0112] In certain embodiments, the pharmaceutical composition also includes interferon, RNA-dependent RNA polymerase inhibitors (e.g., favipiravir, Galidesivir, NHC (EIDD-1931), EIDD-2801), 3CL protease inhibitors (e.g., GC-376), lopinavir, ritonavir, nelfinavir, S-217622 (Ensitrelvir), PF-07321332 (Nirmatrelvir), chloroquine, hydroxychloroquine, cyclosporine, carrimycin, baicalin, baicalein, forsythoside, chlorogenic acid, emodin, mycophenolic acid, mycophenolate mofetil, naphthoquine, ciclesonide, ribavirin, penciclovir, leflunomide, teriflunomide, nafamostat, nitazoxanide, darunavir, arbidol, camostat, niclosamide, baricitinib, ruxolitinib, dasatinib, saquinavir, beclabuvir, simeprevir, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444 (RSV-604), MDT637, BMS-433771, FHPI (4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1,3-dihydro-imidazol-2-ylidene]cyclohexa-2,5-dien-1-one), Aloxistatin, Conivaptan, or other antiviral drugs selected from the group consisting of pharmaceutically acceptable salts thereof, or combinations thereof.,

[0113] In certain embodiments, the pharmaceutical composition also includes other drugs selected from the group consisting of Zinc, Fingolimod, Vitamin C, Olmesartan medoxomil, valsartan, Losartan, Thalidomide, Glycyrrhizic acid, Artemisinin, Dihydroartemisinin, Artesunate, Artemisone, Azithromycin, Escin, Naproxen, or combinations thereof.,

[0114] In certain embodiments, the pharmaceutical composition also includes other drugs selected from the group consisting of (Y1) RNA replicase inhibitors (e.g., favipiravir, Galidesivir, NHC, EIDD-2801), (Y2) lopinavir, (Y3) ritonavir, (Y4) chloroquine, hydroxychloroquine, or pharmaceutically acceptable salts thereof (e.g., chloroquine phosphate), (Y5) nelfinavir, (Y6) any combination of Y1 to Y5 above.,

[0115] In certain embodiments, the pharmaceutical composition also includes other drugs selected from the group consisting of interferon, RNA-dependent RNA polymerase inhibitors (e.g., favipiravir, Galidesivir, NHC, EIDD-2801), 3CL protease inhibitors (e.g., GC-376), Lopinavir, Ritonavir, Nelfinavir, Chloroquine, Hydroxychloroquine, cyclosporine, Carrimycin, baicalin, baicalein, forsythoside, chlorogenic acid, emodin, mycophenolic acid, Mycophenolatemofetil, Naphthoquine, Ciclesonide, Ribavirin, Penciclovir, Leflunomide, Teriflunomide, nafamostat, nitazoxanide, Darunavir, Arbidol, Camostat, Niclosamide, baricitinib, Ruxolitinib, Dasatinib, Saquinavir, Beclabuvir, Simeprevir, Palivizumab, Motavizumab, RSV-IGIVMEDI557, A-60444 (RSV-604), MDT637, BMS-433771, or a pharmaceutically acceptable salt thereof, or a combination thereof. The interferon includes one or more of interferon α-2a, interferon α-2b, interferon α-n1, interferon α-n3, interferon β-1a, interferon β-1b.

[0116] In certain embodiments, the pharmaceutical composition also comprises other drugs selected from the following groups: for example, the use of “anti-inflammatory signaling regulators” (referred to herein as AISTM), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blockade of NFκB by IKK inhibition), or kinase inhibitors (e.g., blockade of P38MAP, JNK, PI3K, EGFR, or Syk), is a logical way to disrupt inflammation, and the targets of these small molecules are a limited number of common intracellular pathways, which are important points of anti-inflammatory therapeutic intervention, those signaling pathways (see overview by P.J. Barnes, 2006).These non-limiting and additional therapeutic agents include 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38Map kinase inhibitor ARRY-797), 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor roflumilast), 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840), N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor oglemilast), N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD12-281), 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch351591), 4-[5-(4-fluorophenyl)-2-(4-methylsulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850), 4-[4-(4-fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-butan-3-yn-1-ol (P38 inhibitor RWJ-67657), 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of cilostazol, PDE-4 inhibitor), (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, EGFR inhibitor), and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, EGFR inhibitor).

[0117] In one embodiment, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0118] In one embodiment, based on the total weight of the composition, the pharmaceutical composition contains 0.01% to 99.99% of the above compound. In one embodiment, the pharmaceutical composition contains 0.1% to 99.9% of the above compound. In one embodiment, the pharmaceutical composition contains 0.5% to 99.5% of the above compound. In one embodiment, the pharmaceutical composition contains 1% to 99% of the above compound. In one embodiment, the pharmaceutical composition contains 2% to 98% of the above compound.

[0119] In one embodiment, based on the total weight of the composition, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable carrier, diluent or excipient.

[0120] All compounds related to the present invention and mixtures, compositions, etc. containing the compounds of the present invention can be administered into the living body by any one of the administration routes. The administration routes may include oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, or local or systemic transdermal administration.

[0121] All compounds related to the present invention, mixtures, compositions, etc. containing the compounds of the present invention can be formulated into single doses containing the active compounds, carriers, excipients, etc. of the present invention, and the dosage forms for administration can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc. In these dosage forms, for example, components generally used in pharmaceutical preparations such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, bacteriostatic agents, isotonicity regulators, anti-adhesion agents, etc. may be contained.

[0122] The appropriate formulations of the above various dosage forms can be obtained from the disclosed routes. For example, Remington: The Science and Practice of Pharmacy, 21th edition, Lippincott Williams & Wilkins, published in 2006, and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, published in 2005. Therefore, those skilled in the art can easily manufacture them.

[0123] Depending on factors such as the nature, intensity, age, gender, weight, and administration route of the diseases suffered by different individuals, different doses may be selected. The dose of the compound of the present invention may be 0.01 - 500 mg / kg per day, preferably the dose per day is 1 - 100 mg / kg, and it may be administered once or multiple times.

[0124] Explanation of terms: Unless otherwise stated, the terms used in the specification and claims have the following meanings. “C 1-20The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched-chain isomers thereof, etc.More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. The alkyl group may or may not be substituted. When substituted, it may be substituted at any available linking point. The above substituents are preferably independently and optionally selected from one or more substituents of D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group.

[0125] “C 1-20 The term “alkanoyl group” means, that is, the group C 1-20 alkyl-C(O)-, wherein “C 1-20 alkyl group” is as defined above.

[0126] “C 3-10The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 10 carbon atoms, preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cyclohexenyl group, cyclohexadienyl group, cycloheptyl group, cycloheptatrienyl group, cyclooctyl group, etc. Polycyclic cycloalkyl groups include spiro-ring, fused-ring, and bridged-ring cycloalkyl groups.

[0127] The cycloalkyl group may or may not be substituted. When substituted, it may be substituted at any available linkage point. The above substituents are preferably independently and optionally selected from one or more substituents of halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0128] 「C 3-10 The term "cycloalkylformyl group" means the group C 3-10 cycloalkyl-C(O)-, where "C 3-10 cycloalkyl" is as defined above.

[0129] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0130] The term "hydroxy group" refers to -OH.

[0131] The term "amino group" refers to -NH2.

[0132] The term "cyano group" refers to -CN.

[0133] The term "substituted" refers to one or more hydrogen atoms in the base, preferably 5 or fewer, more preferably 1 to 3 hydrogen atoms, being independently substituted by a corresponding number of substituents. Of course, the substituents are located only at their chemically possible sites, and those skilled in the art can determine possible or impossible substitutions without much effort (by experiment or theory). For example, when an amino group or a hydroxy group having a free hydrogen is bonded to a carbon atom having an unsaturated (e.g., olefinic) bond, it may become unstable.

[0134] JPEG2025523557000026.jpg16170

[0135] The term "stereoisomer" refers to compounds having the same chemical structure but with atoms or groups arranged in different spatial manners. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, atropisomers, etc.

[0136] The term "isotope derivative" refers to compounds that differ in structure only in that they contain one or more atoms enriched in one or more isotopes. For example, having the structure of the present disclosure, hydrogen is replaced by "deuterium" or "tritium", or fluorine is 18 F-fluorine label ( 18 F isotope), or a carbon atom is 11 C-, 13 C-, or 14 carbon enriched in 11 C-, 13 C-, or 14 C-carbon label, 11 C-, 13 C- or 14Compounds replaced by C-isotopes are within the scope of the present disclosure. Such compounds may be used, for example, as analytical tools or probes in biological measurements, or as imaging tracers for in vivo diagnosis of diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The various deuterated forms of the compounds of the present invention are such that each available hydrogen atom linked to a carbon atom is independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of the compounds with reference to the relevant literature. When producing deuterated forms of the compounds, commercially available deuterated starting materials may be used, or they may be synthesized with deuterated reagents by ordinary techniques. Deuterated reagents include, but are not limited to, deuterated borane, borane trihydride tetrahydrofuran solution, lithium aluminum hydride deuteride, iodoethane deuteride, and iodomethane deuteride. Deuterated compounds can generally retain the activity corresponding to the non-deuterated compounds, and when deuteration is at certain sites, they can obtain better metabolic stability and some therapeutic advantages.

[0137] The term "pharmaceutically acceptable salts" indicates that the compounds of the present invention exist in the form of those pharmaceutically acceptable salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in pharmaceutically salts as described by S.M. Berge in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977). In the present invention, the pharmaceutically acceptable non-toxic acid addition salts refer to salts formed by the compound A in the present invention and organic or inorganic acids, and the organic or inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. The pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds in the present invention and organic or inorganic bases, including alkali metal salts such as lithium, sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts formed with organic bases containing an N group or N + (C 1-6 alkyl group)4 salts and other organic base salts, including, but not limited to, these.

[0138] The term "solvate" refers to the physical bond between the compounds of the present invention and one or more, preferably 1 to 3, solvent molecules, whether organic or inorganic. The physical bond includes hydrogen bonds. In some cases, for example, when one or more, preferably 1 to 3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. Solvatation methods are known in the art.

[0139] The term "prodrug" is one that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to produce the active parent drug compound.

[0140] The term "pharmaceutical composition" refers to a composition containing one or more of the compounds described in this specification, or their physiologically / pharmaceutically acceptable salts or prodrugs, and a mixture of other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living body, contribute to the absorption of the active ingredient, and further exert biological activity.

[0141] The above terms related to the present invention are defined, and those skilled in the art can also understand them in combination with the prior art for the above terms. Further explanations will be given below based on the content of the present invention and the definitions of the terms.

[0142] Hereinafter, the production of the compounds and pharmaceutically acceptable salts described in the present invention will be further explained in combination with the examples, but these examples do not limit the scope within the present invention.

[0143] In the examples of the present invention, experimental methods for which specific conditions are not specified generally follow normal conditions or the conditions proposed by the raw material or product manufacturer. Reagents for which specific sources are not specified are commercially available normal reagents.

[0144] Example 1. Production of Compound 6 JPEG2025523557000027.jpg43170 Compound 6 of the present invention was obtained by the synthesis method of related Compound A50 described in the specification in WO2021213288A1.

[0145] Example 2. Production of Compound 25 JPEG2025523557000028.jpg41170 The compound GS-441524 (CAS RN: 1191237-69-0, 85 mg, 0.292 mmol) was added to N,N-dimethylformamide, and carbonyldiimidazole (48 mg, 0.292 mmol) was added, followed by stirring at room temperature. After 15 minutes, water and ethyl acetate were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 19 mg of a white solid, which is Compound 25, with a yield of 21%. 1 H NMR (500 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.02-6.98 (m, 2H), 5.96 (d, J = 7.9 Hz, 1H), 5.40 (dd, J = 7.8, 4.0 Hz, 1H), 5.28 (t, J = 5.7 Hz, 1H), 4.50 (q, J = 4.7 Hz, 1H), 3.72-3.65 (m, 1H), 3.64-3.58 (m, 1H).

[0146] Example 3, Preparation of Compound 27 JPEG2025523557000029.jpg43170 Compound 27 of the present invention was prepared by the synthetic method of related compound A131 described in the specification in WO2021213288A1.

[0147] Example 4, Preparation of Compound 42 JPEG2025523557000030.jpg40170 Compound 42 of the present invention was prepared by the synthetic method of related compound A151 described in the specification in WO2021213288A1.

[0148] Example 5, Preparation of Compound 4 JPEG2025523557000031.jpg36170 Compound 4 of the present invention was prepared by the synthetic method of related compound A9 described in the specification in WO2021213288A1.

[0149] Example 6, Preparation of Compound 11 JPEG2025523557000032.jpg42170Compound 11 of the present invention was obtained by the synthesis method of related compound A70 described in the specification in WO2021213288A1.

[0150] Example 7, Preparation of Compound 20 JPEG2025523557000033.jpg42170Compound 20 of the present invention was obtained by the synthesis method of related compound A124 described in the specification in WO2021213288A1.

[0151] Example 8, Preparation of Compound 29 JPEG2025523557000034.jpg35170Compound 29 of the present invention was obtained by the synthesis method of related compound A138 described in the specification in WO2021213288A1.

[0152] Example 9, Preparation of Compound 40 JPEG2025523557000035.jpg43170 Compound 4 (2 g, 6.84 mmol) and 4-dimethylaminopyridine (83 mg, 0.68 mmol) were dissolved in N,N-dimethylacetamide (20 mL). Under an ice-water bath, acetic anhydride (2.16 g, 21.20 mmol) was slowly added dropwise. The temperature was raised to room temperature and reacted for 1 h. The reaction of the raw materials was monitored by TLC until completion. Water and ethyl acetate were added to the reaction solution, stirred, allowed to stand, and separated. The organic phase was washed successively with 0.1% dilute hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, and 2.16 g of a foamy solid, which is Compound 40, was obtained by column chromatography with a yield of 76%. 11H NMR (400 MHz, DMSO-d6) δ 8.12 ‐ 7.91 (m, 3H), 6.82 (s, 1H), 6.11 (d, J = 5.9 Hz, 1H), 5.42 ‐ 5.33 (m, 1H), 4.58 (q, J = 4.6 Hz, 1H), 4.39 (dd, J = 12.3, 3.3 Hz, 1H), 4.22 (dd, J = 12.3, 4.9 Hz, 1H), 2.12 (s, 6H), 2.00 (s, 3H). ESI-MS m / z = 419.2 [M+1] + .

[0153] Example 10, Preparation of Compound 52 JPEG2025523557000036.jpg42170 Compound 4 (2 g, 6.84 mmol) was dispersed in tetrahydrofuran (20 mL), warmed to 60 °C, and N,N-dimethylformamide dimethylacetal (3.67 g, 30.79 mmol) was slowly added. The mixture was kept warm and reacted for 4 h. TLC indicated the completion of the reaction of the starting material. The reaction solution was concentrated to dryness to obtain an oily substance which was intermediate 52-1. The next reaction was carried out without separating this intermediate.

[0154] The intermediate 52-1 obtained in the previous step and 4-dimethylaminopyridine (167 mg, 1.37 mmol) were dissolved in dichloromethane (20 mL). Under an ice-water bath, acetic anhydride (908 mg, 8.89 mmol) was slowly added dropwise. The mixture was returned to room temperature and reacted for 1 h. The reaction of the starting material was monitored by TLC for completion. Water and ethyl acetate were added to the reaction solution, stirred, allowed to stand, and separated. The aqueous phase was back-extracted with ethyl acetate. The organic phases were combined, washed successively with 0.1% dilute hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily substance which was compound 52-2. The next reaction was carried out without separating this intermediate.

[0155] The intermediate 52-2 obtained in the previous step was dissolved in acetic acid (6 mL) and ethanol (20 mL), heated to 60 °C and reacted overnight, and the completion of the reaction of the raw materials was monitored by TLC. Saturated sodium bicarbonate was added to the reaction solution until it became basic, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, slurried with methylene chloride, filtered, and dried at 50 °C to obtain 510 mg of an off-white solid of compound 52, with a yield of 22%. 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 3H), 6.81 (s, 1H), 6.33 (d, J = 5.9 Hz, 1H), 5.40 (d, J = 5.9 Hz, 1H), 4.69 (t, J = 5.4 Hz, 1H), 4.32 (dd, J = 11.9, 2.6 Hz, 1H), 4.26 ‐ 4.19 (m, 1H), 4.14 (dd, J = 11.9, 5.9 Hz, 1H), 3.97 ‐ 3.88 (m, 1H), 2.02 (s, 3H). ESI-MS m / z = 335.2 [M+1] + 。

[0156] Example 11, Preparation of Compound 32 Referring to the synthetic method of compound 52, using compound 4 (525 mg, 1.8 mmol) as the raw material, 124 mg of a white solid of product 32 was obtained, with a yield of 47%. 1 H NMR (500 MHz, DMSO) δ 7.92 (s, 3H), 6.81 (s, 1H), 6.35 (d, J = 6.0 Hz, 1H), 5.39 (d, J = 5.8 Hz, 1H), 4.69 (t, J = 5.4 Hz, 1H), 4.29 (t, J = 7.5 Hz, 1H), 4.25 ‐ 4.19 (m, 2H), 3.94 (q, J = 5.8 Hz, 1H), 2.20 ‐ 2.13 (m, 1H), 1.50 ‐ 1.41 (m, 4H), 0.78 (q, J = 7.3 Hz, 6H). ESI-MS m / z = 391.3 [M+1] + 。

[0157] Example 12, Preparation of Compound 53 JPEG2025523557000038.jpg79170At room temperature, Compound 4 (1.01 g, 3.46 mmol) was added to pyridine (40 mL), N,N-dimethylformamide dimethylacetal (1.66 g, 13.95 mmol) was added, and the mixture was stirred. After about 16 hours, the reaction was completed. The solvent was rotary evaporated to obtain an oily substance which is Compound 53-1. Without separating the intermediate, the next reaction was carried out directly.

[0158] At room temperature, the intermediate 53-1 obtained in the previous step was added to pyridine (40 mL), 4-dimethylaminopyridine (48 mg, 0.39 mmol) was added, isobutyric anhydride (826 mg, 5.23 mmol) was added, and the mixture was stirred for 5 hours. Then methanol was added and stirred for 30 min. The solvent was rotary evaporated to obtain an oily substance which is Compound 53-2. Without separating the intermediate, the next reaction was carried out directly.

[0159] In an ice bath, the intermediate 53-2 obtained in the previous step was added to tetrahydrofuran (30 mL), and carbonyldiimidazole (2.07 g, 12.7 mmol) was further added. The mixture was stirred, the ice bath was removed, and after about 12 hours, the reaction was completed. The reaction solution was rotary evaporated to obtain an oily substance which is Compound 53-3. Without separating the intermediate, the next reaction was carried out directly.

[0160] At 50 °C, the intermediate 53-3 obtained in the previous step was added to an 80% glacial acetic acid-ethanol (50 mL) solution, and the mixture was stirred. After about 2 hours, the reaction was completed. The reaction solution was concentrated, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, saturated sodium chloride solution was added, anhydrous sodium sulfate was added, suction filtered, rotary dried, and purified by silica gel column chromatography to obtain 583 mg of a white solid which is Compound 53, with a yield of 43%. 11H NMR (500 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 6.90 (s, 1H), 5.99 (d, J = 7.7 Hz, 1H), 5.49 (dd, J = 7.6, 3.7 Hz, 1H), 4.82 (dt, J = 5.2, 3.8 Hz, 1H), 4.33 (dd, J = 12.3, 3.9 Hz, 1H), 4.22 (dd, J = 12.3, 5.2 Hz, 1H), 2.43 (m, J = 7.0 Hz, 1H), 1.01 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H). ESI-MS m / z = 389.4 [M+1] + .

[0161] Example 13. Measurement of the antiviral inhibitory activity of the compounds of the present invention Take CRFK cells in good growth state, seed them in 96-well plates, when the cells grow until 80% - 90% confluence, add 0.1 MOI feline coronavirus (FIPV) and test compounds at different concentrations to each well, set up cell controls and virus controls simultaneously, and all wells contained 1% DMSO. After incubating at 37 °C for 72 h, the cells were treated with a cell viability detection reagent (Promega, Madison, WI, USA) by the CellTiter-Glo luminescence method, and the half-maximal effective concentration (EC 50 ) value of the compound against virus inhibition was calculated using GraphPad prism7 software. Table 1. Inhibitory activity of the compounds of the present invention against feline infectious peritonitis virus (FIPV) in vitro As can be seen from Table 1 in JPEG2025523557000039.jpg18170, all of the compounds of the present invention, especially 6, 11, 20 and 53, were able to inhibit the replication of feline infectious peritonitis virus (FIPV) in vitro.

[0162] Example 14. Pharmacokinetic evaluation in rats in vivo Male SD rats were fasted before the experiment (rats in the intravenous group were not fasted), allowed free access to water, and uniformly fed 2 h after administration. The intravenous injection dose of Compound 4 was 2.0 mg / kg (n = 3), the intragastric administration dose was 10.0 mg / kg (n = 3), the intravenous injection dose of Compound 53 was 5.0 mg / kg (n = 3), the intragastric administration dose was 20.0 mg / kg (n = 3), and the administration solvent was 5% DMSO + 5% ethanol + 40% PEG300 + 50% saline. After administration, 0.2 mL of blood was collected from the jugular vein at different time points, placed in a heparin sodium anticoagulant tube, gently and uniformly mixed, centrifuged at 2000 g for 10 min to separate the plasma, and frozen in a -70 °C refrigerator for measurement. The concentration of nucleoside (Compound 4) in plasma was measured using the LC-MS-MS method, and the pharmacokinetic parameters were calculated. The results are shown in Table 2. Table 2 Pharmacokinetic parameters of in vivo nucleoside (Compound 4) in rats after single intravenous injection and single oral administration of Compound 4 and Compound 53 As can be seen from Table 2, when Compound 53 was administered intragastrically, the exposure of the nucleoside metabolite in rats in vivo was high, and the oral bioavailability was 71.8%, which was significantly higher than the oral bioavailability of Compound 4.

[0163] Example 15, Pharmacokinetic Evaluation of Cats In Vivo Six male domestic cats were divided into two groups and fasted overnight before dosing. Using isoflurane, they were anesthetized by inhalation at a rate of 5 VOL% / L / min. After the animals entered the third stage of anesthesia, the hair on the left hind leg of the domestic cats was shaved, and an indwelling needle (for blood collection) was inserted into the saphenous vein of the hind limb. Compounds 6 and 27 were orally administered to three animals each at 10 mg / kg and 16 mg / kg, respectively. The compound solvent was 5% ethanol + 30% propylene glycol + 45% PEG400 + 20% water. After dosing, the domestic cats were fixed on the operating table in the prone position to facilitate subsequent blood collection. After oral administration, 0.5 - 1 mL of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. At 4°C and 3000 rpm, 200 μL of whole blood samples were taken and centrifuged for 10 minutes. Then 50 μL of the supernatant was taken and 150 μL of methanol was added. After vortexing, it was centrifuged at 14800 rpm and 4°C for 10 minutes and stored at -80°C. The LC-MS-MS method was used to measure the concentration of the nucleoside metabolite (GS-441524) in plasma, and the pharmacokinetic parameters were calculated. The results are shown in Table 3. Table 3 Pharmacokinetic parameters of in vivo nucleoside (GS-441524) in rats after single oral administration of Compound 6 and Compound 27 As can be seen from Table 3, Compound 6 was orally administered at 10 mg / kg, and the C max of the riboside metabolite in the plasma of the animals was 955 - 2340 ng / mL (3.28 - 8.04 μM). Compound 27 was orally administered at 16 mg / kg, and the C max of the riboside metabolite in the plasma of the animals was 1130 - 7180 ng / mL (3.88 - 24.67 μM). Although the individual differences of the animals were obvious, the C max of the riboside metabolite in plasma were all clearly higher than the EC 50 value of GS-441524 against feline infectious peritonitis virus (FIPV).

[0164] It should be understood that all of the above embodiments are merely illustrative and are not intended to cover all possible embodiments included in the claims. Various modifications and changes can be made based on the above embodiments without departing from the scope of the present disclosure. Similarly, it is also possible to arbitrarily combine the technical features of the above embodiments to form another embodiment of the present invention that is not clearly described. Therefore, the above embodiments merely show some embodiments of the present invention and do not limit the scope of the claims of the present invention.

Claims

1. Use of a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof in the manufacture of an inhibitor that inhibits the replication of feline coronavirus or calicivirus, and / or use of a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof in the manufacture of a drug for the treatment and / or prevention and alleviation of related diseases caused by feline coronavirus or calicivirus infection, wherein, R １ is selected from hydrogen, a substituted or unsubstituted C １－２０ alkanoyl group, a C ３－１０ cycloalkylformyl group, the substitution being by one or more Q １ and is substituted with R ２ is selected from hydrogen, a substituted or unsubstituted C １－２０ alkanoyl group, and a C ３－１０ cycloalkylformyl group, and the substitution is by one or more Q ２ and is substituted with R ３ is selected from hydrogen, a substituted or unsubstituted C １－２０ alkanoyl group, a C ３－１０ cycloalkylformyl group, and the substitution is by one or more Q ３ and is substituted with Q １ , Q ２ , Q ３ are each independently selected from hydrogen, a cyano group, an amino group, a hydroxy group, and a halogen, R ４ is selected from hydrogen, deuterium, cyano group, amino group, hydroxy group and halogen, use.

2. In the formula I, R １ is selected from hydrogen, a substituted or unsubstituted C １－１８ alkanoyl group, and a C ３－７ cycloalkylformyl group, preferably hydrogen, a substituted or unsubstituted C １－１８ alkanoyl group, or a C ３－６ cycloalkylformyl group, more preferably hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, a C １４ alkanoyl group, a C １６ alkanoyl group, a C １８ alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group, and Q １ is selected from hydrogen, an amino group, a hydroxy group, and a halogen, preferably hydrogen, an amino group, and a halogen, and most preferably hydrogen and an amino, characterized in that The use according to claim 1.

3. In the formula I, R ２ is selected from hydrogen, a substituted or unsubstituted C １－１８ alkanoyl group, and a C ３－７ cycloalkylformyl group, preferably hydrogen, a substituted or unsubstituted C １－１８ alkanoyl group, or a C ３－６ cycloalkylformyl group, more preferably hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, a C １４ alkanoyl group, a C １６ alkanoyl group, a C １８ alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group; and Q ２ is selected from hydrogen, an amino group, a hydroxy group, and a halogen, preferably hydrogen, an amino group, and a halogen, and most preferably hydrogen and an amino group, characterized in that The use according to claim 1 or 2.

4. In the formula I, R １ and R ２ are simultaneously not hydrogen, characterized by The use according to any one of claims 1 to 3.

5.

6. In the formula I, R ３ is selected from hydrogen, a substituted or unsubstituted C １－１８ alkanoyl group, and a C ３－７ cycloalkylformyl group, preferably hydrogen, a substituted or unsubstituted C １－１８ alkanoyl group, or a C ３－６ cycloalkylformyl group, more preferably hydrogen, a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group, a 2-ethylbutyryl group, a 3,3-dimethylbutyryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, a decanoyl group, a C １４ alkanoyl group, a C １６ alkanoyl group, a C １８ alkanoyl group, a cyclopropylformyl group, a cyclobutylformyl group, a cyclopentylformyl group, and a cyclohexylformyl group, and the Q ３ is selected from hydrogen, an amino group, a hydroxy group, and a halogen, preferably hydrogen, an amino group, and a halogen, and most preferably hydrogen and an amino group, characterized in that The use according to any one of claims 1 to 5.

7. In the formula I, R ４ is selected from hydrogen, deuterium and halogen, preferably hydrogen, deuterium, fluorine, chlorine and iodine, characterized in that The use according to any one of claims 1 to 6.

8. The compound represented by formula I is

9. Use of a composition containing a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 in the manufacture of an inhibitor that inhibits the replication of feline coronavirus or calicivirus, and / or use of a composition containing a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 in the manufacture of a drug for the treatment and / or prevention and alleviation of related diseases caused by feline coronavirus or calicivirus infection.

10. Characterized in that the related disease caused by feline coronavirus or calicivirus infection is selected from feline infectious peritonitis and feline stomatitis, The use according to any one of claims 1 to 9.

Images