阅读说明：本技术 Hpk1激酶抑制剂在预防和/或治疗动物的病原体感染中的应用 (Use of HPK1 kinase inhibitors for preventing and/or treating pathogen infection in animals ) 是由 林星雨 陆婷婷 于 2020-06-16 设计创作，主要内容包括：本发明公开了一种HPK1激酶抑制剂在预防和/或治疗动物的病原体感染中的应用。该HPK1激酶抑制剂为小分子HPK1激酶抑制剂,特别是通式Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物或氘代化合物。该HPK1激酶抑制剂可有效治疗动物病原体(特别是病毒,如冠状病毒)感染引起的疾病(如猫传染性腹膜炎),改善动物生存情况,在兽用抗病毒(特别是病毒,如冠状病毒)药物领域可具有较佳的商业价值和应用前景。(The invention discloses application of an HPK1 kinase inhibitor in preventing and/or treating pathogen infection of animals. The HPK1 kinase inhibitor is a micromolecular HPK1 kinase inhibitor, in particular to a compound shown as a general formula I or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof. The HPK1 kinase inhibitor can effectively treat diseases (such as feline infectious peritonitis) caused by animal pathogen (particularly virus, such as coronavirus) infection, improve the survival condition of animals, and has better commercial value and application prospect in the field of veterinary antiviral (particularly virus, such as coronavirus) medicines.)

1. Use of an inhibitor of HPK1 kinase in the manufacture of a medicament for the prevention and/or treatment of a disease or condition caused by or associated with a pathogen infection in an animal.

2. The use of claim 1, wherein the HPK1 kinase inhibitor is a small molecule inhibitor;

preferably, the small molecule HPK1 kinase inhibitor is a compound of the following general formula i, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof:

wherein:

a is selected from C or N;

ar is selected from aromatic five-membered heterocyclic group, aromatic six-membered heterocyclic group or phenyl;

R₁selected from: -H, halogen, -NO₂、-CN、C_1-5Straight chain/branched alkyl, C_3-10Cycloalkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -CF₃、-OCF₃、-OCHF₂、-OCH₂F or-OC_0-10An alkyl group;

R₂and R₃Independently selected from: -H, halogen, C_1-10Straight/branched alkyl;

R₄and R₅Independently selected from: -H, deuterium, halogen, C_1-10Straight chain/branched alkyl, deuterated C_1-10Straight/branched alkyl;

q is selected from O or S;

x and z are independently selected from integers between 0 and 6;

y is 0 or 1;

B₁、B₂、B₃、B₄and B₅Independently selected from CR₆Or N; wherein each R is₆Independently selected from: -H, halogen, -CN, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl, O-or N-containing heteroalkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl group), C_3-10Cycloalkyl, -C ≡ C-R₇-O-heterocycloalkyl, -N-heterocycloalkyl, -COO (C)_0-10Alkyl) (C_0-10Alkyl), -CO (C)_0-10Alkyl) (C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl) (C_0-10Alkyl), or two R₆With carbon atoms in between to form C_3-8Cycloalkyl or C containing-O-, -S-_3-8Heterocycloalkyl, -N-heterocyclic aryl, -O-heterocyclic aryl or-S-heterocyclic aryl, phenyl;

R₇selected from H, C_1-5Straight chain/branched alkyl, C_3-10A cycloalkyl group, a,Wherein R is₈And R₉Independently selected from: -H, -CF₃、-CHF₂H、-CH₂F、C_1-10Straight/branched alkyl, -CH ═ C (C)_0-10Alkyl) (C_0-10Alkyl), -C ≡ C (C)_0-10Alkyl group), C_3-10Cycloalkyl, -CO (C)_0-10Alkyl) (C_0-10Alkyl), -CO (C)_0-10Alkyl) (C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl) (C_0-10Alkyl), aromatic five-membered ring group or aromatic sixA cyclic ring group, or R₈And R₉And R₈And R₉Form C with carbon atoms in between_3-8Cycloalkyl or C containing-O-, -S-_3-8Heterocycloalkyl radical, C_4-9Condensed ring alkyl, C_5-10Spiro cycloalkyl, C_4-9Bridged cycloalkyl radical, C_3-7Cyclic lactam, C_3-7Cyclic lactone, C_3-7A cyclic ketone.

3. Use according to claim 2, wherein the aromatic five-membered heterocyclic group is selected from: furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, and selenothiazolyl; and/or, the aromatic six-membered heterocyclic group is selected from: pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

4. The use of claim 2, wherein Ar is selected from the group consisting of:

wherein R is₁₀、R₁₂And R₁₃Independently selected from: -H, C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl and C_3-10A cycloalkyl group;

R₁₁selected from: -H, -O-heterocycloalkyl, -N-heterocycloalkyl, C_1-10Straight chain/branched alkyl, C_3-10Cycloalkyl, -OC_0-10Alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -SO₂(C_0-10Alkyl), -O (C)_0-10Alkyl), -O-phenyl, -S (C)_0-10Alkyl), -N-heterocyclic aromatic group, -O-heterocyclic aromatic group or-S-heterocyclic aromatic group.

5. The use of claim 4, wherein R is₁₁Selected from:

6. the use of claim 2, wherein B is₁、B₂、B₃、B₄And B₅At least one of which is N; or the like, or, alternatively,

b is₁、B₂、B₃、B₄And B₅Are all CR₆In the general formula IIs composed ofWherein R is₆₁、R₆₂、R₆₃、R₆₄And R₆₅Independently selected from: -H, halogen, -CN, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl, O-or N-containing heteroalkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl group), C_3-10Cycloalkyl, -C ≡ C-R₇-O heterocycloalkyl, -N heterocycloalkyl, or R₆₁And R₆₂、R₆₂And R₆₃、R₆₃And R₆₄、R₆₄And R₆₅With carbon atoms in between to form C_3-8Cycloalkyl or C containing-O-, -S-_3-8Heterocycloalkyl, -N-heterocyclic aryl, -O-heterocyclic aryl or-S-heterocyclic aryl, phenyl.

7. The use of claim 6, wherein R is₆₃Selected from: -H, halogen, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl) or C_3-10A cycloalkyl group;

preferably, said R is₆₃Selected from: -H, halogen, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl;

more preferably, said R₆₃Selected from: -H, -F or-OCH₃。

8. The use of claim 6, wherein R is₆₂Selected from: -H, halogen, -OC_0-10Alkyl, -CN, C_3-10Cycloalkyl and-C.ident.C-R₇；

Preferably, said R is₆₂Selected from: -H, -F, -Cl, -OCH₃、-CN、and-C ≡ C-R₇；

More preferably, said R₆₂Is C ≡ C-R₇。

9. The use of claim 6, wherein R is₆₁、R₆₄、R₆₅Independently selected from: -H, halogen, -CN, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl group), C_3-10Cycloalkyl, -C ≡ C-R₇-O-heterocycloalkyl or-N-heterocycloalkyl, C containing O or N_1-5Straight chain/branched alkyl, or R₆₄、R₆₅And R₆₄And R₆₅The carbon atom to which it is attached forming C_3-8Cycloalkyl or C containing-O-, -S-_3-8A heterocycloalkyl group;

preferably, said R is₆₁、R₆₄、R₆₅Independently selected from: -H, halogen, C_1-3Straight chain/branched alkyl, -OC_0-3Alkyl, N-containing C_1-3Straight chain/branched alkyl, or R₆₄、R₆₅And R₆₄And R₆₅The carbon atom to which it is attached forming C_3-8Cycloalkyl or-O-containing C_3-8A heterocycloalkyl group, a heterocyclic alkyl group,

more preferably, said R₆₁、R₆₄、R₆₅Independently selected from: -H, -F, -Cl, -CH₃、-CH₂NH₂、-CN、-OCH₃Or R is₆₄、R₆₅And R₆₄And R₆₅The carbon atoms to which they are attached form a five-membered cycloalkyl group containing-O-.

10. The use of claim 8, wherein R is₈、R₉Independently selected from: -H, -CF₃、-CHF₂、-CH₂F、-CH₃、-CH₂CH₃、-CH＝CH₂、 Or R₈、R₉And R₈And R₉Formation of carbon atoms between

11. The use of claim 2, wherein the compound is selected from the structures:

12. the use of any one of claims 1 to 11, wherein the pathogen is a virus;

preferably, the virus is selected from: herpesviridae, iridoviridae, baculoviridae, rhabdoviridae, reoviridae, dirnaviridae, poxviridae, african swine fever viroridae, adenoviridae, parvoviridae, circoviridae, retroviridae, orthomyxoviridae, paramyxoviridae, coronaviridae, arteriviridae, picornaviridae, caliciviridae, flaviviridae, prions, filoviridae, polyomaviridae, and papilloma viroridae, nematoviridae, retroviridae, hepadnaviridae, bunaviridae, arenaviridae, rhabdoviridae, togaviridae, bicistronic viridae, and nodaviridae;

preferably, the virus is a coronavirus.

13. The use of claim 12, wherein the virus is selected from the group consisting of: avian infectious bronchitis virus, porcine transmissible gastroenteritis virus, porcine epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis virus, mouse hepatitis virus, turkey blueness virus, bovine coronavirus, canine coronavirus, feline infectious peritonitis virus, rat coronavirus, rat sialorrhagic coronavirus and mink epidemic diarrhea virus, sheep pox virus, goat pox virus, bovine pimple skin disease virus, fowl pox virus, cat pox virus, infectious pustule virus, rabbit myxomatosis virus, African swine fever virus, pseudorabies virus, porcine cytomegalovirus, chicken infectious laryngotracheitis virus, duck plague virus, feline viral rhinotracheitis virus, canine herpes virus, bovine infectious rhinotracheitis virus, equine infectious rhinopneumonitis virus, Marek's disease virus, malignant catarrhal fever virus, porcine adenovirus, canine viral hepatitis virus, Feline adenovirus, porcine parvovirus, feline panleukopenia virus, gosling plague virus, canine parvovirus, muscovy duck parvovirus, porcine circovirus, chicken infectious anemia virus, avian leukemia virus, feline leukemia virus, bovine leukemia virus, feline immunodeficiency virus, sydi-visna disease virus, goat viral arthritis-encephalitis virus, equine infectious anemia virus, bovine immunodeficiency virus, feline syncytial forming virus, avian viral arthritis virus, bluetongue virus, herckcastle disease virus, zhongshan disease virus, african horse plague virus, rotavirus, infectious bursal disease virus, canine viral papilloma virus, feline viral papilloma virus, nipag virus, hendela disease virus, porcine cyanosis virus, canine parainfluenza virus, avian paramyxovirus, chicken newcastle disease virus, canine distemper virus, Peste des petits ruminants virus, rinderpest virus, avian pneumovirus, avian mumps virus, feline paramyxosis, rabies virus, vesicular stomatitis virus, bovine ephemeral/tertian fever/transient fever virus, Borna disease virus, influenza virus, rift valley fever virus, akabane virus, hantavirus, feline enterocoronavirus, porcine hemagglutinating encephalomyelitis virus, porcine reproductive and respiratory syndrome virus, equine viral arteritis virus, foot and mouth disease virus, porcine vesicular disease virus, porcine enterovirus, duck viral hepatitis virus, avian encephalomyelitis virus, encephalomyocarditis virus, porcine herpes zoster virus, feline calicivirus, rabbit viral hemorrhagic disease virus, canine hepatitis E virus, beta virus, Japanese encephalitis B/epidemic encephalitis B virus, forest encephalitis virus, duck flavivirus, porcine virus, bovine viral diarrhea-plague virus, mucosal disease virus, rabies virus, swine fever with mucosis virus, swine fever virus, swine fever, swine, A border disease virus;

preferably, the virus is a coronavirus selected from the group consisting of: chicken infectious bronchitis virus, pig infectious gastroenteritis virus, pig epidemic diarrhea virus, pig hemagglutinating encephalomyelitis virus, mouse hepatitis virus, turkey bluecrown disease virus, bovine coronavirus, canine coronavirus, cat infectious peritonitis virus, rat coronavirus, rat sialorrhagic gland virus coronavirus and mink epidemic diarrhea virus;

more preferably, the virus is feline infectious peritonitis virus.

14. The use of claim 12, wherein the animal is a domestic animal;

preferably, the animal is an economic animal, a pet animal or a laboratory animal.

15. The use of claim 12, wherein the disease or condition comprises infectious bronchitis of chicken, transmissible gastroenteritis of pig, epidemic diarrhea of pig, canine coronavirus disease, hemagglutinating encephalomyelitis of pig, hepatitis caused by hepatitis virus of mouse, encephalitis and enteritis, blue crown disease of turkey, diarrhea of newborn calf, bloody dysentery of cow, infectious peritonitis of cat, salivary dacryadenitis of rat, epidemic diarrhea of mink, sheep pox, goat pox, bovine pimple skin disease, fowl pox, cat pox, infectious pustule, rabbit myxomatosis, african swine fever, pseudorabies, cytomegalovirus infection of pig, infectious laryngotracheitis of chicken, duck plague, viral rhinotracheitis of cat, herpes virus infection of dog, infectious rhinotracheitis of cow, infectious rhinopneumonia of dog, marek's disease, malignant catarrhal fever, adenovirus infection of pig, viral hepatitis of cat, adenoviruses, feline adenoviruses, epidemic encephalitis, epidemic rhinotracheitis of cat, canine rhinotracheitis, or murine rhinotracheitis, or bovine rhinovirus, infectious rhinotracheitis, infectious rhinopneumonitis, or rhinopneumonitis disease, or a viral hepatitis of cat, or a viral infection of pig, or a swine, Porcine parvovirus disease, feline panleukopenia (feline distemper, feline infectious enteritis), gosling plague, canine parvovirus disease, muscovy duck parvovirus disease, porcine circovirus disease, avian anemia, avian leukemia, feline leukemia, bovine leukemia, feline immunodeficiency disease, meidi-visna disease, goat viral arthritis-encephalitis, equine infectious anemia, bovine immunodeficiency virus infection, feline syncytial virus (foamy virus) infection, avian viral arthritis, bluetongue disease, hernanhead disease, zhongshan disease, african horse plague, rotavirus disease, infectious bursal disease, canine viral papilloma, feline viral papilloma disease, nepafer disease, hendela disease, porcine reproductive eye disease, canine parainfluenza virus infection, avian paramyxovirus infection, newcastle disease, canine distemper, small ruminant disease, bovine plague, avian pneumovirus infection, avian mumps virus infection, mumps disease, swine fever, small ruminant disease, bovine plague, swine fever, swine, Feline paramyxovirus disease, rabies, vesicular stomatitis, bovine ephemeral/tertian/ephemeral fever, borna disease, influenza, rift valley fever, akabane disease, hantavirus disease, feline enteric coronavirus infection, porcine hemagglutinating encephalomyelitis, porcine reproductive and respiratory syndrome, equine viral arteritis, foot and mouth disease, porcine vesicular disease, porcine enterovirus infection, duck viral hepatitis, avian encephalomyelitis, encephalomyocarditis, porcine herpes zoster, feline calicivirus disease, rabbit viral hemorrhagic disease, canine hepatitis E, Guitar virus disease, Japanese encephalitis B/epidemic encephalitis B, forest encephalitis, duck flavivirus infection, swine fever, bovine viral diarrhea-mucosis, border disease;

preferably, the disease is feline infectious peritonitis.

Technical Field

The invention relates to the technical field of chemical medicines, in particular to application of an HPK1 kinase inhibitor in preventing and/or treating animal pathogen (particularly, viruses such as coronavirus) infection.

Background

Viral diseases are one of the most serious diseases to which animals are clinically harmed in veterinary medicine, and particularly the prevalence of some highly pathogenic viral diseases often causes great economic and mental losses to the breeder. Animal viral diseases usually have fast infection, high morbidity and mortality, and serious harm to animal health and life. Moreover, some viruses can be transmitted to human beings through animals, and threaten the life safety of human beings.

Viral diseases of animals can be caused by a wide variety of viruses, for example, herpesviridae, rhabdoviridae, reoviridae, poxviridae, african swine fever viridae, adenoviridae, parvoviridae, circoviridae, orthomyxoviridae, paramyxoviridae, coronaviridae, and the like. The coronavirus is a large virus family widely existing in nature, is named after being observed in a form similar to a crown under an electron microscope, mainly causes respiratory diseases, and can infect various mammals such as pigs, cows, cats, dogs, minks, camels and the like, various birds and the like. For example, porcine delta coronavirus (PDCoV) is a novel porcine enterocoronavirus, which causes diarrhea and vomiting, rapid dehydration, exhaustion and death of 5-15 day-old suckling piglets, and the morbidity and mortality rate is as high as 50% -100%; infectious bronchitis of chicken is an acute high-contact respiratory infectious disease of chicken caused by infectious bronchitis virus, and the clinical characteristics of the infectious bronchitis are dyspnea, Luoyin, cough, mouth-opening respiration and sneeze, if the pathogeny is not nephrosis variant strain or does not cause complication, the mortality is generally low, the infection of laying hens usually appears and the egg production is reduced, and the egg quality is reduced; bovine Coronavirus (BCV) is a pathogenic virus of cattle, is generally considered as an important pathogen of newborn calf diarrhea at present, and can cause respiratory tract infection of cattle and winter bloody dysentery of adult cattle; the epidemic diarrhea (coronavirus enteritis) of minks, foxes and raccoon dogs is caused by coronavirus except for mink parvovirus enteritis, and after dogs, foxes, raccoon dogs and minks are ill, the epidemic diarrhea is manifested as hemorrhagic gastroenteritis symptoms and easy to cause mass-rising epidemic diarrhea, the transmission speed is high, the mortality rate is up to more than 30 percent, and the disease rate of newborn animals in the year is higher than that of breeding animals.

Although many vaccines related to viral diseases have been developed with the development of medical technology, the viruses may have variation, the effectiveness of the vaccines against newly emerged viruses needs to be evaluated, the cost is high, and the morbidity and mortality of viral diseases remain high, so that there is a great demand for drugs with good antiviral effect in the field of veterinary medicine.

Disclosure of Invention

The invention provides an application of an HPK1 kinase inhibitor in preparing a medicament for preventing and/or treating diseases or symptoms caused by or related to pathogen infection in animals.

In one embodiment of the present invention, the HPK1 kinase inhibitor is a small molecule inhibitor.

Specifically, the small molecule HPK1 kinase inhibitor is a compound of the following general formula i, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof:

wherein:

a is selected from C or N;

ar is selected from aromatic five-membered heterocyclic group, aromatic six-membered heterocyclic group or phenyl, wherein, the aromatic five-membered heterocyclic group can be selected from: furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl or selenothiazolyl, and the aromatic six-membered heterocyclic group may be selected from: pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; optionally, H on the aromatic five-membered heterocyclic group, aromatic six-membered heterocyclic group or phenyl group mentioned above may be substituted with the following group: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl radical, C_3-10Cycloalkyl, -O heterocycloalkyl, -N heterocycloaryl, -O heterocycloaryl or-S heterocycloaryl, wherein the alkyl moiety may be optionally substituted with one or more of the following groups: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、-N(C_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl, -N-heterocyclic aromatic group, -O-heterocyclic aromatic group or-S-heterocyclic aromatic group;

R₁selected from: -H, halogen, -NO₂、-CN、C_1-5Straight chain/branched alkyl, C_3-10Cycloalkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -CF₃、-OCF₃、-OCHF₂、-OCH₂F or-OC_0-10An alkyl group;

R₂and R₃Independently selected from: -H, halogen, C_1-10Straight/branched alkyl;

R₄and R₅Independently selected from: -H, deuterium, halogen, C_1-10Straight chain/branched alkyl, deuterated C_1-10Straight/branched alkyl;

q is selected from O or S;

x and z are independently selected from integers between 0 and 6 (specifically 0, 1,2, 3, 4, 5, 6);

y is 0 or 1;

B₁、B₂、B₃、B₄and B₅Independently selected from CR₆Or N; wherein each R is₆Independently selected from: -H, halogen, -CN, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl, O-or N-containing heteroalkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl group), C_3-10Cycloalkyl, -C ≡ C-R₇-O-heterocycloalkyl, -N-heterocycloalkyl, -COO (C)_0-10Alkyl) (C_0-10Alkyl), -CO (C)_0-10Alkyl) (C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl) (C_0-10Alkyl), or two R₆With carbon atoms in between to form C_3-8Cycloalkyl or C containing-O-, -S-_3-8Heterocycloalkyl, -N-heterocycloaryl, -O-heterocycloaryl or-S-heterocycloaryl, phenyl, in which H on the C atom may be replaced byAnd (3) substitution: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl radical, C_3-10Cycloalkyl, -O heterocycloalkyl, -N heterocycloaryl, -O heterocycloaryl or-S heterocycloaryl;

R₇selected from H, C_1-5Straight chain/branched alkyl, C_3-10A cycloalkyl group, a,R₈And R₉Independently selected from: -H, -CF₃、-CHF₂H、-CH₂F、C_1-10Straight/branched alkyl, -CH ═ C (C)_0-10Alkyl) (C_0-10Alkyl), -C ≡ C (C)_0-10Alkyl group), C_3-10Cycloalkyl, -CO (C)_0-10Alkyl) (C_0-10Alkyl), -CO (C)_0-10Alkyl) (C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl) (C_0-10Alkyl), an aromatic five-membered or aromatic six-membered ring group, or R₈And R₉And R₈And R₉Form C with carbon atoms in between_3-8Cycloalkyl or C containing-O-, -S-_3-8Heterocycloalkyl radical, C_4-9Condensed ring alkyl, C_5-10Spiro cycloalkyl, C_4-9Bridged cycloalkyl radical, C_3-7Cyclic lactam, C_3-7Cyclic lactone, C_3-7Cyclic ketones, wherein H on the C atom may be substituted with: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl) and-CON(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl radical, C_3-10Cycloalkyl, -O heterocycloalkyl, -N heterocycloaryl, -O heterocycloaryl or-S heterocycloaryl, wherein the alkyl moiety may be optionally substituted with one or more of the following groups: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、-N(C_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl, -N-heterocyclic aromatic group, -O-heterocyclic aromatic group or-S-heterocyclic aromatic group.

In one embodiment of the present invention, Q is O.

In one embodiment of the present invention, y is 1.

In one embodiment of the present invention, x is 0.

In one embodiment of the present invention, z is 1.

In one embodiment of the present invention, the above compound has the following structure:

in one embodiment of the present invention, a is C.

In one embodiment of the present invention, the above compound has the following structure:

specifically, the above R₄And R₅Independently selected from: -H, C_1-10Straight/branched alkyl; more specifically, R₄And R₅Independently selected from: -H, C_1-3Straight chain/branched alkyl.

In one embodiment of the present invention, R is₄Is H or-CH₃。

In one embodiment of the present invention, R is₅Is H or-CH₃。

Specifically, at least one H on the aromatic five-membered heterocyclic group, aromatic six-membered heterocyclic group or phenyl group is substituted by a group selected from: -SO₂、-SO₂NH₂、-NHSO₂、-CONH(C_0-10Alkyl), halogen, -CN, -OCF₃-O-heterocycloalkyl, -N-heterocycloalkyl, C_1-10Straight chain/branched alkyl, C_3-10Cycloalkyl, -OC_0-10Alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl groups); more specifically, at least one H on the aromatic five-membered heterocyclic group, aromatic six-membered heterocyclic group or phenyl group is substituted by-O heterocycloalkyl group or-N heterocycloalkyl group.

Specifically, Ar is selected from: thiazolyl, selenothiazolyl, imidazolyl, pyrazolyl and pyridyl.

In one embodiment of the present invention, Ar is selected from:

wherein R is₁₀、R₁₂And R₁₃Independently selected from: -H, C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl and C_3-10A cycloalkyl group;

R₁₁selected from: -H, -O-heterocycloalkyl, -N-heterocycloalkyl, C_1-10Straight chain/branched alkyl, C_3-10Cycloalkyl, -OC_0-10Alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -SO₂(C_0-10Alkyl), -O (C)_0-10Alkyl), -O-phenyl, -S (C)_0-10Alkyl), -N-heterocycloaryl, -O-heterocycloaryl or-S-heterocycloaryl, where the C atom or the H on the heteroatom may be replaced by C_1-3Straight chain alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -CF₃And (4) substitution.

Specifically, the above R₁₀、R₁₂And R₁₃May be independently selected from: -H, C_1-5Straight/branched alkyl and-N (C)_0-10Alkyl) (C_0-10Alkyl groups); more specifically, R₁₀、R₁₂And R₁₃May be independently selected from: -H, -CH₃、-CH₂CH₃and-NH₂。

Specifically, the above R₁₁May be selected from: -O-heterocycloalkyl or-N-heterocycloalkyl, -SO₂(C_0-3Alkyl), -O-phenyl, -S (C)_0-4Alkyl group), C_3-6Cycloalkyl or C_3-5Straight chain/branched alkyl, wherein H on C atom or hetero atom may be replaced by-CH₃、-NH₂、-CF₃Substitution; more specifically, R mentioned above₁₁May be selected from:

when R is₁₀、R₁₂And R₁₃And R₁₁When adjacent to each other, R₁₀、R₁₂Or R₁₃And R₁₁With carbon atoms in between may form C_3-8Cycloalkyl or C containing-O-, -S-_3-8Heterocycloalkyl, -N-heterocyclic aryl, -O-heterocyclic aryl or-S-heterocyclic aryl, phenyl.

In one embodiment of the present invention, the above compound has the following structure:

specifically, the above R₁May be selected from: -H, halogen, -NO₂、-CN、C_1-5Straight chain/branched alkyl, C_3-10Cycloalkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -CF₃、-OCF₃、-OCHF₂、-OCH₂F or-OC_0-10An alkyl group; more specifically, R mentioned above₁May be selected from: -NO₂、-N(C_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl or-OCF₃(ii) a In one embodiment of the present invention, R is₁is-NH₂or-NO₂。

In another embodiment of the present invention, B is₁、B₂、B₃、B₄And B₅At least one of which is N.

In one embodiment of the present invention, B is₂Is CR₆，B₁、B₃、B₄And B₅At least one of which is N.

In one embodiment of the present invention, B is₂Is CR₆，B₁Is N.

In one embodiment of the present invention, B is₂Is CR₆，B₃Is N.

In one embodiment of the present invention, B is₂Is CR₆，B₄Is N.

In one embodiment of the present invention, B is₂Is CR₆，B₅Is N.

In one embodiment of the present invention, B is₂Is CR₆，B₃And B₄Is N or B₃And B₅Is N.

In one embodiment of the present invention, B is₁、B₂、B₃、B₄And B₅Are all CR₆At this timeCan be thatWherein R is₆₁、R₆₂、R₆₃、R₆₄And R₆₅Each having the above-mentioned R of the present invention₆Definition of (1), in particular, R₆₁、R₆₂、R₆₃、R₆₄And R₆₅May be independently selected from: -H, halogen, -CN, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl, O-or N-containing heteroalkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl group), C_3-10Cycloalkyl, -C ≡ C-R₇-O heterocycloalkyl, -N heterocycloalkyl, or R₆₁And R₆₂、R₆₂And R₆₃、R₆₃And R₆₄、R₆₄And R₆₅With carbon atoms in between to form C_3-8Cycloalkyl or C containing-O-, -S-_3-8Heterocycloalkyl, -N-heterocycloaryl, -O-heterocycloaryl or-S-heterocycloaryl, phenyl, wherein H on the C atom may be substituted by: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl radical, C_3-10Cycloalkyl, -O heterocycloalkyl, -N heterocycloaryl, -O heterocycloaryl or-S heterocycloaryl; wherein R is₇Having the above definitions of the invention.

Specifically, the above R₆₃May be selected from: -H. Halogen, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl) or C_3-10A cycloalkyl group; more specifically, R₆₃May be selected from: -H, halogen, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl; still more specifically, R₆₃May be selected from: -H, -F or-OCH₃。

Specifically, the above R₆₂May be selected from: -H, halogen, -OC_0-10Alkyl, -CN, C_3-10Cycloalkyl and-C.ident.C-R₇(ii) a More specifically, R₆₂May be selected from: -H, -F, -Cl, -OCH₃、-CN、and-C ≡ C-R₇(ii) a In one embodiment of the invention, R₆₂Is C ≡ C-R₇。

Specifically, the above R₆₁、R₆₄、R₆₅Independently selected from: -H, halogen, -CN, -OC_0-10Alkyl radical, C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl group), C_3-10Cycloalkyl, -C ≡ C-R₇-O-heterocycloalkyl or-N-heterocycloalkyl, C containing O or N_1-5Straight chain/branched alkyl, or R₆₄、R₆₅And R₆₄And R₆₅The carbon atom to which it is attached forming C_3-8Cycloalkyl or C containing-O-, -S-_3-8Heterocycloalkyl, wherein H on the C atom may be substituted by-F; more specifically, R mentioned above₆₁、R₆₄、R₆₅Independently selected from: -H, halogen, C_1-3Straight chain/branched alkyl, -OC_0-3Alkyl, N-containing C_1-3Straight chain/branched alkyl, or R₆₄、R₆₅And R₆₄And R₆₅The carbon atom to which it is attached forming C_3-8Cycloalkyl or-O-containing C_3-8Heterocycloalkyl, wherein H on the C atom may be substituted by-F; still more specifically, R is as defined above₆₁、R₆₄、R₆₅Independently selected from: -H, -F, -Cl, -CH₃、-CH₂NH₂、-CN、-OCH₃Or R is₆₄、R₆₅And R₆₄And R₆₅The carbon atoms to which they are attached form a five-membered cycloalkyl group containing-O-. In one embodiment of the present invention, R is₆₁、R₆₄、R₆₅Are all H.

Specifically, the above R₇Selected from: H. c_1-5Straight chain/branched alkyl, C_3-10Cycloalkyl radicals and

in one embodiment of the present invention, R is₆₂Is composed of

Specifically, the above R₈、R₉Independently selected from: -H, -CF₃、-CHF₂H、-CH₂F、C_1-10Straight/branched alkyl, -CH ═ C (C)_0-10Alkyl) (C_0-10Alkyl), -C ≡ C (C)_0-10Alkyl group), C_3-10Cycloalkyl, an aromatic five-membered or aromatic six-membered ring group, or R₈、R₉And R₈And R₉Form C with carbon atoms in between_3-8Cycloalkyl or C containing-O, -S_3-8Heterocycloalkyl radical, C_4-9Condensed ring alkyl, C_5-10Spiro cycloalkyl, C_4-9Bridged cycloalkyl radical, C_3-7Cyclic lactam, C_3-7Cyclic lactone, C_3-7Cyclic ketones, wherein H on the C atom may be substituted with: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl, aryl, heteroaryl, and heteroaryl,C_3-10Cycloalkyl, -O heterocycloalkyl, -N heterocycloaryl, -O heterocycloaryl or-S heterocycloaryl, wherein the alkyl moiety may be optionally substituted with one or more of the following groups: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、-N(C_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl, -N-heterocyclic aromatic group, -O-heterocyclic aromatic group or-S-heterocyclic aromatic group.

More specifically, R mentioned above₈、R₉Independently selected from: -H, -CF₃、-CHF₂H、-CH₂F、C_1-10Straight/branched alkyl, -CH ═ C (C)_0-10Alkyl) (C_0-10Alkyl group), C_3-10Cycloalkyl or aromatic six-membered ring radicals, or R₈、R₉And R₈And R₉Form C with carbon atoms in between_3-8Cycloalkyl radical, C_4-7Condensed ring alkyl, C_5-9Spiro cycloalkyl, C_4-9Bridged cycloalkyl radical, C_3-7Cyclic lactam, C_3-7Cyclic lactone, C_3-7Cyclic ketones, wherein H on the C atom may be substituted with: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl radical, C_3-10Cycloalkyl, -O-heterocycloalkyl, -N-heteroCycloalkyl, -N-heterocycloaryl, -O-heterocycloaryl or-S-heterocycloaryl, wherein the alkyl moiety may be optionally substituted with one or more of the following groups: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、-N(C_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl, -N-heterocyclic aromatic group, -O-heterocyclic aromatic group or-S-heterocyclic aromatic group.

Still more specifically, R is as defined above₈、R₉Independently selected from: -H, -CF₃、-CHF₂H、-CH₂F、C_1-5Straight/branched alkyl, -CH ═ CH (C)_0-10Alkyl group), C_3-10Cycloalkyl or aromatic six-membered ring radicals, or R₈、R₉And R₈And R₉Form C with carbon atoms in between_3-6Cycloalkyl radical, C_4-6Condensed ring alkyl, C_5-8Spiro cycloalkyl, C_4-8Bridged cycloalkyl radical, C_3-7Cyclic lactam, C_3-7Cyclic lactone, C_3-7Cyclic ketones, wherein H on the C atom may be substituted with: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、C_1-10Straight/branched alkyl, -N (C)_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl radical, C_3-10Cycloalkyl, -O-heterocycloalkyl, -N-heterocycloaryl, -O-heterocycloaryl or-S-heterocycloarylWherein said alkyl moiety may be optionally substituted with one or more of the following groups: -SO₂、-SO₂N(C_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) SO₂(C_0-10Alkyl), -CON (C)_0-10Alkyl) (C_0-10Alkyl), -N (C)_0-10Alkyl) CO (C)_0-10Alkyl), -N (C)_0-10Alkyl) COO (C)_0-10Alkyl), -OCON (C)_0-10Alkyl) (C_0-10Alkyl), halogen, -CN, -OCH₂F、-OCHF₂、-OCF₃、-N(C_0-10Alkyl) (C_0-10Alkyl), -OC_0-10Alkyl, -N-heterocyclic aromatic group, -O-heterocyclic aromatic group or-S-heterocyclic aromatic group.

In one embodiment of the present invention, R is₈、R₉Independently selected from: -H, -CF₃、-CHF₂、-CH₂F、-CH₃、-CH₂CH₃、-CH＝CH₂、 Or R₈、R₉And R₈And R₉Formation of carbon atoms between

In one embodiment of the present invention, the above compound has the following structure:

specifically, the above compounds of the present invention may have the following structure:

in one embodiment of the present invention, the above compound has the following structure:

the pharmaceutically acceptable salts of the present invention include acid addition salts and base addition salts.

Specifically, the above-mentioned acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, and mesylate, as well as salts of amino acids such as arginate, gluconate, galacturonate, and the like. The above acid addition salts can be prepared by contacting the free base form with a sufficient amount of the desired acid to form a salt in a conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.

In particular, the above base addition salts are formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals useful as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1, 2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

Specifically, the above stereoisomers of the present invention exist in the form of enantiomers, diastereomers and geometric isomers. Some of the compounds of the present invention have cycloalkyl groups, which may be substituted on more than one carbon atom, in which case all geometric forms thereof, including cis and trans, and mixtures thereof, are within the scope of the present invention.

In particular, the solvates of the invention as described above refer to physical association of the compounds of the invention with one or more solvent molecules. The physical bonding includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "solvates" includes both solution phase and isolatable solvates. Representative solvates include ethanolates, methanolates, and the like. A "hydrate" is one in which one or more solvent molecules is H₂A solvate of O.

In particular, the above prodrugs of the present invention refer to the forms of the compounds of formula I, including acetals, esters and zwitterions, which are suitable for administration to patients without undue toxicity, irritation, allergic response, and the like, and which are effective for their intended use. The prodrug is converted in vivo (e.g., by hydrolysis in blood) to yield the parent compound of the above formula.

Specifically, the above-mentioned pathogen of the present invention may be a microorganism, a parasite (protozoa, helminths, etc.) or other vector; specifically, the above microorganisms may be selected from: one or more of viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.

In one embodiment of the present invention, the pathogen of the present invention is a virus.

Specifically, the virus may be herpesviridae (e.g., pseudorabies virus, bovine infectious rhinotracheitis virus, marek's virus, avian infectious laryngotracheitis virus, duck plague virus), iridoviridae (e.g., lymphocystis virus), baculoviridae (e.g., prawn baculovirus), rhabdoviridae (e.g., rabies virus, cyprinivirus), reoviridae (e.g., avian orthoreovirus, bluetongue virus, polyhedrosis virus), biscarviridae (e.g., infectious bursal disease virus), poxviridae (e.g., sheep pox virus, capripoxvirus virus, myxoma virus), african swine fever virus (e.g., african swine fever virus), adenoviridae (e.g., canine infectious hepatitis virus, egg drop syndrome virus), parvoviridae (e.g., porcine parvovirus, canine parvovirus, goose parvovirus, marek's virus, Feline panleukopenia virus, mink enteritis virus, mink aleutian virus), circoviridae (e.g., porcine circovirus), retroviridae (e.g., avian leukosis virus, caprine arthritis/encephalomyelitis virus, equine infectious anemia virus), orthomyxoviridae (e.g., avian influenza virus), paramyxoviridae (e.g., newcastle disease virus, canine distemper virus, rinderpest virus), coronaviridae, arteriviridae (e.g., porcine reproductive and respiratory syndrome virus), picornaviridae (e.g., foot and mouth disease virus, porcine vesicular disease virus, duck hepatitis virus), caliciviridae (e.g., rabbit hemorrhagic disease virus), flaviviridae (e.g., hog cholera virus, bovine viral diarrhea virus, japanese encephalitis virus), prion, filoviridae (e.g., marburg virus, ebola virus), polyomaviridae, and papillomaviridae (e), Leptoviridae, Retroviridae, Hemophilicae, papovaviridae, Ponaviridae, Bunyaviridae, Coincident viridae, Tolyviridae, Pentaviridae, Astroviridae, Togaviridae, Bicistrongyptiridae, nodaviridae, and nodaviridae.

Specifically, the virus may be, for example, Infectious Bronchitis Virus (IBV), transmissible gastroenteritis virus (TGEV), Porcine Epidemic Diarrhea Virus (PEDV), porcine Hemagglutinating Encephalomyelitis Virus (HEV), hepatitis virus in Mice (MHV), blue-crown virus in Turkeys (TCDV), Bovine Coronavirus (BCV), Canine Coronavirus (CCV), Feline Infectious Peritonitis Virus (FIPV), Rat Coronavirus (RCV), rat sialorrhagic coronavirus (SDAV), mink epidemic diarrhea coronavirus, sheep pox virus, goat pox virus, bovine pimple skin disease virus, fowl pox virus, feline pox virus, infectious pustular virus, rabbit myxomatosis virus, african swine fever virus, pseudorabies virus, porcine cytomegalovirus, infectious chicken tracheitis virus, duck plague virus, feline viral rhinotracheitis virus, canine herpes virus, porcine epidemic encephalitis virus, and canine infectious rhinotracheitis virus, Infectious bovine rhinotracheitis virus, infectious equine rhinopneumonitis virus, Marek's disease virus, malignant catarrh virus, porcine adenovirus, canine viral hepatitis virus, feline adenovirus, porcine parvovirus, feline panleukopenia (feline distemper, feline infectious enteritis) virus, gosling plague virus, canine parvovirus, muscovy duck parvovirus, porcine circovirus, infectious chicken anemia virus, avian leukemia virus, feline leukemia virus, bovine leukemia virus, feline immunodeficiency virus, Madin-visna virus, caprine viral arthritis-encephalitis virus, infectious equine anemia virus, bovine immunodeficiency virus, feline syncytial formation virus (foamy virus), avian viral arthritis virus, bluetongue virus, arrowhead disease virus, Zhongshan disease virus, African horse plague virus, rotavirus, infectious bursal disease virus, swine adenovirus, canine viral hepatitis, feline infectious bovine anemia virus, feline infectious swine fever virus, feline infectious rhinovirus, feline virus B virus, feline virus, canine infectious bursal disease virus, canine infectious virus, canine influenza virus, and a, Canine viral papilloma virus, feline viral papilloma virus, nipah disease virus, hendra disease virus, porcine cyanosis virus, canine parainfluenza virus, avian paramyxovirus, newcastle disease virus, canine distemper virus, peste des petits ruminants virus, bovine pestivirus, avian pneumovirus, avian mumps virus (measles virus), feline paramyxosis, rabies virus, vesicular stomatitis virus, bovine ephemeral/tertian/transient fever virus, bona disease virus, influenza virus, rift valley fever virus, akabane virus, hantaan virus, feline enterocoronavirus, porcine hemagglutinating encephalomyelitis virus, porcine reproductive and respiratory syndrome virus, equine viral arteritis virus, foot and mouth disease virus, porcine vesicular disease virus, porcine enterovirus, duck viral hepatitis virus, avian encephalomyelitis virus, porcine herpes virus, porcine reproductive and respiratory syndrome virus, equine viral hepatitis virus, equine viral encephalomyelitis virus, porcine encephalomyelitis virus, and porcine reproductive and respiratory syndrome virus, Feline calicivirus, rabbit viral hemorrhagic disease virus, canine hepatitis E virus, Getavirus, Japanese encephalitis B/epidemic encephalitis B virus, forest encephalitis virus, duck flavivirus, hog cholera virus, bovine viral diarrhea-mucosis virus, border disease virus, and the like.

In one embodiment of the present invention, the virus is a coronavirus, specifically, a chicken Infectious Bronchitis Virus (IBV), a pig transmissible gastroenteritis virus (TGEV), a Pig Epidemic Diarrhea Virus (PEDV), a pig Hemagglutinating Encephalomyelitis Virus (HEV), a Mouse Hepatitis Virus (MHV), a turkey blue crown disease virus (TCDV), a Bovine Coronavirus (BCV), a Canine Coronavirus (CCV), a cat infectious peritonitis virus (FIPV), a Rat Coronavirus (RCV), a rat sialorrhagic arteritis coronavirus (SDAV), a mink epidemic diarrhea coronavirus, and the like.

In one embodiment of the present invention, the virus is feline infectious peritonitis virus.

In the present invention, unless otherwise indicated, an "animal" as referred to herein is a non-human animal, in particular a vertebrate, in particular such as a mammal (e.g. a pig, a cow, a sheep, a horse, a donkey, a dog, a cat, a rabbit, a mouse, a fox, a racoon dog, a mink, a camel), a fish, a bird (e.g. a chicken, a duck, a goose, a pigeon, a quail, a parrot, etc.), an amphibian, a reptile. In particular, the animals of the present invention are domestic animals, i.e., animals domesticated by humans and bred by humans, and are used for functions such as eating, working, fur, pets, experiments, and the like, such as economic animals, pets, experimental animals, and the like.

In one embodiment of the invention, in the above application, the animal is an economic animal, such as domestic animals (e.g. pigs, cattle, sheep, horses, donkeys, foxes, racoon dogs, mink, camels, etc.), poultry (chickens, ducks, geese, pigeons, quails, etc.).

In one embodiment of the invention, in the above application, the animal is a pet, such as a dog, cat, rabbit, mouse (e.g., guinea pig, hamster, gerbil, dragon cat, squirrel, etc.), fish, pigeon, parrot, etc.

In one embodiment of the present invention, in the above application, the animal is an experimental animal, such as monkey, dog, rabbit, cat, rat, etc.

Specifically, the disease or disorder may include infectious bronchitis of chicken, infectious gastroenteritis of pig, epidemic diarrhea of pig, canine coronavirus disease, hemagglutinating encephalomyelitis of pig, hepatitis caused by hepatitis virus of mouse, encephalitis and enteritis, blue crown disease of turkey, diarrhea of newborn calf, bloody dysentery of cow, infectious peritonitis of cat, salivary gland inflammation of rat, epidemic diarrhea of mink, sheep pox, goat pox, bovine pimple skin disease, fowl pox, cat pox, infectious pustule, rabbit mucomatosis, African swine fever, pseudorabies, porcine cytomegalovirus infection, infectious laryngotracheitis of chicken, duck plague, viral rhinotracheitis of cat, herpes virus infection of dog, infectious rhinotracheitis of cow, infectious rhinopneumonitis of horse, Marek's disease, malignant catarrh fever, porcine adenovirus infection, viral hepatitis of dog, adenovirus disease, parvovirus disease of pig, leukopenia of cat (feline infectious rhinotracheitis, feline panleukopenia, Feline infectious enteritis), gosling plague, canine parvovirus disease, muscovy duck parvovirus disease, porcine circovirus disease, chicken infectious anemia, avian leukemia, feline leukemia, bovine leukemia, feline immunodeficiency disease, meidi-visna disease, goat viral arthritis-encephalitis, equine infectious anemia, bovine immunodeficiency virus infection, feline syncytial virus (foamy virus) infection, avian viral arthritis, bluetongue disease, herring disease, zhongshan disease, african horse sickness, rotavirus disease, infectious bursal disease, canine papilloma virus, feline viral papilloma disease, nipa disease, hendra disease, porcine cyanosis, canine parainfluenza virus infection, avian paramyxovirus infection, chicken newcastle disease, canine distemper, peste des petits ruminants, bovine plague, avian pneumovirus infection, avian mumps virus infection (measles virus infection), feline paramyxovirus disease, feline paramyxovirus infection, canine parainfluenza virus infection, avian paramyxovirus infection, avian influenza virus infection, avian newcastle disease, canine distemper, bovine plague, avian pneumovirus infection, avian mumps virus infection (measles virus infection), feline paramyxovirus disease, canine influenza virus infection, bovine plague, canine influenza virus infection, and swine fever, canine influenza virus infection, swine fever, swine, Rabies, vesicular stomatitis, bovine/triviral/transient fever, borna's disease, influenza, rift valley fever, akabane's disease, hantaan virus disease, feline enteric coronavirus infection, porcine hemagglutinating encephalomyelitis, porcine reproductive and respiratory syndrome, equine viral arteritis, foot and mouth disease, porcine vesicular disease, porcine enteric virus infection, duck viral hepatitis, avian encephalomyelitis, encephalomyocarditis, porcine herpes zoster, feline calicivirus disease, rabbit viral hemorrhagic disease, canine hepatitis E, Guitar virus disease, Japanese encephalitis B/epidemic encephalitis B, forest encephalitis, duck flavivirus infection, swine fever, bovine viral diarrhea-mucosis, boundary disease, and the like.

In one embodiment of the present invention, the above-mentioned disease or disorder is selected from: infectious bronchitis of chicken, transmissible gastroenteritis of pig, epidemic diarrhea of pig, canine coronavirus disease, hemagglutinating encephalomyelitis of pig, hepatitis, encephalitis and enteritis caused by hepatitis virus of mouse, blue crown disease of turkey, diarrhea of newborn calf, bloody dysentery of cattle, infectious peritonitis of cat, salivary dacryadenitis of rat, and epidemic diarrhea of mink.

In one embodiment of the invention, the disease is feline infectious peritonitis.

In particular, the above-mentioned medicament may comprise the HPK1 kinase inhibitor as the sole active ingredient, or in combination with one or more other active ingredients for the same or different indications, wherein the HPK1 kinase inhibitor and the other active ingredients are formulated for simultaneous, separate or sequential administration(s).

Specifically, the above-mentioned drugs may be in any dosage form or administration form, and those skilled in the art may select them as appropriate, and for example, the administration form thereof may be, but not limited to, oral, sublingual, inhalation, subcutaneous, intramuscular, intravenous, intraperitoneal, intraorgan, intranasal, intrarectal, transdermal, ocular or rectal forms, etc.; the dosage form can be, but is not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups, solutions, emulsions, suspensions, controlled release preparations, aerosols, films, injections, intravenous drip, transdermal absorption preparations, ointments, lotions, adhesive preparations, suppositories, nasal preparations, pulmonary preparations, eye drops and the like.

In one embodiment of the present invention, the drug is an injection.

The invention also provides application of the HPK1 kinase inhibitor in preparation of products for resisting pathogen infection for animals.

In particular, in the above applications, the HPK1 kinase inhibitor, the pathogen and the animal have the respective definitions of the invention as described above.

In particular, the above products can be used for therapeutic purposes, but also for non-therapeutic purposes.

In one embodiment of the present invention, the above product is a pharmaceutical composition.

In particular, in the above pharmaceutical composition, the above HPK1 kinase inhibitor may be used as the sole active ingredient or in combination with one or more other active ingredients for the same or different indications, wherein the above HPK1 kinase inhibitor and the other active ingredients may be formulated for simultaneous, separate or sequential administration(s).

Specifically, the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials, in particular auxiliary materials acceptable in the veterinary field.

Specifically, the above-mentioned pharmaceutical composition may be in any dosage form or administration form, which may be selected by those skilled in the art according to circumstances, for example, but not limited to, oral, sublingual, inhalation, subcutaneous, intramuscular, intravenous, intraperitoneal, intraorgan, intranasal, intrarectal, transdermal, ocular or rectal forms; the dosage form can be, but is not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups, solutions, emulsions, suspensions, controlled release preparations, aerosols, films, injections, intravenous drip, transdermal absorption preparations, ointments, lotions, adhesive preparations, suppositories, nasal preparations, pulmonary preparations, eye drops and the like.

In one embodiment of the present invention, the pharmaceutical composition is an injection.

The various forms of the above pharmaceutical composition can be prepared according to conventional production methods in the field of veterinary medicine.

In one embodiment of the present invention, the above product is a functional food composition.

In particular, in the above functional food compositions, the compound of formula i may be used as the sole active ingredient or in combination with one or more other active ingredients.

Specifically, the functional food composition may further comprise animal food adjuvants.

Specifically, the functional food composition may take any form, such as tablets, pills, capsules, candies (e.g., tabletted candies, gel candies, gum candies, etc.), solid beverages (e.g., powders, granules, etc.), liquid beverages, etc.

The above-mentioned various forms of functional food composition can be prepared according to the conventional production method in the field of functional foods for livestock.

In one embodiment of the present invention, the above product is an additive, which can be added in a small amount as a trace amount during the production, processing and using processes of animal food (such as livestock and poultry feed, pet ration, pet snacks, etc.).

The present invention also provides a method for preventing and/or treating a disease or condition caused by or associated with a pathogen infection in an animal comprising the step of administering to the subject an effective amount of an inhibitor of HPK1 kinase as described above.

In particular, in the above methods, the HPK1 kinase inhibitor, pathogen, animal, disease or condition has the corresponding definitions of the invention as described above.

The inventor of the invention finds through experiments that the HPK1 kinase inhibitor (especially the compound of the formula I, such as 4- (3- { 2-amino-5- [2- (1-methyl-piperidine-4-yl) -thiazole-5-yl ] -pyridine-3-yloxymethyl } -phenyl) -2-methylbut-3-alkyne-2-ol) can effectively treat diseases (such as feline infectious peritonitis) caused by animal pathogen (especially virus, such as coronavirus) infection, improve animal survival conditions, and have better commercial value and application prospect in the field of veterinary anti-pathogen (especially virus, such as coronavirus) medicines.

Drawings

Figure 1 shows a chest X-ray of a diseased cat in example 1 of the present invention.

FIG. 2 is a graph showing the clinical survival of example 2 of the present invention, wherein the first day is the administration day.

Detailed Description

Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

In the present invention, the term "alkyl" refers to a hydrocarbon chain radical which is linear or branched and does not contain unsaturated bonds, and which is linked to the rest of the molecule by a single bond. Alkyl groups may be substituted, for example, if the alkyl group is substituted with cycloalkyl, it is correspondingly "cycloalkylalkyl", such as cyclopropylmethyl; if an alkyl group is substituted with a halogen, it is correspondingly "haloalkyl"; if an alkyl group is substituted by an aryl group, it is correspondingly "aralkyl"Such as benzyl, benzhydryl or phenethyl; if an alkyl group is substituted with a heterocyclyl group, then it is correspondingly "heterocyclylalkyl"; and the like. In the present invention, said C_0-10Alkyl refers to alkyl containing 0-10 (specifically, 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc., wherein C is C₀Alkyl refers to H.

The term "cycloalkyl" refers to alicyclic hydrocarbons, e.g., having 1 to 4 mono-and/or fused rings, 3 to 18 carbon atoms, preferably 3 to 10 carbon atoms, e.g., cyclopropyl, cyclohexyl, adamantyl, and the like, C in the context of the present invention_3-10Cycloalkyl refers to cycloalkyl groups containing 3 to 10 (specifically, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing monoaryl and/or fused aryl groups, e.g., containing 1-3 monocyclic or fused rings and 6-18 (specifically, e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, e.g., phenyl, naphthyl, biphenyl, indenyl, and the like.

The term "heterocyclyl" includes heteroaromatic and heteroalicyclic groups containing 1 to 3 monocyclic and/or fused rings and 3 to 18 (specifically such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) ring atoms. Preferred heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms. Suitable heteroaryl groups in the compounds of the invention contain 1,2 or 3 heteroatoms, which may be selected from N, O or S atoms.

The above groups may be substituted in the present invention at one OR more available positions with one OR more suitable substituent groups such as, but not limited to, OR ', ═ O, SR ', SOR ', SO₂R'、OSO₂R'、OSO₃R'、NO₂、NHR'、N(R')₂、＝N-R'、N(R')COR'、N(COR')₂、N(R')SO₂R'、N(R')C(＝NR')N(R')R'、N₃CN, halogen, COR ', COOR ', OCOR ', OCOOR ', OCONHR ',OCON(R')₂、CONHR'、CON(R')₂、CON(R')OR'、CON(R')SO₂R'、PO(OR')₂、PO(OR')R'、PO(OR')(N(R')R')、C₁-C₁₂alkyl radical, C₃-C₁₀Cycloalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, aryl and heterocyclyl. Wherein each R' group is independently selected from: hydrogen, OH, NO₂、NH₂SH, CN, halogen, COH, COalkyl, COOH, C₁-C₁₂Alkyl radical, C₃-C₁₀Cycloalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, aryl and heterocyclyl groups; where these groups are themselves substituted, the substituents may be selected from the foregoing list.

The terms "halogen", "halo" or "halo" refer to bromo, chloro, iodo or fluoro.

The term "treating" includes eradicating, removing, reversing, alleviating, altering, or controlling a disease or disorder after its onset.

The term "prevention" refers to the ability to prevent, minimize or make difficult the onset or progression of a disease or condition by treatment prior to the onset of the disease or condition.

The term "pathogen" refers to a microorganism (including viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.), parasite (protozoa, worms, etc.) or other vector that can cause diseases of infection of humans or animals and plants. Among them, the bacteria may be, for example, gram-positive cocci, enterobacteria, vibrios, pasteurella, gram-negative aerobes, gram-negative microaerobes and anaerobes, gram-positive bacillus-free, gram-positive bacillus-producing, mycobacteria, etc.; the fungus may be, for example, Candida, Cryptococcus, Aspergillus, etc. In the present invention, a pathogen generally refers to a microorganism, parasite or other agent that can cause an infectious disease in an animal. In one embodiment of the invention, the pathogen is a virus.

The term "viral infection" refers to the process by which a virus enters the body through a variety of pathways and propagates in susceptible host cells. The body can present different clinical types after being infected by virus. The infection can be classified into dominant infection and recessive infection according to the existence of symptoms. Because of the small amount of virus invading the body, the weak toxicity or the strong resistance of the body, the virus proliferates in host cells, but the body does not present obvious clinical symptoms, which is called recessive infection. Although recessive infection does not show clinical symptoms, viruses are still propagated in vivo and spread to the outside, which is an important source of infection, and thus it is necessary for a recessive host to be resistant to viral infection. Due to the large number of viruses invading the body, strong virulence or weak resistance of the body, the viruses proliferate in large numbers in host cells, and obvious clinical symptoms, called dominant infection, appear.

In the present invention, unless otherwise indicated, an "animal" as referred to herein is a non-human animal, in particular a vertebrate, in particular such as a mammal (e.g. a pig, a cow, a sheep, a horse, a donkey, a dog, a cat, a rabbit, a mouse, a fox, a racoon dog, a mink, a camel), a fish, a bird (e.g. a chicken, a duck, a goose, a pigeon, a quail, a parrot, etc.), an amphibian, a reptile. In particular, the animals of the present invention are domestic animals, i.e., animals domesticated by humans and bred by humans, and are used for functions such as eating, working, fur, pets, experiments, and the like, such as economic animals, pets, experimental animals, and the like. Among them, "economic animals" mean animals raised for meat, milk, fur, working or other economic purposes, such as domestic animals, poultry, etc., and "domestic animals" mean animals raised by humans and bred for use, which is advantageous for agricultural production; "poultry" refers to an artificially housed avian animal, primarily for the purpose of obtaining its meat, eggs and feathers, and also has other uses; "Pet" refers to animals raised for mental purposes (e.g., appreciation and companion purposes) rather than economic purposes; "laboratory animal" means an animal raised for scientific purposes.

The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

1. Experimental methods

British shorthair cats (Lele) 8 months old, females not having been sterilized, 2.5kg body weight. The cat has symptoms of high body temperature, depressed spirit, anorexia, and enlarged abdominal circumference in 1 month of 2020. The patient is admitted to hospital and asked after 1 week, cat infectious peritonitis (FIP) is positive after 18 days in 1 month, and the patient continues to use the quick urine, the suknoo, the prednisolone and the itraconazole (orally taken, q 24h, 10mg/kg) for 1 month after the treatment of the GS-441524 for 3 days, and the medicine is stopped after ascites disappears. The disease condition is repeated in the early 4 months, the appetite is reduced, the spirit is cachexia appears after X-ray detection, and the cat coronavirus positive (CT value is 25.11) is detected by PCR. Group on day 8 at month 4, days 1-14 (D1-14): 2.0mg/kg of the drug of the invention and SC q 24 h. Simultaneously, proper supportive treatment is given, and auxiliary treatment medicines such as morecagan (liver-protecting medicine), Toltz lysine (lysine) and kangling (lactoferrin type) are given.

2. Pharmaceutical preparation and use

The above-mentioned pharmaceutically active compound of the present invention has the following structure, and is a pure powder, and is added with 0.9% physiological saline (50ml of endotoxin-free water, 0.45g of NaCl), uniformly mixed, filtered by filter membrane until the solution is clarified. Storing the diluted medicine in a plastic-sealed sterile vial, storing in a refrigerator at 4 deg.C, slowing to room temperature before injection, and using with a disposable syringe. The injection range spanned the back, starting 2cm from the posterior scapula to the middle of the lumbar spine, half the distance from the adjacent chest and flank.

3. Results of the experiment

After daily morning injections of the drug, body temperature, appetite, mental state, respiratory state were assessed at 15:00 pm, and urination and defecation were recorded, with the results shown in table 1.

TABLE 1 results of the experiment

The operations of groups D0, D7 and D14 were as follows:

1ml serum samples were kept frozen for multi-factor testing and the results are shown in Table 2.

TABLE 2 blood routine test results

3) Chest X-ray

As shown in fig. 1.

4) Analysis of results

As is clear from the above results, in this case, wet FIP (localized in the chest) was detected, and clinical symptoms such as hydrothorax, listlessness, and anorexia were manifested as typical feline abdominal symptoms.

Because the patient has no fever symptom when the patient is taken, no fever reducing effect can be seen during the administration, and the body temperature is always maintained in the normal range of 38-38.5 ℃. Clinical responses were dramatic in cats following 2 weeks of treatment completion, with daily appetite, mental status and weight gain. From about 7 days after treatment, the pleural effusion completely disappeared. Body weight increased by 9% during and after treatment.

Example 2

The clinical diagnosis group had 15 FIP cats with chest/ascites generation, positive CT value by PCR detection, and no neurological symptoms, wherein 8 cats were control groups and 7 cats were experimental groups.

Each group was used 3 days GS-441524 first, followed by control groups D1-D14: given the necessary supportive care, group a observed 3 days later D1-D14: the necessary supportive treatment was given and 2.0mg/kg of drug of the invention, SC q 24 h.

Clinical death was judged if death or neurological symptoms occurred, and the clinical survival curve was calculated 14 days later, with the results shown in FIG. 2. The Log Rank (Mantel-Cox) and Breslow (Genralized Wilcoxon) methods were used for validity testing, both methods testing for significant differences (P < 0.05).

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and the like that are within the spirit and principle of the present invention are included in the present invention.

The foregoing embodiments and methods described in this disclosure may vary based on the abilities, experience, and preferences of those skilled in the art.

The mere order in which the steps of a method are listed in the present invention does not constitute any limitation on the order of the steps of the method.