RU2828661C1 - Use of hpk1 kinase inhibitor in prevention and/or treatment of pathogenic infections in animals - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutics and discloses the use of an HPK1 kinase inhibitor, which is a small molecule inhibitor of general formula (V) or a pharmaceutically acceptable salt thereof, for preparing a drug for preventing and/or treating a disease or condition caused by or associated with a pathogenic infection in an animal; where the pathogen is a coronavirus. In general formula (V), R₁₀ is -H; R₁₁ is -N heterocyclic alkyl containing one monocyclic ring and 5–7 ring atoms, where H on heteroatom can be substituted with direct alkyl C_1-3; R₁ is -NH₂; R₄ and R₅ are -H; R₆₁, R₆₂, R₆₃, R₆₄ and R₆₅ are -H; R₆₂ is C≡C-R₇; R₇ is , where R₈ and R₉ are -CH₃.

EFFECT: use of the invention enables the effective treatment of diseases caused by coronaviruses in animals.

9 cl, 2 dwg, 2 tbl

Description

Field of technology

The present invention relates to the field of chemical medicine, in particular to the use of an HPK1 kinase inhibitor in the prevention and treatment of pathogenic infections in animals (especially viruses such as coronavirus).

Prerequisites for the creation of an invention

Viral diseases are among the most serious animal diseases in veterinary clinics, in particular, the spread of some highly pathogenic viral diseases often causes huge economic and emotional losses for animal owners. Viral diseases of animals usually spread quickly and are associated with high morbidity and mortality. Moreover, some viruses can also be transmitted to humans through animals, which poses a threat to human lives.

Viral diseases of animals can be caused by a wide range of viruses, such as the herpes virus family, rhabdoviruses, reoviruses, poxviruses, African swine fever viruses, adenoviruses, parvoviruses, circoviruses, orthomyxoviruses, paramyxoviruses, coronaviruses, etc. Coronaviruses are a large family of viruses that are widely present in nature, coronavirus is named after its crown-like shape when the virus is observed under an electron microscope, coronavirus mainly causes respiratory diseases and can infect various mammals such as pigs, cattle, cats, dogs, minks and camels, as well as various birds. For example, porcine deltacoronavirus (PDCoV) is a novel enteric coronavirus of swine that can cause diarrhea and vomiting, rapid dehydration and collapse in 5-15 day-old piglets, with morbidity and mortality rates of up to 50%-100%; Chicken infectious bronchitis is an acute respiratory infectious disease caused by close contact between individuals caused by the infectious bronchitis virus of chickens; Clinical features of the disease include difficulty breathing, wheezing, coughing, mouth breathing and sneezing; Complications may occur if the pathogen is not a nephropathic strain; Mortality rates are generally low, and infection of egg-laying hens usually results in reduced egg production and lower egg quality; Bovine coronavirus (BCV) is a pathogenic disease of cattle and is generally considered an important pathogenic cause of neonatal calf diarrhea; It can later cause respiratory tract infections in cattle and winter blood dysentery in adult cattle; Epidemic diarrhea of mink, foxes, and raccoon dogs (enteric coronavirus) is an epidemic diarrhea of mink that is caused by a different coronavirus than canine parvovirus; Affected dogs, foxes, raccoon dogs, and minks exhibit symptoms of hemorrhagic gastroenteritis that are highly likely to cause mass epidemic diarrhea, spread rapidly, and have a mortality rate of more than 30%, with a higher incidence within one year in calving animals than in breeding animals.

With the continuous development of medical technology, many vaccines related to viral diseases have been developed, but viruses may mutate, the effectiveness of vaccines against emerging viruses needs to be evaluated, which is associated with relatively high costs, the morbidity and mortality of viral diseases is still high, so the veterinary field has a great demand for drugs that are effective against viral infections.

The essence of the invention

The present invention relates to an HPK1 kinase inhibitor used as a medicinal product for the prevention and/or treatment of a disease or symptoms in animals that are caused by or associated with a pathogenic infection.

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 Formula I below or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof:

Including the following:

A is chosen from C or N;

Ar is selected from a five-membered aromatic heterocyclic group, a six-membered aromatic heterocyclic group, and a phenyl group. The five-membered aromatic heterocyclic group can be selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazole, thiazolyl, or selenothiazolyl, and the six-membered aromatic heterocyclic group can be selected from pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. Additionally, H in the above five-membered aromatic heterocyclic group, six-membered aromatic heterocyclic group or phenyl group is to be replaced by the following: -SO ₂ , -SO ₂ N(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )SO ₂ (alkyl C _0-10 ), -CON(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C 0-10 )CO(alkyl C _0-10 ), _-N (alkyl C _0-10 )COO(alkyl C _0-10 ), -OCON(alkyl C _0-10 )(alkyl C _0-10 ), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , straight/branched alkyl C _1-10 , -N(alkyl C _0-10 )CO(alkyl C _0-10 ), alkyl -OC _0-10 , cycloalkyl C _3-10 , heterocyclic alkyl -O, heterocyclic alkyl -N, heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, wherein the alkyl portion may optionally be replaced by one or more of the following groups: -SO ₂ , -SO ₂ N(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )SO ₂ (alkyl C _0-10 ), -CON(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )CO(alkyl C _0-10 ), -N(alkyl C _0-10 )COO(alkyl C _0-10 ), -OCON(alkyl C _0-10 )(alkyl C _0-10 ), halogen, -CN, _-OCH2F , _-OCHF2 , _-OCF3 , -N( _alkylC0-10 )( _alkylC0-10 ), alkyl _-OC0-10 , heterocyclic aryl-N, heterocyclic aryl-O or heterocyclic aryl-S;

R ₁ is selected from -H, halogen, -NO ₂ , -CN, linear/branched alkyl C _1-5 , cycloalkyl C _3-10 , -N(alkyl C _0-10 )(alkyl C _0-10 ), -CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F or alkyl -OC _0-10 ;

R ₂ or R ₃ are independently selected from - H, halogen or linear/branched alkyl C _1-10 ;

R ₄ or R ₅ are independently selected from - H, deuterium, halogen, C _1-10 linear/branched alkyl or deuterated C _1-10 linear/branched alkyl;

Q is chosen from O or S;

x or z are independently selected from integers in the range 0-6 (e.g. 0, 1, 2, 3, 4, 5, 6);

y is 0 or 1;

B ₁ , B ₂ , B ₃ , B ₄ or B ₅ are independently selected from CR ₆ or N, wherein each R ₆ is independently selected from -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, heteroalkyl with O or N content, -N(C _0-10 alkyl)(C _0-10 alkyl), C _3-10 cycloalkyl, -C≡CR ₇ , heterocyclic alkyl -O, heterocyclic alkyl -N, -COO(C _0-10 alkyl)(C _0-10 alkyl), -CO(C _0-10 alkyl)(C _0-10 alkyl), -CON(C _0-10 alkyl)(C _0-10 alkyl), -N(C _0-10 alkyl )CO(alkyl C _0-10 )(alkyl C _0-10 ), cycloalkyl C _3-8 or heterocyclic alkyl C _3-8 , heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, phenyl containing -O- and -S-, which are formed by two R ₆ and a carbon atom in between, or phenyl, where H on the C atom can be replaced by the following groups: -SO ₂ , -SO ₂ N(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )SO ₂ (alkyl C _0-10 ), -CON(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )CO(alkyl C _0-10 ), -N(alkyl C _0-10 )COO(alkyl C _0-10 ), -OCON(alkyl C _0-10 )(alkyl C _0-10 ), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , straight/branched alkyl C _1-10 , -N(alkyl C _0-10 )(alkyl C _0-10 ), alkyl -OC _0-10 , cycloalkyl C _3-10 , heterocyclic alkyl -O, heterocyclic alkyl -N, heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic alkyl -S;

R ₇ is selected from H, linear/branched alkyl C _1-5 , cycloalkyl C _3-10 or ; R ₈ or R ₉ are independently selected from -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH＝C(C _0-10 alkyl)(C _0-10 alkyl), -C≡C(C _0-10 alkyl), C _3-10 cycloalkyl, -CO(C _0-10 alkyl)(C _0-10 alkyl), -CO(C _0-10 alkyl)(C _0-10 alkyl), -CON(C _{0-10 alkyl} )(C _0-10 alkyl), -N(C _0-10 alkyl)CO(C _{0-10 alkyl)(C 0-10 alkyl} ), a five-membered aromatic ring group or a six-membered aromatic ring group, cycloalkyl C _3-8 or a heterocyclic C _3-8 alkyl containing -O- and -S-, which are created by R ₈ and R ₉ , as well as the carbon atom between them, a fused C _4-9 cycloalkyl, a C _5-10 spirocycloalkyl, a bridged C _4-9 cycloalkyl, a C _3-7 lactam, a C _3-7 cyclolactones or a C _3-7 cycloketone, where the H on the C atom can be replaced by the following groups: -SO ₂ , -SO ₂ N(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )SO ₂ (alkyl C _0-10 ), -CON(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )CO(alkyl C _0-10 ), -N(C _{0-10 alkyl} )COO(C _0-10 alkyl), -OCON(C _0-10 alkyl)(C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 straight/branched alkyl, -N(C _0-10 alkyl)(C 0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, heterocyclic alkyl -O, heterocyclic alkyl -N, heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, wherein said alkyl moiety may optionally be replaced by one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl)(C _0-10 alkyl ), -N(C _0-10 alkyl)SO ₂ (C _0-10 alkyl), -CON(C _0-10 alkyl)(C _{0-10 alkyl} ), -N(C _0-10 alkyl)CO(C _{0-10 alkyl} ), -N(C _0-10 alkyl)COO(C _{0-10 alkyl} ), -OCON(C _{0-10 alkyl} )(C _0-10 alkyl), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(C _0-10 alkyl)(C _0-10 alkyl), alkyl -OC _0-10 , heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S;

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

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

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

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

In one embodiment of the present invention, the structures of the above connections are shown below:

In one embodiment of the present invention, said A is C.

In one embodiment of the present invention, the structures of the above connections are shown below:

Specifically, said R ₄ or R ₅ is independently selected from linear/branched alkyl -H, C _1-10 ; more specifically, R ₄ or R ₅ is independently selected from linear/branched alkyl -H, C _1-3 .

In one embodiment of the present invention, said R ₄ is H or -CH ₃ .

In one embodiment of the present invention, said R ₅ is H or -CH ₃ .

Specifically, at least one H of the above-mentioned five-membered aromatic heterocyclic group or six-membered aromatic heterocyclic group, or phenyl is replaced by a group selected from _-SO2 , _-SO2NH2 , _-NHSO2 , -CONH( _C0-10 alkyl), halogen, -CN, _-OCF3 , heterocyclic alkyl _-O , heterocyclic alkyl -N, linear/branched _C1-10 alkyl, cycloalkyl _C3-10 , alkyl _-OC0-10 , -N( _C0-10 alkyl)( _C0-10 alkyl); more specifically, at least one H in the above-mentioned five-membered aromatic heterocyclic group, six-membered aromatic heterocyclic group or phenyl group is to be replaced by heterocyclic alkyl -O or heterocyclic alkyl -N.

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

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

Where R ₁₀ , R ₁₂ or R ₁₃ are independently selected from linear/branched alkyl -H, C _1-10 , -N(alkyl C _0-10 )(alkyl C _0-10 ), alkyl -OC _0-10 and cycloalkyl C _3-10 ;

R ₁₁ is selected from -H, heterocyclic alkyl -O, heterocyclic alkyl -N, straight/branched C _1-10 alkyl, cycloalkyl C _3-10 , alkyl -OC _0-10 , -N(alkyl C _0-10 )(alkyl C _0-10 ), -SO ₂ (alkyl C _0-10 ), -O(alkyl C _0-10 ), -O-phenyl, -S(alkyl C _0-10 ), heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, wherein H on a C atom or heteroatom can be replaced with straight C _1-3 alkyl, -N(alkyl C _0-10 )(alkyl C _0-10 ) or -CF ₃ .

Specifically, the above R ₁₀ , R ₁₂ or R ₁₃ can be independently selected from linear/branched alkyl -H, C _1-5 and -N(alkyl C _0-10 )(alkyl C _0-10 ); more specifically, R ₁₀ , R ₁₂ or R ₁₃ can be independently selected from -H, -CH ₃ , -CH ₂ CH ₃ and -NH _2.

Specifically, the above R ₁₁ can be selected from heterocyclic alkyl -O, heterocyclic alkyl -N, -SO ₂ (C _0-3 alkyl), -O-phenyl, -S (C _0-4 alkyl), C _3-6 cycloalkyl or C _3-5 linear/branched alkyl, wherein H on the C atom or heteroatom can be replaced by -CH ₃ , -NH ₂ , -CF ₃ ; more specifically, the above R ₁₁ can be selected from

When R ₁₀ , R ₁₂ and R ₁₃ are located in the vicinity of R ₁₁ , R ₁₀ and R ₁₂ or R ₁₃ and R ₁₁ , or the carbon atom itself between them can create a C _3-8 cycloalkyl, a C _3-8 heterocyclic alkyl, a heterocyclic aryl-N, a heterocyclic aryl-O or a heterocyclic aryl-S, phenyl containing -O- and -S-.

In one embodiment of the present invention, the structures of the above connections are shown below:

Specifically, said R ₁ may be selected from -H, halogen, -NO ₂ , -CN, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl, -N(C _0-10 alkyl)(C _0-10 alkyl), -CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F or phenyl -OC _0-10 ; more specifically, said R ₁ may be selected from -NO ₂ , -N(C _0-10 alkyl)(C _0-10 alkyl), -OC _0-10 alkyl or -OCF ₃ ; in one embodiment of the present invention, said R ₁ is -NH ₂ or -NO ₂ .

In another embodiment of the present invention, at least one of the following elements: B ₁ , B ₂ , B ₃ , B ₄ and B ₅ is N.

In one embodiment of the present invention, said B ₂ is CR ₆ , and at least one of B ₁ , B ₃ , B ₄ and B ₅ is N.

In one embodiment of the present invention, said B ₂ is CR ₆ and B ₁ is N.

In one embodiment of the present invention, said B ₂ is CR ₆ and B ₃ is N.

In one embodiment of the present invention, said B ₂ is CR ₆ and B ₄ is N.

In one embodiment of the present invention, said B ₂ is CR ₆ and B ₅ is N.

In one embodiment of the present invention, said B ₂ is CR ₆ , B ₃ and B ₄ are N, or B ₃ and B ₅ are N.

In one embodiment of the present invention, the above B ₁ , B ₂ , B ₃ , B ₄ and B ₅ are all CR ₆ , and at this time May be , wherein R ₆₁ , R ₆₂ , R ₆₃ , R ₆₄ and R ₆₅ have the definitions of the above R ₆ of the present invention. Specifically, R ₆₁ , R ₆₂ , R ₆₃ , R ₆₄ or R ₆₅ can be independently selected from -H, halogen, -CN alkyl, -OC _0-10 , C _1-10 linear/branched alkyl, O or N containing heteroalkyl, -N(C _0-10 alkyl)(C _0-10 alkyl), C _3-10 cycloalkyl, -C≡CR ₇ , heterocyclic alkyl -O, heterocyclic alkyl -N, C _3-8 cycloalkyl or C _3-8 heterocyclic alkyl, heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, phenyl containing -O- and -S- formed by R ₆₁ and R ₆₂ , R ₆₂ and R ₆₃ , R ₆₃ and R ₆₄ or R ₆₄ and R ₆₅ , and the carbon atom between them, phenyl, where the H on the C atom can be replaced by the following groups: -SO ₂ , -SO ₂ N(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )SO ₂ (alkyl C _0-10 ), -CON(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )CO(alkyl C _0-10 ), -N(alkyl C _0-10 )COO(alkyl C _0-10 ), -OCON(alkyl C _0-10 )(alkyl C _0-10 ), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , straight/branched alkyl C _1-10 , -N(alkyl C _0-10 )(alkyl C _0-10 ), alkyl -OC _0-10 , cycloalkyl C _3-10 heterocyclic alkyl -O, heterocyclic alkyl -N, heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, where R ₇ has the above definition of the present invention.

Specifically, the above-mentioned R ₆₃ can be selected from -H, halogen, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl)(C _0-10 alkyl) or C _3-10 cycloalkyl; more specifically, R ₆₃ can be selected from -H, halogen, -OC _0-10 alkyl and C _1-10 linear/branched alkyl. Moreover, in particular, R ₆₃ can be selected from -H, -F or -OCH ₃ .

Specifically, the above R ₆₂ can be selected from -H, halogen, -OC _0-10 alkyl, -CN, C _3-10 cycloalkyl and -C≡CR ₇ ; more specifically, R ₆₂ can be selected from -H, -F, -Cl, -OCH ₃ , -CN, and -C≡CR ₇ . In one embodiment of the present invention, R ₆₂ is C≡CR ₇ .

Specifically, the above R ₆₁ , R ₆₄ or R ₆₅ are independently selected from -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N(C _0-10 alkyl)(C _0-10 alkyl), C _3-10 cycloalkyl, -C≡CR ₇ , heterocyclic alkyl -O, heterocyclic alkyl -N, C _1-5 linear/branched alkyl containing O or N, or C _3-8 cycloalkyl, or C _3-8 heterocyclic alkyl containing -O- and -S-, formed by R ₆₄ , R ₆₅ and the carbon atoms bonded to R ₆₄ and R ₆₅ , wherein H on the C atom can be replaced by -F. More specifically, said R ₆₁ , R ₆₄ or R ₆₅ are independently selected from -H, halogen, C _1-3 linear/branched alkyl, -OC _0-3 alkyl, C _1-3 linear/branched alkyl containing N or between them, C _3-8 cycloalkyl or C _3-8 heterocyclic alkyl containing -O-, formed by R ₆₄ , R ₆₅ and the carbon atoms bonded to R ₆₄ and R ₆₅ , wherein H on the C atom can be replaced by -F. Moreover, in particular, said R ₆₁ , R ₆₄ or R ₆₅ are independently selected from -H, -F, -Cl, -CH ₃ , -CH ₂ NH ₂ , -CN, -OCH ₃ or -O-five-membered cycloalkyl formed by R ₆₄ , R ₆₅ and carbon atoms attached to R ₆₄ and R ₆₅ . In one embodiment of the present invention, said R ₆₁ , R ₆₄ and R ₆₅ are H.

Specifically, said R ₇ is selected from H, C _1-5 linear/branched alkyl, C _3-10 cycloalkyl and

In one embodiment of the present invention, said R ₆₂ is

Specifically, said R ₈ or R ₉ is independently selected from -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C(C _0-10 alkyl)(C _0-10 alkyl), -C≡C(C _0-10 alkyl), C _3-10 cycloalkyl, a five-membered or six-membered aromatic heterocyclic group, C _3-8 cycloalkyl or C _3-8 heterocyclic alkyl containing -O- and -S- which are formed by R ₈ and R ₉ as well as the carbon atom therebetween, C _4-9 fused cycloalkyl, C _5-10 spirocycloalkyl, C _4-9 bridged cycloalkyl, C _3-7 lactam, C cyclolactones _3-7 or _C3-7 cycloketone, where the H on the C atom can be replaced by the following groups: _-SO2 , _-SO2N ( _C0-10 alkyl)( _C0-10 alkyl), -N( _C0-10 alkyl) _SO2 ( _C0-10 alkyl), -CON( _C0-10 alkyl)(C0-10 alkyl), -N( _{C0-10 alkyl} )CO( _C0-10 alkyl), _-N (C0-10 alkyl)COO( _C0-10 alkyl), _-OCON ( _C0-10 alkyl)( _C0-10 alkyl), halogen, -CN, _-OCH2F , _-OCHF2 , _-OCF3 , straight/branched _C1-10 alkyl, -N(C _0-10 )(C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, heterocyclic alkyl -O, heterocyclic alkyl -N, heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, wherein said alkyl moiety may be replaced by one or more of the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl)(C _0-10 alkyl), -N(C _0-10 alkyl)SO ₂ (C _{0-10 alkyl} ), -CON(C _0-10 alkyl)(C _0-10 alkyl), -N(C _0-10 alkyl)CO(C _0-10 alkyl), -N(C _0-10 alkyl)COO(C _0-10 alkyl), -OCON(C _0-10 )(alkyl C _0-10 ), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(alkyl C _0-10 )(alkyl C _0-10 ), alkyl -OC _0-10 , heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S;

More specifically, said R ₈ or R ₉ is independently selected from -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-10 linear/branched alkyl, -CH=C(C _0-10 alkyl)(C _0-10 alkyl), C _3-10 cycloalkyl, a six-membered aromatic heterocyclic group, C _3-8 cycloalkyl formed by R ₈ and R ₉ as well as the carbon atom between them, fused C _4-7 cycloalkyl, C _5-9 spirocycloalkyl, bridged C _4-9 cycloalkyl, C _3-7 lactam, C _3-7 cyclolactones or C _3-7 cycloketone, wherein H on the C atom can be replaced by the following groups: -SO ₂ , -SO ₂ N(alkyl C _0-10 )(C _{0-10 alkyl} ), -N(C _0-10 alkyl)SO ₂ (C 0-10 alkyl), -CON(C _{0-10 alkyl} )(C _0-10 alkyl), -N(C _0-10 alkyl)CO(C _{0-10 alkyl} ), -N(C _{0-10 alkyl} )COO(C _0-10 alkyl), -OCON(C _{0-10 alkyl} )(C _{0-10 alkyl} ), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , C _1-10 straight/branched alkyl, -N(C _0-10 alkyl)(C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, heterocyclic alkyl -O, heterocyclic alkyl -N, heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, wherein said alkyl moiety may be replaced by one or more of the following groups: -SO ₂ , -SO ₂ N(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )SO ₂ (alkyl C _0-10 ), -CON(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )CO(alkyl C _0-10 ), -N(alkyl C _0-10 )COO(alkyl C _0-10 ), -OCON(alkyl C _0-10 )(alkyl C _0-10 ), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(alkyl C _0-10 )(alkyl C _0-10 ), alkyl -OC _0-10 , heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S;

Moreover, in particular, the above-mentioned R ₈ or R ₉ is independently selected from -H, -CF ₃ , -CHF ₂ H, -CH ₂ F, C _1-5 linear/branched alkyl, -CH=CH(C _0-10 alkyl), C _3-10 cycloalkyl or a six-membered aromatic heterocyclic group formed by R ₈ and R ₉ as well as the carbon atom therebetween, C _3-6 fused cycloalkyl, C _4-6 fused cycloalkyl, C _5-8 spirocycloalkyl, C _4-8 bridged alkyl, C _3-7 lactam, C _3-7 cyclolactones or C _3-7 cycloketone, wherein the H on the C atom can be replaced by the following groups: -SO ₂ , -SO ₂ N(C _0-10 alkyl)(C alkyl _0-10 ), -N(alkyl C _0-10 )SO ₂ (alkyl C _0-10 ), -CON(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )CO(alkyl C _0-10 ), -N(alkyl C _0-10 )COO(alkyl C _0-10 ), -OCON(alkyl C _0-10 )(alkyl C _0-10 ), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , straight/branched C _1-10 alkyl, -N(alkyl C _0-10 )(alkyl C _0-10 ), alkyl -OC _0-10 , cycloalkyl C _3-10 , heterocyclic alkyl -O, heterocyclic alkyl -N, heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S, wherein said alkyl moiety may be replaced by one or more of the following groups: -SO ₂ , -SO ₂ N(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl _{C 0-10} )SO ₂ (alkyl C _0-10 ), -CON(alkyl C _0-10 )(alkyl C _0-10 ), -N(alkyl C _0-10 )CO(alkyl C _0-10 ), -N(alkyl C _0-10 )COO(alkyl C _0-10 ), -OCON(alkyl C _0-10 )(alkyl C _0-10 ), halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -N(alkyl C _0-10 )(alkyl C _0-10 ), alkyl -OC _0-10 , heterocyclic aryl -N, heterocyclic aryl -O or heterocyclic aryl -S;

In one embodiment of the present invention, said R ₈ or R ₉ is independently selected from -H, -CF ₃ , -CHF ₂ ,

formed between R ₈ , R ₉ and the carbon atom between them.

In one embodiment of the present invention, the structures of the above connections are shown below:

Specifically, the above compounds of the present invention have the structure described below:

In one embodiment of the present invention, the structures of the above connections are shown below:

Pharmaceutically acceptable salts of the present invention include acid addition salts, base addition salts and hydroxybenzoic acid salts.

Specifically, the above-mentioned acid addition salts include, but are not limited to, salts of inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid and phosphonic acid, while salts of organic acids such as aliphatic monocarboxylic acid and dicarboxylic acid, phenyl-substituted alkanoic acid, hydroxydecanoic acid, alkanedioic acid, aromatic acid and aliphatic and aromatic sulfonic acid. Thus, salts include, but are not limited to, the following: sulfate, pyrosulfate, bisulfate, sulfite, hydrosulfite, nitrate, phosphate, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromate, iodate, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, dimandelate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate and methanesulfonate, while salts containing amino acids include arginine, gluconate, galacturonate, etc. The above salts obtained by adding an acid can be prepared by combining the base form with a sufficient amount of the desired acid in a conventional manner. The base form is regenerated by combining the salt form and the base, while the free alkali is separated in the traditional way.

Specifically, hydroxides such as alkali metals and alkaline earth metals are formed by combining the above-mentioned base addition salts with metals, amines and organic amines. Examples of metals used as cations specifically include sodium, potassium, magnesium and calcium. Examples of suitable amines specifically include N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1, 2-diamine), N-methylglucosamine and procaine. The above-mentioned base addition salts can be prepared by combining the free acid form with a sufficient amount of the desired base in a conventional manner. The free acid form is regenerated by combining the salt form and the acid, and the free acid is separated in a conventional manner.

Specifically, the above-mentioned stereoisomers of the present invention exist in the form of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention contain a cycloalkyl to be replaced on more than one carbon atom. In this case, all geometric forms of these compounds, including cis- and trans-forms, as well as mixtures thereof, are within the scope of the present invention.

Specifically, the above solvates of the present invention refer to physical combinations of the compounds of the present invention with one or more solvent molecules. Physical bonds include various degrees of ionic and covalent bonds, including hydrogen bonds. In some cases, the solvates can be separated, for example, by incorporating one or more solvent molecules into the lattice of a crystalline solid. The term "solvate" includes the solution phase and the separated solvate. Representative solvates include ethylates, methylates, etc. The term "hydrate" means a solvate in which one or more solvent molecules are H ₂ O.

Specifically, the above-mentioned pre-drugs of the present invention refer to forms of the compound of Formula I, including acetals, esters and zwitterions, which can be administered to patients without excessive toxicity, irritation, allergic reaction, etc., and are also effective for achieving the purposes of their use. The pre-drug is converted in a living organism (for example, by hydrolysis of blood) to obtain the parent compound of the above formula.

Specifically, the above-mentioned pathogen in the present invention may be a microorganism, a parasite (protozoan, worm, etc.) or other sources; Specifically, the microorganism may be selected from one or more viruses: chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.

In an embodiment of the present invention, the above-mentioned pathogen in this invention is a virus.

In particular, the above-mentioned virus may belong to herpesviruses (e.g. pseudorabies virus, infectious bovine rhinotracheitis virus, Marek virus, infectious avian laryngotracheitis virus, duck plague virus), iridoviruses (e.g. lymphocystis virus), baculoviruses (e.g. shrimp baculovirus), rhabdoviruses (e.g. rabies virus, spring carp virus viremia), reovirus (e.g. avian orthoreovirus, bluetongue virus, cytoplasmic polyhedrosis virus), biRNAviruses (e.g. infectious bursal disease virus), poxviruses (e.g. sheeppox virus, goatpox virus, myxoma virus), African swine fever viruses (e.g. African swine fever virus), adenoviruses (e.g. infectious canine hepatitis virus, egg descent syndrome virus), parvoviruses (e.g. porcine parvovirus, canine parvovirus, goose parvovirus, feline panleukopenia virus, mink enteritis virus, Aleutian mink virus), circoviruses (e.g. porcine circovirus), retroviruses (e.g. avian leukemia virus, caprine arthritis/encephalomyelitis virus, equine infectious anemia virus), orthomyxoviruses (e.g. avian influenza virus), paramyxoviruses (e.g. Newcastle disease virus, distemper virus, rinderpest virus), coronaviruses, arteriviruses (e.g. porcine reproductive and respiratory syndrome virus), microRNAviruses (e.g. foot-and-mouth disease virus, swine vesicular disease virus, duck hepatitis virus), caliciviruses (e.g. rabbit hemorrhagic disease virus), flaviviruses (e.g. swine fever virus, bovine viral diarrhea virus, Japanese encephalitis virus), prions, filoviruses (e.g. Marburg virus, Ebola virus), polyomaviruses, papillomaviruses, vispoviruses, retroviruses, hepadnaviruses, papovaviruses, bornaviruses, bunyaviruses, arenaviruses, roniviruses, hepeviruses, astroviruses, togaviruses, dicistroviruses, nodaviruses, etc.

In particular, the above-mentioned virus may be, for example, avian infectious bronchitis virus (IBV), porcine transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine hemagglutinating encephalomyelitis virus (HEV), murine hepatitis virus (MHV), turkey disease virus (TCDV), bovine coronavirus (BCV), canine coronavirus (CCV), feline infectious peritonitis virus (FIPV), rat coronavirus (RCV), rat sialodacryoadenitis coronavirus (SDAV), mink epidemic diarrhea coronavirus, sheeppox virus, goatpox virus, bovine lumpy skin disease virus, fowl pox virus, feline pox virus, infectious pustular virus, rabbit myxoma virus, African swine fever virus, pseudorabies virus, porcine cytomegalovirus, avian infectious laryngotracheitis virus, duck distemper virus, feline viral rhinotracheitis virus, canine herpes virus, infectious bovine 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 (feline distemper, feline infectious enteritis), goose plague virus, canine parvovirus, musk duck parvovirus, porcine circovirus, chicken infectious anemia virus, avian leukemia virus, feline leukemia virus, bovine leukemia virus, feline immunodeficiency virus, copper-visna disease virus, viral Caprine arthritis encephalitis, Equine infectious anemia virus, Bovine immunodeficiency virus, Feline syncytium virus (foam virus), Avian viral arthritis virus, Bluetongue virus, Ibaraki disease virus, Chuzan disease virus, African horse sickness virus, Rotavirus, Infectious bursal disease virus, Canine viral papillomavirus, Feline viral papillomavirus, Nipah virus, Hendra virus, Porcine blue eye virus, Canine parainfluenza virus, Avian paramyxovirus, Fowl Newcastle disease virus, Canine distemper virus, Peste des petits ruminants virus, Rinderpest virus, Avian pneumovirus, Mumps virus (measles virus), Feline paramyxovirus, Rabies virus, Vesicular stomatitis virus, RHF virus cattle/thirty-day fever/transient fever, Borna disease virus, influenza virus, Rift Valley fever virus, Akabane virus, hantavirus, feline enteric coronavirus, 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 vesicular ectanthema virus, feline calicivirus, rabbit viral hemorrhage virus, canine viral hepatitis E virus, Getah virus, Japanese encephalitis B virus/epidemic encephalitis virus, sylvatic encephalitis virus, duck flavivirus, swine fever virus, bovine diarrhea virus, sheep border disease virus, etc.

In an embodiment of the present invention, the above-mentioned virus is a coronavirus, specifically, for example, an infectious bronchitis virus of chickens (IBV), a transmissible gastroenteritis virus of pigs (TGEV), a porcine epidemic diarrhea virus (PEDV), a porcine hemagglutinating encephalomyelitis virus (HEV), a mouse hepatitis virus (MHV), a turkey disease virus (TCDV), a bovine coronavirus (BCV), a canine coronavirus (CCV), a feline infectious peritonitis virus (FIPV), a rat coronavirus (RCV), a rat sialodacryoadenitis coronavirus (SDAV), a mink epidemic diarrhea coronavirus, etc.

In an embodiment of the present invention, the above-mentioned virus is feline infectious peritonitis virus.

Unless otherwise specified, in the present invention, the "animals" described in this document do not belong to the human race, in particular are vertebrates, especially mammals (for example, pigs, cows, sheep, horses, donkeys, cats, rabbits, mice, foxes, raccoon dogs, minks, camels), aquarium fish, birds (for example, chickens, ducks, geese, pigeons, quails, parrots, etc.), amphibians and reptiles. In particular, the above-mentioned animals related to the present invention are domestic animals, i.e. animals raised and domesticated by humans, whose reproduction can be controlled by artificial methods, with respect to such functions as nutrition, work, fur, pets and experiments, for example, farm animals, laboratory animals, etc.

In an embodiment of the present invention, in the above-mentioned application, the animals are farm animals such as livestock (i.e. pigs, cattle, sheep, horses, donkeys, foxes, raccoon dogs, minks, camels, etc.) and birds (chickens, ducks, geese, pigeons, quails, etc.)

In an embodiment of the present invention, in the above-mentioned application, the animals are domestic animals such as dogs, cats, rabbits, mice (e.g. guinea pigs, hamsters, dwarf gerbils, chinchillas, squirrels, etc.), aquarium fish, pigeons and parrots.

In an embodiment of the present invention, in the above-mentioned application, the animals are experimental animals such as monkeys, dogs, rabbits, cats and mice.

Specifically, the above-mentioned disease or symptom may include infectious bronchitis of chickens, transmissible gastroenteritis of pigs, porcine epidemic diarrhea, canine coronavirus disease, porcine hemagglutinating encephalomyelitis, murine hepatitis virus hepatitis, encephalitis and enteritis, turkey coronavirus enteritis, neonatal calf diarrhea, bovine dysentery, feline infectious peritonitis, rat sialodacryoadenitis, mink epidemic diarrhea, sheep pox, goat pox, bovine lumpy skin disease, fowl pox, cat pox, infectious pustule, rabbit myxoma, African swine fever, pseudorabies, porcine cytomegalovirus infection, infectious laryngotracheitis of chickens, duck plague, feline viral rhinotracheitis, Canine herpesvirus infection, infectious bovine rhinotracheitis, infectious equine rhinopneumonitis, Marek's disease, malignant catarrhal fever, porcine adenovirus infection, canine viral hepatitis, feline adenovirus disease, porcine parvovirus disease, feline panleukopenia (feline distemper, feline infectious enteritis), goose plague, canine parvovirus disease, musk duck parvovirus disease, porcine circovirus disease, chicken infectious anemia, avian leukemia, feline leukemia, bovine leukemia, feline immunodeficiency disease, Medi-Visna disease, caprine viral arthritis, encephalitis, equine infectious anemia, bovine immunodeficiency virus infection, feline syncytium virus infection (foam virus), avian viral arthritis, bluetongue, Ibaraki disease, Chuzan disease, African horse sickness, rotavirus disease, infectious bursal disease, canine viral papillomavirus, feline viral papillomavirus, Nipah virus disease, Hendra disease, swine blue eye disease, canine parainfluenza infection, avian paramyxovirus infection, Newcastle disease, canine distemper, peste des petits ruminants, rinderpest, avian pneumovirus infection, avian mumps virus infection (measles virus infection), feline paramyxovirus disease, rabies, vesicular stomatitis, rinderpest/three-day fever/short-term fever, Borna disease, influenza, Rift Valley fever, Akabana disease, hantavirus disease, hemagglutinating encephalomyelitis pigs, porcine blood cell agglutinating 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 vesicular exanthem, feline calicivirus disease, rabbit viral hemorrhage, canine viral hepatitis E, Geta virus disease, Japanese encephalitis B/epidemic encephalitis, sylvatic encephalitis, duck flavivirus infection, swine fever, bovine viral diarrhea, border disease, etc.

In an embodiment of the present invention, the above-mentioned disease or symptom is selected from the following: infectious bronchitis of chickens, transmissible gastroenteritis of pigs, epidemic diarrhea of pigs, coronavirus disease of dogs, hemagglutinating encephalomyelitis of pigs, hepatitis, encephalitis and enteritis caused by mouse hepatitis viruses, coronavirus enteritis of turkeys, diarrhea of newborn calves, blood dysentery of cattle, infectious peritonitis of cats, sialodacryoadenitis of rats, epidemic diarrhea of minks.

In an embodiment of the present invention, the above-mentioned disease is feline infectious peritonitis.

Specifically, in the above preparations, the above-mentioned HPK1 kinase inhibitor may be the only active ingredient, or it may be used in combination with one or more active ingredient components for the same or different indications, wherein the above-mentioned HPK1 kinase inhibitor may be formulated together with other active ingredients for simultaneous, separate or sequential administration to a patient.

Specifically, any dosage or administration form of the above preparations may be used. Persons with relevant skills may perform the selection and application depending on the situation. The administration forms may be in particular the following: oral, sublingual, by inhalation, subcutaneous, intramuscular, intravenous, intraperitoneal, intra-organ, intranasal, intrarectal, intradermal, ophthalmic or rectal. The dosage forms may in particular be tablets, pills, powder, granules, capsules, lozenges, syrup, solutions, emulsions, suspensions, controlled-release preparations, aerosols, films, injections, preparations for intravenous administration via a dropper, preparations for transdermal absorption, ointments, lotions, adhesive preparations, suppositories, preparations for the nose, preparations for the lungs, eye drops, etc.

In one embodiment of the present invention, the above-mentioned medicinal product is an injectable one.

The present invention also provides for the use of the above-mentioned HPK1 kinase inhibitor in the preparation of agents for combating pathogenic infections of animals.

Specifically, the HPK1 kinase inhibitor, pathogens and animals in the above-mentioned methods of use in the present invention have corresponding definitions.

In a certain way, the above mentioned drug can be used for therapeutic purpose as well as for non-therapeutic purpose.

In an embodiment of the present invention, the above-mentioned preparation is a medicinal preparation.

Specifically, in the above-mentioned combinations of medicinal products, the above-mentioned HPK1 kinase inhibitor may be the only active component, or it may be used in combination with one or more active constituent components for the same or different indications, wherein the above-mentioned HPK1 kinase inhibitor may be formulated together with other active constituents for simultaneous, separate or sequential administration to a patient.

In a certain way, the above-mentioned medicinal product additionally includes permissible accessories, which are acceptable, in particular, in the veterinary field.

Specifically, the above-mentioned medicinal product may have any dosage or administration form, the selection of which can be made by skilled professionals depending on the situation, for example, the administration form, in particular but not limited to, may be oral, sublingual, by inhalation, subcutaneous, intramuscular, intravenous, intraperitoneal, intraorgan, intranasal, rectal, intradermal, or ophthalmic, the dosage form, in particular but not limited to, may be tablets, pills, powder, granules, capsules, lozenges, syrup, solution, emulsion, suspension, controlled-release preparation, aerosol, films, injections, droppers, transdermal absorption preparation, ointment, lotion, binder, suppository, preparation for nasal administration, inhalation preparation, eye drops, etc.

In an embodiment of the present invention, the above-mentioned medicinal product is an injection.

Various forms of the above-mentioned medicinal product can be prepared according to traditional production methods in the field of veterinary medicine.

In an embodiment of the present invention, the above-mentioned preparation is a functional feed composition.

Specifically, the above-mentioned functional feed composition, the composition according to formula I, can be used as a unique active ingredient or can be used with another active ingredient, or more.

In a certain way, the above-mentioned functional composition of feed may also include accessories for animal feed.

Specifically, the above-mentioned functional feed composition may be in any form such as tablets, pills, capsules, candies (such as tablet candies, gel candies, gum-based candies, etc.), solid drinks (such as powders, granules, etc.) and liquid drinks.

It is possible to prepare various forms of the above-mentioned feed medicinal product in accordance with traditional production methods in the field of functional veterinary feed production.

In an embodiment of the present invention, the above-mentioned preparation is an additive, a negligible amount of which can be added during the production, processing and use of animal feed (for example, feed for cattle and poultry, diets for pets, treats for pets, etc.).

The present invention also provides a method for the prevention and/or treatment of a disease or symptoms caused by or associated with a pathogenic infection in animals, which comprises the steps required to administer to patients an effective amount of the HPK1 kinase inhibitor of the present invention.

Specifically, the HPK1 kinase inhibitor, pathogens, animals, disease or symptom according to the above-mentioned method in the present invention have corresponding definitions.

The inventor of the present invention has experimentally found that an HPK1 kinase inhibitor (especially a compound of Formula I of the present invention, such as 4-(3-{2-amino-5-[2-(1-methylpiperidin-4-yl)thiazol-5-yl]pyridine-3-oxymethyl}-phenyl)-2-methylbutyl-3-alkyne-2-alcohol) can be effectively used in the treatment of diseases (such as feline infectious peritonitis) caused by infection with animal pathogens (especially viruses, such as coronavirus), increasing the survival rate of animals, and also has better prospects for commercial value and application in the field of veterinary antipathogenic drugs (for example, drugs against viruses, such as coronavirus).

Brief description of graphic materials

Fig. 1 shows an X-ray image of a sick cat in Example 1 of the present invention.

Fig. 2 shows a clinical survival graph in Example 2 of the present invention, where the day of drug administration is used as the first day.

Detailed description of the invention

Unless otherwise defined, all scientific and technical terms used in this invention have the meaning assigned to them by those skilled in the art to which this invention pertains.

In the present invention, the term "alkyl" refers to a straight or branched chain hydrocarbon radical containing no unsaturated bonds and attached to the rest of the molecule by a single bond. Alkyl is subject to substitution. For example, if alkyl is replaced by cycloalkyl, it changes to "cycloalkyl alkyl", such as cyclopropylmethyl. If alkyl is replaced by halogen, the name changes to "haloalkyl". If alkyl is replaced by aryl, the name changes to "aralkyl", such as benzyl, benzhydryl or phenethyl. If alkyl is replaced by heteroalkyl, the name changes to "heterocyclic alkyl". If alkyl is substituted by heterocyclyl, the name is replaced by "heterocyclylalkyl", etc. Alkyl C _0-10 in the present invention refers to alkyl containing 0-10 (e.g. 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-amyl, isopentyl, neopentyl, tert-amyl, n-hexyl and isohexyl. Alkyl C ₀ refers to H.

The term "cycloalkyl" refers to an alicyclic hydrocarbon, including alicyclic hydrogen, containing from 1 to 4 monocyclic rings and/or fused rings, 3-18 hydrocarbon atoms and, desirably, 3-10 hydrocarbon atoms, such as cyclopropyl, cyclohexyl or adamantyl. Cycloalkyl _C3-10 in the present invention refers to cycloalkyl containing 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

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

The term "heterocyclyl" includes a heteroaromatic group and a heteroalicyclic group containing 1-3 monocyclic rings or fused rings and 3-18 (particularly 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) ring atoms. Preferred heteroaromatic group and heteroalicyclic group contain from 5 to about 10 ring atoms. A suitable heteroaryl in a compound of the present invention contains 1, 2 or 3 heteroatoms, which can be selected from N, O or S atoms.

In the present invention, the above group can be replaced by one or more suitable groups at one or more available positions, for example, in particular: OR', =O, SR', SOR', SO ₂ R', OSO ₂ R', OSO ₃ R', NO ₂ , NHR', N(R') ₂ , =N-R', N(R')COR', N(COR') ₂ , N(R')SO ₂ R', N(R')C(=NR')N(R')R', N ₃ , CN, halogen, COR', COOR', OCOR', OCOOR', OCONHR', OCON(R') ₂ , CONHR', CON(R') ₂ , CON(R')OR', CON(R')SO ₂ R', PO(OR') ₂ , PO(OR')R', PO(OR')(N(R')R'), _C1 - _C12 alkyl, _C3 - _C10 cycloalkyl, _C2 - _C12 alkenyl, _C2 - _C12 alkynyl, aryl and heterocyclyl. Each R' is independently selected from the following: hydrogen, OH, _NO2 , _NH2 , SH, CN, halogen, COH, alkyl CO, COOH, _C1 - _C12 alkyl, _C3 - _C10 cycloalkyl, _C2 - _C12 alkenyl, _C2 - _C12 alkynyl, aryl and heterocyclyl. This group is replaceable, and the elements to be replaced can be selected from the above list.

The terms "halogen", "halogenation" or "halo" refer to the prefixes bromo-, chloro-, iodo- or fluoro.

The term "treatment" includes eradication, removal, alleviation, modification, or control of a disease or symptom when it occurs.

The term "prevention" refers to the ability to avoid, minimize, or delay the onset or progression of a disease or symptom by treating before the disease or symptom occurs.

The term "pathogen" refers to microorganisms (including viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.), parasites (protozoa, worms, etc.) or other carriers of infection that can cause diseases in humans, animals and plants. For example, bacteria can be: gram-positive cocci, enterobacteria, vibrios, pasteurella, gram-negative aerobasils, gram-negative microaerophilic and anaerobic bacteria, gram-positive non-spore-forming rod-shaped bacteria, gram-negative spore-forming rod-shaped bacteria, mycobacteria, etc.; and fungi may be, for example, Candida, Cryptococcus, Aspergillus, etc. In the present invention, the term "pathogens" generally means microorganisms, parasites and other infectious agents capable of causing diseases in animals. In an embodiment of the present invention, the pathogen is a virus.

The term "viral infection" refers to the process in which the virus enters the body through many routes and proliferates in the susceptible cells of the host. After the virus infects the body, various clinical manifestations may occur. Depending on the presence or absence of symptoms, the infection can be divided into apparant and inapparant infection. Due to the small number of viruses that enter the body, weak virulence or strong resistance of the body, the viruses proliferate in the cells, but the body does not show obvious clinical symptoms, this is called "inapparent infection". Although the "dormant infection" has no clinical symptoms, the viruses continue to proliferate in the body and spread outward, becoming an important source of infection, so the carrier of the inapparent infection needs to resist the viral infection. Due to the large number of viruses that have entered the body, strong virulence or weak resistance of the body, the viruses proliferate strongly in the cells of the host, and obvious clinical symptoms appear in the body, this is called "hardware infection".

Unless otherwise stated, in the present invention, the "animals" described in this document are not of the human race, in particular are vertebrates, in particular mammals (e.g. pigs, cows, sheep, horses, donkeys, cats, rabbits, mice, foxes, raccoon dogs, minks, camels), aquarium fish, birds (e.g. chickens, ducks, geese, pigeons, quails, parrots, etc.), amphibians and reptiles. In particular, the above-mentioned animals related to the present invention are domestic animals, i.e. animals raised and domesticated by humans, whose reproduction can be controlled by artificial methods, with respect to such functions as food, work, fur, pets and experiments, for example, farm animals, laboratory animals, etc. The term "farm animals" refers to animals raised by humans for meat, milk, fur, use in work or for other economic purposes, for example, cattle and poultry; The term "cattle" refers to domestic animals that are raised by humans for reproduction and use in agricultural production; The term "poultry" refers to birds that are raised by humans in captivity, mainly for meat, eggs and feathers, but also for other purposes; The term "pets" refers to animals that are kept for hobbies (e.g., pleasure and companionship) rather than for economic purposes, and the term "experimental animals" refers to animals kept for use in scientific research.

The technical solution in the present invention will be clearly and completely described below with reference to the embodiment examples of the present invention, it is obvious that the described embodiment examples are only some embodiments of the present invention, but not all embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by persons having ordinary skills in this specialized field and without making any creative efforts are included in the scope of protection of the present invention.

Implementation option 1

1. Method of conducting the experiment

An eight-month-old female British Shorthair cat (named Lele), not spayed, weighing 2.5 kg. In January 2020, the cat developed symptoms of fever, depression, loss of appetite, increased abdominal circumference, etc. One week later, the cat was admitted to the hospital for consultation, on January 18, the cat was diagnosed with positive feline infectious peritonitis (FIP), after three days of treatment with GS-441524, furosemide, sonolone, prednisolone and itraconazole (orally, q 24 h, 10 mg / kg) were prescribed, the drugs were taken for 1 month, and after the disappearance of ascites, the administration was stopped. In early April, the disease relapsed, resulting in symptoms of decreased appetite and lethargy, pleural effusion was found in the X-ray, and the PCR test for feline coronavirus was positive (CT value 25.11). On April 8, day 1-14 (D1-14), the cat was administered the drug of the present invention at 2.0 mg/kg, SC q 24 h. At the same time, appropriate supportive treatment and additional treatment were carried out, and Moringa (a liver protective drug), Fenzilai (lysine), and Kangjianling (lactoferrin) were administered.

2. Preparation and use of the medicine

The above-mentioned pharmaceutically active composition according to the present invention has the following structure and is a pure powder, 0.9% sodium chloride solution (50 ml of endotoxin-free water was added 0.45 g of NaCl), followed by thorough mixing and filtration through a membrane until the solution was transparent. The dissolved preparation was stored in the form of a sterile penicillin bottle with a plastic cap in a refrigerator at a temperature of 4 ° C, before the administration of the preparation by means of a disposable syringe, the preparation was warmed up to room temperature. The injection site was on the back, starting from a point 2 cm behind the scapula to the middle of the lumbar spine at half the distance from the chest and sides.

3. Experimental results

After drug administration, temperature was measured every morning, appetite, mental state and respiratory status were assessed, urination and defecation data were recorded at 15:00, the results are shown in Table 1.

Table 1 Experimental results

Number Time Body temperature
Before noon Body temperature
Afternoon Mental state State of food intake Breathing condition Defecation Note D0 4-8 38.5 Discomfort -3 points Eats less -3 points Norm -5 points Norm -5 points At the time of registration, body weight was 2.5 kg. D1 4-9 38.6 Minor improvement -3.5 points Eats less -3 points Normal Normal D2 4-10 38.1 Improvement -4 points Improvement -4 points Normal Normal D3 4-11 38 Good -5 points Good -5 points Normal Normal D4 4-12 38.3 Fine Fine Normal Normal D5 4-13 38.3 Fine Fine Normal Normal D6 4-14 38.3 Fine Fine Normal Normal D7 4-15 38.1 Fine Fine Normal Normal Body weight 2.75 kg D8 4-16 38 Fine Fine Normal Normal D9 4-17 38.2 Fine Fine Normal Normal D10 4-18 38.3 Fine Fine Normal Normal D11 4-19 38.4 Fine Fine Normal Normal D12 4-20 38.5 Fine Fine Normal Normal D13 4-21 38.9 38.5 Fine Fine Normal Normal D14 4-22 38.4 38.4 Fine Fine Normal Normal Body weight 2.75 kg

After registration in D0, D7 and D14 the following operations were performed:

One milliliter of serum sample was stored frozen for multifactorial testing, the results are shown in Table 2.

Table 2 Results of a routine blood test

Routine blood test Normal range D0 D7 D14 WBC White blood cells 5.5~19.5 13.5 18.7 19.7 RBC Red blood cells 5.0~10.0 10.5 7.94 7.94 HGB Hemoglobin 80~150 117 94 91 HCT Hematocrit 24.0~45.0 37.5 28.9 29.9 MCV Mean hematocrit value 39.0~55.0 35.9 36.4 37.7 MCH Mean corpuscular hemoglobin 12.5~17.5 11.2 11.8 11.5

3) Chest X-ray

As shown in Fig. 1.

4) Analysis of results

According to the above results, this case was tested for feline infectious peritonitis wet (chest), the clinical symptoms showed pleural effusion, lethargy and loss of appetite, indicating typical intra-abdominal symptoms of cats.

Since the patient was asymptomatic at presentation, no fever-reducing effect was observed during drug administration, and body temperature was maintained in the normal range of 38°C to 38.5°C throughout the treatment. The cat's clinical response after two weeks of treatment was dramatic, with improved appetite, mental status, and weight gain. Approximately seven days after treatment, the thoracic effusion had completely resolved. Body weight increased by 9% during and after treatment.

Design 2

A total of 15 cats with clinically diagnosed FIP were admitted, the cats showed thoracic/ascites reaction, had a positive CT value determined by PCR, no neurological signs, this number of animals was divided into eight cats in the control group and seven cats in the experimental group.

In each group, the drug GS-441524 was first administered for three days, then the drug D1-D14 was administered in the control group, necessary supportive treatment was administered, group A was observed for three days after administration of the drug D1-D14, necessary supportive treatment was administered, and the drug of the present invention was administered in an amount of 2.0 mg/kg, SC q 24 h.

Cases of death or neurological symptoms were defined as clinical death, and the clinical survival curve was calculated after 14 days, the results are shown in Fig. 2. The log-rank (Mantel-Cox) and Breslow (generalized Wilcoxon test) methods were used to test the accuracy of the readings, and the results obtained based on these two methods were significantly different (P<0.05).

The above is a preferred embodiment of the present invention, but it is not intended to limit the present invention, any changes and equivalent substitutions made in the spirit and according to the principles of the present invention are to be included within the scope of protection of the present invention.

The above embodiments and methods described in the present invention may vary depending on the capabilities, experience and preferences of specialists skilled in the art.

The steps and methods are presented in a specific order only in the present invention, which does not constitute any limitation on the order of the steps of this method.

Claims (21)

1. Use of an HPK1 kinase inhibitor for the production of a medicinal product for the prevention and/or treatment of a disease or condition caused by or associated with a pathogenic infection in an animal; wherein the HPK1 kinase inhibitor is a small molecule inhibitor; wherein the small molecule HPK1 kinase inhibitor is a compound of the general formula below or a pharmaceutically acceptable salt thereof: where R ₁₀ is -H; R ₁₁ is -N heterocyclic alkyl containing one monocyclic ring and 5-7 ring atoms, wherein the H on the heteroatom may be substituted by a straight C _1-3 alkyl; R ₁ is -NH ₂ ; R ₄ and R ₅ represent -H; R ₆₁ , R ₆₂ , R ₆₃ , R ₆₄ and R ₆₅ represent -H; R ₆₂ is C≡CR ₇ ; R ₇ is , where R ₈ and R ₉ are -CH ₃ ; and The pathogen is a coronavirus. 2. The use according to item 1, where R ₁₁ is selected from: , And . 3. The use according to item 1, where the compound is selected from: 4. The use according to paragraph 1, wherein the coronavirus is selected from the chicken infectious bronchitis virus, porcine transmissible gastroenteritis virus, porcine epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis virus, mouse hepatitis virus, turkey disease virus, bovine coronavirus, canine coronavirus, feline infectious peritonitis virus, rat coronavirus, rat sialodacryoadenitis coronavirus, and mink epidemic diarrhea coronavirus. 5. The use according to claim 1, wherein the virus is feline infectious peritonitis virus. 6. Use according to paragraph 1, where the animal is a domestic animal. 7. Use according to paragraph 1, where the animal is a farm animal, a pet or an experimental animal. 8. The use according to claim 1, wherein the disease or condition is selected from avian infectious bronchitis, porcine transmissible gastroenteritis, porcine epidemic diarrhea, canine coronavirus, porcine hemagglutinating encephalomyelitis, hepatitis, encephalitis and enteritis caused by mouse hepatitis virus, turkey disease, neonatal calf diarrhea, bovine blood dysentery, feline infectious peritonitis, rat sialodacryoadenitis and mink epidemic diarrhea. 9. The use according to claim 1, wherein the disease or condition is feline infectious peritonitis.