A compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and uses thereof

Abstract

The present invention relates to the field of medical technology, and specifically discloses a compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition thereof, as well as use of the compound or pharmaceutical composition in antiviral treatment, such as coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus and Filoviridae virus, in particular feline coronavirus.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more particularly to a compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and use thereof. Background Art

[0002] Feline coronavirus (FCoV) is widespread in cats, with an estimated 40-80% of cats worldwide carrying the virus. In nature, FCoV exists as two distinct biotypes: feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV). The latter is a mutated form of the former. The mechanism of this transformation is still unclear, but it is associated with the feline immune response, genetic variation of the virus, and environmental factors. While most cats infected with FECV are asymptomatic, FIPV infection can easily invade other organs and develop into feline infectious peritonitis (FIP).

[0003] FIP is divided into dry (non-exudative) and wet (exudative) forms. Wet FIP is characterized by a large accumulation of fluid in the abdominal or thoracic cavity, leading to significant abdominal distension or difficulty breathing; while dry FIP presents with more localized lesions, such as inflammation of the eyes, nervous system, and internal organs. Symptoms vary and may include weight loss, loss of appetite, fever, etc.

[0004] Incidence: ① The incidence of FIP in cats infected with feline coronavirus is approximately 7.8-12%; ② In single-cat households, the infection rate of feline coronavirus is as high as 50%, while in multi-cat environments, this proportion can rise to 80-90%; ③ In summary, the overall incidence of FIP in single cats is approximately 3.9-6%, and the overall incidence of FIP in multi-cat environments is approximately 6.6-10.2%

[0005] This disease is common in young cats aged 3-9 months, especially in cats that are kept in groups. The course of the disease may be sudden (more common in kittens) or slow and last for several weeks. The mortality rate of this disease is as high as 95%, and there are certain difficulties in early diagnosis. It is generally believed that only histopathological examination can provide 100% diagnosis. In terms of treatment, there is currently no specific drug for FIP. Once the infection is discovered, supportive therapy is usually adopted: forced feeding (through esophageal or gastric tube), infusion to correct dehydration, thoracocentesis to relieve respiratory symptoms, etc. Immunosuppressive and anti-inflammatory drugs are also often used, such as high-dose steroids, cytotoxic drugs, etc.

[0006] In recent years, the development of antiviral drugs has brought new hope for the treatment of FIP. GS-441524, developed by Gilead Sciences, has been shown to significantly inhibit the FIP virus (WO2018169946). Clinical studies have shown that GS-441524 has excellent clinical control effects on both wet and dry forms of FIP. Cats treated with GS-441524 have shown significant improvement in symptoms and a significantly increased survival rate.

[0007] However, due to its short half-life and low bioavailability, GS-441524 requires a long treatment cycle of approximately three months for FIP, resulting in high total costs. Currently, there are no approved original drug products for this drug in China. Summary of the Invention

[0008] In order to solve the above technical problems, the present invention provides an active ingredient that can effectively inhibit viral replication and has a long half-life, and its use in antiviral treatment, such as coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus and Filoviridae virus, in particular feline coronavirus.

[0009] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:

[0010]

[0011] in,

[0012] R 1 Selected from H, -C(=O)R 5 ,-C(=O)OR 5 or optionally one or more R 6 Substituted C1-C8 alkyl; preferably, R 1 is n-pentyloxycarbonyl;

[0013] R 2 Selected from H, -C(=O)R 6 、-C(=O)OR 6 、-C(=O)NR 6 R 7 、-C(=O)SR 6 、-S(O)R 6 、

[0014] -S(O)R 6 、-S(O)(OR 6 )、-S(O)2(OR 6 ),-SONR 6 R 7 or

[0015] Y is O or S;

[0016] W 1 and W 2 Each independently selected from the group of formula Ia:

[0017]

[0018] in:

[0019] Each X is independently selected from O, OR 5 NR 5 、N(O)(R 5 )、N(OR 5 )、N(O)(OR 5 ), N-NR 5 , SS, S(O) or S(O)2; preferably, R 2 is H;

[0020] R 3 and R 4 Each independently selected from H, OR 5 、N(R 5 )2、N3、CN、NO2、S(O) n R 5 , halogen, C1-C8 alkyl, C4-C8 carbocyclylalkyl, C1-C8 substituted alkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl, C2-C8 substituted alkynyl, or arylC1-C8 alkyl; or R 3 and R 4 forming a C4-C16 carbocycle, a C4-C16 unsaturated carbocycle, a C4-C16 carbon-oxygen heterocycle, a C4-C16 carbon-nitrogen heterocycle, or a C4-C16 carbon-sulfur heterocycle;

[0021] Each n is independently 0, 1, or 2;

[0022] R 5 selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl C1-C8 alkyl, C4-C8 carbocyclylalkyl, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 ,-C(=O)SR 6 ,-SC(=O)R 6 , -S(O)R 6 , -S(O)R 6 ,-S(O)(OR 6 ), -S(O)2(OR 6) or -SONR 6 R 7 ;

[0023] R 6 and R 7 Each independently selected from -CN, -OH, -OR 5 、-NR 5 R 5 , halogen, alkyl, cycloalkyl or heterocycloalkyl;

[0024] The above R 1 、R 2 、R 3 and R 4 Not H at the same time.

[0025] Preferably, the compound is one or more combinations of compounds represented by Formula II to Formula VI:

[0026]

[0027] in,

[0028] R 1 Selected from H, -C(=O)R 5 ,-C(=O)OR 5 or optionally one or more R 6 Substituted C1-C8 alkyl; preferably, R 1 is n-pentyloxycarbonyl;

[0029] R 2 Selected from H, -C(=O)R 6 、-C(=O)OR 6 、-C(=O)NR 6 R 7 、-C(=O)SR 6 、-S(O)R 6 、

[0030] -S(O)R 6 、-S(O)(OR 6 )、-S(O)2(OR 6 ),-SONR 6 R 7 or

[0031] Y is O or S;

[0032] W 1 and W 2 Each independently selected from the group of formula Ia:

[0033]

[0034] in:

[0035] Each X is independently selected from O, OR 5 NR 5 、N(O)(R 5 )、N(OR 5 )、N(O)(OR 5 ), N-NR 5 , SS, S(O) or S(O)2; preferably, R 2 is H;

[0036] R 5 selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl C1-C8 alkyl, C4-C8 carbocyclylalkyl, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 ,-C(=O)SR 6 ,-SC(=O)R 6 , -S(O)R 6 , -S(O)R 6 ,-S(O)(OR 6 ), -S(O)2(OR 6 ) or -SONR 6 R 7 ;

[0037] R 6 and R 7 Each independently selected from -CN, -OH, -OR 5 、-NR 5 R 5 , halogen, alkyl, cycloalkyl or heterocycloalkyl;

[0038] The above R 1 、R 2 Not H at the same time.

[0039] Preferably, the compound is one or more combinations of Compound C1 to Compound C35:

[0040]

[0041]

[0042] On the other hand, the present invention also provides a pharmaceutical composition comprising any of the above compounds or pharmaceutically acceptable salts or hydrates or solvates or prodrugs thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0043] Furthermore, the pharmaceutically acceptable excipients include at least one of a binder, a filler, a disintegrant, a lubricant and a glidant.

[0044] Furthermore, the pharmaceutically acceptable carrier includes at least one of a cream, an emulsion, a gel, a liposome and a nanoparticle.

[0045] On the other hand, the compounds provided by the present invention, or their pharmaceutically acceptable salts, or their hydrates, or their solvates, or their prodrugs, or any of the pharmaceutical compositions described above, can be used in the preparation of oral or injectable drugs for preventing, inhibiting and treating diseases caused by viral infections.

[0046] Furthermore, the virus is a coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus and Filoviridae virus that infect mammals.

[0047] Furthermore, the coronavirus includes feline enteric coronavirus (FECV), feline infectious peritonitis virus (FIPV) or porcine epidemic diarrhea virus (PEDV).

[0048] Furthermore, the disease caused by the viral infection is feline enteritis caused by feline enteric coronavirus (FECV) infection, feline infectious peritonitis caused by feline infectious peritonitis virus (FIPV) infection, or porcine epidemic diarrhea caused by porcine epidemic diarrhea virus (PEDV) infection.

[0049] Furthermore, the compound or its pharmaceutically acceptable salt or hydrate or solvate or its prodrug or pharmaceutical composition is suitable for oral administration or injection administration.

[0050] Furthermore, the subject for oral administration or injection administration is a mammal, including a cat, a pig, a mouse or a dog, preferably a cat.

[0051] The compounds, or pharmaceutically acceptable salts, or hydrates, or solvates, or prodrugs, or pharmaceutical compositions provided herein, upon administration to a mammal, exhibit at least one of the following advantages: good oral or injectable bioavailability and a long half-life. In view of these characteristics, the compounds, or pharmaceutically acceptable salts, or hydrates, or solvates, or prodrugs, or pharmaceutical compositions provided herein can also be used to prepare oral or injectable medications for preventing, inhibiting, and treating diseases caused by viral infections. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The effect of the test substance / control drug on FIPV-infected CRFK cells.

[0053] Figure 2 This is the effect of GS-441524 on FIPV-infected CRFK cells.

[0054] Figure 3 The effect of compound C1 on FIPV-infected CRFK cells.

[0055] Figure 4 This is the effect of compound C2 on FIPV-infected CRFK cells.

[0056] Figure 5 This is the effect of compound C3 on FIPV-infected CRFK cells.

[0057] Figure 6 This is the effect of compound C4 on FIPV-infected CRFK cells.

[0058] Figure 7 This is the effect of compound C5 on FIPV-infected CRFK cells. DETAILED DESCRIPTION

[0059] In order to provide a clear and consistent understanding of the terms used in the specification of the present invention, some definitions are provided below. In addition, unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0060] As used herein, unless otherwise indicated, the term "treat," ...

[0061] The term "pharmaceutically acceptable" as used herein means that the drugs, medicines, inert ingredients, etc. described by the term are suitable for use in contact with the tissues of animals without undue toxicity, incompatibility, instability, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio.

[0062] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable compound. The desired salt of the compound retains or improves the biological activity and properties of the parent compound as defined herein and is biologically desirable. Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with a stoichiometric amount of a base or acid in water or an organic solvent, or a mixture of the two. In addition, the term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing a cationic group covalently bonded to an anionic group, i.e., "inner salts."

[0063] As used herein, the term "prodrug" or its equivalent refers to an agent that is generally pharmaceutically inactive but can be directly or indirectly converted into an active form in vitro or in vivo. Prodrugs can be used to alter the biodistribution or pharmacokinetics of a particular drug. Compounds are modified using various groups such as esters, ethers, phosphates / salts, etc. to form prodrugs. When the prodrug is applied to a subject, the group cleaves enzymatically or non-enzymatically, by reduction, oxidation, or hydrolysis, or otherwise releases the active compound. As used herein, "prodrugs" include pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates, or pharmaceutically acceptable solvates.

[0064] The term "prevention" as used in the present invention refers to starting an action in some way (e.g., before the onset of a disease, disorder, condition, or its symptoms) to temporarily or permanently prevent, inhibit, suppress, or reduce the risk of a subject suffering from a disease, disorder, or condition, etc. (as determined by, for example, the lack of clinical symptoms) or to delay its onset in the case of a subject susceptible to a specific disease, disorder, or condition. In some cases, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting its development into a harmful or otherwise undesirable state. Specifically, the term "prevention" as used in the present invention is used to refer to the administration of a compound or composition according to the present invention to prevent the occurrence of related diseases caused by viral infection. The term "prevention" also encompasses preventing at least one viral infection by administering to patients susceptible to viral infection or patients at risk of viral infection, according to the administration of a compound or composition of the present invention.

[0065] The term "treat" refers to taking action, after a disease, disorder or condition or its symptoms have been diagnosed, observed, to temporarily or permanently eliminate, alleviate, suppress, slow down or improve at least one potential cause of the disease, disorder or condition afflicting the subject, or the symptoms associated with the disease, disorder or condition afflicting the subject. Thus, treatment includes inhibiting (e.g., preventing or alleviating the development or further development of) an active disease. Specifically, the term "treat" as used in the present invention is used to specifically refer to administering a therapeutic comprising a compound or composition according to the present invention to a patient already suffering from an infection. The term "treat" also relates to administering a compound or composition according to the present invention, optionally together with one or more antibacterial agents, to alleviate or alleviate one or more symptoms associated with a viral infection; or to slow the development of a viral infection or one or more symptoms associated with a viral infection; or to reduce the severity of one or more symptoms associated with a viral infection; or to suppress the clinical manifestations of a viral infection; or to suppress the manifestation of adverse symptoms of a viral infection.

[0066] The term "feline coronavirus" refers to feline coronavirus (FCoV), the causative agent of feline infectious peritonitis (FIP), a fatal disease in domestic and wild cats. The FCoV virus has four main structural proteins: spike protein (S), membrane protein (M), small envelope protein (E), and nucleocapsid protein (N). The S protein is a glycoprotein arranged on the protrusions of the envelope, with a molecular weight of approximately 180 to 200 kDa. It is important for inducing host antibody responses and cellular immunity. Coronaviruses can bind to specific cell receptors through the S protein, which is a key factor in determining the pathogenicity and tissue tropism of the virus. The S protein is a protective antigen that induces the body to produce neutralizing antibodies, and current vaccine research is also focused on the S protein region.

[0067] FCoV is divided into two serotypes: type I and type II, based on differences in the amino acid sequence of the S protein and antibody cross-neutralization. Serotype I is the predominant type of strain, and its S protein is entirely derived from FCoV. Serotype II FCoV is clinically uncommon and is derived from dual recombination between canine coronavirus (CCoV) and FCoV. FCoV-I is widely prevalent worldwide, with infection rates as high as 80-95% in the United States and some European countries. In Asia, FCoV-II is predominant, with infection rates as high as 25%. Both serotypes I and II FCoV strains exist in two antigenically and morphologically distinct biotypes (or pathotypes): feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV).

[0068] The compounds and compositions provided by the present invention can be administered to a subject in any appropriate manner known in the art. Suitable routes of administration include, but are not limited to, oral; parenteral, such as intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisternal, intraarticular, intracerebral (intracerebral parenchyma and intracerebral ventricle); nasal; vaginal; sublingual; intraocular; rectal; topical (e.g., transdermal); oral and inhalation. Deposit injections, typically administered subcutaneously or intramuscularly, can also be used to release the compounds or compositions disclosed herein within a limited time period.

[0069] In some embodiments, the compounds or pharmaceutical compositions provided herein are in forms suitable for oral administration, such as tablets, capsules, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. The compounds or pharmaceutical compositions for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavorings, colorants, and preservatives to provide pharmaceutically acceptable formulations. Tablets, capsules, and the like typically contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable carrier or excipient suitable for the manufacture of tablets. These carriers or excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0070] In some embodiments, the compounds or pharmaceutical compositions provided herein are in a form suitable for injection. For example, a sterile injectable aqueous or oily suspension can be prepared using a suitable dispersant or wetting agent mixed with a suspending agent according to techniques known in the art. Alternatively, the suspension can be a sterile injectable solution in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, or isotonic sodium chloride solution. Additionally, sterile oils can be used as solvents or suspending media, including synthetic mono- and diglycerides.

[0071] In some embodiments, the compound or pharmaceutical composition provided by the invention is combined with a carrier material to produce a single dosage form for an amount to be administered that varies according to the object being treated and a specific mode of administration. For example, a time-release formulation for oral administration to a feline animal can contain 0.001-1000 mg of active substance, which is mixed with a suitable and convenient amount of carrier material, and the carrier can be 5-95 wt % of the total pharmaceutical composition. The pharmaceutical composition can be prepared to provide an amount of administration that is easy to measure. For example, an aqueous solution for intravenous infusion can contain 3-500 μg of active substance per milliliter of solution.

[0072] In some embodiments, the compounds or pharmaceutical compositions provided herein can be administered for any suitable period of time. This depends on whether the compound or pharmaceutical composition is administered prophylactically or for the treatment of a mammal infected with a coronavirus. For example, it can be 1-100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days; or it can be 1-15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks.

[0073] In order to better understand the present invention and more clearly show how to implement the present invention, the features of the embodiments according to the present invention are now described by way of examples in conjunction with the accompanying drawings.

[0074] The present invention will be more readily understood by reference to the following examples, which are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way.

[0075] Unless otherwise defined or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. Unless otherwise specified, the materials and instruments used in the present invention were all commercially available.

[0076] Example

[0077] Example 1 Preparation of Compound C1:

[0078]

[0079] Compound SM was synthesized according to the method of patent WO2016069826.

[0080] To 10 mL of 2-butanone, 1 g (3.43 mmol) of compound SM was added, followed by the dropwise addition of 0.81 g (6.86 mmol) of 2,2-dimethoxybutane. The mixture was cooled to 0-5°C, and 1.18 g (6.86 mmol) of p-toluenesulfonic acid was added portionwise. The reaction was allowed to continue incubation until TLC indicated completion. An appropriate amount of saturated sodium bicarbonate solution was added to the mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate-petroleum ether) to afford compound C1a (0.90 g, 76.0% yield). MS: m / z = 346.15 [M+1] + .

[0081] At 0 ℃, to 0.9g (2.61mmol) compound C1a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml) and extracted with ethyl acetate (20mL×3).Then the combined organic layer was dried over sodium sulfate and concentrated in vacuo to obtain residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether) to obtain solid C1 (0.74g, yield: 62%).

[0082] The structure of C1 was characterized and the results are as follows:

[0083] 1 HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H),

[0084] 7.18-7.19(d,1H),5.39-5.40(d,1H),5.06-5.08(d,1H),4.68(s,1H),4.23-4.26(t,2H),3.95-3.99(d,1 H), 3.83-3.86 (d, 1H), 3.10 (s, 1H), 2.27-2.40 (m, 2H), 1.69-1.76 (m, 6H), 1.27 (s, 3H), 0.89-0.96 (m, 6H).

[0085] MS: m / z = 460.22 [M+1] + .

[0086] Example 2 Preparation of Compound C2:

[0087]

[0088] Compound SM was synthesized according to the method of patent WO2016069826.

[0089] The preparation method of C2a is the same as that of C1a in Example 1, except that 2,2-dimethoxybutane is replaced with an equal molar amount of 3,3-dimethoxypentane. The product yield is 80%, MS: m / z = 360.16 [M+1] + .

[0090] At 0 ℃, to 0.94g (2.61mmol) compound C2a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer merged was dried over sodium sulfate, and concentrated in a vacuum to obtain residue. Residue was passed through flash column chromatography (ethyl acetate / petroleum ether) purification, to obtain solid C2 (0.80g, yield: 65%).

[0091] The structure of C2 was characterized and the results are as follows:

[0092] 1 HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H),

[0093] 7.18-7.19(d,1H),5.39-5.40(d,1H),5.06-5.08(d,1H),4.68(s,1H),4.23-4.26(t,2H),3.95-3.9 9(d,1H),3.83-3.86(d,1H),3.10(s,1H),2.27-2.40(m,2H),1.69-1.76(m,8H),0.89-0.96(m,9H).

[0094] MS: m / z = 474.23 [M+1] + .

[0095] Example 3 Preparation of Compound C3:

[0096]

[0097] Compound SM was synthesized according to the method of patent WO2016069826.

[0098] The preparation method of C3a is the same as that of C1a in Example 1, except that 2,2-dimethoxybutane is replaced with an equal molar amount of 2,2-dimethoxypentane. The product yield is 79%, MS: m / z = 360.16 [M+1] + .

[0099] At 0 ℃, to 0.93g (2.61mmol) compound C3a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer combined was dried over sodium sulfate, and concentrated in vacuo to obtain residue. Residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C3 (0.83g, yield: 67%).

[0100] The structure of C3 was characterized and the results are as follows:

[0101] 1 HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H),

[0102] 7.18-7.19(d,1H),5.39-5.40(d,1H),5.06-5.08(d,1H),4.68(s,1H),4.23-4.26(t,2H),3.95-3.99(d,1 H), 3.83-3.86 (d, 1H), 3.10 (s, 1H), 2.27-2.40 (m, 2H), 1.69-1.76 (m, 8H), 1.27 (s, 3H), 0.89-0.96 (m, 6H).

[0103] MS: m / z = 474.23 [M+1] +.

[0104] Example 4 Preparation of Compound C4:

[0105]

[0106] Compound SM was synthesized according to the method of patent WO2016069826.

[0107] The preparation method of C4a is the same as that of C1a in Example 1, except that 2,2-dimethoxybutane is replaced with an equal molar amount of 1,1-dimethoxycyclopentane. The product yield is 73%, MS: m / z = 358.15

[0108] [M+1] + .

[0109] At 0 ℃, to 0.93g (2.61mmol) compound C4a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer merged was dried over sodium sulfate, and concentrated in a vacuum to obtain residue. Residue was passed through flash column chromatography (ethyl acetate / petroleum ether) purification, to obtain solid C4 (0.78g, yield: 63%).

[0110] The structure of C4 was characterized and the results are as follows:

[0111] 1HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H), 7.18-7.19 (d, 1H), 5.39-5.40 (d, 1H), 5.06-5.08 (d, 1H), 4.68 (s, 1H), 4.23-4.2 6 (t, 2H), 3.95-3.99 (d, 1H), 3.83-3.86 (d, 1H), 3.10 (s, 1H), 2.27-2.40 (m, 2H), 1.69-1.76 (m, 6H), 1.35-1.40 (m, 6H), 0.90-0.96 (t, 3H).

[0112] MS: m / z = 472.22 [M+1] + .

[0113] Example 5 Preparation of Compound C5:

[0114]

[0115] Compound SM was synthesized according to the method of patent WO2016069826.

[0116] The preparation method of C5a is the same as that of C1a in Example 1, except that 2,2-dimethoxybutane is replaced with an equal molar amount of 1,1-dimethoxycyclohexane. The product yield is 75%, MS: m / z = 372.16

[0117] [M+1] + .

[0118] At 0 ℃, to 0.97g (2.61mmol) compound C4a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer merged was dried over sodium sulfate, and concentrated in a vacuum to obtain residue. Residue was passed through flash column chromatography (ethyl acetate / petroleum ether) purification, to obtain solid C4 (0.84g, yield: 66%).

[0119] The structure of C5 was characterized and the results are as follows:

[0120] 1HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H), 7.18-7.19 (d, 1H), 5.39-5.40 (d, 1H), 5.06-5.08 (d, 1H), 4.68 (s, 1H), 4.23-4.2 6(t,2H),3.95-3.99(d,1H),3.83-3.86(d,1H),3.10(s,1H),2.27-2.40(m,2H),1.69-1.76(m,6H),1.35-1.40(m,8H),0.90-0.96(t,3H).

[0121] MS: m / z = 486.23 [M+1] + .

[0122] Example 6 General preparation procedure of compounds C6-C10:

[0123]

[0124] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0125] The acetal intermediates C1a-C5a were separately dissolved in a mixed solution of toluene and acetic anhydride (volume ratio of 10:1), heated to reflux, and kept warm for the reaction. When TLC showed complete conversion of the starting material, the system was evaporated to dryness, and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether) to obtain solids C6a-C10a (yield: 15-30%).

[0126] At 0 ℃, to 2.61mmol compound C6a-C10a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer combined was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C6-C10.

[0127] C6, based on C1a, molar yield 11%, MS: m / z = 502.23 [M+1] + .

[0128] C7, based on C2a, molar yield 13%, MS: m / z = 516.24 [M+1] + .

[0129] C8, based on C3a, molar yield 12%, MS: m / z = 516.24 [M+1] + .

[0130] C9, based on C4a, molar yield 8%, MS: m / z = 514.23 [M+1] + .

[0131] C10, based on C5a, molar yield 7%, MS: m / z = 528.24 [M+1] + .

[0132] Example 7 General preparation procedure of compounds C11-C15:

[0133]

[0134] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0135] To a solution of compound C1a-C5a (0.098 mmol) and 1H-tetrazole (30 mg, 0.43 mmol) in anhydrous acetonitrile (1 mL) at 0°C was added 2,2-dimethyl-thiopropionic acid S-(2-{diisopropylamino-[2-(2,2-dimethyl-propionylsulfanyl)-ethoxy]-phosphanyloxy}-ethyl) ester (90 mg, 0.2 mmol) (described in J. Med. Chem, 1995, 38(20), 3941). The reaction mixture was stirred at 0°C for 1 h, then hydrogen peroxide (30%, 80 uL) was added and stirred at 0°C for 0.5 h. The reaction was quenched with sodium thiosulfate (1 M, 1 mL) and sodium bicarbonate and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound C11a-C15a.

[0136] At 0 ℃, to 2.61mmol compound C11a-C15a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml) and extracted with ethyl acetate (20mL×3).Then the combined organic layer was dried over sodium sulfate and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether) to obtain solid C11-C15.

[0137] C11, based on C1a, molar yield 33%, MS: m / z = 828.30 [M+1] + .

[0138] C12, based on C2a, molar yield 37%, MS: m / z = 842.32 [M+1] + .

[0139] C13, based on C3a, molar yield 31%, MS: m / z = 842.32 [M+1] + .

[0140] C14, based on C4a, molar yield 40%, MS: m / z = 840.30 [M+1] + .

[0141] C15, based on C5a, molar yield 38%, MS: m / z = 854.32 [M+1] + .

[0142] Example 8 General preparation procedure of compounds C16-C20:

[0143]

[0144] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0145] A pear-shaped flask (5-15 mL) was charged with C1a-C5a (20 mg), trimonomethyl phosphate (0.5-1.0 mL) was added, and the solution was cooled with an ice-water bath. Phosphorus oxychloride (40-45 mg) was added and stirred at 0°C until the reaction was complete. A solution of pyrophosphate-Bu3N (250 mg) and Bu3N (90-105 mg) in acetonitrile or DMF (1-1.5 mL) was then added. The mixture was stirred at 0°C for 0.3-2.5 h, and then the reaction was quenched with 1.0 M ethylammonium carbonate (5 mL). The resulting mixture was stirred. The mixture was concentrated to dryness, redissolved in water (4 mL), and purified by ion exchange HPLC. The fractions containing the target product were concentrated to dryness, dissolved in water (5 mL), concentrated to dryness, and dissolved again in water (5 mL). Sodium bicarbonate (30-50 mg) was added and concentrated to dryness. The residue was dissolved in water and concentrated to dryness again. This process was repeated 2-5 times. The residue was then subjected to HPLC preparative purification to afford compounds C16a-C20a.

[0146] At 0 ℃, to 2.61mmol compound C16a-C20a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer merged was dried over sodium sulfate, and concentrated in a vacuum to obtain residue. Residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C16-C20.

[0147] C16, based on C1a, molar yield 12%, MS: m / z = 540.18 [M+1] + .

[0148] C17, based on C2a, molar yield 16%, MS: m / z = 554.20 [M+1] + .

[0149] C18, based on C3a, molar yield 24%, MS: m / z = 554.20 [M+1] + .

[0150] C19, based on C4a, molar yield 21%, MS: m / z = 552.18 [M+1] + .

[0151] C20, based on C5a, molar yield 22%, MS: m / z = 565.52 [M+1] + .

[0152] Example 9 General preparation procedure of compounds C21-C25:

[0153]

[0154] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0155] A pear-shaped flask (5-15 mL) was charged with C1a-C5a (20 mg), trimethyl phosphate (0.5-1.0 mL) was added, and the solution was cooled with an ice-water bath. Phosphorus oxychloride (40-45 mg) was added and stirred at 0°C until the reaction was complete. A solution of pyrophosphate-Bu3N (250 mg) and Bu3N (90-105 mg) in acetonitrile or DMF (1-1.5 mL) was then added. The mixture was stirred at 0°C for 0.3-2.5 h, and then the reaction was quenched with 1.0 M ethylammonium carbonate (5 mL). The resulting mixture was stirred. The mixture was concentrated to dryness, redissolved in water (4 mL), and purified by ion exchange HPLC. The fractions containing the target product were concentrated to dryness, dissolved in water (5 mL), concentrated to dryness, and dissolved again in water (5 mL). Sodium bicarbonate (30-50 mg) was added and concentrated to dryness. The residue was dissolved in water and concentrated again to dryness. This process was repeated 2-5 times. The residue was then purified by HPLC to afford compounds C21a-C25a.

[0156] At 0 ℃, to 2.61mmol compound C21a-C25a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer merged was dried over sodium sulfate, and concentrated in a vacuum to obtain residue.Residue was passed through flash column chromatography (ethyl acetate / petroleum ether) purification, to obtain solid C21-C25.

[0157] C21, based on C1a, molar yield 22%, MS: m / z = 604.15 [M+1] + .

[0158] C22, based on C2a, molar yield 21%, MS: m / z = 618.17 [M+1] + .

[0159] C23, based on C3a, molar yield 23%, MS: m / z = 618.17 [M+1] + .

[0160] C24, based on C4a, molar yield 21%, MS: m / z = 616.15 [M+1] + .

[0161] C25, based on C5a, molar yield 22%, MS: m / z = 630.17 [M+1] + .

[0162] Example 10 General Preparation Procedure for Compounds C26-C30

[0163]

[0164] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0165] A pear-shaped flask (5-15 mL) was charged with C1a-C5a (20 mg) and trimethyl phosphate (0.5-1.0 mL). The solution was cooled with an ice-water bath. Phosphorus oxychloride (40-45 mg) was added and stirred at 0°C until the reaction was complete. A solution of pyrophosphate-Bu3N (250 mg) and Bu3N (90-105 mg) in acetonitrile or DMF (1-1.5 mL) was then added. The mixture was stirred at 0°C for 0.3-2.5 h and then quenched with 1.0 M ethylammonium carbonate (5 mL). The resulting mixture was stirred. The mixture was concentrated to dryness, redissolved in water (4 mL), and purified by ion exchange HPLC. The fractions containing the target product were concentrated to dryness, dissolved in water (5 mL), concentrated to dryness, and dissolved again in water (5 mL). Sodium bicarbonate (30-50 mg) was added and concentrated to dryness. The residue was dissolved in water and concentrated to dryness again. This process was repeated 2-5 times. The residue was then subjected to HPLC preparative purification to afford compounds C26a-C30a.

[0166] At 0 ℃, to 2.61mmol compound C26a-C30a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer merged was dried over sodium sulfate, and concentrated in a vacuum to obtain residue.Residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C26-C30.

[0167] C26, based on C1a, molar yield 25%, MS: m / z = 668.12 [M+1] + .

[0168] C27, based on C2a, molar yield 25%, MS: m / z = 682.14 [M+1] + .

[0169] C28, based on C3a, molar yield 22%, MS: m / z = 682.14 [M+1] + .

[0170] C29, based on C4a, molar yield 25%, MS: m / z = 680.12 [M+1] + .

[0171] C30, based on C5a, molar yield 24%, MS: m / z = 694.14 [M+1] + .

[0172] Example 11 General Preparation Procedure for Compounds C31-C35

[0173]

[0174] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0175] Compounds C16a-C20a (1.19 mmol) were dried overnight in vacuo over phosphorus pentoxide. The dried material was suspended in 4 ml of anhydrous DMF and 4.92 mmol of DIPEA. 7.34 mmol of isopropyl chloromethyl carbonate (Antiviral Chemistry & Chemotherapy 8:557 (1997)) was added, and the mixture was heated to approximately 25-60°C for approximately 30 minutes to 24 hours. After cooling, the reaction was filtered. The filtrate was diluted with water, extracted with dichloromethane, dried, evaporated to dryness, and purified by HPLC preparative purification to yield the desired products C31a-C35a.

[0176] At 0 ℃, to 2.61mmol compound C31a-C35a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the organic layer merged was dried over sodium sulfate, and concentrated in a vacuum to obtain residue.Residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C31-C35.

[0177] C31, based on C16a, molar yield 58%, MS: m / z = 740.29 [M+1] + .

[0178] C32, based on C17a, molar yield 60%, MS: m / z = 754.30 [M+1] + .

[0179] C33, based on C18a, molar yield 54%, MS: m / z = 754.30 [M+1] + .

[0180] C34, based on C19a, molar yield 59%, MS: m / z = 752.29 [M+1] + .

[0181] C35, based on C20a, molar yield 62%, MS: m / z = 766.30 [M+1] + .

[0182] Compounds C1-C5 for the treatment of feline coronavirus

[0183] 1. FIPV Culture

[0184] Crandell Rees Feline Kidney (CRFK) cells (Depository: Cell Bank of the Chinese Academy of Sciences, Type Culture Collection, No. 3101MAMGNO16) were seeded into culture flasks. When the cell density reached 70-80%, some medium was removed, leaving just enough to cover the cells. An appropriate amount of FIP virus was added. After the virus adhered to the cell surface (approximately 3 hours, with the culture plate gently rocked every 30 minutes to ensure uniform viral adsorption), fresh MEM medium without fetal bovine serum (FBS) was replaced and the cells were cultured in a 37°C, 5% CO2 humidified incubator. Cells were observed to develop typical lesions such as rounding, shedding, stringing, and fusion until they no longer developed lesions (generally 2-7 days). Repeated freeze-thaw cycles were performed. Cell debris was removed by centrifugation at 3000 rpm for 10 minutes. The supernatant was collected and aliquoted into cryovials. Labeled tubes were stored at -80°C for short-term storage or in liquid nitrogen for long-term storage until later use.

[0185] 2. FIPV Titer Detection

[0186] 100 μL of CRFK single cell suspension was inoculated into 96-well cell culture plates. When the cell monolayer grew to a density of 70-80%, virus inoculation was performed. 100 μL of virus solution was diluted 10-fold, with a total of 6 dilution gradients, namely 10 -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , 10 -6 Virus inoculation: Discard the existing culture medium in the 96-well plate and wash the cells twice with PBS before virus inoculation. Set up 8 replicate wells for each virus dilution concentration and add 100 μL of virus dilution to each well. Simultaneously, set up 2 replicate wells of uninoculated control wells and add 100 μL of cell culture medium.

[0187] After virus inoculation, place the 96-well cell plate in a 37°C, 5% CO2 cell culture incubator for 1 hour. Every 15 minutes, remove the culture plate and gently shake it to promote virus adsorption to the cells. Transfer the 96-well cell culture plate to the incubator, add 100 μL of virus maintenance solution, and mark it. Observe the cells for CPE under an inverted microscope every day, twice a day, for 5 consecutive days. Record the number of wells with CPE and calculate the TCID of the virus according to the Reed-Mench formula. 50 .

[0188] TCID 50 = the highest logarithm of virus dilution with a CPE higher than 50% + the distance ratio value × the logarithm of the dilution factor;

[0189] Wherein, the distance ratio value = (percentage above 50% CPE - 50%) / (percentage above 50% CPE - percentage below 50% CPE).

[0190] The test results are recorded in Table 1.

[0191] Table 1 Half viral infection dose of FIPV on CRFK cells

[0192]

[0193] 3. Antiviral Testing of Compounds

[0194] From the test results in Table 1, we can see that the TCID of FIPV is 50 10 respectively -4.22 / 0.1mL, making 1.66×10 4 When diluted 1 / 2, 0.1 mL is used to inoculate cells, which can cause 50% of cells to become pathological. 50 The virus amount was diluted 166 times for in vitro antiviral test.

[0195] CRFK cells were collected by digestion and 10 5 Cells / well were seeded in a 96-well plate and cultured overnight in a cell culture incubator until a monolayer of cells was formed. The test substance was diluted with culture medium at multiple concentrations. When the cells were about 80% full, the culture medium was discarded and 100 TCID 50Virus solution 100 μL / well. After continuing to culture for 2 hours, replace it with 100 μL / well of the above-mentioned different concentrations of drug-containing serum-free culture medium. Set up a positive drug control group (GS-441524, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.), a model control group and a normal control group in parallel. Set up 8 replicate wells for each sample group. After mixing by cross-shaking, place the wells in a cell culture incubator for further culture. Observe the cytopathic effect. Using the model group as a reference, record the cytopathic effect (CPE well number) in each sample well under a microscope and calculate the EC 50 .

[0196] The in vitro anti-FIPV effects of GS-441524 and compounds C1-C5 are shown in Tables 2 and Figures 1 to 7 .

[0197] Table 2 Effects of test substances / control drugs on FIPV-infected CRFK cells

[0198]

[0199]

[0200] From Table 2, Appendix Figure 1-7 It can be seen that the present invention tested the in vitro antiviral effect of 8 kinds of remdesivir metabolites GS-441524 and compounds C1-C5 on FIPV. After 4 hours of drug administration, cells were infected with 100 times the TCID50 virus amount to detect the interference effect of each compound on the ability of FIPV to infect cells. It was found that compounds C1 to C5 all had in vitro anti-FIPV effects, and the effect was better than GS-441524. Among them, the test result of compound C5 was the best, and its EC 50 It is 0.517μM, and its antiviral infection effect is much better than GS-441524.

[0201] Pharmacokinetic evaluation of compounds C1-C5 in rats

[0202] Compounds C1-C5 and GS-441524 were administered intravenously or orally to fasted SD male rats, and blood samples were collected at 0.08h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration. Plasma was centrifuged and frozen at -20°C, and the concentrations of compounds C1-C5 and GS-441524 in plasma were determined by HPLC-MS / MS. Plasma was added to a test tube containing internal standard and methanol or acetonitrile, shaken vigorously for 5 minutes to achieve deproteinization, and then centrifuged at 6000 rpm for 8 minutes. The supernatant was transferred to an automatic sampling bottle and injected into the chromatography analysis system, and the pharmacokinetic parameters were calculated using winMolin6.3 software.

[0203] The calculation results are recorded in Table 3, where t 1 / 2 is the half-life. The larger the value, the slower the elimination or distribution process of the active ingredient. max Peak drug concentration is the highest blood drug concentration after administration.

[0204] Table 3 Pharmacokinetic parameters of compounds C1-C5 and GS-441524 in rats

[0205]

[0206] The test results in Table 3 demonstrate that, compared to GS-441524, compounds C1-C5 exhibit significantly improved bioavailability following injection / oral administration, with higher Cmax values and t1 / 2. Combining the test results in Tables 2 and 3, it can be seen that the compounds disclosed herein possess outstanding antiviral and pharmacokinetic properties both in vitro and in vivo.

[0207] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form or substance. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is one or more combinations of Compound C1 to Compound C5: 。 2. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient or carrier.

3. The pharmaceutical composition according to claim 2, characterized in that The excipient is selected from one or more of a binder, a filler, a disintegrant, a lubricant and a glidant, and the carrier is selected from one or more of a cream, an emulsion, a gel, a liposome and a nanoparticle.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 2 to 3 in the preparation of a medicament for preventing, inhibiting and treating diseases caused by viruses.

5. The use according to claim 4, characterized in that The virus is one of coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus and Filoviridae virus.

6. The use according to claim 5, characterized in that The coronavirus is one of feline enteric coronavirus, feline infectious peritonitis virus and porcine epidemic diarrhea virus.

7. The use according to claim 5, characterized in that The disease caused by the virus is one of feline enteritis caused by feline enteric coronavirus infection, feline infectious peritonitis caused by feline infectious peritonitis virus infection, and porcine epidemic diarrhea caused by porcine epidemic diarrhea virus infection.

8. The use according to claim 4, characterized in that The subject of application of the compound or pharmaceutical composition is mammals.

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