Triazine-derived compounds and uses thereof

Abstract

The present application relates to a kind of compound shown in formula I or its pharmaceutically acceptable salt and its use, belong to the field of medicine.The compound or its pharmaceutically acceptable salt is high to the inhibition activity of SARS-Cov-2's Mpro main protease, low toxicity, good metabolic stability.The compound or its pharmaceutically acceptable salt can be used for the purpose of preparing the drug for inhibiting the Mpro main protease of SARS-Cov-2, and for the purpose of being used in the product for preventing, treating or reducing the replication or reproduction of coronavirus infection or its homologous variant virus and the cytopathic effect generated by it.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a triazine derivative compound and its uses. Background Technology

[0002] COVID-19 is a respiratory illness caused by SARS-CoV-2 infection.

[0003] Coronavirus main protease M pro Also known as 3C-like protease (3CL) pro ), because M pro Proteases play a crucial role in the viral life cycle, and since there are no homologous proteins in the human body, M... pro The main protease is an ideal target for antiviral drug development. pro Selective inhibitors have a high safety profile in vivo. Pfizer's oral drug PF-07321332 is a covalently linked M... pro Inhibitors, but their poor selectivity and peptide-like structure lead to poor membrane permeability and short half-life.

[0004] Existing Mpro main protease inhibitors still suffer from problems such as low activity, short half-life, high toxicity, significant adverse reactions, and poor stability.

[0005] Therefore, there is still an urgent need for an Mpro inhibitor that has high Mpro main protease activity, long half-life, low toxicity or few adverse reactions, and good stability. Summary of the Invention

[0006] To address the above problems, a compound or a pharmaceutically acceptable salt thereof or a deuterated derivative thereof is provided, as well as pharmaceutical compositions thereof and uses thereof.

[0007] In a first aspect, a compound of formula I or a pharmaceutically acceptable salt thereof or a deuterated thereof is provided.

[0008] The compound represented by Formula I, or its pharmaceutically acceptable salt or its deuterated derivative:

[0009]

[0010] in:

[0011] R1 is selected from H, F,

[0012] R4 is selected from H, F, Alkyl, alkyl containing heteroatoms, cycloalkyl, or cycloalkyl containing heteroatoms, halogen, hydroxyl, amino, ether, cyano, alkenyl, alkynyl, nitro, phenyl, nitrogen-containing aromatic ring, nitro;

[0013] R2 and R3 are independently selected from...

[0014]

[0015] R5 is selected from -Cl or

[0016] R6 is selected from H, hydroxyl, or cyano;

[0017] R7 is selected from H, saturated alkyl, aromatic ring, heterocyclic, halogen, nitro, cyano or dimethylamino;

[0018] R8 is selected from H, hydroxymethyl, or...

[0019] X is selected from C or N;

[0020] Y is selected from C, N, O, or S;

[0021] n is 0, 1, 2, or 3;

[0022] Real and virtual keys It indicates a single key, a double key, or a triple key.

[0023] In some embodiments of the present invention, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, comprises a subset selected from:

[0024]

[0025]

[0026] The meanings of the symbols in the formula are the same as those described above (i.e., if any of the following symbols exist in the formula, the possible options for each symbol are as follows:

[0027] R1 is selected from H, F,

[0028] R4 is selected from H, F, Alkyl groups, alkyl groups containing heteroatoms, cycloalkyl groups, or cycloalkyl groups containing heteroatoms, halogens, hydroxyl groups, amino groups, ether groups, cyano groups, alkenyl groups, alkynyl groups, nitro groups, benzene groups

[0029] group, nitrogen-containing aromatic ring, nitro group;

[0030] R2 and R3 are independently selected from...

[0031]

[0032]

[0033] R5 is selected from -Cl or

[0034] R6 is selected from H, hydroxyl, or cyano;

[0035] R7 is selected from H, saturated alkyl, aromatic ring, heterocyclic, halogen, nitro, cyano or dimethylamino;

[0036] R8 is selected from H, hydroxymethyl, or...

[0037] X is selected from C or N;

[0038] Y is selected from C, N, O, or S;

[0039] n is 0, 1, 2, or 3;

[0040] Real and virtual keys (Indicates a single bond, double bond, or triple bond).

[0041] In some embodiments of the present invention, the compound represented by Formula I or its pharmaceutically acceptable salt or deuterated derivative thereof includes compounds selected from: compounds represented by Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII.

[0042]

[0043] The meanings of the symbols in the formula are the same as those described above (i.e., if any of the following symbols exist in the formula, the possible options for each symbol are as follows:

[0044] R1 is selected from H, F, R4 is selected from H, F, Alkyl, alkyl containing heteroatoms, cycloalkyl, or cycloalkyl containing heteroatoms, halogen, hydroxyl, amino, ether, cyano, alkenyl, alkynyl, nitro, phenyl, nitrogen-containing aromatic ring, nitro;

[0045] R2 and R3 are independently selected from...

[0046]

[0047] R5 is selected from -Cl or

[0048] R6 is selected from H, hydroxyl, or cyano;

[0049] R7 is selected from H, saturated alkyl, aromatic ring, heterocyclic, halogen, nitro, cyano or dimethylamino;

[0050] R8 is selected from H, hydroxymethyl, or... X is selected from C or N;

[0051] Y is selected from C, N, O, or S;

[0052] n is 0, 1, 2, or 3;

[0053] Real and virtual keys (Indicates a single bond, double bond, or triple bond).

[0054] In some embodiments, the saturated alkyl group may include a group selected from methyl, ethyl, n-propyl, isopropyl, or tert-butyl.

[0055] In some embodiments, the aromatic ring may include a ring selected from benzene or naphthalene.

[0056] In some embodiments, the heterocycle may include a selection from pyridine, piperidine, pyrrole, pyrazole, imidazole, furan, thiophene, triazole, indole, pyrimidine, or quinoline.

[0057] In some embodiments, the halogen may include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0058] In some embodiments, the alkyl group is a hydrocarbon comprising a positive carbon atom, a secondary carbon atom, a tertiary carbon atom, or a cyclic carbon atom. In some embodiments, the alkyl group may have 1 to 10 carbon atoms (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, or C1 alkyl). 10Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). In some embodiments, the alkyl group includes, but is not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (i-Pr, i-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, ... -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl 2-Methyl-1-butyl (-CH2CH2CH(CH3)2), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)C H(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 or octyl (-(CH2)7CH3).

[0059] In some embodiments, the alkenyl group comprises having at least one unsaturated site, i.e., carbon-carbon sp. 2 Hydrocarbons with a double bond consisting of a positive, secondary, tertiary, or cyclic carbon atom. In some embodiments, the alkenyl group may have 2 to 10 carbon atoms (C2-C4). 10 alkenyl), 2 to 12 carbon atoms (C2-C) 12 Alkenyl groups, such as C2-alkenyl, C3-alkenyl, C4-alkenyl, C5-alkenyl, C6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C... 10 alkenyl, C 11alkenyl or C 12 Alkenyl (or 2 to 6 carbon atoms, C2-C6 alkenyl). In some embodiments, the alkenyl group includes, but is not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7) and 5-hexenyl (-CH2CH2CH2CH2CH=CH2), propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl or pentadecenyl, etc.

[0060] In some embodiments, the alkynyl group is a hydrocarbon comprising a carbon atom, secondary carbon atom, tertiary carbon atom, or cyclic carbon atom having at least one unsaturated site, i.e., a carbon-carbon sp triple bond. In some embodiments, the alkynyl group may have 2 to 10 carbon atoms (C2-C4). 10 alkynyl group), 2 to 12 carbon atoms (C2-C) 12 Alkynyl groups, such as C2-alkynyl, C3-alkynyl, C4-alkynyl, C5-alkynyl, C6-alkynyl, C7-alkynyl, C8-alkynyl, C9-alkynyl, C 10 alkynyl group, C 11 alkynyl or C 12 The alkynyl group consists of 2 to 6 carbon atoms (C2-C6 alkynyl). In some embodiments, the alkynyl group includes, but is not limited to, ethynyl (-C=CH), propynyl (-CH2C=CH), or the like.

[0061] In some embodiments, the aryl group refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. In some embodiments, the aryl group may have 6 to 20 carbon atoms (e.g., C6 aryl, C7 aryl, C8 aryl, C9 aryl, C2 aryl, C3 aryl, C4 aryl, C5 aryl ...2 aryl, C3 aryl, C4 aryl, C5 aryl, C6 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C2 aryl, C2 aryl, C2 10 Aryl, C 11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C 17 Aryl, C 18 Aryl, C 19 Aryl or C 20 Aryl groups (6 to 14 carbon atoms or 6 to 10 carbon atoms). In some embodiments, the aryl group includes, but is not limited to, benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and other derivative groups or similar groups.

[0062] In some embodiments, the cycloalkyl group is a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms. In one embodiment, the cycloalkyl group comprises 3-12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms). In some embodiments, the cycloalkyl group comprises 3-8 carbon atoms. In some embodiments, the cycloalkyl group comprises 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0063] In some embodiments, the term “substituted” refers to alkyl, aryl, arylalkyl, heterocyclic, heteroaryl, carbocyclic, etc., for example, “substituted C1-C”. 10 Alkyl, substituted C6-C 20 "Aryl", "Substituted arylalkyl", "Substituted C1-C" 20 "Heterocyclic" and "substituted carbocyclic" refer to C1-C rings in which one or more hydrogen atoms are independently replaced by non-hydrogen substituents, respectively. 10 Alkyl, C6-C 20 Aryl, arylalkyl, C1-C 20 Heterocyclic, carbocyclic. Unless otherwise stated, when the term “substituted” is used in conjunction with a group having two or more moieties capable of substitution, such as an arylalkyl group, the substituent may be attached to the aryl moieties, alkyl moieties, or both.

[0064] In some embodiments of the present invention, the compound represented by Formula I or a pharmaceutically acceptable salt thereof or a deuterated derivative thereof comprises a structure selected from the following:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] In some preferred embodiments of the present invention, the compound represented by Formula I has the following structure:

[0074] Or the deuterated form of the compound shown in Formula I is Compound 73 or Compound 1 exhibits high Mpro main protease inhibitory activity and high SARS-CoV-2 inhibitory activity, and has higher Mpro main protease inhibitory activity and higher SARS-CoV-2 inhibitory activity than other compounds and S-217622 compound, with Compound 1 having higher Mpro main protease inhibitory activity and higher SARS-CoV-2 inhibitory activity.

[0075] In some more preferred embodiments of the present invention, the compound represented by Formula I has the following structure:

[0076] Compound 1 exhibits higher Mpro main protease inhibitory activity and higher SARS-CoV-2 inhibitory activity than other compounds and compound S-217622.

[0077] In some embodiments of the present invention, the compound represented by Formula I does not include compound S-217622:

[0078]

[0079] In some embodiments of the present invention, the compound represented by Formula I includes a racemic, enantiomer, or tautomer of the compound represented by Formula I.

[0080] The compounds of Formula I described in the first aspect, or pharmaceutically acceptable salts thereof, are suitable for administration via any route of treatment for the condition. Suitable routes include oral, rectal, nasal, pulmonary, local (including oral and sublingual), and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. The advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

[0081] In a second aspect, the present invention provides a pharmaceutical composition.

[0082] A pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt thereof or a deuterated form thereof, and optionally a pharmaceutically acceptable excipient.

[0083] In some embodiments, the dosage form of the pharmaceutical composition is a tablet, pill, cream, emulsion, ointment, suspension, lyophilized agent, capsule, sustained-release agent, granule, powder, injectable agent, or nasal spray.

[0084] Thirdly, the use of the aforementioned compound or a pharmaceutically acceptable salt thereof or a deuterated form thereof or a pharmaceutical composition thereof is provided.

[0085] In some embodiments of the present invention, a compound described in the first aspect or a pharmaceutically acceptable salt thereof or a deuterated form thereof, or a pharmaceutical composition described in the second aspect, is used in the preparation of a drug for inhibiting the SARS-CoV-2 major protease (i.e., M). pro The main protease, also known as 3CL pro Use of proteases in pharmaceuticals.

[0086] In some embodiments of the invention, the use of a compound of the first aspect or a pharmaceutically acceptable salt thereof or a deuterated form thereof, or a pharmaceutical composition of the second aspect, in the preparation of products for the prevention, treatment, or mitigation of coronavirus infection or the replication or propagation of its homologous variants and the resulting cytopathic effects.

[0087] In some embodiments of the invention, the use of a compound described in the first aspect or a pharmaceutically acceptable salt thereof or a deuterated form thereof, or a pharmaceutical composition described in the second aspect, in the preparation of a product for detecting coronavirus infection or its homologous variants.

[0088] In some embodiments of the present invention, the coronavirus includes MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, mouse hepatitis virus, feline infectious peritonitis virus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus, or porcine coronavirus.

[0089] In some embodiments, the SARS-CoV-2 may include mutant or non-mutated strains of SARS-CoV-2. In some embodiments, the mutant strains of SARS-CoV-2 include SARS-CoV-2 mutant strain B.1, SARS-CoV-2 mutant strain B.1.351, SARS-CoV-2 mutant strain B.1.617.2, SARS-CoV-2 mutant strain C.37, SARS-CoV-2 mutant strain P.1 family, SARS-CoV-2 mutant strain B.1.525, SARS-CoV-2 mutant strain B.1.427, or SARS-CoV-2 mutant strain B.1.429 or other homologous mutant strains.

[0090] In some embodiments, the compound represented by Formula I of the first aspect or a pharmaceutically acceptable salt thereof may be suitable for human or animal use.

[0091] In some embodiments, the animals include bovines, equines, sheep, suidae, canines, felines, rodents, primates, birds, or fish.

[0092] Beneficial effects

[0093] Compared with the prior art, one embodiment of the present invention has at least one of the following beneficial effects:

[0094] (1) The Mpro main protease plays a crucial role in viral RNA replication and transcription, and has no homologous protein in the human body. Therefore, inhibitors targeting the Mpro protease can effectively inhibit viral replication and have high in vivo safety. The novel non-peptide, covalent, or non-covalent Mpro inhibitors provided by this invention bind well to the Mpro main protease. Based on the basic framework of the non-peptide, non-covalent Mpro inhibitor S-217622, ​​the metabolic stability of the drug can be effectively improved, enhancing its efficacy. Representative compounds (e.g., compounds 1 and 73) exhibit superior activity compared to S-217622.

[0095] (2) The compounds provided by the present invention (e.g., compound 1 and compound 73) have good activity in inhibiting SARS-CoV-2 replication. Attached Figure Description

[0096] Figure 1 The graphs show the inhibitory activity curves of S217622, ​​compounds 1, 6 and 73 on 3CLpro enzyme in Example 13.

[0097] Terminology Explanation

[0098] In this invention, "room temperature" refers to the ambient temperature, which can be 10℃-40℃, 20℃-30℃; in some embodiments, it is 22℃-28℃; in some embodiments, it is 24℃-26℃; and in some embodiments, it is 25℃.

[0099] In this invention, the structure in It indicates a single key, a double key, or a triple key.

[0100] In the foregoing description of this invention, all figures disclosed herein, whether or not the words “approximately” or “about” are used, are approximate values. Based on the disclosed figures, the value of each figure may vary by less than ±10% or by a difference that is considered reasonable by those skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0101] The terms “optional,” “optional,” or “optionally” mean that the event or situation described below may, but is not necessarily, occur. For example, “optional surfactant” means that the surfactant may or may not be present.

[0102] The term “and / or” should be understood to mean any one of the options or any combination of two or more of the options.

[0103] "Alkyl" is a hydrocarbon containing a positive, secondary, tertiary, or cyclic carbon atom. For example, alkyl can have 1 to 10 carbon atoms (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, or C1 alkyl). 10 Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (i-Pr, i-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), and 2-butyl (s-Bu, s-butyl, -CH2CH2CH2CH3). (CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl ( -CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 or octyl (-(CH2)7CH3).

[0104] "Alkenyl" refers to a group containing at least one unsaturated site, i.e., carbon-carbon sp.2 Hydrocarbons with double bonds consisting of a positive, secondary, tertiary carbon atom, or a cyclic carbon atom. For example, alkenyl groups can have 2 to 10 carbon atoms (C2-C4). 10 alkenyl), 2 to 12 carbon atoms (C2-C) 12 Alkenyl groups, such as C2-alkenyl, C3-alkenyl, C4-alkenyl, C5-alkenyl, C6-alkenyl, C7-alkenyl, C8-alkenyl, C9-alkenyl, C... 10 alkenyl, C 11 alkenyl or C 12 Alkenyl (or 2 to 6 carbon atoms, C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7) and 5-hexenyl (-CH2CH2CH2CH2CH=CH2), propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl or pentadecenyl, etc.

[0105] "Alynyl" is a hydrocarbon containing at least one unsaturated carbon atom, namely a carbon-carbon sp triple bond, or a cyclic carbon atom. For example, an alkynyl group can have 2 to 10 carbon atoms (C2-C4). 10 alkynyl group), 2 to 12 carbon atoms (C2-C) 12 Alkynyl groups, such as C2-alkynyl, C3-alkynyl, C4-alkynyl, C5-alkynyl, C6-alkynyl, C7-alkynyl, C8-alkynyl, C9-alkynyl, C 10 alkynyl group, C 11 alkynyl or C 12 Alkyne group (or 2 to 6 carbon atoms, C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C=CH), propynyl (-CH2C=CH), or the like.

[0106] "Aryl" refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms (e.g., C6 aryl, C7 aryl, C8 aryl, C9 aryl, C2 aryl, C3 aryl, C4 aryl, C5 aryl ...2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 aryl, C2 10 Aryl, C 11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C 17 Aryl, C 18 Aryl, C 19 Aryl or C 20Aryl groups (6 to 14 carbon atoms or 6 to 10 carbon atoms). Typical aryl groups include, but are not limited to, benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and other derivative groups or similar groups.

[0107] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group comprises 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms); in another embodiment, the cycloalkyl group comprises 3 to 8 carbon atoms; and in yet another embodiment, the cycloalkyl group comprises 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0108] The term "substituted" refers to alkyl, aryl, arylalkyl, heterocyclic, heteroaryl, carbocyclic, etc., such as "substituted C1-C". 10 Alkyl, substituted C6-C 20 "Aryl", "Substituted arylalkyl", "Substituted C1-C" 20 "Heterocyclic" and "substituted carbocyclic" refer to C1-C rings in which one or more hydrogen atoms are independently replaced by non-hydrogen substituents, respectively. 10 Alkyl, C6-C 20 Aryl, arylalkyl, C1-C 20 Heterocyclic, carbocyclic. Unless otherwise stated, when the term “substituted” is used in conjunction with a group having two or more moieties capable of substitution, such as an arylalkyl group, the substituent may be attached to the aryl moieties, alkyl moieties, or both.

[0109] The term "V / V" indicates a volume ratio.

[0110] The term "wt%" indicates a percentage by mass.

[0111] In this article, the term "treatment" refers to a clinical intervention intended to alter the natural course of a disease in an individual receiving treatment. Desired therapeutic effects include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or mitigating the disease state, and alleviating or improving prognosis.

[0112] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0113] In this application, the "composition" can be conveniently presented in unit dose form and can be prepared by any method well known in the pharmaceutical industry. All methods involve the step of combining the active ingredient with a carrier constituting one or more adjunct components. Typically, the composition is prepared by uniformly and sufficiently combining the active compound with a liquid carrier, a finely pulverized solid carrier, or both. Detailed Implementation

[0114] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0115] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0116] Example 1: Preparation of intermediate b

[0117]

[0118] Compound a (10.0 g, 0.07 mol), 1-(bromomethyl)-2,4,5-trifluorobenzene (16.0 g, 0.07 mol), and potassium carbonate (5.7 g, 0.04 mol) were mixed and dissolved in 100 mL of DMF (N,N-dimethylformamide). The mixture was stirred at room temperature for 24 h, and the reaction was confirmed to be complete by TLC (thin-layer chromatography). Then, 200 mL of water was added, and the mixture was stirred thoroughly, resulting in the precipitation of a large amount of white solid. The solid was filtered, the filter cake was washed with water, and then dried under vacuum at 50 °C to obtain 15.3 g of intermediate b (white solid). A suitable amount of intermediate b was taken, and its proton NMR spectrum was analyzed. The results were as follows:

[0119] 1 H NMR (600MHz, DMSO-d6) δ11.74(s,1H),7.60(q,J=9.4Hz,1H),7.51(q,J=9.0Hz,1H),6.03(s,1H),5.14(s,2H).

[0120] Example 2: Preparation of intermediate c

[0121]

[0122] Intermediate b (10.0 g, 0.03 mol), 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (11.6 g, 0.07 mol), potassium carbonate (19.0 g, 0.14 mol), and potassium iodide (0.6 g, 3.40 μmol) were mixed and dissolved in 100 mL of DMF. The mixture was heated to 60 °C and reacted for 24 h. The reaction was confirmed to be complete by TLC. The reaction solution was poured into 200 mL of water and stirred thoroughly. A large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed with water and dried under vacuum at 50 °C to obtain 6.4 g of intermediate c (white solid). A suitable amount of the obtained intermediate c was analyzed by 1H NMR. The results are as follows:

[0123] 1 H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.73–7.56(m,1H),7.50–7.31(m,1H),6. 27(d,J=1.4Hz,1H), 5.24(s,2H), 5.01(d,J=1.3Hz,2H), 3.79(d,J=1.5Hz,3H).

[0124] Example 3: Preparation of Compound 1

[0125]

[0126] Palladium acetate (22.6 mg, 0.10 mmol) and BINAP (binaphthyl diphenylphosphine, 62.3 mg, 0.1 mmol) were mixed with 20 mL of ultra-dry toluene. Under argon protection, the mixture was stirred at room temperature for 10 min. Then, intermediate c (1.0 g, 2.59 mmol), 6-chloro-2-methyl-2H-indazole-5-amine (0.5 g, 2.75 mmol), and cesium carbonate (3.3 g, 0.01 mmol) were added under argon atmosphere. The mixture was heated to 100 °C and reacted for 8 h. TLC (thin-layer chromatography) monitoring showed that intermediate c was essentially complete. The mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was evaporated to dryness. The residue was purified by column chromatography (dichloromethane:methanol = 40:1 (V / V)) to give 800 mg of compound 1 (white solid). An appropriate amount of the obtained compound 1 was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows:

[0127] Hydrogen spectrum: 1H NMR(600MHz,DMSO-d6)δ8.85(s,1H),8.46(s,1H),8.30(s,1H),7.94–7.85(m,1H),7.79(s,1H),7.69– 7.56(m,1H),7.28(q,J=8.4Hz,1H),5.33(s,2H),4.95(s,2H),4.19(s,3H),4.16(s,1H),3.77(s,3H).

[0128] Carbon spectrum: 13 C NMR(150MHz,DMSO-d6)δ161.30,160.9,155.40(ddd,J=232.5,7.5,1.5Hz),154.01,15 1.68,148.63(dt,J=247.64,15.1Hz),147.40,146.70(ddd,J=237,13.5,4.5Hz),145. 38,129.99,127.68,126.56,122.49,121.20(dq,J=16.5,3.0Hz),120.0,118.26,115. 75(dd,J=19.5,4.5Hz),106.62(dd,J=232.5,7.5,1.5Hz),77.67,40.75,38.33,36.07.

[0129] Mass spectrometry: LC-MS [M+H] + :531.2.

[0130] Example 4: Preparation of intermediate e

[0131]

[0132] Lithium tetradeuterium aluminum (0.9 g, 21.43 mmol) was mixed with 40 mL of THF (tetrahydrofuran) and cooled in an ice bath. Methyl 1-methyl-1H-1,2,4-triazol-3-carboxylic acid ester d (2.0 g, 14.17 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and the reaction was continued for 4 h. The reaction was monitored by TLC until it was complete (no absorption of the product at 254 nm). Under ice bath conditions, 1 mL of water and 1 mL of 15 wt% sodium hydroxide aqueous solution were slowly added. When no gas was produced, anhydrous sodium sulfate was added for drying. The mixture was filtered, evaporated to dryness, and 0.8 g of crude intermediate e (oily substance) was obtained. This crude product was used directly in the next reaction without purification.

[0133] Example 5: Preparation of intermediate f

[0134]

[0135] The crude intermediate e obtained in Example 4 was mixed with 10 mL of DMF (N,N-dimethylformamide) and dissolved. Phosphorus tribromide (1.0 mL, 10.64 mmol) was added dropwise under ice bath. After the addition was complete, the mixture was moved to room temperature and the reaction was continued for 8 h. The reaction was detected by TLC and found to be complete. The reaction solution was poured into water and the pH was adjusted to 9-10 with saturated sodium carbonate aqueous solution. The mixture was extracted three times with ethyl acetate, and the ethyl acetate layers were combined. The combined ethyl acetate layers were washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 1.5 g of crude intermediate f (colorless oily substance). The product was used directly in the next step without further purification.

[0136] Example 6: Preparation of intermediate g

[0137]

[0138] The crude intermediate f obtained in Example 5 was mixed with intermediate b (1.0 g, 3.44 mmol), potassium carbonate (1.8 g, 13.04 mmol), and potassium iodide (54 mg, 0.33 mmol), dissolved in 10 mL of DMF (N,N-dimethylformamide), and reacted at 50 °C for 6 h. TLC monitoring showed the reaction was complete. 20 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined EA layers were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was purified by column chromatography (dichloromethane:methanol = 40:1 (V / V)) to obtain 313 mg of intermediate g (pale yellow solid). The 1H NMR spectrum of the obtained intermediate g was analyzed, and the results are as follows:

[0139] 1 H NMR (400MHz, Chloroform-d) δ7.97–7.90(m,1H),7.23–7.12(m,1H),7.01–6.88(m,1H),6.04(s,1H),5.30(q,J=1.0Hz,2H),3.87(s,3H).

[0140] Example 7: Preparation of Compound 73

[0141]

[0142] Palladium acetate (5.4 mg, 0.02 mmol) and BINAP (12.5 mg, 0.02 mmol) were mixed with 5 mL of ultra-dry toluene. Under argon protection, the mixture was stirred at room temperature for 10 min. Then, intermediate g (300.0 mg, 0.77 mmol), 6-chloro-2-methyl-2H-indazole-5-amine (131.0 mg, 0.72 mmol), and cesium carbonate (589.0 mg, 1.81 mmol) were added under Ar atmosphere. The mixture was heated to 100 °C and reacted for 8 h. TLC monitoring showed that intermediate g was almost completely reacted. The mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was evaporated to dryness, and the residue was purified by column chromatography (dichloromethane:methanol = 40:1 (V / V)) to obtain 100 mg of compound 73 (near-white solid). An appropriate amount of the obtained compound 73 was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows:

[0143] Hydrogen spectrum: 1 H NMR(600MHz,DMSO-d6)δ8.86(s,1H),8.46(s,1H),8.31(s,1H),7.89(s,1H),7.79(s,1H), 7.68–7.56(m,1H),7.37–7.16(m,1H),5.34(s,2H),4.19(s,3H),4.17(s,1H),3.78(s,3H).

[0144] Carbon spectrum: 13 C NMR (151MHz, DMSO) δ161.32, 159.95, 155.40 (ddd, J = 232.5, 7.5, 1.5Hz), 154.02, 151.6 7,148.73(dt,J=247.64,13.59Hz),147.40,146.70(ddd,J=237,13.5,4.5Hz),145.38, 129.99,127.69,126.56,122.48,121.20(dt,J=16.5,3.0Hz),120.90,118.26,115.75( dd,J=19.5,4.5Hz),106.62(dd,J=27.18,21.14Hz),77.68,40.75,37.91,36.07,36.05.

[0145] Mass spectrometry: LC-MS [M+H] + :533.2.

[0146] Example 8: Preparation of intermediate h

[0147]

[0148] 5.0 g (27.53 mmol) of 6-chloro-2-methyl-2H-indazole-5-amine was dissolved in 25 mL of 6N HCl. 10 mL of 30 wt% NaNO₂ aqueous solution was slowly added dropwise at 0–5 °C. After the addition was complete, the reaction was carried out at 0–5 °C for 1 h. Then, 20 mL of 40 wt% potassium xanthate aqueous solution was added dropwise at room temperature. After the addition was complete, the reaction was carried out at room temperature for 0.5 h. TLC analysis confirmed the completeness of the reaction. The mixture was then extracted with ethyl acetate, washed with saturated brine, and the ethyl acetate layer was collected. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The mixture was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:2 (V / V)) to obtain intermediate h (yellow solid) 3.9 g. A suitable amount of intermediate h was analyzed by mass spectrometry, and the results are as follows:

[0149] LC-MS, m / z: 287.2 [M+H] + .

[0150] Example 9: Preparation of intermediate i

[0151]

[0152] Intermediate h (1.0 g, 3.49 mmol) was mixed with 12 mL of water and dissolved. Then, 12 mL of 12 wt% NaOH aqueous solution was added dropwise at room temperature. After the addition was complete, the reaction was allowed to proceed for 1 h at room temperature. TLC analysis confirmed the reaction was complete. Then, 3N HCl aqueous solution was added dropwise to adjust the pH to 5, resulting in the precipitation of a large amount of yellow solid. This solid was filtered and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 2:1 (V / V)) to obtain intermediate i (yellow solid) 173.4 mg. A suitable amount of the obtained intermediate i was analyzed by 1H NMR. The results are as follows:

[0153] 1 ¹H NMR (600MHz, DMSO-d6) δ 8.36 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 4.14 (s, 3H). (The hydrogen in -SH is an active hydrogen and could not be detected).

[0154] Example 10: Preparation of Compound 6

[0155]

[0156] Under argon atmosphere, intermediates c (80.0 mg, 0.21 mmol), i (50.0 mg, 0.25 mmol), and sodium hydroxide (12 mg, 0.30 mmol) were mixed, dissolved in 1 mL DMSO, and reacted at 120 °C for 24 h. The reaction was confirmed to be complete by TLC. The reaction solution was quenched dropwise with methanol, and purified by silica gel column chromatography (ethyl acetate:methanol = 20:1 (V / V)) to obtain 13.2 mg of compound 6 (white solid). The proton and carbon spectra of compound 6 were analyzed, and the results are as follows:

[0157] Hydrogen spectrum: 1 H NMR(600MHz,Chloroform-d)δ8.04(s,1H),7.98(s,1H),7.91(d,J=16.3Hz,2H),7.25–7.17( m,1H),7.03–6.87(m,1H),5.37(s,2H),5.25(s,2H),5.08(s,1H),4.25(s,3H),3.85(s,3H).

[0158] Carbon spectrum: 13 C NMR(151MHz,Chloroform-d)δ160.21,159.88,156.56,155.04(ddd,J=247.64,9.06,1.51Hz), 151.78,149.55(ddd,J=252.17,13.59,1.51Hz),149.49,147.18(ddd,J=244.62,10.57,1.51Hz) ),144.22,134.39,132.70,125.13,121.43,119.64,119.51(dq,J=16.61,4.53Hz),117.60,116 .08(dd,J=21.14,4.53Hz),105.72(dd,J=27.18,21.14Hz),98.45,41.96,40.85,38.76,36.13.

[0159] Example 11: Preparation of other compounds

[0160] Compounds 2 to 5, 7 to 72 and 74 were prepared using a similar preparation method as in Examples 1-3, and mass spectrometry was performed. The binding free energy of the compounds and S-217622 to the main protease of coronavirus Mpro was then evaluated.

[0161] Table 1 lists some preferred compounds of the present invention and M. proThe binding energy ΔG of the main protease was found in most compounds, which were comparable to or lower than that of compound S-217622 (ΔG = -7.81 kcal / mol), indicating that these compounds had a similar or stronger binding ability to the Mpro main protease as compound S-217622.

[0162] The above results indicate that the compound provided by this invention and S-217622 are similar to M. pro The main protease has a similar or even stronger binding affinity, which can inhibit M. pro The use of the main protease to inhibit coronavirus replication and transcription demonstrates that the compound designed in this invention has antiviral activity comparable to compound S-217622 and can serve as a potential candidate drug for anti-coronavirus infection.

[0163] Table 1: Structural information of the preferred compounds of this invention and S-217622, ​​and their relationship with M pro The binding energy ΔG of the main protease.

[0164]

[0165]

[0166]

[0167]

[0168]

[0169] Example 12: Enzyme activity test of compound 3CLpro

[0170] In vitro protein activity assay: This invention uses 3CL pro The inhibitor kit uses a SARS-CoV-2 protease with an amino acid sequence identical to the main protease of the novel coronavirus, and employs fluorescence detection technology to screen and detect 3CL. pro Protease inhibitors. The specific steps are as follows:

[0171] A. The test sample was diluted four times from 100 μM, and the inhibition rate of eight samples with different concentrations was determined. The concentrations were 100 μM, 25 μM, 6.25 μM, 1.56 μM, 0.39 μM, 0.09 μM, 0.02 μM, 0.06 μM, and 0.01 μM.

[0172] B. Prepare an appropriate amount of Assay Reagent. Add 92 μL of Assay Buffer and 1 μL of 2019-nCoV M to one sample. pro / 3CL pro Mix thoroughly.

[0173] C. Prepare a blank control group. Add 93 μL of Lassay Buffer and 5 μL of DMSO, and mix thoroughly.

[0174] D. Prepare a 100% enzyme activity control group. Add 93 μL of Lasay Reagent and 5 μL of DMSO, and mix thoroughly.

[0175] E. Prepare the test sample group. Add 93 μL of Lasay Reagent and 5 μL of the test sample, and mix thoroughly.

[0176] F. Quickly add 2 μL of Substrate to each well and mix thoroughly.

[0177] G. Incubate at 37℃ in the dark for 5 minutes, then perform fluorescence assay using a multifunctional enzyme-linked immunosorbent assay (ELISA). The excitation wavelength is 340 nm, and the emission wavelength is 490 nm.

[0178] H. Calculate the fluorescence value of the blank control group, the 100% enzyme activity control group, and each sample well, and record them as RFU. 空白对照 RFU 100％酶活性对照 and RFU 样品 Calculate the inhibition percentage for each sample using the following formula: Inhibition percentage (%) = (RFU) / (RFU) 100％酶活性对照 -RFU 样品 ) / (RFU 100％酶活性对照 -RFU 空白对照 The IC50 of this compound can be calculated by detecting its dose-effect. 50 .

[0179] Table 2. Effects of some compounds on 3CL pro half-maximal inhibitory concentration of protease

[0180] compound <![CDATA[3CLIC 50 (μM)]]> S-217622 0.033 1 0.015 6 0.200 73 0.027

[0181] The results showed that compounds 1 and 73, which have a pyrimidine ring structure, exhibited superior Mpro inhibitory activity compared to S-217622, ​​with compound 1 showing more than double the activity of S-217622 at the enzyme level. Meanwhile, replacing the amino group on the pyrimidine ring with S resulted in compound 6, which showed a significant decrease in 3CLpro inhibitory activity, contrary to the aforementioned docking results. Therefore, it could not be detected by M... pro The binding energy ΔG of the main protease is used to determine the activity of a compound. The compounds 1 and 73 of this invention have unexpected technical effects.

[0182] Example 13: In vitro anti-SARS-CoV-2 live virus assay of the compound

[0183] HEK 293T cells were seeded in 24-well plates. When the cells reached a confluence density of 40%-50%, 250 ng of SARS-CoV-2 replicon plasmid was transfected using LIPO2000. 6-8 h after transfection, the cell supernatant was discarded, and fresh DMEM medium was added. One of the following compounds was added: compound 1, compound 73, compound 2 through compound 72, or compound 74, to a final concentration of 50 μM, 10 μM, 5 μM, 2 μM, 1 μM, 0.1 μM, or 0.01 μM. 60 h after transfection, the cell supernatant was discarded, and cellular RNA was collected using TRIZOL. Total RNA was extracted, and cDNA was obtained via reverse transcriptase. Finally, quantitative real-time PCR was used to detect the internal reference gene Gapdh and the SARS N gene subgenome in the cDNA to reflect viral replication in the SARS replicon. The inhibitory effect of different drug concentrations on the virus was calculated, and the IC50 of the drug was determined. 50 The inhibitory effects of different compounds on SARS replicons in HEK 293T cells are shown in Table 3.

[0184] Table 3. Inhibitory effects of the compounds on SARS-CoV-2 replicons in HEK 293T cells.

[0185] compound Virus inhibition rate (%) at 5 μM concentration of compound Virus inhibition rate (%) at 1 μM concentration of compound 1 89.4 86.4 73 88.0 88.7

[0186] In vitro SARS-CoV-2 replicon inhibition experiments showed that compounds 1 and 73 had comparable inhibitory activity against SARS-CoV-2 replicon activity in HEK 293T cells. qPCR quantitative analysis of SARS-CoV-2 concentrations at different drug concentrations revealed that the compounds effectively inhibited SARS-CoV-2 replication in a dose-dependent manner. These compounds hold promise for development as anti-coronavirus drugs.

[0187] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A compound selected from compound 1 or a pharmaceutically acceptable salt thereof: 。 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

3. The pharmaceutical composition according to claim 2, wherein the dosage form of the pharmaceutical composition is tablets, pills, creams, emulsions, ointments, suspensions, lyophilized agents, capsules, sustained-release agents, granules, powders, injectable drugs, or nasal sprays.

4. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 2-3, in the preparation of a medicament for inhibiting the major protease of SARS-CoV-2.

5. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 2-3, in the preparation of a product for the prevention, treatment, or mitigation of coronavirus infection or the replication or propagation of its homologous variants and the resulting cytopathic effects.

6. The use according to claim 5, wherein the coronavirus is selected from MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, mouse hepatitis virus, feline infectious peritonitis virus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus, or porcine coronavirus.

7. The use according to claim 4, wherein the SARS-CoV-2 comprises a mutant strain or a non-mutant strain of SARS-CoV-2.

8. The use according to claim 7, wherein the SARS-CoV-2 mutant strains include SARS-CoV-2 mutant strain B.1, SARS-CoV-2 mutant strain B.1.351, SARS-CoV-2 mutant strain B.1.617.2, SARS-CoV-2 mutant strain C.37, SARS-CoV-2 mutant strain P.1 family tree, SARS-CoV-2 mutant strain B.1.525, SARS-CoV-2 mutant strain B.1.427, or SARS-CoV-2 mutant strain B.1.

429.

9. The use according to any one of claims 5-8, characterized in that, The compound or a pharmaceutically acceptable salt thereof is suitable for human or animal use; and / or the animal is selected from bovine, equine, sheep, suidae, canine, feline, rodent, primate, avian, or fish animals.

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