Use of a nucleoside analogue in the manufacture of a medicament for the treatment of rabies virus infection

Abstract

This invention relates to the use of a nucleoside analog in the preparation of a medicament for treating rabies virus infection, the nucleoside analog being shown in Formula I. The compound shown in Formula I can efficiently inhibit the replication of rabies virus, has low toxicity and side effects, high oral bioavailability, and good drug-like properties, and can be used to treat diseases caused by rabies virus infection.

Description

Technical Field

[0001] This invention relates to the use of a nucleoside analogue, and more specifically, to the use of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, and combinations thereof, in the preparation of a medicament for treating rabies virus infection. Background Technology

[0002] Rabies virus (RABV) belongs to the genus Lyssavirus of the family Rhabdoviridae. It is bullet-shaped with a helical nucleocapsid and an envelope containing single-stranded RNA. It is the pathogen that causes rabies. Rabies virus has two main antigens: one is a glycoprotein antigen on the outer membrane, which binds to acetylcholine receptors, making the virus neurotoxic and inducing the production of neutralizing antibodies and hemagglutination inhibitory antibodies in the body; neutralizing antibodies provide protection. The other is an inner nucleoprotein antigen, which induces the production of complement-fixing antibodies and precipitins, but provides no protection.

[0003] Rabies is an acute infectious disease caused by the rabies virus. Susceptible animals primarily include canines, felines, and chiropterans. Rabies is also a zoonotic disease, mainly transmitted through the saliva of infected animals, especially through bites. After infection, the virus spreads along the nervous system to the central nervous system, causing fatal encephalitis; the main clinical symptoms include fever, headache, hyperactivity, hydrophobia, and convulsions, ultimately leading to coma and death. The incubation period for rabies is usually from several weeks to several months, but can be longer or shorter. The mortality rate of rabies is almost 100%, and there is currently no cure. Immediate medical intervention after rabies exposure is crucial and the only way to prevent it, including wound treatment, vaccination, and passive immunization.

[0004] Currently, there is no effective antiviral treatment for rabies, and once symptoms appear, there is no effective medical treatment. Therefore, there is a great need to develop effective drugs for treating rabies virus infection-related diseases, especially convenient oral medications. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a class of drugs for treating rabies virus infection-related diseases. These drugs have significant anti-rabies virus activity and high oral bioavailability, and can be used for the prevention and treatment of diseases caused by rabies virus.

[0006] Technical solution

[0007] This invention provides the use of a compound of Formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts in the preparation of inhibitors that inhibit the replication of rabies virus.

[0008] The use of a compound of Formula I or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotope derivative or pharmaceutically acceptable salt in the preparation of a medicine for the treatment and / or prevention and relief of diseases related to rabies virus infection;

[0009]

[0010] in,

[0011] B is selected from

[0012]

[0013] X is selected from O, NH, and S;

[0014] R1 and R2 are each independently selected from hydrogen and C. 1-20 Alkyl group, C 3-20 Cycloalkylyl, 3-20 member heterocycloalkylyl, C 2-20 alkenyl acyl, C 2-20 alkynyl group, C 6-20 Aromatic acyl, 5-15 member heteroaromatic acyl, amino C 1-20 Alkyl group, C 1-20 Alkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-20 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Alkoxy C 1-20 Alkyl group, C 3-20 Cycloalkoxy C 1-20 Alkyl groups, the groups remaining after the hydroxyl group is removed from the carboxyl group of amino acids, wherein C 1-20 Alkyl and C 3-20 The cycloalkanoyl group is either unsubstituted or substituted with a halogen.

[0015] Or formed by connecting R1 and R2 together.

[0016] R3 is selected from hydrogen, deuterium, halogen, azide, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Azide C 1-6 Alkyl, cyano C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-6 cycloalkyl, C 1-6 Alkoxy C 1-6 alkyl;

[0017] R4 is selected from hydrogen, C 1-20 Alkyl group, C 3-20 Cycloalkylyl, 3-20 member heterocycloalkylyl, C 2-20 alkenyl acyl, C 2-20 alkynyl group, C 6-20 Aromatic acyl group, 5-15 member heteroaromatic acyl group, C 1-20 Alkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-20 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Alkoxy C 1-20 Alkyl group, C 3-20 Cycloalkoxy C 1-20 Alkyl group, the group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid, C 6-20 Arylamino C 1-6 Alkyl group, 3-20 membered heterocyclic alkyl group 1-6 Alkyl group,

[0018]

[0019] Where C 1-20 Alkyl group, C 2-20 alkenyl acyl and C 3-20 The cycloalkanoyl group is unsubstituted or substituted with aryl, amino, and / or halogen groups, and the 3-20 membered heterocycloalkanoyl group is unsubstituted or substituted with C 1-6 Alkyl substitution;

[0020] R5 is selected from hydroxyl, amino, hydroxylamine (-NHOH), and -NHOR groups. 11 ;

[0021] R6 is selected from hydrogen, deuterium, and halogens;

[0022] R7 is selected from C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 6-20 Aryl, 5-15 quinone heteroaryl, C 3-20 cycloalkyl C 1-20 Alkyl, C 1-20 Alkylamino C 1-20 Alkyl, C 1-20 Dialkylamino C 1-20 Alkyl, C 3-20Cycloalkylamino C 1-20 Alkyl, C 1-20 Alkoxy C 1-20 Alkyl, C 3-20 Cycloalkoxy C 1-20 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-20 Alkyl, R2NH-C 1-20 Alkyl, R2O-C 3-20 cycloalkyl, R2NH-C 3-20 cycloalkyl;

[0023] R8 is selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-20 Aryl, 5-15 quinone heteroaryl;

[0024] R9 is selected from C 1-18 Alkyl, C 6-20 arylmethyl;

[0025] R 10 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-20 Aryl, 5-15 quinone heteroaryl;

[0026] R 11 Selected from C 1-20 Alkyl group, C 3-20 Cycloalkyl acyl, amino C 1-20 Alkyl group, C 1-20 Alkylamino C 1-6 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-6 Alkyl group, C 1-20 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxycarbonyloxymethylene;

[0027] R 12 Selected from hydrogen and C 1-6 alkyl.

[0028] This invention provides the use of a composition comprising a compound of Formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt in the preparation of an inhibitor that inhibits the replication of rabies virus.

[0029] The use of a composition comprising a compound of Formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt in the preparation of a medicament for the treatment and / or prevention and relief of diseases related to rabies virus infection;

[0030]

[0031] The definitions of each substituent are the same as those above.

[0032] In some embodiments, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, isotope label, or prodrug thereof, is represented by the following Formula II:

[0033]

[0034] Among them, R1, R2, R4, R 11 It has the definition described in Equation I above.

[0035] In some embodiments, the compound represented by Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, isotope label, or prodrug thereof, is represented by the following Formula III:

[0036]

[0037] in,

[0038] B is selected from

[0039] Specifically, selected from

[0040] Among them, R2, R3, R5, R7, R 10 It has the definition described in Equation I above.

[0041] In some preferred embodiments,

[0042] R1 and R2 are each independently selected from hydrogen and C. 2-10 Alkyl group, C 3-10 Cycloalkylyl, 3-10 member heterocycloalkylyl, C 3-10 alkenyl acyl, C 3-10 alkynyl group, C 6-12 Aromatic acyl group, 5-10 member heteroaromatic acyl group, amino C 1-10 Alkyl group, C 1-10 Alkylamino C 1-10 Alkyl group, C 1-10 Dialkylamino C 1-10 Alkyl group, C 3-10 Cycloalkylamino C 1-10Alkyl group, C 1-10 Alkoxy C 1-10 Alkyl group, C 3-10 Cycloalkoxy C 1-10 Alkyl groups, the groups remaining after the hydroxyl group is removed from the carboxyl group of amino acids, wherein C 2-10 Alkyl and C 3-10 The cycloalkanoyl group is either unsubstituted or halogenated; or R1 and R2 are linked together to form...

[0043] R3 is selected from hydrogen, deuterium, halogen, azide, cyano, and C. 1-5 Alkyl, Halogenated C 1-5 Alkyl, Azide C 1-5 Alkyl, cyano C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 cycloalkyl, C 1-5 Alkoxy C 1-5 alkyl;

[0044] R4 is selected from hydrogen, C 2-20 Alkyl group, C 3-10 Cycloalkylyl, 3-10 member heterocycloalkylyl, C 2-10 alkenyl acyl, C 2-10 alkynyl group, C 6-15 Aromatic acyl group, 5-12 heteroaryl group, C 1-10 Alkylamino C 1-10 Alkyl group, C 1-10 Dialkylamino C 1-10 Alkyl group, C 3-10 Cycloalkylamino C 1-10 Alkyl group, C 1-10 Alkoxy C 1-10 Alkyl group, C 3-10 Cycloalkoxy C 1-10 Alkyl group, the group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid, C 6-15 Arylamino C 1-5 Alkyl group, 3-10 membered heterocyclic alkyl group 1-5 Alkyl group,

[0045]

[0046] Where C 2-20 Alkyl group, C 2-10 alkenyl acyl and C 3-10 The cycloalkanoyl group is unsubstituted or substituted with an aryl, amino, and / or halogen group, and the 3-10 member heterocycloalkanoyl group is unsubstituted or substituted with a C- group. 1-6 Alkyl substitution;

[0047] R7 is selected from C 1-20 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 2-10 alkenyl, C 3-10 alkynyl group, C 6-12 Aryl, 5-12 heteroaryl, C 3-10 cycloalkyl C 1-10 Alkyl, C 1-10 Alkylamino C 1-10 Alkyl, C 1-10 Dialkylamino C 1-10 Alkyl, C 3-10 Cycloalkylamino C 1-10 Alkyl, C 1-10 Alkoxy C 1-10 Alkyl, C 3-10 Cycloalkoxy C 1-10 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-10 Alkyl, R2NH-C 1-10 Alkyl, R2O-C 3-10 cycloalkyl, R2NH-C 3-10 cycloalkyl;

[0048] R8 is selected from C 1-5 Alkyl, C 3-5 cycloalkyl, C 6-14 Aryl, 5-12 heteroaryl;

[0049] R9 is selected from C 1-10 Alkyl, C 6-15 arylmethyl;

[0050] R 10 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-14 Aryl, 5-12 heteroaryl;

[0051] R 11 Selected from C 1-10 Alkyl group, C 3-10 Cycloalkyl acyl, amino C 1-10 Alkyl group, C 1-10 Alkylamino C 1-6 Alkyl group, C 3-10 Cycloalkylamino C 1-10 Alkyl group, C 1-10 Dialkylamino C 1-6 Alkyl group, C 1-10 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxycarbonyloxymethylene.

[0052] In some preferred embodiments,

[0053] R1 and R2 are each independently selected from hydrogen and C. 1-20 Alkyl group, C 6-20 Aromatic acyl groups, 5-20 heteroaryl groups, or R1 and R2 linked together, form Preferably, R1 and R2 are each independently selected from hydrogen and C. 2-10 Alkyl group, C 6-12 Aromatic acyl groups, 5-10 heteroaryl groups, or R1 and R2 linked together form Preferably, R1 and R2 are each independently selected from hydrogen and C. 2-10 Alkyl group, C 6-10 Aromatic acyl groups, 5-6 heteroaryl groups, or R1 and R2 linked together form Preferably, C 6-10 The aryl group in the aromatic acyl group is selected from phenyl and naphthyl; the heteroaryl group in the 5-6 member heteroaryl group is selected from pyridinyl, pyrimidinyl, pyrazinyl, furanyl, and thiopheneyl, preferably an aromatic heteroaryl containing an N atom, including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrazin-2-yl;

[0054] R3 is selected from hydrogen, deuterium, halogen, azide, cyano, and C. 1-6 Alkyl group; preferably, R3 is selected from hydrogen, deuterium, and halogen; most preferably, hydrogen and fluorine;

[0055] R4 is selected from hydrogen, C 1-20 Alkyl group, C 3-20 Cycloalkylyl, 3-20 member heterocycloalkylyl, C 6-20 Aromatic acyl group, 5-15 membered heteroaromatic acyl group, or the group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid; preferably, R4 is selected from hydrogen, C 2-16 Alkyl group, C 3-10 Cycloalkylyl, 3-10 member heterocycloalkylyl, C 6-12 Aromatic acyl group, 5-10 membered heteroaromatic acyl group, or a group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid; preferably, R4 is selected from hydrogen, C 2-16 Alkyl group, C 3-6 Cycloalkylyl, 3-6 membered heterocycloalkylyl, C 6-10 Aromatic acyl group, 5-6 membered heteroaromatic acyl group, or a group obtained by removing the hydroxyl group from the carboxyl group of an amino acid; preferably, the C 6-10The aryl group in the aromatic acyl group is selected from phenyl and naphthyl; preferably, the 3-6 membered heterocyclic alkyl acyl group is an azacyclic alkyl acyl group, such as azacyclic butane-3-yl acyl or piperidin-4-yl acyl; preferably, the heteroaryl group in the 5-6 membered heteroaryl acyl group is selected from pyridinyl, pyrimidinyl, pyrazinyl, furanyl, and thiopheneyl, and more preferably is an aromatic heteroaryl group containing an N atom, including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrazin-2-yl; the amino acid is selected from L-alanine, L-valine, and L-phenylglycine;

[0056] R7 is selected from C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 2-20 alkenyl, C 6-20 Aryl, 5-15 quinone heteroaryl, C 3-20 cycloalkyl C 1-20 Alkyl, C 1-20 Alkylamino C 1-20 Alkyl, C 1-20 Dialkylamino C 1-20 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-20 Alkyl group; wherein R2 is C 1-20 Alkyl group; preferably, R7 is selected from C 1-20 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-10 cycloalkyl C 1-10 Alkyl, C 1-10 Alkylamino C 1-10 Alkyl, C 1-10 Dialkylamino C 1-10 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-10 Alkyl group; wherein R2 is C 2-10 Alkyl group; more preferably, R7 is selected from C 1-16 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 alkenyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl C 1-8 Alkyl, C 1-4 Alkylamino C 1-8 Alkyl, C 1-4 Dialkylamino C 1-8 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-8 Alkyl group; wherein R2 is C 2-8Alkyl group; preferably, the 3-8 membered heterocyclic alkyl group is an azahexacyclic alkyl group, such as azahexacyclic butane-3-yl, pyrrolidinyl, piperidin-4-yl; preferably, the C 6-10 The aryl group is selected from phenyl and naphthyl; preferably, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group selected from pyridyl, pyrimidinyl, pyrazinyl, furanyl, and thiopheneyl, and more preferably an aromatic heteroaryl group containing an N atom, including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrazin-2-yl; the amino acid is preferably selected from L-alanine, L-valine, and L-phenylglycine;

[0057] Other substituents are defined as described above.

[0058] In some embodiments, the compound represented by Formula I is selected from any of the following:

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] Preferably, the compound represented by Formula I is selected from any of the following:

[0074]

[0075]

[0076]

[0077] Beneficial effects

[0078] (a) The compound of formula I described in this invention can effectively inhibit the replication of rabies virus.

[0079] (b) The compound of formula I described in this invention has high in vivo inhibitory activity against rabies virus.

[0080] (c) The compound of Formula I described in this invention has high oral bioavailability, stable metabolism, and good drug-like properties, which suggests that the active compound of this invention has a good pharmaceutical prospect in the field of treating rabies virus infection. Detailed Implementation

[0081] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0082] On the one hand, the present invention provides the use of a compound of Formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts in the preparation of inhibitors that inhibit the replication of rabies virus.

[0083]

[0084] in,

[0085] B is selected from

[0086]

[0087] X is selected from O, NH, and S;

[0088] R1 and R2 are each independently selected from hydrogen and C. 1-20 Alkyl group, C 3-20 Cycloalkylyl, 3-20 member heterocycloalkylyl, C 2-20 alkenyl acyl, C 2-20 alkynyl group, C 6-20 Aromatic acyl, 5-15 member heteroaromatic acyl, amino C 1-20 Alkyl group, C 1-20 Alkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-20 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Alkoxy C 1-20 Alkyl group, C 3-20 Cycloalkoxy C 1-20Alkyl groups, the groups remaining after the hydroxyl group is removed from the carboxyl group of amino acids, wherein C 1-20 Alkyl and C 3-20 The cycloalkanoyl group is either unsubstituted or substituted with a halogen.

[0089] Or formed by connecting R1 and R2 together.

[0090] R3 is selected from hydrogen, deuterium, halogen, azide, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Azide C 1-6 Alkyl, cyano C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy C 1-6 alkyl;

[0091] R4 is selected from hydrogen, C 1-20 Alkyl group, C 3-20 Cycloalkylyl, 3-20 member heterocycloalkylyl, C 2-20 alkenyl acyl, C 2-20 alkynyl group, C 6-20 Aromatic acyl, 5-15 member heteroaromatic acyl, amino C 1-20 Alkyl group, C 1-20 Alkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-20 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Alkoxy C 1-20 Alkyl group, C 3-20 Cycloalkoxy C 1-20 Alkyl group, the group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid, C 6-20 Arylamino C 1-6 Alkyl group, 3-20 membered heterocyclic alkyl group 1-6 Alkyl group,

[0092]

[0093] Where C 1-20 Alkyl and C 3-20 The cycloalkanoyl group is unsubstituted or halogenated, and the 3-20 membered heterocyclic alkyl group is unsubstituted or C-substituted. 1-6 Alkyl substitution;

[0094] R5 is selected from hydroxyl, amino, hydroxylamine (-NHOH), and -NHOR groups. 11 ;

[0095] R6 is selected from hydrogen, deuterium, and halogens;

[0096] R7 is selected from C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 6-20 Aryl, 5-15 membered heteroaryl, amino C 1-20 Alkyl, C 3-20 cycloalkyl C 1-20 Alkyl, C 1-20 Alkylamino C 1-20 Alkyl, C 1-20 Dialkylamino C 1-20 Alkyl, C 3-20 Cycloalkylamino C 1-20 Alkyl, C 1-20 Alkoxy C 1-20 Alkyl, C 3-20 Cycloalkoxy C 1-20 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-20 Alkyl, R2NH-C 1-20 Alkyl, R2O-C 3-20 cycloalkyl, R2NH-C 3-20 cycloalkyl;

[0097] R8 is selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-20 Aryl, 5-15 quinone heteroaryl;

[0098] R9 is selected from C 1-18 Alkyl, methylene C 6-20 Aryl;

[0099] R 10 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-20 Aryl, 5-15 quinone heteroaryl;

[0100] R 11 Selected from C 1-20 Alkyl group, C 3-20 Cycloalkyl acyl, amino C 1-20 Alkyl group, C 1-20 Alkylamino C 1-6 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-6 Alkyl group, C 1-20 Alkoxy C 1-6 Alkyl group, C1-6 Alkoxycarbonyloxymethylene;

[0101] R 12 Selected from hydrogen and C 1-6 alkyl.

[0102] On the other hand, the present invention provides the use of a compound of Formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts in the preparation of medicaments for treating and / or preventing or alleviating diseases related to rabies virus infection.

[0103] On the other hand, the present invention provides the use of a composition comprising a compound of Formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt in the preparation of an inhibitor that inhibits the replication of rabies virus.

[0104] On the other hand, the use of a compound of Formula I or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt in the preparation of a medicament for treating and / or preventing or alleviating diseases related to rabies virus infection;

[0105] In some embodiments, the diseases caused by the rabies virus infection are selected from rabies and its complications.

[0106] In some embodiments, the pharmaceutical composition includes at least one of the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, as well as pharmaceutically acceptable carriers, diluents or excipients.

[0107] In some embodiments, the pharmaceutical composition further comprises other antiviral agents selected from the group consisting of: PF-07321332 (Nirmatrelvir), S-217622 (Ensitrelvir), FHPI (4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1,3-dihydro-imidazol-2-yl]cyclohexyl-2,5-dien-1-one), aloxistatin, conivaptan, favipiravir, Galidesivir, and NHC (EIDD). -1931), EIDD-2801, GC-376, Lopinavir, Ritonavir, Nelfinavir; Chloroquine, Hydroxychloroquine, Cyclosporine, Carrimycin, Baicalin, Baicalein, Forsythoside, Chlorogenic acid acid), emodin, mycophenolic acid, mycophenolate mofetil, naphthoquine, ciclesonide, ribavirin, penciclovir, leflunomide, teriflunomide, nafamostat, nitazoxanide, darunavir, arbidol, carmostat, niclosamide, baricitinib, ruxolitinib, dasatinib, saquinavir, beclabuvir, simeprevir, palilizumab, motavizumab, RSV-IGIV MEDI557, A-60444 (RSV-604), MDT-637, BMS-433771, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0108] In some embodiments, the pharmaceutical composition further comprises other antiviral drugs selected from the group consisting of: PF-07321332 (Nirmatrelvir), S-217622 (Ensitrelvir), FHPI (4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1,3-dihydro-imidazol-2-yl]cyclohexyl-2,5-dien-1-one), aloxistatin, conivaptan, favipiravir, NHC (EIDD-1931), EIDD-2801, baicalin, baicalein, forsythoside, chlorogenic acid, emodin, glycyrrhizic acid, chloroquine, hydroxychloroquine, and nelfinavir.

[0109] In some embodiments, the pharmaceutical composition further comprises other antiviral drugs selected from the group consisting of: interferon, RNA-dependent RNA polymerase inhibitors (such as favipiravir, Galidesivir, NHC (EIDD-1931), EIDD-2801), 3CL protease inhibitors (such as GC-376), lopinavir, ritonavir, nelfinavir, S-217622 (Ensitrelvir), PF-07321332 (Nirmatrelvir); chloroquine, hydroxychloroquine, cyclosporine, carrimycin, baicalin, baicalein, forsythoside, chlorogenic acid, emodin, and mycophenolic acid. cid), Mycophenolate mofetil, Naphthoquine, Ciclesonide, Ribavirin, Penciclovir, Leflunomide, Teriflunomide, Nafamostat, Nitazoxanide, Darunavir, Arbidol, Camostat, Niclosamide, Baricitinib, Rucote Ruxolitinib, dasatinib, saquinavir, beclabuvir, simeprevir, palizumab, motavizumab, RSV-IGIVMEDI-557, A-60444 (RSV-604), MDT637, BMS-433771, FHPI (4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1,3-dihydro-imidazol-2-yl]cyclohexyl-2,5-dien-1-one), aloxistatin, conivaptan, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0110] In some embodiments, the pharmaceutical composition further comprises other drugs selected from the group consisting of: zinc, fingolimod, vitamin C, olmesartan medoxomil, valsartan, losartan, thalidomide, glycyrrhizic acid, artemisinin, dihydroartemisinin, artesunate, artemisone, azithromycin, escin, naproxen, or combinations thereof.

[0111] In some embodiments, the pharmaceutical composition further comprises other drugs selected from the group consisting of: (Y1) RNA replicase inhibitors (such as favipiravir, Galidesivir, NHC, EIDD-2801); (Y2) lopinavir; (Y3) ritonavir; (Y4) chloroquine, hydroxychloroquine, or a pharmaceutically acceptable salt thereof (such as chloroquine phosphate); (Y5) nelfinavir; and (Y6) any combination of Y1 to Y5 above.

[0112] In some embodiments, the pharmaceutical composition further comprises other drugs selected from the group consisting of: interferon, RNA-dependent RNA polymerase inhibitors (such as favipiravir, Galidesivir, NHC, EIDD-2801); 3CL protease inhibitors (such as GC-376), lopinavir, ritonavir, nelfinavir; chloroquine, hydroxychloroquine, cyclosporine, carrimycin, baicalin, baicalein, forsythoside, chlorogenic acid, emodin, mycophenolic acid, and mycophenolate. mofetil, Naphthoquine, Ciclesonide, Ribavirin, Penciclovir, Leflunomide, Teriflunomide, Nafamostat, Nitazoxanide, Darunavir, Arbidol, Camostat, Niclosamide The interferon comprises (Niclosamide), baricitinib, ruxolitinib, dasatinib, saquinavir, beclabuvir, simeprevir, palizumab, motavizumab, RSV-IGIVMEDI557, A-60444 (RSV-604), MDT-637, BMS-433771, or pharmaceutically acceptable salts thereof, or combinations thereof. The interferon includes one or more of interferon α-2a, interferon α-2b, interferon α-n1, interferon α-n3, interferon β-1a, and interferon β-1b.

[0113] In some embodiments, the pharmaceutical composition may also contain other drugs selected from the group consisting of, for example, “anti-inflammatory signal transduction modulators” (referred to herein as AISTMs) such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB via IKK inhibition), or kinase inhibitors (e.g., blocking P38MAP, JNK, PI3K, EGFR, or Syk), which is a logical approach to cutting off inflammation because these small molecules target a limited number of common intracellular pathways—those signal transduction pathways that are key points of anti-inflammatory therapeutic intervention (see review by PJ Barnes, 2006). These non-restrictive additional therapeutic agents include: 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor roflumilast); 4-[2-(3-cyclopentoxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor) CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methanesulfonyl)amino]-1-dibenzofuran carboxamide (PDE-4 inhibitor Omister); N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy) 4-pyridin-4-yl)-amide (PDE-4 inhibitor Sch351591); 4-[5-(4-fluorophenyl)-2-(4-methylsulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentoxy-4-methoxy) 2-Diethylamino-ethyl ester of (-phenyl)-cyclohexanecarboxylic acid (2-diethyl-ethyl ester prodrug of silostabdominal, PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, EGFR inhibitor); and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, EGFR inhibitor).

[0114] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0115] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound.

[0116] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable carriers, diluents, or excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable carriers, diluents, or excipients.

[0117] All compounds involved in this invention, as well as mixtures and compositions comprising compounds of this invention, can be administered to a living organism via any route of administration. Routes of administration may include oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, or local or systemic transdermal administration.

[0118] All compounds involved in this invention, as well as mixtures and compositions containing compounds of this invention, can be formulated into single doses, containing the active compounds of this invention, as well as carriers, excipients, etc. The dosage forms can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalers, suspensions, dry suspensions, patches, lotions, etc. These dosage forms may contain commonly used pharmaceutical ingredients, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonic adjusters, anti-adhesives, etc.

[0119] Suitable formulations for the aforementioned dosage forms are available from publicly available sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2006, and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. Therefore, those skilled in the art can readily prepare them.

[0120] Depending on the nature and severity of the disease suffered by different individuals, as well as factors such as age, sex, weight, and route of administration, different dosages can be selected. The dosage of the compound of the present invention can be from 0.01 to 500 mg / kg per day, preferably 1-100 mg / kg per day, and can be administered once or multiple times.

[0121] Terminology Explanation:

[0122] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0123] Term "C" 1-20"Alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, and 1,1-dimethylbutyl. 1,2-Dimethylbutyl, 2,2-Dimethylbutyl, 1,3-Dimethylbutyl, 2-Ethylbutyl, 2-Methylpentyl, 3-Methylpentyl, 4-Methylpentyl, 2,3-Dimethylbutyl, n-Heptyl, 2-Methylhexyl, 3-Methylhexyl, 4-Methylhexyl, 5-Methylhexyl, 2,3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3- Ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from the group consisting of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0124] Term "C" 1-20 "alkylyl" means that the group C 1-20 Alkyl-C(O)-, where "C1-20 "alkyl" means as defined above.

[0125] Term "C" 3-10 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 10 carbon atoms, preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0126] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0127] Term "C" 3-10 "Cycloalkylformyl" means that the group C 3-10 cycloalkyl-C(O)-, where "C 3-10 "Cycloalkyl" means as defined above.

[0128] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0129] The term "hydroxyl group" refers to -OH.

[0130] The term "amino" refers to -NH2.

[0131] The term "cyano" refers to -CN.

[0132] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, that are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0133] In the chemical structure of the compound described in this invention, the bond... No configuration was specified, i.e., key It can be Or simultaneously include Two configurations.

[0134] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and hindered isomers, etc.

[0135] The term "isotope derivative" refers to compounds whose structure differs only in the presence of one or more isotope-enriched atoms. For example, compounds with the structure of this invention use "deuterium" or "tritium" instead of hydrogen, or use... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this invention. Such compounds can be used as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds in this invention refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to relevant literature. Commercially available deuteration starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, thus providing certain therapeutic advantages.

[0136] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in SMBerge's description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the compounds of the present invention with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of this invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts or N-containing organic bases. + (C 1-6 Alkyl)4 salt.

[0137] The term "solvent" refers to the physical bond between the compound of the present invention and one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonds. In some cases, for example, when one or more, preferably one to three, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0138] The term "prodrug" refers to a compound that can be converted in the body to produce an active drug substance under physiological conditions, such as through hydrolysis in the blood.

[0139] The term "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0140] The terms involved in this invention have been defined above. Those skilled in the art can also understand the above terms in conjunction with the prior art. The following is a further description based on the content of this invention and the definition of the terms.

[0141] The following examples further describe the preparation of the compounds and pharmaceutically acceptable salts of the present invention, but these examples are not intended to limit the scope of the present invention.

[0142] Experimental methods in the embodiments of this invention that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0143] In the following examples, the uridine raw material was purchased from Shanghai Haohong Biomedical Technology Co., Ltd. or Wuhu Nuowei Chemical Technology Co., Ltd. The starting materials, intermediates, and some compounds were prepared according to the methods described in the literature (Chemical Communications, 2020, 56, 13363-13364; Nature, 2016, 531, 381-385; Science, 2022, 375, 161; Chinese patent applications CN114096543A and CN 115215914 A).

[0144] Example 1: Preparation of compound B34

[0145]

[0146] Compound B34 of the present invention was prepared by the synthetic method of related compound A1 described in the specification of CN 115215914 A.

[0147] Example 2: Preparation of compound B35

[0148]

[0149] Compound B35 of the present invention was prepared by the synthetic method of related compound A2 described in the specification of CN 115215914 A.

[0150] Example 3: Preparation of compound B57

[0151]

[0152] Compound B57 of the present invention was prepared by the synthetic method of related compound A54 described in the specification of CN 115215914 A.

[0153] Example 4: Preparation of compound B52

[0154]

[0155] Compound B52 of the present invention was prepared by the synthetic method of related compound A39 described in the specification of CN 115215914 A.

[0156] Example 5: Preparation of compound B54

[0157]

[0158] Compound B54 of the present invention was prepared by the synthetic method of related compound A41 described in the specification of CN 115215914 A.

[0159] Example 6: Preparation of compound B60

[0160]

[0161] Compound B60 of the present invention was prepared by the synthetic method of related compound A56 described in the specification of CN 115215914 A.

[0162] Example 7: Preparation of compound B37

[0163]

[0164] Compound B37 of the present invention was prepared by the synthetic method of related compound A4 described in the specification of CN 115215914 A.

[0165] Example 8: Preparation of compound C1

[0166]

[0167] Compound C1 of the present invention was prepared with reference to the method described in PCT patent WO2014100505.

[0168] Example 9: Preparation of compounds C52, C114 and C305

[0169]

[0170] To a 500 mL three-necked flask, add 160 g (247 mmol) of 40% tetrabutylammonium hydroxide, 32 g (281 mmol) of trifluoroacetic acid, 20 g (50.20 mmol) of C52-0 (prepared according to the method described in Science, 2022, 375, 161), and 150 mL of dichloromethane. Stir at room temperature, and add 50 g (246 mmol) of 85% m-chloroperoxybenzoic acid in portions. React overnight; TLC showed complete reaction. Filter, and purge the filter cake with 30 mL of 2-butanone. After 1 hour, filter again, wash the filter cake with 2-butanone, and dry under vacuum at 40 °C for 5 hours to give intermediate C52-1, 11 g, yield 76%.

[0171] C52-1 (11 g, 38.20 mmol), 4-dimethylaminopyridine (280 mg, 2.30 mmol), triethylamine (9.7 g, 95.90 mmol), isobutyric anhydride (7.3 g, 46.11 mmol), and ethyl acetate (220 mL) were added to a 500 mL three-necked flask. The mixture was stirred at room temperature for 30 minutes, and TLC showed that the reaction was complete. Water and ethyl acetate were added, and the mixture was stirred. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound C305 (also used as an intermediate for subsequent compounds), 7.6 g, yield 56%.

[0172] C305 (200 mg, 0.60 mmol) was added to N,N-dimethylformamide (2 mL) under nitrogen protection. Potassium carbonate (77 mg, 0.60 mmol) was added in an ice bath, and the mixture was stirred for 5 minutes. Then, chloromethyl isopropyl ester (153 mg, 1.20 mmol) was added, and the mixture was brought to room temperature and stirred overnight. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain C114, 205 mg. 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=8.1Hz,1H),6.42(s,1H),5.93(d,J=8.1Hz,1H ),5.81–5.63(m,4H),4.44–4.36(m,2H),2.65–2.50(m,2H),1.15–1.03(m,12H). ESI-MS m / z=481.2[M+1] + .

[0173] C114 (205 mg, 0.45 mmol) was added to methanol (2 mL), followed by potassium carbonate (38 mg, 0.30 mmol) at room temperature. The mixture was stirred for 7 minutes at room temperature, and TLC showed that the reaction was complete. Acetic acid was added dropwise to the reaction solution until the pH reached approximately 7. Water and 2-methyltetrahydrofuran were then added, and the mixture was stirred. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain C52, 90 mg, with a two-step yield of 37%. 1 H NMR (400MHz, chloroform-d) δ7.34(d,J=8.2Hz,1H),5.92(s,2H),5.82(d,J=8.2Hz,1H),5.76(d,J=1.5Hz,1H),4.60–4.45(m,2 H), 4.41 (d, J = 7.9Hz, 2H), 3.39 (d, J = 4.3Hz, 1H), 3.10 (dd, J = 9.7, 2.1Hz, 1H), 2.67–2.49 (m, 2H), 1.24–1.11 (m, 12H). 19F NMR (377 MHz, chloroform-d) δ -121.74. ESI-MS m / z = 433.2 [M+1] + .

[0174] Example 10: Preparation of compound C23

[0175]

[0176] Compound C52-2 (i.e., compound C305) (300 mg, 0.84 mmol) was added to pyridine (3 mL), followed by N,N-diisopropylethylamine (433 mg, 3.40 mmol). Ethyl chloroformate (227 mg, 2.11 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature, and the reaction was allowed to proceed for 10 minutes. TLC showed that the reaction was complete. Copper sulfate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain C38 (269 mg), which was then directly used in the next reaction step. 1 H NMR (400MHz, methanol-d4) δ7.58(d,J=8.1Hz,1H),5.88(d,J=2.1Hz,1H),5.69(d,J=8.0Hz,1H),4.55(dd,J=19.2,6.9H z,1H),4.43–4.35(m,2H),4.29(dd,J=12.0,8.2Hz,1H),4.03–3.66(m,2H),2.68–2.56(m,1H),1.23–1.09(m,9H). ESI-MSm / z=431.3[M+1] + .

[0177] The C38 obtained in the previous step was added to methanol (2 mL), potassium carbonate (17 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. TLC showed that the reaction was complete. Acetic acid was added dropwise to the reaction solution until the pH was about 7. Water and 2-methyltetrahydrofuran were added, and the mixture was stirred. The organic phase was separated, dried with anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain compound C23, 96 mg. The two-step yield was 28%. 1 ¹H NMR (400MHz, chloroform-d) δ 7.32 (d, J = 8.2Hz, 1H), 5.81 (d, J = 8.3Hz, 1H), 5.71 (s, 1H), 4.59–4.36 (m, 6H), 3.40–3.31 (m, 1H), 3.13–3.02 (m, 1H), 2.66–2.54 (m, 1H), 1.42 (t, J = 7.2Hz, 3H), 1.23–1.15 (m, 6H). 19F NMR (377 MHz, chloroform-d) δ -121.73. ESI-MS m / z = 405.1 [M+1] + .

[0178] Example 11: Preparation of compound C44

[0179]

[0180] Compound B (800 mg, 1.25 mmol, prepared according to the method described in Science, 2022, 375, 161) was dissolved in acetone (8 mL), and potassium carbonate (173 mg, 1.25 mmol) was added. Under nitrogen protection, chloromethyl isobutyrate (257 mg, 1.88 mmol) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 h, and TLC showed that the starting material reacted completely. The reaction solution was diluted with ethyl acetate, filtered, concentrated, and purified by silica gel column chromatography to give intermediate C44-1, 770 mg, as an oil, in 83% yield.

[0181] 40% tetrabutylammonium hydroxide (3.37 g, 5.20 mmol) was dissolved in dichloromethane (7.7 mL), and trifluoroacetic acid (593 mg, 5.20 mmol) was added under ice-water bath conditions, with stirring for 10 min. Then, a solution of C44-1 (770 mg, 1.04 mmol) in dichloromethane (7.7 mL) was added dropwise, followed by the addition of 85% m-chloroperoxybenzoic acid (1.06 g, 5.20 mmol) in portions. The reaction was allowed to proceed overnight at room temperature, and TLC monitoring showed that the starting material had essentially disappeared. Water and dichloromethane were added to the reaction mixture, and the mixture was stirred and allowed to stand for phase separation. The organic phase was separated, washed successively with water and saturated brine, dried, concentrated, and purified by silica gel column chromatography to obtain intermediate C44-2, 320 mg of oil, in 49% yield.

[0182] C44-2 (320 mg, 0.51 mmol) was dissolved in tetrahydrofuran (3.2 mL), and 10% palladium on carbon (160 mg) was added. The mixture was purged with hydrogen three times, and reacted at room temperature and atmospheric pressure for 2 h. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give compound C44, 90 mg, in 49% yield. 1H NMR (400MHz, DMSO-d6) δ7.83(d,J=8.2Hz,1H),6.01(d,J=2.4Hz,1H),5.86(d,J=8.2Hz,1H),5.77(s,2H),5.73(d,J=5.5Hz,1H) ,5.53(t,J=5.8Hz,1H),5.21(d,J=8.7Hz,1H),4.31–4.14(m,2H),3.61–3.54(m,2H),2.58–2.50(m,1H),1.06(d,J=6.9Hz,6H). ESI-MS m / z=363.2[M+1] + .

[0183] Example 12: Preparation of compound C45

[0184]

[0185] Following the procedure in Preparation Example 11, B (1 g, 1.56 mmol) reacted with chloromethyl 2-ethylbutyrate (770 mg, 4.68 mmol) to give intermediate C45-1; C45-1 was oxidized with m-chloroperoxybenzoic acid to give intermediate C45-2; C45-2 was deprotected with hydrogen / palladium on carbon, and the product was purified by silica gel column chromatography to give compound C45, 100 mg, with a three-step yield of 16%. 1 H NMR (400MHz, DMSO-d6) δ7.84(d,J=8.2Hz,1H),6.01(d,J=2.6Hz,1H),5.86(d,J=8.2Hz,1H),5.79(s,2H),5.73(d,J=5.4Hz,1H),5.53(t, J=5.9Hz,1H),5.22(d,J=8.7Hz,1H),4.31–4.12(m,2H),3.62–3.53(m,2H),2.23–2.14(m,1H),1.56–1.37(m,4H),0.82(t,J=7.4Hz,6H). ESI-MS m / z=391.2[M+1] + .

[0186] Example 13: Preparation of compounds C182 and C183

[0187]

[0188] In a three-necked flask, C52-2 (i.e., compound C305) (1.5 g, 4.18 mmol) and acetonitrile (15 mL) were added and stirred. Cerium ammonium nitrate (1.33 g, 2.41 mmol) and iodine (740 mg, 2.92 mmol) were added sequentially. The reaction was carried out overnight at 90 °C, and TLC showed complete reaction. The reaction solution was concentrated, and the crude product was obtained by column chromatography. The crude product was then slurried with isopropyl ether (6 mL) to give C182-1, 1.2 g, yield 59%.

[0189] In a high-pressure reactor, tetrahydrofuran (12 mL), C182-1 (600 mg, 1.22 mmol), triethylamine (250 mg, 2.50 mmol), and palladium on carbon (600 mg) were added sequentially. Deuterium gas was introduced, and the pressure was increased to 1.1 MPa. The reaction was carried out overnight at room temperature, and TLC showed that the reaction was complete. The mixture was filtered, and the filtrate was concentrated to obtain crude C182-2, 777 mg, which was directly used for the next step of the reaction.

[0190] In a three-necked flask, crude C182-2 obtained in the previous step and N,N-dimethylformamide (16 mL) were added, followed by potassium carbonate (298 mg, 2.20 mmol). Under nitrogen protection, chloromethyl isobutyrate (442 mg, 3.20 mmol) was added dropwise in an ice bath. After the addition was complete, the mixture was brought to room temperature and reacted overnight. TLC showed that the reaction was complete. Water and ethyl acetate were added to the reaction solution, and the mixture was stirred. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to obtain crude C182. Column chromatography was used to separate the crude product, yielding 265 mg. The two-step yield was 48%. 1 HNMR (400MHz, DMSO-d6) δ7.91 (s, 1H), 6.42 (s, 1H), 5.81–5.63 (m, 4H), 4.40 (d, J = 15.4Hz, 2H), 2.65–2.49 (m, 2H), -1.15–1.03 (m, 12H). ESI-MS m / z=504.1[M+1] + .

[0191] Following the synthesis method of C52, C182 (200 mg, 0.44 mmol) and potassium carbonate (18 mg, 0.13 mmol) were reacted in methanol to give C183, 118 mg, in a yield of 62%. 1 H NMR (400MHz, DMSO-d6) δ7.78 (s, 1H), 5.96 (d, J = 2.5Hz, 1H), 5.82–5.73 (m, 3H), 5.37 (d, J = 8. 8Hz,1H),4.43–4.26(m,3H),4.21(t,J=11.3Hz,1H),2.66–2.51(m,2H),1.15–0.99(m,12H). ESI-MS m / z=434.2[M+1]+ .

[0192] Example 14: Preparation of compound C103

[0193]

[0194] C52-2 (i.e., compound C305) (200 mg, 0.56 mmol) and N,N-dimethylformamide (2 mL) were added to a 25 mL three-necked flask. Under nitrogen protection, potassium carbonate (77 mg, 0.56 mmol) was added in an ice bath. After stirring for 5 minutes, chloromethyl ethyl carbonate (155 mg, 1.12 mmol) was added, and the mixture was brought to room temperature and stirred overnight. TLC showed that the reaction was complete. Water and ethyl acetate were added, and the mixture was stirred. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give C103-1, 248 mg, in 97% yield.

[0195] C103-1 (200 mg, 0.43 mmol), methanol (2 mL), and potassium carbonate (3 mg, 0.02 mmol) were added to a 25 mL three-necked flask. The mixture was stirred at room temperature for 5 minutes, and TLC showed that the reaction was complete. Acetic acid was added to the reaction solution until the pH reached approximately 7. Water and ethyl acetate were then added, and the mixture was stirred. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain C103, 50 mg, in a yield of 26%. 1 H NMR (400MHz, chloroform-d) δ7.32(d,J=8.2Hz,1H),5.96(s,2H),5.82(d,J=8.2Hz,1H),5.73(d,J=1.4Hz,1H),4.64–4.46(m,2H),4.40(d,J=7.8Hz, 2H), 4.24 (q, J = 7.1Hz, 2H), 3.30 (d, J = 4.2Hz, 1H), 3.05 (dd, J = 9.8, 2.2Hz, 1H), 2.67–2.55 (m, 1H), 1.31 (t, J = 7.1Hz, 3H), 1.23–1.17 (m, 6H). 19 F NMR (377 MHz, chloroform-d) δ -121.58. ESI-MS m / z = 435.2 [M+1] + .

[0196] Example 15: Preparation of compounds C199 and C292

[0197]

[0198] C199-1 (1.50 g, 4.03 mmol, prepared according to the method described in PCT patent WO2014100505) was added to dichloromethane (15 mL), followed by triethylamine (1.60 g, 16.12 mmol), 4-dimethylaminopyridine (0.24 g, 2.02 mmol), and isobutyric anhydride (1.30 g, 8.10 mmol). The mixture was stirred at room temperature for 1 hour, and TLC showed that the reaction was complete. Dichloromethane was added to the reaction solution, and the mixture was washed successively with 1 M dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 2:1). The concentrate yielded compound C199-2, a white foamy solid, 1.67 g, in 81% yield. 1 H NMR(500MHz,DMSO-d6)δ11.60(s,1H),7.79(d,J=8.1Hz,1H),6.01(d,J=2.3Hz,1H),5.79–5.71 (m,2H),5.58(dd,J=7.3,2.3Hz,1H),3.64–3.47(m,2H),2.64–2.53(m,2H),1.14–1.08(m,12H).

[0199] Under ice bath conditions, trifluoroacetic acid (2.07 g, 18.21 mmol) was added to an aqueous solution of tetrabutylammonium hydroxide (8.46 g, 16.30 mmol), and the pH was adjusted to approximately 4. This solution was then added to a solution of C199-2 (1.67 g, 3.30 mmol) in dichloromethane (20 mL), followed by the addition of 85% m-chloroperoxybenzoic acid (3.31 g, 16.30 mmol). After the addition was complete, the mixture was brought to room temperature and stirred overnight. TLC showed that the reaction was complete. Sodium thiosulfate was added to the reaction solution, and after stirring for 30 minutes, the mixture was extracted with ethyl acetate. The organic phase was then washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether:acetone = 4:1 → 1:1). The concentration yielded compound C199-3, 1 g of a white, foamy solid, with a yield of 77%. 1 HNMR(500MHz,DMSO-d6)δ11.54(s,1H),7.79(d,J=8.1Hz,1H),6.01(d,J=2.5Hz,1H),5.72–5.66(m,2H),5. 54(dd,J=7.1,2.5Hz,1H),5.50(t,J=6.3Hz,1H),3.64–3.54(m,2H),2.62–2.53(m,2H),1.12–1.08(m,12H).

[0200] C199-3 (817.4 mg, 2.03 mmol) was added to dichloromethane (10 mL), followed by triethylamine (308.2 mg, 3.05 mmol), 4-dimethylaminopyridine (49.6 mg, 0.41 mmol), and isobutyric anhydride (385.9 mg, 2.44 mmol). The mixture was stirred at room temperature for 10 minutes, and TLC showed that the reaction was complete. Dichloromethane was added to the reaction solution, and the mixture was washed successively with 1 M dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to give compound C292, which was directly added to the next step. 1 H NMR (400MHz, DMSO-d6) δ11.58(d,J=2.1Hz,1H),7.79(d,J=8.0Hz,1H),6.03(d,J=2.2Hz,1H),5.82(dd,J=20.0,7.2Hz,1 H),5.70(dd,J=8.1,2.1Hz,1H),5.59(dd,J=7.3,2.1Hz,1H),4.45–4.21(m,2H),2.67–2.52(m,3H),1.20–1.00(m,18H).

[0201] C292 (250 mg, 0.53 mmol), potassium carbonate (147 mg, 1.06 mmol), and sodium iodide (79 mg, 0.53 mmol) were added to acetone (5 mL), and methyl isobutyrate (145 mg, 1.06 mmol) was added dropwise. The reaction was carried out overnight at room temperature, and the starting material was monitored for complete conversion by TLC. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give compound C199, 270 mg, as an oil, in 89% yield. 1 HNMR(400MHz,DMSO-d6)δ7.91(d,J=8.2Hz,1H),6.11(d,J=2.1Hz,1H),5.97–5.74(m,4H) ,5.61(dd,J=7.2,2.1Hz,1H),4.42–4.25(m,2H),2.67–2.50(m,4H),1.17–1.02(m,24H). ESI-MS m / z=573.3[M+1] + .

[0202] Example 16: Preparation of compound C99 hydrochloride

[0203]

[0204] C99-01 (2.0 g, 9.21 mmol) was added to ethanol (20 mL), followed by the dropwise addition of a cesium carbonate (3.0 g, 9.21 mmol) solution in water (7 mL). The mixture was stirred at room temperature for 30 min and concentrated to dryness. Toluene was added, and the mixture was concentrated to dryness. This process was repeated twice. N,N-dimethylformamide (10 mL) was added, and chloroiodomethane (7 mL, 92.10 mmol) was added dropwise at 0–10 °C. The mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture, and the mixture was allowed to stand to separate the layers. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give compound C99-1, 1.10 g, in 45% yield.

[0205] C292 (300 mg, 0.63 mmol), C99-1 (502 mg, 1.89 mmol), potassium carbonate (174 mg, 1.26 mmol), and sodium iodide (94 mg, 0.63 mmol) were added to acetone (10 mL) and stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture, and the mixture was allowed to stand to separate the layers. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound C99-2, 350 mg, in 79% yield.

[0206] C99-2 (300 mg, 0.43 mmol) was dissolved in ethyl acetate (2 mL), and 4 M hydrogen chloride-ethyl acetate solution (5 mL) was added. The mixture was stirred at room temperature for 2 h, concentrated to dryness, and water and ethyl acetate were added. The mixture was allowed to stand and separate into layers. The separated aqueous phase was freeze-dried to give 160 mg of the hydrochloride salt of compound C99, with a yield of 62%. 1 H NMR (400MHz, DMSO-d6) δ8.50(s,3H),7.95(d,J=8.2Hz,1H),6.13(d,J=2.0Hz,1H),6.00–5.93(m,2H),5.86–5.73(m,2H),5.58(dd,J=7 .3,2.0Hz,1H),4.42–4.24(m,2H),3.92(d,J=4.4Hz,1H),2.66–2.53(m,3H),2.20–2.08(m,1H),1.17–1.04(m,18H),0.98–0.88(m,6H). ESI-MS m / z=602.3[M+1] + .

[0207] Example 17: Preparation of compound C204

[0208]

[0209] C204-01 (5 g, 40.61 mmol) and tetrabutylammonium bisulfate (1.38 g, 4.06 mmol) were added to dichloromethane (50 mL) and water (50 mL). Sodium bicarbonate solid (12.97 g, 154.38 mmol) was added in portions, and the mixture was stirred for 10 min. Chloromethyl chlorosulfonate (7.37 g, 44.67 mmol) was added dropwise under an ice-water bath. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 3 h. TLC monitoring showed no starting material remaining. Water and dichloromethane were added, and the mixture was allowed to stand to separate the layers. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound C204-1, 4.0 g of oil, yield 57.6%.

[0210] C292 (300 mg, 0.63 mmol), potassium carbonate (174 mg, 1.26 mmol), potassium iodide (105 mg, 0.63 mmol), and C204-1 (218 mg, 1.27 mmol) were added to acetone (5 mL) and reacted overnight at room temperature. TLC showed no starting material remaining. The reaction solution was filtered, the filtrate was concentrated to dryness, and purified by column chromatography to give compound C204, 104 mg, an off-white solid, in 28% yield. 1 H NMR (X206, 400MHz, DMSO-d6) δ9.06 (s, 1H), 8.83 (d, J = 4.4Hz, 1H), 8.27 (d, J = 8.0Hz, 1H), 7.9 4(d,J=8.2Hz,1H),7.57(dd,J=8.0,4.9Hz,1H),6.14(s,1H),6.11–6.01(m,2H),5.96(d,J=8. 1Hz,1H),5.83(dd,J=20.1,7.2Hz,1H),5.66(d,J=7.2Hz,1H),4.39–4.26(m,2H),2.68–2.53 (m,2H),2.49–2.40(m,1H),1.16–1.08(m,12H),1.02(d,J=7.0Hz,3H),0.98(d,J=7.0Hz,3H). ESI-MS m / z=608.3[M+1] + .

[0211] Example 18: Preparation of compound C206

[0212]

[0213] In a 50 mL reaction flask, C44-2 (see Example 11) (800 mg, 1.27 mmol), nicotinic acid (237 mg, 1.91 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (966 mg, 2.54 mmol), N,N-diisopropylethylamine (DIEA) (492 mg, 2.54 mmol), DMAP (155 mg, 1.27 mmol), and dichloromethane (16 mL) were added sequentially. The reaction was carried out under nitrogen protection at room temperature for 1 h, and TLC monitoring showed that the starting material had essentially disappeared. The reaction solution was concentrated and purified by silica gel column chromatography to give compound C206-1, 730 mg, as an oil, with a yield of 78%.

[0214] C206-1 (200 mg), 10% palladium on carbon (200 mg), and tetrahydrofuran (4 mL) were added sequentially to a 25 mL reaction flask. The mixture was purged with hydrogen three times and reacted at atmospheric pressure for 3 h. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain compound C206, 100 mg, a white solid, with a yield of 79%. 1 H NMR (400MHz, DMSO-d6) δ9.14(d,J=2.2Hz,1H),8.85(dd,J=4.6Hz,1.5Hz,1H),8.34(d,J=7.9Hz,1H),7.84(d,J=8.2Hz,1H),7.59(dd,J=7.9,4.9Hz,1H),5. 98(d,J=2.3Hz,1H),5.81–5.75(m,2H),5.72(s,2H),5.42(d,J=9.0Hz,1H),4. 69–4.47(m,3H),4.38–4.28(m,1H),2.50–2.43(m,1H),1.03(d,J=7.0Hz,6H). ESI-MS m / z = 468.2 [M+1] + .

[0215] Example 19: Preparation of compound C212

[0216]

[0217] Following the procedure in Preparation Example 17, C52-2 (i.e., compound C305) (400 mg, 1.12 mmol) and C204-1 (384 mg, 2.24 mmol) were reacted to give compound C212, 340 mg of off-white solid, in a yield of 62%. 1H NMR (400MHz, DMSO-d6) δ9.07(d,J=2.2Hz,1H),8.84(dd,J=4.8,1.7Hz,1H),8.31–8.24(m,1H),7.95(d,J=8.1Hz,1H),7.57(dd,J=8.0,4.9Hz,1H ),6.44(s,1H),6.06–5.95(m,3H),5.83(d,J=7.4Hz,1H),5.68(dd,J=12 .0,7.4Hz,1H),4.50–4.32(m,2H),2.64–2.51(m,1H),1.10–1.03(m,6H). ESI-MS m / z=494.2[M+1] + .

[0218] Example 20: Preparation of compound C217

[0219]

[0220] C1 (500 mg, 1.91 mmol), p-dimethylaminopyridine (47 mg, 0.38 mmol), and triethylamine (966 mg, 9.55 mmol) were dissolved in tetrahydrofuran (10 mL), and acetic anhydride (780 mg, 7.64 mmol) was added dropwise. The reaction was carried out at room temperature for 2 h, and the reaction was monitored by TLC until the starting material was completely reacted. The reaction solution was concentrated to dryness, water was added and stirred, a solid precipitated, filtered, and dried at 60 °C to give intermediate C217-1, 550 mg of off-white solid, yield 74%. 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),7.76(d,J=8.0Hz,1H),6.06(d,J=2.3Hz,1H),5.79(dd,J=20.2,7.5Hz,1H),5.70(d ,J=8.0Hz,1H),5.55(dd,J=7.4,2.2Hz,1H),4.48–4.38(m,1H),4.30–4.20(m,1H),2.10(s,3H),2.09(s,3H),2.04(s,3H).

[0221] C217-1 (550 mg, 1.42 mmol), C204-1 (487 mg, 2.84 mmol), cesium carbonate (925 mg, 2.84 mmol), and sodium iodide (213 mg, 1.42 mmol) were added to N,N-dimethylformamide (11 mL). Under nitrogen protection, the mixture was stirred at 70 °C for 2 h. TLC showed that the reaction proceeds were completely reacted. Water and ethyl acetate were added to the reaction solution, and the mixture was allowed to stand to separate the layers. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give compound C217, 560 mg of bubbly solid, in 75% yield. 1 H NMR(400MHz, DMSO-d6)δ9.06(d,J=2.2Hz,1H),8.83(dd,J=4.9,1.7Hz,1H),8.27(dt,J=8.1, 2.0Hz,1H),7.91(d,J=8.2Hz,1H),7.57(dd,J=8.0,4.9Hz,1H),6.16(d,J=2.1Hz,1H),6.11– 6.01(m,2H),5.96(d,J=8.1Hz,1H),5.80(dd,J=20.2,7.4Hz,1H),5.62(dd,J=7.3,2.1Hz,1H ),4.48–4.39(m,1H),4.24(dd,J=12.0,10.0Hz,1H),,2.11(s,3H),2.09(s,3H),1.95(s,3H). ESI-MS m / z=524.2[M+1] + .

[0222] Example 21: Preparation of compound C218

[0223]

[0224] Following the procedure of Preparation Example 20, C1 (200 mg, 0.76 mmol) and propionic anhydride (396 mg, 3.04 mmol) were reacted to give intermediate C218-1; then C218-1 was reacted with C204-1 to give compound C218, 105 mg of bubbly precipitate, with a two-step yield of 24%. 1H NMR (400MHz, DMSO-d6) δ9.07 (d, J=2.3, 0.9Hz, 1H), 8.84 (dd, J=4.8, 1.7Hz, 1H), 8.28 (dt, J=8.0, 2.0Hz,1H),7.93(d,J=8.1Hz,1H),7.62–7.54(m,1H),6.16(d,J=2.1Hz,1H),6.12–6.01(m,2H),5 .97(d,J=8.1Hz,1H),5.83(dd,J=20.2,7.4Hz,1H),5.65(dd,J=7.3,2.1Hz,1H),4.48–4.36(m,1H ), 4.28 (dd, J = 12.3, 9.2Hz, 1H), 2.47–2.16 (m, 6H), 1.05 (t, J = 7.5Hz, 6H), 0.94 (t, J = 7.5Hz, 3H). ESI-MS m / z=566.2[M+1] + .

[0225] Example 22: Preparation of compound C208

[0226]

[0227] Compound C (800 mg, 1.51 mmol, prepared according to the method described in Chinese Patent CN201980030574.4), 4-dimethylaminopyridine (92 mg, 0.76 mmol), diisopropylethylamine (487 mg, 3.78 mmol), and dichloromethane (10 mL) were stirred until dissolved. Pteropenoyl chloride (218 mg, 1.81 mmol) was added dropwise under an ice-water bath, and the reaction was carried out for 30 min at this temperature. The reaction mixture was monitored by TLC to ensure complete reaction of the starting materials. Dichloromethane was added to the reaction solution, and the mixture was washed four times with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound C208-1, 850 mg crude product, which was directly used in the next reaction step.

[0228] Add C208-1 (800 mg, 1.30 mmol), potassium carbonate (180 mg, 1.30 mmol), and N,N-dimethylformamide (10 mL) to a 25 mL three-necked flask and stir. Under an ice-water bath, add C204-1 (446 mg, 2.60 mmol) dropwise. After the addition is complete, bring to room temperature and react overnight. Monitor the reaction mixture by TLC until the starting material is fully reacted. Add water and ethyl acetate to the reaction mixture, allow to stand and separate the layers, separate the organic phase, concentrate the organic phase, and purify by silica gel column chromatography to give compound C208-2, 450 mg, with a two-step yield of 40%.

[0229] C208-2 (400 mg, 0.53 mmol), 10% Pd / C (200 mg), and tetrahydrofuran (10 mL) were added to a 25 mL single-necked flask. The mixture was purged with hydrogen three times and reacted at room temperature and atmospheric pressure for 3 h. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give compound C208, 250 mg, in 63% yield. 1 H NMR (400MHz, DMSO-d6) δ9.06(d,J=2.2Hz,1H),8.83(dd,J=4.8,1.6Hz,1H),8.30–8.24(m,1H),7.82(d,J=8.2Hz,1H),7.56(dd,J=8.0,4.8Hz,1H),6. 10–6.00(m,2H),5.95(s,1H),5.89(d,J=8.2Hz,1H),5.76(d,J=4.7Hz,1H) ,5.34(d,J=8.6Hz,1H),4.43–4.27(m,3H),4.24–4.16(m,1H),1.11(s,9H). ESI-MS m / z=482.2[M+1] + .

[0230] Example 23: Preparation of compound C220

[0231]

[0232] C (1 g, 1.89 mmol), potassium carbonate (261 mg, 1.89 mmol), and sodium iodide (283 mg, 1.89 mmol) were dissolved in acetone (10 mL). Chloromethyl tert-pivalate (427 mg, 2.84 mmol) was added dropwise, and the reaction was carried out overnight at room temperature. The reaction mixture was monitored by TLC until complete. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give intermediate C220-1, 900 mg, as an oily substance, in 74% yield.

[0233] In a 50 mL reaction flask, C220-1 (800 mg, 1.24 mmol), nicotinic acid (229 mg, 1.86 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (707 mg, 1.86 mmol), N,N-diisopropylethylamine (DIEA) (480 mg, 3.72 mmol), DMAP (155 mg, 1.27 mmol), and dichloromethane (16 mL) were added sequentially. The reaction was carried out under nitrogen protection at room temperature for 1 h, and TLC monitoring showed that the starting material had essentially disappeared. The reaction solution was concentrated and purified by silica gel column chromatography to give compound C220-2, 750 mg, as an oily substance, with a yield of 81%.

[0234] C220-2 (500 mg, 0.67 mmol), 10% Pd / C (200 mg), and tetrahydrofuran (10 mL) were added to a 25 mL single-necked flask. The mixture was purged with hydrogen three times and reacted at room temperature and atmospheric pressure for 3 h. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give compound C220, 250 mg, in 78% yield. 1 H NMR (400MHz, DMSO-d6) δ9.14(d,J=2.0Hz,1H),8.85(d,J=4.6Hz,1H),8.34(d,J=7.6Hz,1H),7.85(d,J=8.1Hz,1H),7.60(dd,J=7.9,4.8H z,1H),5.98(d,J=1.6Hz,1H),5.83–5.75(m,2H),5.72(s,2H),5.44(d,J=9.0Hz,1H),4.67–4.48(m,3H),4.38–4.30(m,1H),1.08(s,9H). ESI-MS m / z=482.2[M+1] + .

[0235] Example 24: Preparation of compound C264 hydrochloride

[0236]

[0237] Following the procedure in Preparation Example 16, C264-01 (5 g, 23.23 mmol) was reacted with chloromethyl chlorosulfonate (4.95 g, 30.20 mmol) to give intermediate C264-1, 4.7 g of oil, yield 77%; C292 (300 mg, 0.63 mmol) was reacted with C264-1 (332 mg, 1.26 mmol) to give C264-2; C264-2 was reacted with a solution of hydrogen chloride and ethyl acetate to give compound C264, 145 mg of solid, with a two-step yield of 36%. 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=8.2Hz,1H),6.14(d,J=2.0Hz,1H),6.01–5.87(m,3H),5.80(dd,J=20.2,7.2Hz,1H),5.60(dd,J=7 .2,2.0Hz,1H),4.46–4.25(m,3H),3.27–3.12(m,2H),2.69–2.53(m,3H),2.31–2.18(m,1H),2.03–1.84(m,3H),1.22–1.00(m,18H). ESI-MS m / z=600.3[M+1] + .

[0238] Example 25: Determination of the virus inhibitory activity of the compound of the present invention:

[0239] Healthy mouse neuroblastoma cells (Neuro-2a) were seeded into 24-well plates. Cell status was observed, and when cell confluence reached 90%, a suspension containing 0.1 MOI of rabies virus (DRV-Mexico) was added to each well. After incubation at 37°C for 1 hour, different concentrations of test compounds were added. Cell controls and virus controls were also included. Forty-eight hours after virus infection, the cell supernatant was collected. The rabies virus titer was determined according to the titration method for rabies virus in General Chapter 3512 of the 2020 edition of the Chinese Pharmacopoeia.

[0240] Table 1. In vitro inhibitory activity of the compounds of this invention against rabies virus (DRV-Mexico).

[0241]

[0242]

[0243] In vitro antiviral activity tests showed that the compounds listed in Table 1 significantly inhibited the replication of rabies virus (DRV-Mexico).

[0244] Example 26: Pharmacokinetic Evaluation in Rats

[0245] Male SD rats were divided into six groups (n=3 per group) and six groups (IV and PO). The PO group was fasted for 12 hours before the experiment but had free access to water, and was fed 4 hours after administration. The IV group was not fed. Compound C1 was administered intravenously at a dose of 5 mg / kg. Compounds C1, C99, C204, C21, and C292 were administered orally at equimolar doses of 10 mg / kg, 24 mg / kg, 23 mg / kg, 20 mg / kg, and 18 mg / kg, respectively. The solvent was 5% DMSO + 5% ethanol + 40% PEG400 + 50% saline. In the intravenous group, blood samples of approximately 150–200 μL were collected via the jugular vein at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h after administration. In the gavage group, blood samples of approximately 150–200 μL were collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h after administration. The blood was placed in EDTA-K2 tubes and temporarily stored in an ice-water bath. The plasma was separated by centrifugation at 11,000 rpm for 5 min within 30 min and then frozen at –70°C for analysis. The entire process was performed using an ice-water bath. The concentration of nucleoside C1 in the plasma was determined by LC-MS-MS, and pharmacokinetic parameters were calculated. The results are shown in Table 2.

[0246] Table 2. Pharmacokinetic parameters of nucleoside C1 in rats after single intravenous and gavage administration of compounds C1, C99, C204, C217 and C292 of the present invention.

[0247]

[0248] In vivo pharmacokinetic experiments in rats showed that C1, C99, C204, C217, and C292 all had good pharmacokinetic properties. Among them, the oral bioavailability of the prodrug forms C217 and C292 in rats was higher than that of nucleoside C1.

[0249] Example 27: Pharmacokinetic Evaluation in Cynomolgus Monkeys

[0250] Male cynomolgus macaques were divided into three groups: an intravenous (IV) group and a gavage (PO) group, with three macaques in each group. The gavage group was fasted for 12 hours before the experiment but had free access to water, and was fed uniformly 4 hours after drug administration; the intravenous group was not fasted. Compound C1 was administered intravenously at a dose of 2 mg / kg; compounds C1 and C204 were administered by gavage at equimolar doses of 5 mg / kg and 11.6 mg / kg, respectively; the solvent was 5% DMSO + 5% ethanol + 40% PEG400 + 50% saline. In the intravenous group, blood samples of approximately 300–500 μL were collected via the jugular vein at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h after drug administration. In the gavage group, blood samples of approximately 300–500 μL were collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h after drug administration. The blood samples were placed in EDTA-K2 tubes and temporarily stored in an ice-water bath. The plasma was separated by centrifugation at 2000 rpm for 10 min within 30 min and then frozen at –70°C for analysis. The entire process was performed using an ice-water bath. The concentration of nucleoside C1 in the plasma was determined by LC-MS-MS, and pharmacokinetic parameters were calculated. The results are shown in Table 3.

[0251] Table 3. Pharmacokinetic parameters of nucleoside C1 in cynomolgus monkeys after single intravenous and gavage administration of compounds C1 and C204 of the present invention.

[0252]

[0253] Pharmacokinetic studies in cynomolgus monkeys showed that the prodrug form C204 had higher oral bioavailability compared to nucleoside C1.

[0254] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. The use of a compound of Formula I or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotope derivative or pharmaceutically acceptable salt in the preparation of an inhibitor for inhibiting the replication of rabies virus; The use of a compound of Formula I or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotope derivative or pharmaceutically acceptable salt in the preparation of remedies for treating and / or preventing or alleviating diseases related to rabies virus infection; in, B is selected from X is selected from O, NH, and S; R1 and R2 are each independently selected from hydrogen and C. 1-20 Alkyl group, C 3-20 Cycloalkylyl, 3-20 member heterocycloalkylyl, C 2-20 alkenyl acyl, C 2-20 alkynyl group, C 6-20 Aromatic acyl, 5-15 member heteroaromatic acyl, amino C 1-20 Alkyl group, C 1-20 Alkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-20 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Alkoxy C 1-20 Alkyl group, C 3-20 Cycloalkoxy C 1-20 Alkyl groups, the groups remaining after the hydroxyl group is removed from the carboxyl group of amino acids, wherein C 1-20 Alkyl and C 3-20 The cycloalkanoyl group is either unsubstituted or substituted with a halogen. Or formed by connecting R1 and R2 together. R3 is selected from hydrogen, deuterium, halogen, azide, cyano, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, Azide C 1-6 Alkyl, cyano C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy C 1-6 alkyl; R4 is selected from hydrogen, C 1-20 Alkyl group, C 3-20 Cycloalkylyl, 3-20 member heterocycloalkylyl, C 2-20 alkenyl acyl, C 2-20 alkynyl group, C 6-20 Aromatic acyl group, 5-15 member heteroaromatic acyl group, C 1-20 Alkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-20 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Alkoxy C 1-20 Alkyl group, C 3-20 Cycloalkoxy C 1-20 Alkyl group, the group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid, C 6-20 Arylamino C 1-6 Alkyl group, 3-20 membered heterocyclic alkyl group 1-6 Alkyl group, Where C 1-20 Alkyl group, C 2-20 alkenyl acyl and C 3-20 The cycloalkanoyl group is unsubstituted or substituted with aryl, amino, and / or halogen groups, and the 3-20 membered heterocycloalkanoyl group is unsubstituted or substituted with C 1-6 Alkyl substitution; R5 is selected from hydroxyl, amino, hydroxylamine (-NHOH), and -NHOR groups. 11 ; R6 is selected from hydrogen, deuterium, and halogens; R7 is selected from C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 6-20 Aryl, 5-15 quinone heteroaryl, C 3-20 cycloalkyl C 1-20 Alkyl, C 1-20 Alkylamino C 1-20 Alkyl, C 1-20 Dialkylamino C 1-20 Alkyl, C 3-20 Cycloalkylamino C 1-20 Alkyl, C 1-20 Alkoxy C 1-20 Alkyl, C 3-20 Cycloalkoxy C 1-20 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-20 Alkyl, R2NH-C 1-20 Alkyl, R2O-C 3-20 cycloalkyl, R2NH-C 3-20 cycloalkyl; R8 is selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-20 Aryl, 5-15 quinone heteroaryl; R9 is selected from C 1-18 Alkyl, C 6-20 arylmethyl; R 10 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-20 Aryl, 5-15 quinone heteroaryl; R 11 Selected from C 1-20 Alkyl group, C 3-20 Cycloalkyl acyl, amino C 1-20 Alkyl group, C 1-20 Alkylamino C 1-6 Alkyl group, C 3-20 Cycloalkylamino C 1-20 Alkyl group, C 1-20 Dialkylamino C 1-6 Alkyl group, C 1-20 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxycarbonyloxymethylene; R 12 Selected from hydrogen and C 1-6 alkyl.

2. The application according to claim 1, wherein, The compound has chemical formula II. in, R1, R2, R4 and R 11 The definition is the same as in claim 1.

3. The application according to claim 1, wherein, The compound has chemical formula III. in, B is selected from Among them, R2, R3, R5, R7, R 10 The definition is the same as in claim 1.

4. The application according to any one of claims 1-3, characterized in that, R1 and R2 are each independently selected from hydrogen and C. 2-10 Alkyl group, C 3-10 Cycloalkylyl, 3-10 member heterocycloalkylyl, C 3-10 alkenyl acyl, C 3-10 alkynyl group, C 6-12 Aromatic acyl group, 5-10 member heteroaromatic acyl group, amino C 1-10 Alkyl group, C 1-10 Alkylamino C 1-10 Alkyl group, C 1-10 Dialkylamino C 1-10 Alkyl group, C 3-10 Cycloalkylamino C 1-10 Alkyl group, C 1-10 Alkoxy C 1-10 Alkyl group, C 3-10 Cycloalkoxy C 1-10 Alkyl groups, the groups remaining after the hydroxyl group is removed from the carboxyl group of amino acids, wherein C 2-10 Alkyl and C 3-10 The cycloalkanoyl group is unsubstituted or substituted with a halogen; or R1 and R2 are linked together to form... R3 is selected from hydrogen, deuterium, halogen, azide, cyano, and C. 1-5 Alkyl, Halogenated C 1-5 Alkyl, Azide C 1-5 Alkyl, cyano C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 cycloalkyl, C 1-5 Alkoxy C 1-5 alkyl; R4 is selected from hydrogen, C 2-20 Alkyl group, C 3-10 Cycloalkylyl, 3-10 member heterocycloalkylyl, C 2-10 alkenyl acyl, C 2-10 alkynyl group, C 6-15 Aromatic acyl group, 5-12 heteroaryl group, C 1-10 Alkylamino C 1-10 Alkyl group, C 1-10 Dialkylamino C 1-10 Alkyl group, C 3-10 Cycloalkylamino C 1-10 Alkyl group, C 1-10 Alkoxy C 1-10 Alkyl group, C 3-10 Cycloalkoxy C 1-10 Alkyl group, the group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid, C 6-15 Arylamino C 1-5 Alkyl group, 3-10 membered heterocyclic alkyl group 1-5 Alkyl group, Where C 2-20 Alkyl group, C 2-10 alkenyl acyl and C 3-10 The cycloalkanoyl group is unsubstituted or substituted with an aryl, amino, and / or halogen group, and the 3-10 member heterocycloalkanoyl group is unsubstituted or substituted with a C- group. 1-6 Alkyl substitution; R7 is selected from C 1-20 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 2-10 alkenyl, C 3-10 alkynyl group, C 6-12 Aryl, 5-12 heteroaryl, C 3-10 cycloalkyl C 1-10 Alkyl, C 1-10 Alkylamino C 1-10 Alkyl, C 1-10 Dialkylamino C 1-10 Alkyl, C 3-10 Cycloalkylamino C 1-10 Alkyl, C 1-10 Alkoxy C 1-10 Alkyl, C 3-10 Cycloalkoxy C 1-10 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-10 Alkyl, R2NH-C 1-10 Alkyl, R2O-C 3-10 cycloalkyl, R2NH-C 3-10 cycloalkyl; R8 is selected from C 1-5 Alkyl, C 3-5 cycloalkyl, C 6-14 Aryl, 5-12 heteroaryl; R9 is selected from C 1-10 Alkyl, C 6-15 arylmethyl; R 10 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-14 Aryl, 5-12 heteroaryl; R 11 Selected from C 1-10 Alkyl group, C 3-10 Cycloalkyl acyl, amino C 1-10 Alkyl group, C 1-10 Alkylamino C 1-6 Alkyl group, C 3-10 Cycloalkylamino C 1-10 Alkyl group, C 1-10 Dialkylamino C 1-6 Alkyl group, C 1-10 Alkoxy C 1-6 Alkyl group, C 1-6 Alkoxycarbonyloxymethylene.

5. The application according to any one of claims 1-4, characterized in that, R1 and R2 are each independently selected from hydrogen and C. 1-20 Alkyl group, C 6-20 Aromatic acyl groups, 5-20 heteroaryl groups, or R1 and R2 linked together, form Preferably, R1 and R2 are each independently selected from hydrogen and C. 2-10 Alkyl group, C 6-12 Aromatic acyl groups, 5-10 heteroaryl groups, or R1 and R2 linked together form Preferably, R1 and R2 are each independently selected from hydrogen and C. 2-10 Alkyl group, C 6-10 Aromatic acyl groups, 5-6 heteroaryl groups, or R1 and R2 linked together form Preferably, the C 6-10 The aryl group in the aromatic acyl group is selected from phenyl and naphthyl; the heteroaryl group in the 5-6 member heteroaryl group is selected from pyridinyl, pyrimidinyl, pyrazinyl, furanyl, and thiopheneyl, preferably an aromatic heteroaryl containing an N atom, including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrazin-2-yl; R3 is selected from hydrogen, deuterium, halogen, azide, cyano, and C. 1-6 Alkyl group; preferably, R3 is selected from hydrogen, deuterium, and halogen; most preferably, hydrogen and fluorine; R4 is selected from hydrogen, C 1-20 Alkyl group, C 3-20 Cycloalkylyl, 3-20 member heterocycloalkylyl, C 6-20 Aromatic acyl group, 5-15 membered heteroaromatic acyl group, or the group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid; preferably, R4 is selected from hydrogen, C 2-16 Alkyl group, C 3-10 Cycloalkylyl, 3-10 member heterocycloalkylyl, C 6-12 Aromatic acyl group, 5-10 membered heteroaromatic acyl group, or a group remaining after the hydroxyl group is removed from the carboxyl group of an amino acid; preferably, R4 is selected from hydrogen, C 2-16 Alkyl group, C 3-6 Cycloalkylyl, 3-6 membered heterocycloalkylyl, C 6-10 Aromatic acyl group, 5-6 membered heteroaromatic acyl group, or a group obtained by removing the hydroxyl group from the carboxyl group of an amino acid; preferably, the C 6-10 The aryl group in the aromatic acyl group is selected from phenyl and naphthyl; preferably, the 3-6 membered heterocyclic alkyl acyl group is an azacyclic alkyl acyl group, such as azacyclic butane-3-yl acyl or piperidin-4-yl acyl; preferably, the heteroaryl group in the 5-6 membered heteroaryl acyl group is selected from pyridinyl, pyrimidinyl, pyrazinyl, furanyl, and thiopheneyl, and more preferably is an aromatic heteroaryl group containing an N atom, including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrazin-2-yl; the amino acid is selected from L-alanine, L-valine, and L-phenylglycine; R7 is selected from C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 2-20 alkenyl, C 6-20 Aryl, 5-15 quinone heteroaryl, C 3-20 cycloalkyl C 1-20 Alkyl, C 1-20 Alkylamino C 1-20 Alkyl, C 1-20 Dialkylamino C 1-20 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-20 Alkyl group; wherein R2 is C 1-20 Alkyl group; Preferably, R7 is selected from C 1-20 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 3-10 alkenyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-10 cycloalkyl C 1-10 Alkyl, C 1-10 Alkylamino C 1-10 Alkyl, C 1-10 Dialkylamino C 1-10 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-10 Alkyl group; wherein R2 is C 2-10 Alkyl group; more preferably, R7 is selected from C 1-16 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 alkenyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl C 1-8 Alkyl, C 1-4 Alkylamino C 1-8 Alkyl, C 1-4 Dialkylamino C 1-8 Alkyl groups, groups formed after the carboxyl group is removed from amino acids, R2O-C 1-8 Alkyl group; wherein R2 is C 2-8 Alkyl group; preferably, the 3-8 membered heterocyclic alkyl group is an azahexacyclic alkyl group, such as azahexacyclic butane-3-yl, pyrrolidinyl, piperidin-4-yl; preferably, the C 6-10 The aryl group is selected from phenyl and naphthyl; preferably, the 5-10 member heteroaryl group is a 5-6 member heteroaryl group selected from pyridyl, pyrimidinyl, pyrazinyl, furanyl, and thiopheneyl, and more preferably an aromatic heteroaryl group containing an N atom, including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrazin-2-yl; the amino acid is preferably selected from L-alanine, L-valine, and L-phenylglycine.

6. The application according to any one of claims 1-5, wherein, The compound is selected from the following compounds: 。 7. The application according to claim 6, wherein, The compound is selected from the following compounds: 。 8. The use of one or more compositions comprising the compound of any one of claims 1-7, its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts in the preparation of an inhibitor for inhibiting rabies virus replication; and / or The use of a composition comprising one or more of the compounds, stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts according to any one of claims 1-7 in the preparation of a medicament for treating and / or preventing or alleviating diseases related to rabies virus infection.

9. The application according to any one of claims 1-8, characterized in that, The diseases related to rabies virus infection mentioned are selected from rabies and its complications.

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