A clodronic acid ester derivative and use thereof

Abstract

The application discloses a kind of clividine phosphonate ester derivatives and its application, belong to the technical field of medicine preparation.The clividine phosphonate ester derivative provided in the application includes the compound as shown in general formula (I), its deuterium or pharmaceutically acceptable salt:;The amino acid ester in the structure of this compound has liver-targeted delivery capacity, it can utilize the first effect of liver and be hydrolyzed by Cat A and CES-1 esterase, rapidly release the carboxylic acid group that cannot penetrate cell membrane, and then make drug molecules be sealed in hepatocyte, further metabolism can produce the two antiviral active ingredients of clividine and tenofovir with synergistic effect, can show excellent anti-HBV virus activity, and the compound has no cytotoxicity to the host cell of HBV virus.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to the preparation and application of a clevudine derivative. Background Technology

[0002] Hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma, and is one of the public health problems facing my country.

[0003] Currently, the clinical treatment for hepatitis B virus infection mainly involves the combined use of immunomodulators and oral medications. There are two main types of oral hepatitis B medications used clinically: one type consists of nucleoside analogs that directly target viral proteins (entecavir, tenofovir, lamivudine, telbivudine, adefovir dipivoxil, etc.); these have drawbacks including low cure rates (1-4%) and the need for lifelong medication. The other type targets the host's immune system with alpha-interferon, achieving a cure rate of up to 10% with long-term injections; however, it suffers from significant side effects and poor tolerability. Given the low cure rates and high risk of drug resistance mutations associated with existing hepatitis B medications, there is an urgent need to develop drugs with high drug resistance barriers and long-term efficacy.

[0004] Clevudine Launched in South Korea in 2006 and the Philippines in 2009, respectively, it is currently undergoing Phase III clinical trials in China. It is a polymerase active site inhibitor, and due to its mechanism of action differing from existing hepatitis B drugs, it can produce synergistic effects with drugs such as tenofovir disoproxil fumarate. ATI-2173 Clevudine is a liver-targeted aminophosphate prodrug, and its combination with tenofovir disoproxil fumarate (TDF) showed significant efficacy in a phase II clinical trial. However, a case of bradycardia occurred in a phase II trial of its combination with TDF and vebicorvir, leading to the suspension of the clinical trial. Given that bradycardia has not been reported in long-term clinical use of clevudine itself, through extensive review of clinical trial literature, we realized that the aminophosphate prodrug structural unit in the ATI-2173 structure is composed of natural alanine ester and phenol. It is likely a significant factor contributing to bradycardia. This aminophosphate structural unit was first observed in the "miracle drug" sofosbuvir for hepatitis C. In the structure of sofosbuvir aminophosphate, the aliphatic chains and benzene rings interact strongly with the aliphatic chains of amiodarone, exhibiting both hydrophobic interactions and π-alkyl nonpolar interactions. This eutectic effect blocks calcium ion channels, leading to bradycardia, a phenomenon previously confirmed by Academician Yan Ning's team through structural biology [Cell (2022). DOI: 10.1016 / j.cell.2022.10.024]. Therefore, we aim to overcome the potential adverse drug-drug interactions by modifying the aminophosphate structural units, particularly increasing the polarity of the aminophosphate prodrug structure, to obtain a new chemical entity with high hepatitis B cure rates and good safety profile.

[0005] The present invention aims to provide a clevudine phosphonate derivative with high antiviral activity, high viral resistance barrier, and low cytotoxicity. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention proposes a clevudine phosphonate derivative and its applications.

[0007] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0008] This invention provides a clevudine phosphonate derivative comprising a compound of formula (I) or a deuterated form of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009] The amino acid esters in this type of compound have liver-targeted delivery capabilities. They can utilize the first-pass effect of the liver to rapidly release carboxylic acid groups that cannot penetrate cell membranes through hydrolysis by Cat A and CES-1 esterases, thereby sealing the drug molecules inside hepatocytes. Further metabolism can produce two antiviral active ingredients, clevudine and tenofovir, which have a synergistic effect and can exhibit excellent anti-HBV virus activity. Moreover, this type of compound has no cytotoxicity to HBV virus host cells.

[0010] in,

[0011] R1, R2, and R3 are independent and selected from hydrogen, deuterium, amino, hydroxyl, carbonyl, α-amino acid side chain, deuterated α-amino acid side chain, cyano, C1-C. 20 Alkyl groups, or R2 and R3 together with the carbon atoms they are attached to, constitute a C group. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0012] R4 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Deuterated haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted;

[0013] R5 and R6 are independent of each other and can be selected from H, straight chain, or C1-C with branches. 20Acyl group; the straight-chain or branched C2-C group 20 Acyl group, optionally further replaced by deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0014] The clividine phosphonate derivative further comprises a compound of general formula (II), its deuterated form, or a pharmaceutically acceptable salt thereof:

[0015] ;

[0016] in,

[0017] R1, R2, and R3 are independent and selected from hydrogen, deuterium, amino, hydroxyl, carbonyl, α-amino acid side chain, deuterated α-amino acid side chain, cyano, C1-C. 20 Alkyl groups, or R2 and R3 together with the carbon atoms they are attached to, constitute a C group. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0018] R4 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0019] The clividine phosphonate derivative further comprises a compound of general formula (IIIa), (IIIb) or (IIIc), its deuterated form or a pharmaceutically acceptable salt thereof:

[0020] ;

[0021] The substitution position of the clefdinyl ester fragment on the linker benzene ring can be at the para position (IIIa), the meta position (IIIb), or the ortho position (IIIc) of the phosphonate group.

[0022] R1, R2, and R3 are independent and selected from hydrogen, deuterium, amino, hydroxyl, carbonyl, α-amino acid side chain, deuterated α-amino acid side chain, cyano, C1-C. 20 Alkyl groups, or R2 and R3 together with the carbon atoms they are attached to, constitute a C group. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0023] R4 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted;

[0024] R5 and R6 are independent of each other and can be selected from H, straight chain, or C1-C with branches. 20 Acyl group; the straight-chain or branched C2-C group 20 Acyl group, optionally further replaced by deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0025] The clividine phosphonate derivative further comprises a compound of general formula (Ⅳa) or (Ⅳb), its deuterated form, or a pharmaceutically acceptable salt thereof:

[0026] ;

[0027] The α-amino acid ester is preferably derived from alanine ester, and can be a natural L-configuration (IVa), a non-natural D-configuration (IVb), or a mixture of the two in any proportion, with a natural L-configuration alanine ester (IVa) being preferred.

[0028] R1 is selected from hydrogen, deuterium, amino, hydroxyl, carbonyl, α-amino acid side chain, deuterated α-amino acid side chain, cyano, C1-C 20 Alkyl groups, or R2 and R3 together with the carbon atoms they are attached to, constitute a C group. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0029] R4 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0030] The clividine phosphonate derivative further comprises a compound of general formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf), its deuterated form or a pharmaceutically acceptable salt thereof:

[0031] ;

[0032] in,

[0033] R1 is selected from hydrogen, deuterium, amino, hydroxyl, carbonyl, α-amino acid side chain, deuterated α-amino acid side chain, cyano, C1-C 20 Alkyl groups, or R2 and R3 together with the carbon atoms they are attached to, constitute a C group. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0034] R4 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0035] The clividine phosphonate derivative further comprises a compound of general formula (VIa) or (VIb), its deuterated form, or a pharmaceutically acceptable salt thereof:

[0036] ;

[0037] Among them, the spatial three-dimensional configuration at R1 includes two configurations (VIa, VIb), or it can be a mixture of the two in any proportion;

[0038] R1 is selected from hydrogen, deuterium, amino, hydroxyl, carbonyl, α-amino acid side chain, deuterated α-amino acid side chain, cyano, C1-C 20 Alkyl groups, or R2 and R3 together with the carbon atoms they are attached to, constitute a C group. 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0039] R4 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0040] Preferably, in the general formula (I):

[0041] R1 is hydrogen or amino;

[0042] R2 and R3 are each independently selected from hydrogen or C. 1-6 alkyl;

[0043] R4 is C 1-8 alkyl;

[0044] R5 and R6 are hydrogen;

[0045] m = 0 or 1.

[0046] The clividine phosphonate derivatives are selected from the following compounds, their deuterated derivatives, or pharmaceutically acceptable salts:

[0047] .

[0048] This invention provides the use of the aforementioned clevudine phosphonate derivatives, their deuterated forms, or their pharmaceutically acceptable salts in the preparation of medicaments for the treatment or prevention of various viral infections and their secondary disease states and conditions, including HIV and hepatitis B virus, as well as drug-resistant and other mutant forms of these viruses.

[0049] The present invention also provides a pharmaceutical composition in which the active ingredient comprises the aforementioned clevudine phosphonate derivative, its deuterated form, or its pharmaceutically acceptable salt.

[0050] The beneficial effects of this invention are:

[0051] This invention successfully combines the HBV reverse transcriptase inhibitor (NRTI) D-nucleoside tenofovir disoproxil fumarate (TDF) and the HBV polymerase active site inhibitor (ASPIN) L-nucleoside clevudine (CLV) into a single molecule. The alanine ester in this structure is crucial for the hepatocyte enrichment of nucleoside drugs. Our design maintains the liver-targeted delivery capability of the entire molecule (I) while enhancing the polarity of the nucleoside aminophosphate prodrug (by eliminating phenol from the McGuigan prodrug structure), avoiding potential adverse drug interactions with low-polarity HBV capsid protein inhibitors such as VBR. Furthermore, it fully leverages the inherent synergistic effect between NRTI and ASPIN, resulting in efficacy superior to TDF, currently the best-performing HBV drug. The synergistic effect of L-nucleoside clevudine and D-nucleoside tenofovir disoproxil fumarate (1+1>2) has been demonstrated in a phase II clinical trial (SAVE-1: NCT04847440). Unfortunately, the phase II clinical trial of TDF+ATI-2173 combination therapy was halted due to adverse drug interactions between ATI-2173 and VBR. Our drug design uses tenofovir to replace phenol to optimize the structure of clevudine prodrug. The compound has been proven to be safe and non-toxic through cardiomyocyte experiments and beagle dog telemetry experiments, allowing this therapy, which is expected to greatly improve the cure rate of hepatitis B, to be reborn. Detailed Implementation

[0052] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0053] All reagents and raw materials used were commercially purchased.

[0054] Example 1

[0055] A method for preparing a clevudine phosphonate derivative (compound 6) is described below:

[0056] ;

[0057] The specific steps are as follows:

[0058] Synthesis of intermediate 1:

[0059] 0 o At C, p-hydroxyphenylacetic acid (1.5 g, 1.0 eq.) and imidazole (2.5 eq.) were dissolved in 100 mL of dichloromethane; tert-butyldiphenylchlorosilane (2.0 eq.) was added. The reaction system was gradually brought to room temperature and reacted overnight at room temperature. Dichloromethane was removed under reduced pressure, ethyl acetate / water was added, and the mixture was washed separately. The organic phase was dried and the solvent was removed under reduced pressure; the crude product was separated by normal phase (ethyl acetate / n-heptane = 1 / 20) to give intermediate 1 (4.0 g, colorless oil, yield: 65%). 1 H NMR (400MHz, Chloroform-d) δ 7.79 – 7.72 (m, 4H), 7.60 – 7.54 (m, 4H), 7.44 – 7.41(m, 4H), 7.41 – 7.33 (m, 8H), 7.12 – 7.06 (m, 2H), 6.81 – 6.75 (m, 2H), 3.63 (s, 2H), 1.13 (s, 9H), 1.01 (s, 9H).

[0060] Synthesis of intermediate 2:

[0061] 0 oAt temperature C, intermediate 1 (4.0 g, 1.0 eq.) was dissolved in 60 mL of tetrahydrofuran, and potassium carbonate (2.0 eq.) was dissolved in 30 mL of water and then added; the reaction system was two-phase. The reaction system was gradually brought to room temperature and reacted overnight at room temperature. After intermediate 1 was completely eliminated by TLC monitoring, 1M hydrochloric acid was added to adjust the pH to 7. Ethyl acetate / water was added, and the mixture was washed separately. The organic phase was dried and the solvent was removed under reduced pressure. The crude product was separated by normal phase separation (ethyl acetate / n-heptane = 2 / 1) to give intermediate 2 (1.1 g, white solid, yield: 44%). 1 H NMR (400 MHz, Chloroform-d) δ 7.77 – 7.71 (m, 4H), 7.49 – 7.42(m, 2H), 7.39 (dd, J = 7.9, 6.3 Hz, 4H), 7.06 – 6.99 (m, 2H), 6.77 – 6.70 (m,2H), 3.51 (s, 2H), 1.12 (s, 9H).

[0062] Synthesis of intermediate 3:

[0063] 0 o At room temperature (C), intermediate 2 (600 mg, 1.0 eq.) was dissolved in 10 mL of dichloromethane, and 2.0 eq. of thionyl chloride was added. The reaction mixture was gradually brought to room temperature and reacted at room temperature for 3 h. The solvent and thionyl chloride were removed under reduced pressure, and the mixture was redissolved in 10 mL of dichloromethane and cooled to 0 °C. o C. TES-protected clevudine (200 mg, 1.0 eq.) and N,N-diisopropylethylamine (3.0 eq.) were added, and the reaction mixture was gradually brought to room temperature and reacted at room temperature for 6 h. Ethyl acetate / water was added, and the mixture was washed separately. The organic phase was dried and the solvent was removed under reduced pressure. The crude product was separated by normal phase (ethyl acetate / n-heptane = 1 / 8) to give intermediate 3 (250 mg, white solid, yield: 63%). 1H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 7.66– 7.60 (m, 4H), 7.39 – 7.24 (m, 6H), 7.18 (d, J = 6.6 Hz, 1H), 6.92 (d, J =8.3 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 6.14 (dd, J = 21.6, 3.0 Hz, 1H), 4.80 (dd, J = 51.7, 3.0 Hz, 1H), 4.29 (dd, J = 12.0, 6.1 Hz, 1H), 4.20 – 4.11 (m,2H), 4.06 – 3.97 (m, 1H), 3.46 (s, 2H), 1.80 (s, 3H), 1.01 (s, 9H), 0.87 (t,J = 7.9 Hz, 9H), 0.54 (q, J = 7.9 Hz, 6H). 19 F NMR (376 MHz, Chloroform-d) δ -198.78 (dt, J = 51.7, 19.2 Hz).

[0064] Synthesis of intermediate 4:

[0065] At room temperature, intermediate 3 (250 mg, 1.0 eq.) was dissolved in 5 mL of tetrahydrofuran, and triethylamine trihydrofluoride (2.0 eq.) was added. The reaction system was reacted at room temperature for 4 h. TLC monitoring showed that intermediate 3 had completely disappeared, and the solvent was removed under reduced pressure. The crude product was separated by normal phase (methanol / dichloromethane = 1 / 10) to give intermediate 4 (105 mg, white solid, yield: 80%). 1HNMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.34 (s, 1H), 7.36 (s, 1H), 7.06 (d,J = 8.0 Hz, 2H), 6.70 (d, J = 8.0 Hz, 2H), 6.17 (dd, J = 17.4, 4.2 Hz, 1H), 6.07 (d, J = 4.8 Hz, 1H), 5.05 (dt, J = 52.8, 3.4 Hz, 1H), 4.25 (dq, J =19.6, 3.7 Hz, 1H), 4.14 (q, J = 5.3 Hz, 1H), 4.00 (q, J = 5.1 Hz, 1H), 3.60 (s, 2H), 1.76 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -198.72 (dt, J = 52.8,18.5 Hz). HRMS (ESI) m / z calcd for C 18 H 20 FN2O7 [M + H] + , 395.1249; found:395.1270.

[0066] Synthesis of compound 6:

[0067] At room temperature, intermediate 4 (60 mg, 1.0 eq.) and intermediate 5 (2.0 eq.) were dissolved in 2 mL of DMF, and DIPEA (2.5 eq.) and PyBOP (2.0 eq.) were added. The reaction system was heated at 50 °C. o The reaction was carried out overnight in an oil bath. The crude product was separated by reverse phase (Column: C18, 25 g, Mobile Phase A: Water; Mobile Phase B: ACN, 30%-50%) to give product 6 (7 mg, white solid, yield: 6%). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H),8.15 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.39 (t, J = 1.7 Hz, 1H),7.28 – 7.19 (m, 4H), 7.11 – 7.00 (m, 2H), 6.19 (ddd, J = 17.4, 4.2, 1.3 Hz,1H), 6.10 – 6.05 (m, 1H), 5.58 (ddd, J = 50.6, 12.2, 10.2 Hz, 1H), 5.06(dddd, J = 52.8, 4.3, 2.9, 1.2 Hz, 1H), 4.85 (dhept, J = 8.5, 5.9 Hz, 1H), 4.42 – 4.12 (m, 4H), 4.05 – 3.90 (m, 2H), 3.90 – 3.79 (m, 2H), 3.73 (d, J =4.3 Hz, 2H), 1.78 (d, J = 1.2 Hz, 3H), 1.18 – 1.11 (m, 9H), 1.07 (dd, J =6.3, 4.5 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -198.83 (dt, J = 52.6, 18.5Hz). 31 P NMR (162 MHz, DMSO-d6) δ 23.00, 22.26. HRMS (ESI) m / z calcd forC 33 H 43 FN8O 11 P [M + H] + Theoretical value: 777.2767; Measured value: 777.2792.

[0068] Using the same synthetic method, the following compounds can also be prepared:

[0069] Compound 7:

[0070] ; 1H NMR (400 MHz, CDCl3) δ 11.41 (s, 1 H),8.27 (d, J = 1.6 Hz, 1 H), 8.05 (d, J = 2.6 Hz, 1 H), 7.43−7.48 (m, 1 H),7.39 (m, 1 H), 7.13-7.28 (m, 4 H), 6.19 (m, 1 H), 6.05 – 6.10 (m, 1 H), 5.57-5.58 (m, 1 H), 5.04-5.06 (m, 1 H), 4.97−5.12 (m, 2 H), 4.85 (m, 1 H), 4.50−4.53 (m, 1 H), 4.42 – 4.08 (m, 4 H), 4.05 – 3.90 (m, 1 H), 3.90 – 3.79 (m, 2H), 3.73 (d, J = 4.3 Hz, 2 H), 2.93−3.02 (m, 2 H), 2.58−2.62 (m, 2 H),1.78(d, J = 1.2 Hz, 3 H), 1.18 – 1.11 (m, 15H); MS(ESI) m / z = 791 [M+H] + ...

[0071] Compound 8:

[0072] MS(ESI) m / z = 806 [M+H] + .

[0073] Compound 6 was separated to yield two isomers, compound 9 and compound 10, as detailed below:

[0074] ;

[0075]

[0076] Chiral isomers were separated by HPLC using a 0.46 cm ID × 25 cm L chiral column CHIRALPAK IK (cellulose-tris(3-chloro-5-methylphenylcarbamate)). The corresponding fractions were collected to obtain white flocculent products, which were compounds 9 and 10.

[0077] Compound 9: 11H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1 H), 8.13 (s, 1 H), 8.11 (d, J = 2.6 Hz, 1 H), 7.37 (s, 1 H), 7.26 – 7.15 (m, 4 H), 7.04 (dd, J = 15.8, 8.1 Hz, 2 H), 6.17 (dd, J = 17.4, 4.2 Hz, 1 H), 6.06 (br s, 1 H), 5.70 – 5.43 (m, 1 H), 5.04 (dt, J = 52.7, 3.6 Hz, 1 H), 4.87 – 4.79 (m, 1 H), 4.36 – 4.19 (m, 4 H), 3.98 (dq, J = 16.8, 6.0, 5.5 Hz, 2 H), 3.84 (dt, J = 13.6, 6.1 Hz, 2 H), 3.71 (d, J = 4.2 Hz, 2 H), 1.77 (s, 3 H), 1.17 – 1.10 (m, 9 H), 1.06 (t, J = 5.4 Hz, 3 H). 19 19F NMR (376 MHz, DMSO-d6) δ -198.83 (dt, J = 52.6, 18.8 Hz). 31 31P NMR (162 MHz, DMSO-d6) δ 22.98, 22.25.

[0078] Compound 10: 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1 H), 8.13 (d, J = 1.5Hz, 1 H), 8.10 (d, J = 2.5 Hz, 1 H), 7.37 (t, J = 1.7 Hz, 1 H), 7.26 – 7.15(m, 4 H), 7.09 – 6.99 (m, 2 H), 6.22 – 6.12 (m, 1 H), 6.06 (s, 1 H), 5.55 (ddd, J = 49.8, 12.2, 10.1 Hz, 1 H), 5.04 (dt, J = 52.7, 3.7 Hz, 1 H), 4.83(dp, J = 8.4, 6.2 Hz, 1 H), 4.37 – 4.17 (m, 4 H), 4.04 – 3.89 (m, 2 H), 3.89 – 3.75 (m, 2 H), 3.71 (d, J = 4.2 Hz, 2 H), 1.78 – 1.76 (m, 3 H), 1.16 – 1.10(m, 9 H), 1.06 (dd, J = 6.2, 4.4 Hz, 3 H). 19 F NMR (376 MHz, DMSO-d6) δ -198.78 (dt, J = 52.6, 18.4 Hz). 31 P NMR (162 MHz, DMSO-d6) δ 22.98, 22.25.

[0079] Example of implementation effect 1

[0080] The HBV DNA was measured by real-time PCR using the clevudine phosphonate derivatives (compounds 6-10) prepared in Example 1, as detailed below:

[0081] According to 6.0×10 4HepG2.2.15 cells were seeded into 24-well plates and cultured overnight for adherent growth. The culture medium was then aspirated, and 600 μl of DMEM containing the drug was added to each well at final concentrations of 0, 0.0064, 0.032, 0.16, 0.8, 4, and 20 μM, with three replicates per treatment. After 3 days, the medium was replaced with fresh medium containing the same concentration of drug. HBV DNA was extracted from the collected medium using a hepatitis B virus nucleic acid extraction kit and stored at -20°C for later use. After 6 days of drug treatment, the culture supernatant and cells were collected, and HBV DNA was extracted using the hepatitis B virus nucleic acid extraction kit. The copy number of HBV DNA at each concentration was detected by qPCR, and the inhibition rate and EC50 were calculated. 50 .

[0082] HBV DNA inhibition rate = (number of copies in control group - number of copies in treatment group) / number of copies in control group × 100%

[0083] EC of each compound 50 The test results are shown in Table 1:

[0084] Table 1 EC50 values ​​for each compound 50 result

[0085]

[0086] In vitro activity assays confirmed that compounds 6-10 all released active ingredients that inhibited hepatitis B virus replication within hepatocytes, exhibiting excellent antiviral activity and demonstrating significant development potential. The two isomers 9 and 10, resulting from the resolution of compound 6, showed comparable in vitro antiviral activity. Although in vitro activity does not equate to in vivo efficacy, nor does it guarantee consistency in toxicity or metabolic behavior, compound 6 can serve as a candidate starting point for further evaluation.

[0087] Example of implementation effect 2

[0088] hERG experiments were performed on the clividine phosphonate derivatives (compounds 6-10) prepared in Example 1, as follows:

[0089] hERG currents were recorded using whole-cell patch-clamp technique. Before patch-clamp recording, HEK-293-hERG cells were passaged and cultured to a suitable state. Cell suspension was added to small culture dishes, ensuring a certain cell density and that cells were individually isolated, and placed on the stage of an inverted microscope. After cell attachment, the cells were perfused with extracellular fluid. The glass microelectrode was drawn in two steps using a microelectrode drawing instrument, and its water resistance was 2-5 MΩ after filling with the electrode fluid. After establishing whole-cell recording mode, the clamping potential was maintained at -80 mV. A depolarization voltage of +60 mV was applied for 850 ms, followed by repolarization to -50 mV for 1275 ms to extract the hERG tail current. This pulse program was repeated every 15 seconds throughout the experiment.

[0090] Stimulus delivery and signal acquisition were performed using PatchMaster software; the signal was amplified using a patch-clamp amplifier.

[0091] Further data analysis and curve fitting were performed using FitMaster, Excel, Graphpad Prism, or SPSS 21.0. All data are expressed as mean and standard deviation. During data processing, the peak value and baseline of the tail current were corrected when determining the blocking effect on hERG. The inhibition rate (IR) of the tail current was used to represent the effect of each compound at different concentrations.

[0092] IR = 100% × (peak tail current before administration - peak tail current after administration) / peak tail current before administration.

[0093] IC 50 The values ​​were obtained by fitting the Hill equation. If the maximum inhibition rate of all concentrations of the test substance is less than 50%, the IC50 is not calculated. 50 Numerical value.

[0094] At room temperature, the inhibitory effect of compound 6 on hERG current in HEK293 cells stably transfected with hERG potassium channels was tested using manual patch clamp at concentrations of 0.3, 1, 3, 10, and 30 μM.

[0095] Under experimental conditions, the positive control terfenadine exhibited a concentration-dependent inhibitory effect on hERG current, with an IC50 value of [missing information]. 50 The value was 0.034 µM (N=2). Compound 6 had no significant inhibitory effect on hERG potassium channels, with an average inhibition rate of 20.90% (N=2) of hERG current at the maximum detectable concentration of 30 µM, and no cardiotoxicity at the high concentration of 30 μM.

[0096] Example of implementation effect 3

[0097] The stability of the clevudine phosphonate derivative (compound 6) prepared in Example 1 to human liver microsomes was tested, as follows:

[0098] Add buffer, magnesium chloride, microsomes, and the test drug to a 96-well plate in the following order, setting up duplicate wells, and gently vortex to mix. Incubate the 96-well plate in a water bath at 37°C and 75 rpm for 5 minutes. Add nicotinamide adenine dinucleotide phosphate (NADPH) to initiate the reaction and vortex to mix. Continue incubation in a water bath at 37°C and 75 rpm for up to 60 minutes. At the designated time points (0, 5, 15, 30, and 60 minutes; for the negative control group, samples were collected only at 0 and 60 minutes), transfer 80 μL of sample to a new 96-well plate, add 3 volumes of methanol solution containing the internal standard, vortex for 10 minutes, and then freeze at -80°C. After thawing, centrifuge at 4°C and 6000 times gravity for 10 minutes. Transfer 100 μL of the supernatant to a 96-well plate pre-filled with 100 μL of deionized water and mix well. The mixed sample was injected into a liquid chromatography-tandem mass spectrometry system for analysis. The results are shown in Table 2:

[0099] Table 2 Results of human liver microparticle experiment

[0100]

[0101] As shown in Table 2, compound 6 is rapidly hydrolyzed and metabolized after entering hepatocytes, releasing highly polar amino acid derivatives, which are then enriched in hepatocytes, thus facilitating liver-targeted drug delivery.

[0102] Example of implementation effect 4

[0103] The plasma stability of the clividine phosphonate derivative (compound 6) prepared in Example 1 was tested as follows:

[0104] The frozen plasma was rapidly thawed at 37°C. A stock solution was prepared by mixing compound 6 with the reference compound bromopropylamine: 10 μL of the 10 mM stock solution of the reference compound and compound 6 was added to 990 μL of dimethyl sulfoxide (DMSO).

[0105] Add plasma to a 96-well plate, set up duplicate wells, and gently vortex to mix. Incubate the 96-well plate in a water bath at 37°C and 75 rpm for 5 minutes. Add the stock solutions of the reference compound and test compound 6, start the reaction, and vortex to mix. Incubate the 96-well plate in a water bath at 37°C and 75 rpm for up to 120 minutes. At the set time points (0, 15, 30, 60, and 120 minutes), transfer 70 μL of sample to another 96-well plate, add 3 times the volume of a methanol-acetonitrile mixture containing the internal standard (1:1 v / v), and vortex for 10 minutes. Centrifuge the sample at 4°C and 6000 × g for 10 minutes. Transfer 100 μL of the supernatant to a 96-well plate containing 100 μL of deionized water, mix, and inject the mixture into a liquid chromatography-tandem mass spectrometry (LC-MS / MS) system for analysis. The half-life T of human plasma for mixture 6 was determined. 1 / 2 The reference concentration was 19.7 min, and the T value was 19.7 min. 1 / 2 It takes 53.9 minutes.

[0106] Example of implementation effect 5

[0107] The cardiovascular and respiratory systems of beagle dogs were remotely monitored using the clividine phosphonate derivative (compound 6) prepared in Example 1, as detailed below:

[0108] Compound 6 was administered orally in capsule form to conscious beagle dogs, and the potential effects of the test substance on the canine cardiovascular and respiratory systems were detected using physiological signal telemetry.

[0109] This experiment was designed with three groups: a control group and two groups receiving compound 6 at 3.42 and 6.84 mg / kg. Six healthy beagle dogs (half male and half female) were used. A modified 6x3 Latin square design was employed, with administration divided into three phases. Compound 6 was administered orally via empty capsules or the corresponding dose. Data was washed off one day after each phase before proceeding to the next phase. Data were collected using a non-invasive physiological signal telemetry system from before administration to approximately 10 hours after administration. SPSS Statistics 27.0 software was used to analyze the following data from before administration to approximately 10 hours after administration: systolic blood pressure, diastolic blood pressure, mean arterial pressure, and ECG parameters in lead II (heart rate, QRS duration, PR interval, RR interval, QT interval, corrected QT interval), respiratory rate, tidal volume, and minute ventilation. Results showed that during the experiment, the dogs in all groups were in good general condition, had normal spontaneous activity, and no other abnormal reactions were observed.

[0110] Effects on blood pressure: Within approximately 10 hours after administration, no abnormal changes were observed in systolic blood pressure, diastolic blood pressure, or mean arterial pressure in any of the compound 6 groups of dogs.

[0111] Effects on lead II electrocardiogram: Within approximately 10 hours after administration, no arrhythmias were observed in lead II electrocardiograms of dogs in all groups of Compound 6. No abnormal changes were observed in heart rate, PR interval, QRS duration, RR interval, QT interval, or corrected QT interval.

[0112] Effects on respiration: Within approximately 10 hours after administration, no abnormal changes were observed in respiratory rate, tidal volume, or minute ventilation in dogs in all groups of Compound 6.

[0113] In conclusion, under the conditions of this experiment, a single oral administration of 3.42 and 6.84 mg / kg of compound 6 to awake, unrestrained Beagle dogs did not show significant effects on the canine cardiovascular and respiratory systems.

[0114] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A clevudine phosphonate derivative, characterized in that, The clividine phosphonate derivative comprises a compound of formula (I) or a deuterated form of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ； in, R1, R2, and R3 are independent and selected from hydrogen, deuterium, amino, hydroxyl, carbonyl, α-amino acid side chain, deuterated α-amino acid side chain, cyano, C1-C. 20 Alkyl groups, or R2 and R3 together with the atoms they are attached to, constitute C. 3-8 cycloalkyl or 3-8 membered heterocyclic groups; R4 is selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Halogenated deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted; R5 and R6 are independent of each other and can be selected from H, straight chain, or C1-C with branches. 20 Acyl group; the straight-chain or branched C2-C group 20 Acyl group, optionally further replaced by deuterium, halogen, amino, nitro, hydroxyl, cyano, azide, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 mercaptoalkyl, C 1-6 Deuterated mercaptoalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

2. The cliftidine phosphonate derivative according to claim 1, characterized in that, The clividine phosphonate derivative further comprises a compound of general formula (II), its deuterated form, or a pharmaceutically acceptable salt thereof: ； in, The definitions of R1, R2, R3 and R4 are as described in claim 1.

3. The cliftine phosphonate derivative according to claim 1, characterized in that, The clividine phosphonate derivative further comprises a compound of general formula (IIIa), (IIIb) or (IIIc), its deuterated form or a pharmaceutically acceptable salt thereof: ； The substitution position of the clefdinyl ester fragment on the linker benzene ring can be at the para position (IIIa), the meta position (IIIb), or the ortho position (IIIc) of the phosphonate group. The definitions of R1, R2, R3, R4, R5 and R6 are as described in claim 1.

4. The cliftine phosphonate derivative according to claim 2, characterized in that, The clividine phosphonate derivative further comprises a compound of general formula (Ⅳa) or (Ⅳb), its deuterated form, or a pharmaceutically acceptable salt thereof: ； The α-amino acid ester is preferably derived from alanine ester, and can be a natural L-configuration (IVa), a non-natural D-configuration (IVb), or a mixture of the two in any proportion, with a natural L-configuration alanine ester (IVa) being preferred. The definitions of R1 and R4 are as described in claim 1.

5. The cliftidine phosphonate derivative according to claim 4, characterized in that, The clividine phosphonate derivative further comprises a compound of general formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf), its deuterated form or a pharmaceutically acceptable salt thereof: ； in, The definitions of R1 and R4 are as described in claim 1.

6. The cliftidine phosphonate derivative according to claim 4, characterized in that, The clividine phosphonate derivative further comprises a compound of general formula (VIa) or (VIb), its deuterated form, or a pharmaceutically acceptable salt thereof: ； Among them, the spatial three-dimensional configuration at R1 includes two configurations (VIa, VIb), or it can be a mixture of the two in any proportion; The definitions of R1 and R4 are as described in claim 1.

7. The cliftidine phosphonate derivative according to claim 1, characterized in that, In the general formula (Ⅰ): R1 is hydrogen or amino; R2 and R3 are each independently selected from hydrogen or C. 1-6 alkyl; R4 is C 1-8 alkyl; R5 and R6 are hydrogen; m = 0 or 1.

8. The cliftidine phosphonate derivative according to any one of claims 1-6, characterized in that, The clividine phosphonate derivatives are selected from the following compounds, their deuterated derivatives, or pharmaceutically acceptable salts: 。 9. The use of the clevudine phosphonate derivative, its deuterated form, or its pharmaceutically acceptable salt as described in any one of claims 1-7 in the preparation of a medicament for the treatment or prevention of various viral infections and their secondary disease states and conditions, said viruses including HIV and hepatitis B virus, as well as drug-resistant and other mutant forms of these viruses.

10. A pharmaceutical composition, characterized in that: The active ingredient of the pharmaceutical composition comprises a clevudine phosphonate derivative, a deuterated thereof, or a pharmaceutically acceptable salt thereof as described in any one of claims 1-7.

Images