A heterocyclic derivative, pharmaceutical composition thereof, and use thereof

Abstract

The application discloses a heterocyclic derivative with a structure shown in formula (I) or a stereoisomer, a pharmaceutically acceptable salt thereof. The heterocyclic derivative or the stereoisomer has high activity in inhibiting HCMV, and the activity is increased by 8-40 times compared with that of letermovir, and the patients with HCMV virus infection after allogeneic hematopoietic stem cell transplantation, kidney transplantation and lung transplantation can be better protected in clinic.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a heterocyclic derivative and its pharmaceutical composition and application. Background Technology

[0002] Human cytomegalovirus (HCMV) possesses double-stranded DNA and belongs to the p subfamily of the herpesvirus family. After infection, HCMV can remain latent in the host for a long period. When the immune system is weakened or compromised, the latent HCMV virus can be reactivated, leading to repeated active infections. HCMV often presents as an asymptomatic infection in immunocompetent individuals, but it has a high morbidity and mortality rate in HIV patients, organ transplant recipients, or other immunocompromised individuals. HCMV is also a major viral cause of congenital developmental delays and intellectual disability in newborns. The standard treatment for HCMV infection is intravenous ganciclovir, foscarnet, cidofovir, or oral valganciclovir. Although these nucleoside analogues are clinically effective, their significant nephrotoxicity and widespread drug resistance make their use in allogeneic hematopoietic cell transplant recipients challenging.

[0003] Letemurovir is a potent viral telomerase inhibitor that prevents reactivation and recurrent infection of CMV in CMV seropositive patients who have received allogeneic hematopoietic stem cell transplantation by specifically inhibiting the CMV viral telomerase complex encoded by the CMV genes UL56, UL51, and UL89. Because letemurovir specifically inhibits the viral complex enzymes and does not act on any enzymes in the human body, it has a good safety profile and clinical efficacy. After 28 days of treatment, CMV was undetectable in the patient's body, and no cross-resistance was observed with other approved anti-HCMV drugs.

[0004] The oral dose of letermovir, when administered alone, is 480 mg once daily. If co-administered with cyclosporine, the dose is adjusted to 240 mg once daily. Although letermovir is rapidly absorbed from the small intestine, its bioavailability in hematopoietic cell transplant recipients (HCT) is approximately 37%. Cyclosporine, as a broad-spectrum inhibitor of efflux proteins (P-gp, MRP-1, BCRP, and LRP), effectively enhances the bioavailability of letermovir to 85%.

[0005] Although standard treatments using DNA polymerase inhibitors such as valganciclovir, foscarnet, or cidofovir have shown good clinical efficacy, they also present serious toxic side effects, widespread drug resistance, and the need for concomitant use of lemetmovir with cyclosporine. Furthermore, their activity and dosage require further improvement. Therefore, clinical practice demands drugs with appropriate administration methods, high activity, and low clinical doses to better serve clinical needs. This includes providing safe, potent, low-toxicity anti-HCMV drugs that do not require boosters for organ transplant patients. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a class of heterocyclic derivatives with higher anti-HCMV virus activity in order to address the shortcomings and deficiencies of the prior art.

[0007] To solve the above technical problems, the present invention adopts the following technical solution:

[0008] Heterocyclic derivatives or their stereoisomers having the structure shown in formula (I), and pharmaceutically acceptable salts.

[0009]

[0010] in:

[0011] R1 is selected from C1-6 alkyl groups, or two independent R1s are connected to different carbon atoms on the piperazine ring to form a bridged ring;

[0012] n is selected from 0, 1, or 2;

[0013] R2 is selected from hydroxyl, C1-6 alkylcarbonyloxyC1-6 alkyloxy, C3-6 cycloalkylcarbonyloxyC1-6 alkyloxy or substituted, C1-6 alkyloxycarbonyloxyC1-6 alkyloxy, C3-6 cycloalkoxycarbonyloxyC1-6 alkyloxy or unsubstituted C4-6 heterocyclic alkylC1-6 alkyloxy.

[0014] X is selected from N atoms or CH;

[0015] When n is 0 and X is CH, R2 is not a hydroxyl group.

[0016] According to a preferred aspect of the invention, the structure of the heterocyclic derivative is shown in formula (Ia):

[0017]

[0018] in:

[0019] R2 is selected from C1-6 hydrocarbon carbonyloxy C1-6 hydrocarbon oxy, C3-6 cycloalkyl carbonyloxy C1-6 hydrocarbon oxy, C1-6 hydrocarbon oxy carbonyloxy C1-6 hydrocarbon oxy, C3-6 cycloalkoxy carbonyloxy C1-6 hydrocarbon oxy, or substituted or unsubstituted C4-6 heterocyclic alkyl C1-6 hydrocarbon oxy.

[0020] According to another preferred aspect of the invention: the structure of the heterocyclic derivative is shown in formula (Ib):

[0021]

[0022] in:

[0023] R1 is selected from C1-6 alkyl groups;

[0024] X is selected from N atoms or CH;

[0025] R2 is selected from hydroxyl, C1-6 hydrocarbon carbonyloxy C1-6 hydrocarbon oxygen, C3-6 cycloalkyl carbonyloxy C1-6 hydrocarbon oxygen, C1-6 hydrocarbon oxygen carbonyloxy C1-6 hydrocarbon oxygen, C3-6 cycloalkoxy carbonyloxy C1-6 hydrocarbon oxygen, or substituted or unsubstituted C4-6 heterocyclic alkyl C1-6 hydrocarbon oxygen.

[0026] According to another preferred aspect of the invention: the structure of the heterocyclic derivative is shown in formula (Ic):

[0027]

[0028] in:

[0029] X is selected from N atoms or CH;

[0030] R2 is selected from hydroxyl, C1-6 hydrocarbon carbonyloxy C1-6 hydrocarbon oxygen, C3-6 cycloalkyl carbonyloxy C1-6 hydrocarbon oxygen, C1-6 hydrocarbon oxygen carbonyloxy C1-6 hydrocarbon oxygen, C3-6 cycloalkoxy carbonyloxy C1-6 hydrocarbon oxygen, or substituted or unsubstituted C4-6 heterocyclic alkyl C1-6 hydrocarbon oxygen.

[0031] According to one specific aspect of the invention, R1 is selected from methyl, ethyl, and isopropyl.

[0032] According to one specific aspect of the invention, R1 is selected from methyl.

[0033] In some embodiments, R2 is selected from hydroxyl groups,

[0034] In some embodiments, in formula (Ia), R2 is selected from...

[0035] In some embodiments, in formula (Ib) or (Ic), R2 is selected from hydroxyl groups.

[0036] In some embodiments, the heterocyclic derivative or its stereoisomer is selected from compounds with the following structures:

[0037]

[0038]

[0039] Through research, the inventors discovered that the bioavailability of letermovir in HCT patients is low, requiring co-administration with cyclosporine to improve bioavailability. This is because letermovir is a substrate for efflux proteins in gastrointestinal epithelial cells. Drugs actively transported via proteins typically possess significant polar or ionized groups. Appropriate carboxyl esterification can reduce drug polarity, improve absorption efficiency, and mitigate efflux effects, thereby enhancing drug activity and bioavailability. Furthermore, it may eliminate the need for cyclosporine in clinical practice, further reducing drug toxicity and improving patient compliance.

[0040] Furthermore, this invention incorporates an R1 substituent on the piperazine ring of lemetmovir, which stabilizes the drug's active conformation and significantly enhances its activity. This makes it possible to eliminate the need for cyclosporine in clinical use, and the highly active compound may deliver significant therapeutic or preventative antiviral effects. Due to the significantly increased compound activity, reduced clinical dosage, improved toxicity, and strong viral suppression, this class of compounds can be more widely used in organ transplant patients.

[0041] The present invention also relates to a pharmaceutical composition comprising one or more heterocyclic derivatives or stereoisomers thereof described in the present invention, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0042] Preferably, the pharmaceutical composition is an anti-HCMV virus pharmaceutical composition.

[0043] In some embodiments, the pharmaceutical composition further includes one or more therapeutic or preventive agents selected from one or more combinations of vaccines, antibody drugs, antibody-drug conjugates (ADCs), nucleoside analogs, and other drugs against human cytomegalovirus infection.

[0044] In some embodiments, the pharmaceutically acceptable carrier is selected from one or more combinations of pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, flavorings, and sweeteners.

[0045] In some embodiments, the pharmaceutical composition is selected from tablets, powders, capsules, granules, oral solutions, and injectable formulations. The preferred dosage form of the pharmaceutical composition is tablets, capsules, or injections. All of the above dosage forms can be prepared using conventional methods in the pharmaceutical field.

[0046] In some embodiments, the pharmaceutically acceptable salt refers to the carboxylate salt of the compound of the present invention, which may be a sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt, or other similar metal ion salt.

[0047] In some embodiments, the pharmaceutically acceptable salt refers to a salt formed by the addition reaction with a pharmaceutically acceptable acid, which includes inorganic acids and organic acids; the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, bicarbonate, nitric acid, etc. The organic acids include acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, citric acid, edetate, fumaric acid, maleic acid, malic acid, tartaric acid, mandelic acid, gluconic acid, glutamic acid, lactic acid, dodecyl sulfonic acid, oxalic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, etc.

[0048] In some embodiments, the pharmaceutical composition comprises the following components by weight percentage:

[0049]

[0050]

[0051] The preferred polyethylene glycol is PEG6000.

[0052] This invention also relates to the use of the aforementioned heterocyclic derivatives or their stereoisomers, pharmaceutically acceptable salts, and the aforementioned pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases caused by human cytomegalovirus infection.

[0053] According to the invention, either alone or in a pharmaceutical composition, the compound of the invention is preferably present in a therapeutic / preventive effective amount.

[0054] The present invention also provides a compound suitable for preparing heterocyclic derivatives or their stereoisomers, and pharmaceutically acceptable salts, said compound having the structure shown in formula (II-c):

[0055]

[0056] in:

[0057] X is selected from N atoms or CH.

[0058] Typical compounds (II-c) are, for example, the compounds synthesized in the examples below or compounds that they can directly conceive of.

[0059] The present invention also provides a method for preparing heterocyclic derivatives or their stereoisomers, or pharmaceutically acceptable salts, comprising preparing the aforementioned compounds having the general formula (II-c) or With compounds The process involves reacting to form an ester, hydrolyzing it to form an acid, and then further esterifying it to form compound (Ic), (Ia), or (Ib).

[0060] In some embodiments, the preparation method includes the following key steps:

[0061]

[0062] Step 1: Dissolve A and B in 1,4-dioxane solution, add 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), react at 80-100℃ for 1-12 h, and then purify to obtain intermediate C.

[0063] Step 2: Compound C was added to an aqueous solution of tetrahydrofuran (THF) and sodium hydroxide. The reaction solution was stirred at room temperature for 2–12 h. Dilute hydrochloric acid was added to adjust the pH to 5–6. The solution was then concentrated and purified to obtain compound D.

[0064] Step 3: The halogenated product of the prodrug structure is added to an acetone solution of compound D and cesium carbonate. The reaction solution is reacted at 40-100℃ for 1-12 hours, cooled, water is added, ethyl acetate is extracted, dried over anhydrous sodium sulfate, and concentrated and purified to obtain prodrug E.

[0065] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0066] The heterocyclic derivative of this invention exhibits high HCMV inhibition activity by shielding the polarity of the carboxyl group and optimizing the active conformation of piperazine. Compared with letemovir, its activity is increased by 8-40 times, which can better protect patients with HCMV virus infection after allogeneic hematopoietic stem cell transplantation, kidney transplantation, and lung transplantation in clinical practice. Detailed Implementation

[0067] Terminology Definition

[0068] In the compounds described in this invention, when any variable (e.g., R1, R2, etc.) appears more than once in any component, the definition of each occurrence is independent of the definitions of other occurrences. Similarly, combinations of substituents and variables are permitted, provided such combinations stabilize the compound. Lines drawn from substituents into the ring system indicate that the referred bond can be attached to any substituted ring atom. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic carbon and heteroatom substituents of organic compounds. It will be understood that those skilled in the art can select the substituents and substitution patterns of the compounds of this invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques in the art and the methods described below. If a substituent itself is substituted by more than one group, it should be understood that these groups can be on the same carbon atom or different carbon atoms, as long as structural stability is achieved.

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0070] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. This includes cis-trans isomers, enantiomers, and conformational isomers. All stereoisomers are within the scope of this invention. The compounds of this invention can be individual stereoisomers or mixtures of other isomers, such as racemates, or mixtures of all other stereoisomers.

[0071] The term "salt" refers to a pharmaceutically acceptable salt formed by the compound of the present invention with an acid, which may be an organic or inorganic acid, specifically selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or analogs thereof.

[0072] The term "solvent" refers to the form of the compounds of this invention that form solid or liquid complexes by coordination with solvent molecules. Hydrates are a specific form of solvate in which coordination with water occurs. Within the scope of this invention, hydrates are preferred solvates.

[0073] The term "crystallization" refers to the various solid forms formed by the compounds described in this invention, including crystalline and amorphous forms.

[0074] The term "hydrocarbon group" refers to saturated alkyl, alkenylalkyl, and alkynylalkyl groups.

[0075] The term "saturated alkyl" refers to a straight-chain, branched, or cyclic saturated or unsaturated substituent mainly composed of carbon and hydrogen. Preferably, it has 1-20 carbon atoms, more preferably 1-12 carbon atoms. The term "alkyl" refers to a straight-chain, branched, or cyclic saturated hydrocarbon group. Alkyl groups specifically include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2,2'-methylbutyl and 2,3'-dimethylbutyl, 16-alkyl, and 18-alkyl. The term "C 1-20 Alkyl refers to a straight-chain, branched, or cyclic saturated hydrocarbon group containing 1-20 carbon atoms. Alkyl groups include substituted and unsubstituted alkyl groups. When an alkyl group is substituted, the substituent can be substituted at any usable connection point, and the substituent can be monosubstituted or polysubstituted. Substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and oxo. In naming, the substituent is usually placed before the alkyl group, for example, C10. 1-3 Alkoxy C 3-8 cycloalkyl C 1-6 Alkyl refers to C 1-6 Alkyl groups, which are C 3-8 Cycloalkyl substitution, and the C 3-8 Cycloalkyl groups are also C 1-3 Alkoxy substitution, for example: the structural formula of methoxycyclobutylmethyl is:

[0076]

[0077] The terms "alkenyl" and "alkynyl" refer to straight-chain, branched, or cyclic unsaturated hydrocarbon groups containing double and triple bonds, respectively, preferably with 2-20 carbon atoms, more preferably 2-12 carbon atoms. Alkenyl and alkynyl groups include substituted and unsubstituted alkenyl and alkynyl groups. When substituted, the substituent can be substituted at any usable linker, and the substituent can be monosubstituted or polysubstituted. The substituent is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and oxo. In nomenclature, the substituent is usually placed before the alkenyl or alkynyl group.

[0078] The term "ring" refers to both carbon rings and heterocycles. "Carbocyclic group" or "carbon ring" refers to a carbon cyclic group having 3 to 20 carbon atoms, preferably 3 to 16, and more preferably 4 to 12, including cycloalkyl, cycloalkenyl, aryl, bicyclic carbon rings, and polycyclic carbon cyclic groups. "Heterocyclic group" or "heterocycle" includes heteroaryl, non-aromatic heterocyclic groups, bicyclic heterocyclic groups, and polycyclic heterocyclic groups having one or more identical or different heteroatoms chosen arbitrarily from O, S, and N within the ring. The term "ring" includes monocyclic, bridged, spirocyclic, fused, and polycyclic rings.

[0079] The term "cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic cycloalkyl group. A monocyclic group may include 3-10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups include unsubstituted and substituted groups. Substituents are selected from one or more substituent groups, including but not limited to the following groups, independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester, amino, amide, hydroxy, cyano, nitro, aryl, and heteroaryl groups.

[0080] The term "aryl" refers to two types: carbocyclic aryl and heteroaryl.

[0081] The term "carbocyclic aryl" refers to an aromatic group consisting of a 6-10 member, all-carbon monocyclic or polycyclic ring, including phenyl, naphthalene, biphenyl, etc. Aryl groups can be substituted or unsubstituted. Substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, and cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, alkylsilyl, etc.

[0082] The term "heteroaryl" refers to a group in a heteroaromatic system containing 1-10 heteroatoms. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, etc. Monoheterocyclic groups include, but are not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline, etc. Fused heterocyclic groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromone, fluorenone, quinoxaline, 3,4-dihydronaphthone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, etc. Heteroaryl groups can be substituted or unsubstituted. The substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, and cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, alkylsilyl, etc.

[0083] The term "halogen" refers to fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine being preferred.

[0084] The term "deuterium" is an isotope of hydrogen, with an atomic mass twice that of hydrogen and a stronger bond to carbon. "Deuteration" and "deuterium" indicate that hydrogen is replaced with deuterium at a specified position. A "deuterated substituent" is a substituent in which at least one hydrogen atom is replaced by deuterium enriched in a specified percentage.

[0085] The term "halogenated alkyl" refers to an alkyl group that is substituted by at least one halogen atom.

[0086] The term "heterocyclic group" refers to a cyclic group containing at least one heteroatom, such as nitrogen, oxygen, sulfur, or thiocyanate. Heterocyclic groups include monocyclic and polycyclic groups.

[0087] In addition to standard methods known in the literature or illustrated in experimental procedures, the compounds of the present invention can be prepared using the following synthetic schemes.

[0088] A better understanding of the compounds and synthetic methods described in this invention can be achieved by referring to the following synthetic schemes. The synthetic schemes describe methods that can be used to prepare the compounds described in this invention. These methods are merely illustrative descriptions for explanatory purposes and do not constitute a limitation on the scope of this invention.

[0089] The present invention will be further described below with reference to embodiments, but these embodiments are not intended to limit the scope of protection of the present invention.

[0090] The technical features of the embodiments described below can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the embodiments below are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0091] The following embodiments are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this invention should be determined by the appended claims.

[0092] The abbreviations of the compound names used in the examples are as follows:

[0093] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0094] DPPA: Diphenyl azidophosphate

[0095] DCM: Dichloromethane

[0096] EtOAc: Ethyl acetate

[0097] PE: Petroleum ether

[0098] EA: Ethyl acetate

[0099] THF: Tetrahydrofuran

[0100] MTBE: Methyl tert-butyl ether

[0101] 1,4-Dioxane: 1,4-Dioxane

[0102] TFA: Trifluoroacetic acid.

[0103] Example 1: Synthesis of Compound I-5

[0104]

[0105] Synthesis of Compound 2: Compound 1 (10.00 g, 45.66 mmol) was dissolved in toluene (100 ml) and cooled in an ice bath. DPPA (18.85 g, 68.49 mmol) and triethylamine (13.86 g, 136.98 mmol) were weighed and added to the reaction system, and stirred at room temperature for 1 h. The reaction system was heated to 80 °C and stirred for 1 h. SM1 (12.22 g, 63.92 mmol) was added, and stirring was continued for 2 h. The reaction solution was cooled and poured into water (300 ml). It was extracted twice with ethyl acetate (300 ml). The organic layer was washed with saturated brine (300 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by slurrying with (PE:EA = 3:1, 200 ml) to obtain 15.9 g of gray solid.

[0106] Synthesis of Compound 3: Compound 2 (11.40 g, 27.99 mmol) was dissolved in isopropyl acetate (80 ml), and methyl acrylate (7.23 g, 83.97 mmol), c-Hex2NMe (6.56 g, 33.59 mmol) and (t-Bu)3P-Pd (1.43 g, 2.80 mmol) were added. The mixture was heated to 80 °C and stirred for 4 h under nitrogen protection. The reaction solution was cooled and poured into water (300 ml). The mixture was extracted twice with ethyl acetate (300 ml). The organic layer was passed through a silica gel pad, and the silica gel pad was washed with ethyl acetate (300 ml). The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by slurry mixing with PE:EA = 5:1, 150 ml to give 8.4 g of a white solid.

[0107] Synthesis of compound 4: Compound 3 (7.7 g, 18.67 mmol) and DBU (1.42 g, 9.34 mmol) were weighed and dissolved in toluene (120 ml). The reaction system was heated to 100 °C and stirred for 1 h. The reaction solution was cooled and poured into water (200 ml). The mixture was extracted twice with DCM (200 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by pulping (PE:EA = 5:1, 50 ml) to obtain 6.4 g of yellow solid.

[0108] Synthesis of Compound 5: Compound 4 (6.4 g, 15.19 mmol) was added to phosphorus oxychloride (100 ml), and the reaction system was heated to 105 °C and stirred for 3 h. The reaction solution was concentrated under reduced pressure to remove most of the phosphorus oxychloride, cooled, and poured into MTBE (300 ml). Water (300 ml) was added to separate the layers. The organic phase was washed with saturated sodium bicarbonate (300 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain 6.6 g of yellow oil.

[0109] Synthesis of Compound 6: Compound 5 (6.6 g, 15.32 mmol) was weighed and dissolved in 1,4-dioxane (60 ml). SM2 (3.5 g, 15.32 mmol) and DBU (7.0 g, 45.96 mmol) were added, and the reaction system was heated to 100 °C and stirred for 1 h. The reaction solution was cooled and poured into water (200 ml). Extraction was performed with ethyl acetate (200 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1 ~ DCM:MeOH = 100:1) to obtain 6.5 g of pale yellow solid.

[0110] Synthesis of compound 7: Compound 6 (6.5 g, 11.08 mmol) was prepared and resolved to give 2.8 g of off-white solid.

[0111] Synthesis of Compound 8: Compound 7 (2.00 g, 3.41 mmol) was weighed and dissolved in THF (27 ml), and 0.5 M sodium hydroxide aqueous solution (27 ml, 13.64 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction solution was poured into water (200 ml), and the pH was adjusted to 5-6 with citric acid solid. The mixture was extracted with MTBE (200 ml), and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 1.8 g of white solid.

[0112] Synthesis of Compound I-5: Compound 8 (200 mg, 0.35 mmol) was weighed and dissolved in acetone (5 mL). Dimethyl chloromethyl carbonate (66 mg, 0.53 mmol), potassium iodide (58 mg, 0.35 mmol), and cesium carbonate (456 mg, 1.40 mmol) were added. The reaction mixture was heated to 56 °C and stirred for 2 h. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 2:1) to obtain 120 mg of white solid. LCMS ESI m / z: 661.6 (M+H) +;1H NMR (400MHz, Chloroform-d): δ7.40 (d, J=8.0Hz, 1H), 7.16–7.12 (m, 2H), 7.04–6.9 9(m,2H),6.90–6.85(m,1H),6.76(d,J=4.0Hz,1H),6.46–6.40(m,2H),6.37(s,1H), 5.84(d,J=4.0Hz,1H),5.70(d,J=4.0Hz,1H),4.89–4.85(m,1H),3.90(s,3H),3.81 (s,3H),3.76(s,3H),3.53(d,J=36.0Hz,4H),3.07–2.87(m,5H),2.71–2.66(m,1H).

[0113] Example 2: Synthesis of Compound I-8

[0114]

[0115] Compound 8 (250 mg, 0.44 mmol) was weighed and dissolved in acetone (5 mL). Bromomethyl acetate (101 mg, 0.66 mmol) and cesium carbonate (573 mg, 1.76 mmol) were added. The reaction mixture was heated to 56 °C and stirred for 2 h. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 2:1) to obtain 88 mg of a white solid. LCMSESI m / z: 645.6 (M+H) + ;1H NMR (400MHz, Chloroform-d): δ7.40(d,J=8.4Hz,1H),7.16–7.12(m,2H),7.04–6.99(m,2H),6.90–6.85(m,1H),6.77–6.76(m,1H),6.46–6.37(m, 3H),5.80–5.69(m,2H),4.87–4.84(m,1H),3.90(s,3H),3.76(s,3H),3. 53(d,J=36.0Hz,4H),3.09–2.79(m,5H),2.72–2.67(m,1H),2.08(s,3H).

[0116] Example 3: Synthesis of compound I-13

[0117]

[0118] Compound 8 (250 mg, 0.44 mmol) was weighed and dissolved in acetone (5 mL). Chloromethyl tert-pentanoate (99 mg, 0.66 mmol), potassium iodide (73 mg, 0.44 mmol), and cesium carbonate (573 mg, 1.76 mmol) were added. The reaction mixture was heated to 56 °C and stirred for 2 h. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 2:1) to obtain 130 mg of a white solid. LCMS ESI m / z: 687.7 (M+H) + ; 1 H NMR (400MHz, Chloroform-d): δ7.40 (d, J=12.0Hz, 1H), 7.16–7.11 (m, 2H), 7.04 –6.99(m,2H),6.89–6.84(m,1H),6.79–6.77(m,1H),6.46–6.36(m,3H),5.78(d ,J=8.0Hz,1H),5.72(d,J=8.0Hz,1H),4.87–4.84(m,1H),3.91(s,3H),3.76(s, 3H), 3.53 (d, J = 36.0Hz, 4H), 3.09–2.79 (m, 5H), 2.74–2.68 (m, 1H), 1.18 (s, 9H).

[0119] Example 4: Synthesis of compound I-17

[0120]

[0121] Compound 8 (200 mg, 0.35 mmol) was weighed and dissolved in acetone (5 mL). 4-Chloromethyl-5-methyl-1,3-dioxane-2-one (79 mg, 0.53 mmol), potassium iodide (58 mg, 0.35 mmol), and cesium carbonate (456 mg, 1.40 mmol) were added. The reaction mixture was heated to 56 °C and stirred for 2 h. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 2:1) to obtain 125 mg of a white solid. LCMS ESI m / z: 685.6 (M+H) + ; 1H NMR (400MHz, Chloroform-d): δ7.41(d,J=8.0Hz,1H),7.16–7.12(m,2H),7.04–7.00(m,2H),6.89–6.84(m,1H),6.70(d,J=8.0Hz,1H),6.46–6.4 0(m,2H),6.37(s,1H),4.89–4.82(m,2H),3.91(s,3H),3.76(s,3H),3.5 3(d,J=36.0Hz,4H),3.04–2.79(m,5H),2.75–2.69(m,1H),2.15(s,3H).

[0122] Example 5: Synthesis of Compound I-19

[0123]

[0124] Synthesis of compound 7b: Compound 7a (500 mg, 2.36 mmol), m-bromoanisole (662 mg, 3.54 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), tri-tert-butylphosphine (40 mg, 0.02 mmol), and potassium tert-butoxide (397 mg, 3.54 mmol) were weighed and dissolved in toluene (10 mL). The mixture was heated to 100 °C and stirred for 6 h under nitrogen protection. The reaction system was cooled, and the reaction solution was poured into water (200 mL). The mixture was extracted with ethyl acetate (200 mL), and the organic phase was washed with brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain 620 mg of yellow solid.

[0125] Synthesis of compound 7c: Compound 7b (620 mg, 1.95 mmol) was dissolved in DCM (6 ml), and TFA (3 ml) was added dropwise. The mixture was stirred at room temperature for 1 h. The reaction solution was poured into water (100 ml), and the pH was adjusted to 8–9 with saturated sodium bicarbonate aqueous solution (100 ml). The solution was extracted with ethyl acetate (100 ml), the organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 280 mg of crude yellow solid.

[0126] Synthesis of compound 7d: Compound 5 (180 mg, 0.42 mmol), compound 7c (92 mg, 0.42 mmol), potassium iodide (6.6 mg, 0.04 mmol), and potassium carbonate (174 mg, 1.26 mmol) were weighed and dissolved in NMP (3 ml). The mixture was heated to 80 °C and stirred for 1 h. The reaction system was cooled, and the reaction solution was poured into water (100 ml). The mixture was extracted with ethyl acetate (100 ml), and the organic phase was washed with brine (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain 55 mg of yellow solid.

[0127] Synthesis of Compound I-19: Compound 7d (55 mg, 0.09 mmol) was weighed and dissolved in THF (1 ml). 0.5 M sodium hydroxide aqueous solution (0.7 ml, 0.44 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction solution was poured into water (100 ml), and the pH was adjusted to 5–6 with citric acid solid. Extraction was performed with ethyl acetate (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to give 14 mg of a white solid. LCMS ESI m / z: 599.6 (M+H) + ; 1HNMR (400MHz, Chloroform-d): δ7.40 (d, J=8.0Hz, 1H), 7.11–6.92 (m, 4H), 6. 80–6.70(m,2H),6.34–6.22(m,3H),4.83(s,1H),4.50–4.27(m,3H),3.83(s,3H) ),3.74(s,3H),3.66(s,1H),3.34(d,J=4.0Hz,1H),3.14(d,J=4.0Hz,1H),2.98 –2.94(m,1H),2.72(d,J=8.0Hz,1H),2.65–2.60(m,1H),1.70(d,J=40.0Hz,4H).

[0128] Example 6: Synthesis of compounds I-23 and I-29

[0129]

[0130] Synthesis of compound 9b: Compound 9a (1.00 g, 5.00 mmol), m-bromoanisole (1.12 g, 6.00 mmol), X-HPOS (95 mg, 0.20 mmol), Pd2(dba)3 (183 mg, 0.20 mmol), and cesium carbonate (3.16 g, 10.00 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to 100 °C and stirred for 3 h under nitrogen protection. The reaction solution was cooled and poured into water (10 mL). Extraction was performed with ethyl acetate (10 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 8:1) to obtain 1.3 g of a yellow oil.

[0131] Synthesis of compound 9c: Compound 9b (1.3 g, 4.24 mmol) was weighed and dissolved in DCM (10 ml), and TFA (5 ml) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate (200 ml), and then saturated sodium bicarbonate aqueous solution (200 ml) was added. The aqueous phase was kept at pH 7-8 and separated into layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by slurry mixing (PE:EA = 5:1, 20 ml) to obtain 1.04 g of pink solid.

[0132] Synthesis of compound 9d: Compound 5 (500 mg, 1.16 mmol) was weighed and dissolved in 1,4-dioxane (5 mL). Compound 9c (239 mg, 1.16 mmol) and DBU (457 mg, 3.48 mmol) were added, and the mixture was heated to 100 °C and stirred for 1 h. The reaction solution was cooled and poured into water (200 mL). Extraction was performed with ethyl acetate (200 mL). The organic phase was washed with Brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain 137 mg of white solid.

[0133] Synthesis of Compound I-23: Compound 9d (137 mg, 0.23 mmol) was dissolved in THF (2 ml), and 0.5 M sodium hydroxide aqueous solution (1.8 ml, 0.92 mmol) was added. The mixture was stirred at room temperature for 2 h. The pH of the reaction solution was adjusted to 5–6 with dilute hydrochloric acid. The reaction solution was concentrated under reduced pressure to remove THF and water, yielding a crude product. The crude product was dissolved in DCM:MeOH = 10:1 (50 ml), and insoluble matter was removed by filtration. The filtrate was enriched and purified by column chromatography to give 73 mg of a white solid. LCMS ESI m / z: 587.3 (M+H) +;1H NMR (400MHz, Chloroform-d): δ7.48–7.38(m,1H),7.13–7.09(m,1H),7.03–6.86(m,3H),6.82–6.80(m,1H),6.46–6.22(m,3H),4.88–4.83 (m,1H),3.83(s,2H),3.74(d,J=1.6Hz,3H),3.73(s,6H),3.55(s,1H),3.38(s,1H),3.07–2.91(m,2H),2.68(s,1H),2.02(d,J=4.0Hz,2H).

[0134] Synthesis of compound I-29: Compound I-25 (61 mg, 0.10 mmol) was dissolved in acetone (2 mL), and cesium carbonate (98 mg, 0.30 mmol) and bromomethyl acetate (23 mg, 0.15 mmol) were added. The mixture was heated to 56 °C and stirred for 1 h. The reaction solution was poured into water (50 mL), and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to give 15 mg of white solid. LCMS ESI m / z: 659.4 (M+H) + ;1H NMR (400MHz, Chloroform-d): δ7.45–7.38(m,1H),7.13(t,J=8.0Hz,1H),7.06–6.97(m,2H ),6.95–6.82(m,1H),6.77(d,J=4.0Hz,1H),6.45–6.41(m,1H),6.41–6.32(m,2H),5.80–5. 68(m,1H),5.36–5.35(m,1H),4.87–4.79(m,1H),3.92(s,3H),3.84–3.53(m,6H),3.53–3. 24(m,2H),3.17–2.85(m,3H),2.79–2.63(m,1H),2.09(t,J=4.0Hz,3H),2.07–2.06(m,1H).

[0135] Example 7: Synthesis of compounds I-24 and I-49

[0136]

[0137] Synthesis of compound 10b: Compound 9a (1.00 g, 5.00 mmol), p-4-bromo-2-methoxypyridine (1.13 g, 6.00 mmol), X-HPOS (95 mg, 0.20 mmol), Pd2(dba)3 (183 mg, 0.20 mmol), and cesium carbonate (3.16 g, 10.00 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to 100 °C and stirred for 3 h under nitrogen protection. The reaction solution was cooled and poured into water (10 mL). The solution was extracted with ethyl acetate (10 mL), and the organic phase was washed with brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 8:1) to give 1.6 g of a yellow oil.

[0138] Synthesis of compound 10c: Compound 10b (1.6 g, 5.21 mmol) was weighed and dissolved in DCM (10 ml), and TFA (5 ml) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate (200 ml), and then saturated sodium bicarbonate aqueous solution (200 ml) was added. The aqueous phase was kept at pH 7–8, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 40:1) to obtain 970 mg of a yellow oily substance.

[0139] Synthesis of compound 10d: Compound 5 (200 mg, 0.46 mmol) was weighed and dissolved in 1,4-dioxane (3 ml). Compound 10c (95 mg, 0.46 mmol) and DBU (210 mg, 1.38 mmol) were added, and the mixture was heated to 100 °C and stirred for 1 h. The reaction solution was cooled and poured into water (100 ml). Extraction was performed with ethyl acetate (100 ml). The organic phase was washed with Brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain 82 mg of white solid.

[0140] Synthesis of Compound I-24: Compound 10d (82 mg, 0.14 mmol) was dissolved in THF (1 ml), and 0.5 M sodium hydroxide aqueous solution (1.0 ml, 0.56 mmol) was added. The mixture was stirred at room temperature for 2 h. The pH of the reaction solution was adjusted to 5–6 with dilute hydrochloric acid. The reaction solution was concentrated under reduced pressure to remove THF and water, yielding a crude product. The crude product was dissolved in DCM:MeOH = 10:1 (50 ml), and insoluble matter was removed by filtration. The filtrate was enriched and purified by column chromatography to give 66 mg of a white solid. LCMS ESI m / z: 588.2 (M+H) +;1H NMR (400MHz, Chloroform-d): δ7.85(d,J=8.0Hz,1H),7.53–7.39(m,1H),7.12–6.86(m,3H),6.82(t,J=8.0Hz,1H),6.27–6.21(m,1H),5.94–5.82(m,1 H),4.93–4.80(m,1H),4.18–3.90(m,2H),3.87(s,3H),3.75(s,6H),3.68– 3.57(m,1H),3.44(d,J=12.0Hz,1H),3.31–3.14(m,2H),3.05–2.86(m,2H).

[0141] Synthesis of compound I-49: Compound I-24 (51 mg, 0.09 mmol) was dissolved in acetone (2 mL), and cesium carbonate (88 mg, 0.27 mmol) and bromomethyl acetate (21 mg, 0.14 mmol) were added. The mixture was heated to 56 °C and stirred for 1 h. The reaction solution was poured into water (50 mL), and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to give 13 mg of white solid. LCMS ESI m / z: 660.2 (M+H) + ;1H NMR (400MHz, Chloroform-d): δ7.85 (d, J=16.0Hz, 1H), 7.43 (t, J=8.0Hz, 1H), 7.06–6.99 (m, 2H), 6 .94–6.89(m,1H),6.78(d,J=4.0Hz,1H),6.30–6.26(m,1H),5.96–5.87(m,1H),5.80–5.79(m,1H),5 .70–5.68(m,1H),5.40–5.20(m,2H),4.87–4.80(m,1H),4.13(s,1H),3.88(s,3H),3.77(s,3H),3.4 7(d,J=9.4Hz,1H),3.32–2.93(m,4H),2.73–2.67(m,1H),2.10(d,J=8.0Hz,3H),2.06–1.92(m,1H).

[0142] Using the same synthetic method, the following compounds were synthesized and chirally resolved:

[0143]

[0144]

[0145] Example 8: In vitro bioactivity study

[0146] Test compounds: Compounds of the present invention: Compound I-5, Compound I-8, Compound I-13, Compound I-17, Compound I-19, Compound I-23, Compound I-24, Compound I-25, Compound I-26, Compound I-29, Compound I-33, Compound I-41, Compound I-49, Compound I-53; Control compound: Letemovir (racemic).

[0147] Methods for in vitro bioactivity studies: The HCMV virus used in this study contains a reporter gene, GFP. The inhibitory activity of the compound against HCMV was detected by measuring GFP expression levels, and cytotoxicity was simultaneously assessed. The compound was tested at eight concentrations, with three-fold serial dilutions and double replicates. MRC5 cells were seeded at a specific density in microplates and cultured overnight at 37°C and 5% CO2. The compound and virus were added the following day. Since terminal enzyme inhibitors only inhibit the release and reinfection of progeny viruses and have no inhibitory activity against initially added HCMV virus, a 100% virus inhibition control group (cells infected with virus and treated with 1 μM letermovir) and a virus-infected control group (cells infected with virus but without compound treatment) were set up. The final concentration of DMSO in the cell culture medium was 0.5%. Cells were cultured at 37°C and 5% CO2 for 7 days. Fluorescence values ​​in each well were detected using Acumen, and the raw data were used to calculate the antiviral activity of the compound. The cytotoxicity assay was the same as the antiviral assay, but without virus infection; cell viability was detected using the CCK-8 assay, and the raw data were used to calculate the cytotoxicity of the compound. The dose-response curves of the compounds were analyzed using GraphPad Prism software, and the EC values ​​were calculated. 50 and CC 50 Values ​​(see Table 1 for results).

[0148] Table 1. Inhibitory activity of compounds against HCMV

[0149] CPD ID <![CDATA[EC 50 (nM)]]> <![CDATA[CC 50 (μM)]]> 1-5 2.62 >50 I-8 1.47 >50 I-13 2.76 >50 I-17 1.52 43.49 I-19 2.81 23.76 I-23 0.28 >50 I-24 0.46 >50 I-25 0.17 >50 I-26 0.26 >50 I-29 0.10 37.14 I-33 0.06 >50 I-41 0.15 39.28 I-49 0.46 >50 I-53 0.32 >50 Letmore (racemosis) 3.92 36.48

[0150] Conclusion: Compared with letemovir, the compounds of the present invention have stronger inhibitory activity against HCMV, especially compounds I-23, I-24, I-25, I-26, I-29, I-33, I-41, I-49, and I-53, whose activity is below 1 nM, and they have good prospects for clinical application.

[0151] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. Heterocyclic derivatives or stereoisomers thereof having the structure shown in formula (Ia), and pharmaceutically acceptable salts. (I-a); in: R2 is selected from , , , , , or .

2. Heterocyclic derivatives or stereoisomers thereof having the structure shown in formula (Ib), and pharmaceutically acceptable salts. (I-b); in: R1 is selected from methyl; X is selected from N atoms or CH; R2 is selected from hydroxyl groups.

3. Heterocyclic derivatives or stereoisomers thereof having the structure shown in formula (Ib), and pharmaceutically acceptable salts. (I-b); in: R1 is selected from methyl; X is selected from CH; R2 is selected from , , , , , or .

4. Heterocyclic derivatives or stereoisomers thereof having the structure shown in formula (Ib), and pharmaceutically acceptable salts. (I-b); in: R1 is selected from methyl; X is selected from N; R2 is selected from , , , , .

5. A heterocyclic derivative or its stereoisomer, or a pharmaceutically acceptable salt, characterized in that: The heterocyclic derivative or its stereoisomer is selected from compounds with the following structures: ； ； ； ； ； ； ； 。 6. A pharmaceutical composition, characterized in that: It includes one or more heterocyclic derivatives or stereoisomers thereof as described in any one of claims 1 to 5, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

7. The pharmaceutical composition according to claim 6, characterized in that: The pharmaceutical composition further includes one or more therapeutic or preventive agents selected from one or more combinations of vaccines, antibody drugs, nucleoside analogs, and other drugs for combating human cytomegalovirus infection.

8. The pharmaceutical composition according to claim 6, characterized in that: The pharmaceutical composition further includes one or more therapeutic or preventive agents selected from one or more combinations of vaccines, antibody-drug conjugates, nucleoside analogs, and other drugs for combating human cytomegalovirus infection.

9. The use of the heterocyclic derivative or stereoisomer thereof, a pharmaceutically acceptable salt, or the pharmaceutical composition of claim 6, 7, or 8 in the preparation of a medicament for the prevention and / or treatment of human cytomegalovirus infection.

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