CN113248539B

CN113248539B - Imidazopyrimidines compounds

Info

Publication number: CN113248539B
Application number: CN202110649511.6A
Authority: CN
Inventors: 孔丽君; 陈明键; 仇思念; 李瑛颖; 司小兴; 冀斌
Original assignee: China Israel Hyde Artificial Intelligence Drug Research And Development Co ltd
Current assignee: China Israel Hyde Artificial Intelligence Drug Research And Development Co ltd
Priority date: 2021-06-10
Filing date: 2021-06-10
Publication date: 2021-09-07
Anticipated expiration: 2041-06-10
Also published as: CN113248539A

Abstract

The application provides an imidazopyrimidine compound. The imidazopyrimidine compound has a structure shown in a general formula 1, wherein Q is-OH, R1 is H, R2 is nitro, m is 1, and n is 4. The imidazopyrimidine compound has activity of resisting hepatitis B virus.

Description

Imidazopyrimidines compounds

Technical Field

The invention relates to a heterocyclic compound, in particular to an imidazopyrimidine compound.

Background

Many heterocyclic compounds exhibit excellent properties in antitumor and antiviral activities, and improvement of the properties of such compounds is an important issue of attention of many researchers.

Human Hepatitis B Virus (HBV) infection is a major public health problem worldwide. After acute hepatitis B virus infection, about 8% of hepatitis B virus still develops into chronic hepatitis B infection, and persistent HBV infection can cause cirrhosis and even liver cancer.

In order to avoid the formation of liver cancer, the best strategy is to prevent the liver cancer and inhibit or even eliminate hepatitis B virus as soon as possible. There are many hepatitis b therapeutic drugs on the market today, mainly by antiviral treatment with interferon or nucleoside analogues. In the case of interferon, recombinant DNA leukocyte interferon (IFN-. alpha.) inhibits the replication of HBV. However, when the interferon is used for treating hepatitis B, strong adverse reactions are often accompanied, including bone marrow suppression, thyroid function influence, depression and the like.

Nucleoside analogues inhibit HBV production primarily by inhibiting reverse transcriptase activity during HBV replication, and clinically useful drugs include: lamivudine, famciclovir, acyclovir, adefovir, entecavir, tenofovir, foscarnet and the like, and the medicaments have certain HBV inhibiting effect.

Although these reverse transcriptase inhibitors can effectively reduce HBV DNA level and make patients control HBV level, they have no effect on the clearance of HBV cccDNA and HBsAg because their target is the process of RNA reverse transcription into DNA. Therefore, the seroconversion probability of HBsAg is very low in single-drug treatment of nucleoside analogue, hepatitis B cannot be really cured, and patients need to take the drug for a long time or even for life.

The problems of drug resistance, high medical costs, serious side effects of the drugs, etc. which are caused by long-term administration of the above drugs, are a heavy burden on patients with hepatitis B. The key point is that at present, no medicine can simultaneously reduce the HBV DNA level and reduce the HBsAg so as to achieve serological transformation of the HBsAg, further completely eliminate viruses and achieve functional cure of the hepatitis B.

Disclosure of Invention

The application provides a heterocyclic compound, in particular provides an imidazopyrimidine compound, a pharmaceutically acceptable salt or a deuteron thereof, wherein the imidazopyrimidine compound is represented by a general formula 1:

，

wherein Q is-OH, R₁Is H, R₂Is nitro, m is 1, and n is 4.

The inventors surprisingly found that the imidazopyrimidine compound of the present application can significantly reduce the HBV DNA load and reduce the level of HBsAg, thereby enabling a promising functional cure for hepatitis b. Overcomes the defect that the nucleoside analogue serving as a mainstream anti-hepatitis B medicament only reduces HBV DNA, is expected to functionally cure hepatitis B and eliminate hepatitis B virus.

In a preferred embodimentWherein the deutero-compound of the imidazo pyrimidine compound is at least one R of the compound of the general formula 1₁A compound substituted with deuterium, or a compound in which the methyl group in formula 1 is substituted with at least one deuterium, or a compound containing a combination of both deuterations, for example:

。

the deuterated compound can replicate the activity of the original compound and prolong the half-life of the compound, thereby playing a role in synergism on the compound with faster metabolism and lower bioavailability. Most preferred according to the metabolite characteristics of the compounds of the present application are HDLY002 and HDLY003, which increase the half-life of this part of the metabolite and thus increase the drug efficacy.

In a preferred embodiment, the pharmaceutically acceptable salt is selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, toluenesulfonate, undecanoate, sodium salt, calcium salt, potassium salt, ammonium salt, tetraethylammonium salt, methylammonium salt, dimethylammonium salt, and ethanolamine salt.

In a preferred embodiment, the imidazopyrimidine-based compound is represented by general formula 1-1:

，

q, R therein₁、R₂M and n are as defined for formula 1. The chiral molecules are more potent than the racemic mixture.

In a preferred embodiment, the imidazopyrimidine compound, its pharmaceutically acceptable salt or deuterogen thereof is selected from the group consisting of the following compounds and deuterogens thereof:

compound HDLY001 compound 1-1,

the deuterons include compounds HDLY001 and compounds in which at least one H in compound 1-1 is substituted with deuterium. Such as HDLY002, HDLY003, and HDLY004 described above.

The application also provides a pharmaceutical composition, which comprises the imidazo pyrimidine compound or the pharmaceutically acceptable salt thereof or the deuterate thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present application can be used for treating hepatitis b.

In a preferred embodiment, the pharmaceutical composition of the present application further comprises one or more additional therapeutic or prophylactic agents for hepatitis b, preferably nitazoxanide, interferon and nucleoside analogs. The nucleoside analogue may be entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide. The combined medicine can more effectively eliminate hepatitis B virus to a certain extent.

The application also provides the application of the pharmaceutical composition in preparing a medicament for treating hepatitis B. Particularly pharmaceutical compositions comprising HDLY 001.

In a preferred embodiment, the imidazopyrimidine compound is a deutero-compound thereof, and the deuterium-substituted compound is capable of increasing the half-life of the compound, retarding or slowing the metabolic process of the compound while replicating the activity of the original compound, thereby increasing the drug effect.

In a preferred embodiment, the imidazopyrimidine-based compound or the medicament of the present application is capable of reducing the Hepatitis B Virus (HBV) load and HBsAg levels.

In a preferred embodiment, the medicament is formulated for administration by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.

The present application also provides a pharmaceutical composition for treating hepatitis b, comprising a therapeutically effective amount of the imidazopyrimidine-based compound or a pharmaceutically acceptable salt or deutero-derivative thereof, and optionally one or more additional therapeutic or prophylactic agents, and a pharmaceutically acceptable carrier.

The technical scheme of the invention has the following beneficial effects:

1. the imidazopyrimidine compound or a pharmaceutically acceptable salt or deutero thereof of the present application is applied to the treatment of hepatitis b, thereby providing a novel viral hepatitis treatment option.

2. The imidazopyrimidine compound or pharmaceutically acceptable salt thereof can effectively reduce the load of Hepatitis B Virus (HBV) and the level of HBsAg at the same time, and has better effect than the TAF (tenofovir alafenamide, which can only reduce HBV DNA) used in the existing common medicine for hepatitis B and the nitazoxanide (which shows that the load of Hepatitis B Virus (HBV) and the level of HBsAg cannot be reduced on mice) which is a compound with a part of structure similar to that of the compound, thereby having wide application prospect in the treatment of hepatitis B.

3. The imidazopyrimidine-based compounds of the present application, or a pharmaceutically acceptable salt thereof, can optionally be combined with one or more additional therapeutic or prophylactic agents, thereby providing a broad idea for subsequent combination drug administration design with the potential for synergy.

Drawings

Fig. 1 is an NMR spectrum of an imidazopyrimidine-based compound HDLY001 of the present application.

FIG. 2 is a graph showing the results of HBV DNA inhibition of HDLY001 for hepatitis B model mice in example 1 and comparative example 1.

FIG. 3 is a result of the reduction of HBsAg of HDLY001 for hepatitis B model mice in example 1 and comparative example 1.

FIG. 4 shows the results of comparative examples 2 to 4 on the inhibition of HBV DNA of hepatitis B model mice.

FIG. 5 is a graph showing the results of HBsAg inhibition in comparative examples 2 to 4 for hepatitis B model mice.

FIG. 6 shows the results of HBV DNA examination after halving the dose of example 1 and continuing the administration for 42 days.

FIG. 7 is the result of HBsAg detection by the administration of example 1 after halving the dose for a period of 42 days.

Detailed Description

In one aspect, the present invention provides an imidazopyrimidine compound of the present application, or a pharmaceutically acceptable salt or deuteron thereof, and its use in the manufacture of a medicament for the treatment of hepatitis b. The technical solution of the present application will be described below with reference to specific examples.

Imidazopyrimidine compounds of the present application

Provided are an imidazopyrimidine-based compound represented by general formula 1:

，

wherein Q is-OH, R₁Is H, R₂Is nitro, m is 1, and n is 4.

In a preferred embodiment, the deutero-compound of the imidazopyrimidine compound is at least one R of the compound of formula 1₁A compound substituted with deuterium, or a compound in which the methyl group in formula 1 is substituted with at least one deuterium, or a compound containing a combination of both deuterations, for example:

。

，

compound HDLY001 compound 1-1,

The most preferred imidazopyrimidine compounds are the following compounds HDLY001 and its deuteroides HDLY002-HDLY 004:

compound HDLY 001.

Viral hepatitis

The etiological typing of viral hepatitis is currently recognized by five hepatitis viruses, namely hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus and hepatitis E virus, which are respectively written as HAV, HBV, HCV, HDV and HEV, and the rest are RNA viruses except the hepatitis B virus which is a DNA virus.

Hepatitis b is an infectious disease mainly caused by hepatitis b virus, and is a liver disease. Clinically, the symptoms of anorexia, nausea, epigastric discomfort, liver pain and hypodynamia are mainly manifested. Some patients may have jaundice fever and hepatomegaly with impaired liver function. Some patients can become chronic, even develop cirrhosis of the liver, and a few can develop liver cancer.

The etiological agent of hepatitis b is hepatitis b virus, abbreviated as HBV, which is DNA virus. The genome is a double-stranded, circular, incompletely closed DNA. The outermost layer of the virus is the outer membrane or coat membrane of the virus, the inner layer is the core part, and the nucleoprotein is the core antigen (HBcAg) and cannot be detected in the serum. Serum from HBsAg positive patients was observed under electron microscope to have 3 kinds of particles, circular and filamentous particles with a diameter of 22nm, and a smaller number of particles with a diameter of 42 nm. The spherical particles of (a), also known as Dane's particles, are intact HBV particles.

The markers for hepatitis b were detected as follows: (ii) HBsAg and anti-HBs: HBsAg positive indicates that HBV is currently in the stage of infection, and anti-HBs positive for immunoprotective antibodies indicates that immunity to HBV has developed. The diagnosis basis of the chronic HBsAg carrier is that the chronic HBsAg carrier has no clinical symptoms and physical signs, the liver function is normal, and the HBsAg is continuously positive for more than 6 months. (vii) HBeAg and anti-HBe: HBeAg positive is an index of HBV active replication and strong infectivity, and the change of the detected serum from HBeAg positive to anti-HBe positive indicates that the disease has remission and weakened infectivity. ③ HBcAg and anti-HBc: HBcAg positive suggests that there is a direct reaction of complete HBV particles, and active replication of HBV is less clinically useful due to the complex detection method. anti-HBc is a marker of HBV infection, and anti-HBc IgM positive indicates that the virus is replicated in vivo at an early stage of infection. HBsAg, HBeAg and anti-HBc are all positive in chronic mild hepatitis B and HBsAg carriers, and have high infectivity index and are difficult to convert from negative to positive. In clinical practice, the negative conversion of HBsAg is the most important index for the therapeutic effect.

Additional therapeutic or prophylactic agents

In some embodiments, the additional therapeutic or prophylactic agent is selected from one or more of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, for example, one selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide or at least two selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.

Entecavir (Entecavir) is chemically known as 2-amino-1, 9-dihydro-9- [ (1S,3R,4S) -4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentane ] -6H-purin-6-one and has the following structural formula:

US patent US5206244 discloses entecavir and its use for the treatment of hepatitis b virus; a novel synthesis of entecavir is disclosed in WO 9809964; WO0164421 discloses low dose entecavir solid formulations.

Entecavir is a highly effective antiviral agent, developed by schrobo corporation in the 90 s of the 20 th century, and has a strong anti-HBV effect. It can be phosphorylated to active triphosphate, which has a half-life in cells of 15 h. Entecavir triphosphate inhibits all three activities of the viral polymerase (reverse transcriptase) by competing with deoxyguanosine triphosphate, the natural substrate of HBV polymerase: (1) the start of HBV polymerase; (2) formation of a reverse transcribed negative strand of a pregenomic mRNA; (3) synthesis of HBV DNA plus strand.

Tenofovir disoproxil fumarate (the name of England: (TDF); (R) - [ [2- (6-amino-9H-purin-9-yl) -1-methylethoxy ] methyl ] phosphonic acid diisopropoxycarbonylmethyl ester fumarate) is an ester precursor of Tenofovir, belongs to a novel nucleotide reverse transcriptase inhibitor, and has the activity of inhibiting HBV viruses.

TDF is another novel open-ring nucleoside phosphonate successfully developed by Gilidard company in the United states following Adefovir dipivoxil, is first marketed in the United states in 10 months in 2001, and is currently marketed in countries such as Europe, Australia, and Canada.

TDF inhibits viral polymerase in vivo by competitively binding to the natural deoxyribose substrate and terminates DNA strand synthesis by insertion into DNA. The main action mechanism is that the tenofovir is hydrolyzed into tenofovir after being orally taken, the tenofovir is phosphorylated by cell kinase to generate a metabolite tenofovir diphosphate with pharmacological activity, the tenofovir diphosphate competes with 5 '-triphosphate deoxyadenosine monophosphate to participate in the synthesis of virus DNA, and after entering the virus DNA, the DNA is prevented from being prolonged due to the lack of 3' -OH groups, so that the replication of the virus is blocked. Clinical application shows that TDF has obvious curative effect on HBV virus and less toxic side effect, so that TDF has wide clinical application foreground.

Tenofovir Alafenamide (Tenofovir Alafenamide), a prodrug of the new Nucleoside Reverse Transcriptase Inhibitor (NRTI) Tenofovir (Tenofovir) developed by Gilidard scientific, USA. Compared with the prior generation of similar anti-hepatitis B medicine tenofovir disoproxil TDF, the antiviral activity of tenofovir alafenamide is 10 times, the stability in blood plasma is 200 times, and the half-life period is improved by 225 times. Compared with TDF, the tenofovir alafenamide only needs one tenth of TDF administration dosage to achieve the same antiviral curative effect as TDF. Therefore, the tenofovir alafenamide is used for preventing or/and treating Hepatitis B Virus (HBV) infection and has better curative effect, higher safety and lower drug resistance.

As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that is effective at a dose and for a period of time required to achieve a desired therapeutic result. A therapeutically effective amount of a therapeutic agent for hepatitis b will depend on the nature of the disorder or condition and on the particular agent, and can be determined by standard clinical techniques known to those skilled in the art.

The therapeutic outcome may be, for example, alleviation of symptoms, prolongation of survival, increased mobility, and the like. The therapeutic result need not be a "cure". The therapeutic outcome may also be prophylactic.

In a preferred embodiment, the medicament is formulated for oral administration, preferably in the form of a tablet or capsule.

Route of administration

The medicaments or pharmaceutical compositions of the present disclosure are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. In certain embodiments, the medicament or pharmaceutical composition disclosed herein is administered by intravenous injection. It will be appreciated that the preferred route may vary depending on, for example, the condition of the recipient. One advantage of the disclosed medicaments or pharmaceutical compositions is that they are orally bioavailable and can be administered orally.

Pharmaceutical composition

In certain embodiments, the imidazopyrimidine-based compound of the present application, or a pharmaceutically acceptable salt or deuteron thereof, is included in a pharmaceutical composition. The pharmaceutical compositions of the present disclosure may be formulated with conventional carriers and excipients, which will be selected in accordance with common practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and, when used for delivery by non-oral administration, are generally isotonic. All formulations will optionally contain Excipients such as those described in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. The pH of the formulation ranges from about 3 to about 11, but is typically from about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but typically from about 3 to 4.

The formulations include those suitable for the aforementioned routes of administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences (Mack Publishing co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which is composed of one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then shaping the product as necessary.

Formulations of the invention suitable for oral administration may exist as follows: discrete units, such as capsules or tablets, each containing a predetermined amount of active ingredient; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by: the active ingredient in a free-flowing form such as a powder or granules is compressed in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally formulated so as to provide sustained or controlled release of the active ingredient therefrom.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

The pharmaceutical compositions of the present disclosure may also be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol, or as a lyophilized powder. Acceptable carriers and solvents that may be employed include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Acceptable carriers and solvents that may be employed include water, ringer's solution, isotonic sodium chloride solution and hypertonic sodium chloride solution.

Additional objects, advantages and novel features of the present invention will become apparent to one of ordinary skill in the art upon examination of the following examples.

Synthesis example 1

Synthesis of Compound HDLY001

As shown in the chemical equation of the following figure, compound 1 is used as a raw material, compound 2 is added, and SOCl is added₂And MeCN at 80 deg.C to obtain compound HDLY 001. The NMR results of the product are shown in figure 1.

Examples

Example 1

Animal model: witonda AAV HBV model mice, namely a recombinant adeno-associated virus (rAAV) vector carried HBV whole genome DNA infection mice model. Purchased from Beijing Wintoda Biotechnology Ltd.

Experimental materials: compound HDLY001, dissolved in physiological saline containing 1% Tween 80 and 0.5% methylcellulose, TAF and nitazoxanide available from Shanghai Dow Biotech Ltd.

The experimental process comprises the following steps: the Wintoda AAV HBV model mice are modeled for about 8 weeks, then the animals are randomly divided into 5 animals in each group, and the animals are divided into HDLY001 group (example 1), alanine fumarate Tenofovir (TAF) group, nitazoxanide group, TAF + nitazoxanide combined administration group, and are orally administrated by intragastric gavage every day, blood is collected from orbital venous plexus every week, and HBV DNA and HBsAg are detected.

Comparative example 1:

the same mouse model and experimental procedure as in example 1, except that the drug was changed to 1% Tween 80 and 0.5% methylcellulose in saline.

Comparative example 2:

the same mouse model and experimental procedure as in example 1, except that the drug was changed to nitazoxanide.

Nitazoxanide molecular formula

Comparative example 3:

the same mouse model and experimental procedure as in example 1, except that the drug was changed to propiofovir disoproxil fumarate TAF.

Comparative example 4

The same mouse model and experimental procedure as in example 1, except that the drug was changed to a drug combination of Propofovir fumarate TAF and Nitazoxanide.

Results and analysis of the experiments

As a result of weekly observation of the administration to the animals of examples and comparative examples, 5 mice in the group of HDLY001 showed a significant reduction in HBV DNA (average 2.3 log) (fig. 2), while the overall average showed a reduction of at least 0.5log for HBsAg, of which 3 mice showed a significant reduction in HBsAg of about 1log and 1 slight reduction in HBsAg, see fig. 2 and 3.

To determine the effect of dose variation, the dose of HDLY001 was halved starting on day 22 and continued until day 42, with no change in the downward trend of HBV DNA and HBsAg observed, see fig. 6 and 7.

Nitazoxanide (NTZ), as a structurally similar drug to a portion of the compounds of the present application, did not see a reduction in HBV DNA and HBsAg in mice, see fig. 4 and 5.

Only a reduction in HBV DNA was observed in TAF group, and no reduction in HBsAg was observed in any of the mice. See fig. 4 and 5.

The mice of comparative example 4, which had been treated with the TAF + nitazoxanide drug combination, showed only a reduction in HBV DNA, and none of the mice showed a reduction in HBsAg, see FIGS. 4 and 5.

Combining the above results, it can be seen that in the case where neither of the two control compounds nor their combination administration were able to reduce HBsAg, HDLY001 unexpectedly observed HBsAg reduction activity, with an average reduction of 0.5 log. It is possible that the new compounds will behave differently during drug metabolism, thereby producing unexpected effects. On the basis of the effect of reducing HBV DNA and HBsAg simultaneously, the compound HDLY001 of the application has stronger and faster effect on treating hepatitis B and clearing hepatitis B virus than both TAF and nitazoxanide, especially on seroconversion of HBsAg.

Therefore, the imidazopyrimidine compound, particularly HDLY001 and the deuterate thereof, can reduce the HBV DNA and HBsAg levels at the same time, so that functional cure of hepatitis B virus is expected, and even hepatitis B virus is completely eliminated.

While the invention has been described with reference to specific embodiments, those skilled in the art will recognize that changes or modifications can be made to the described embodiments without departing from the spirit and scope of the invention, which is defined by the appended claims.

Claims

1. An imidazopyrimidine-based compound represented by general formula 1, a pharmaceutically acceptable salt thereof, or a deutero-derivative thereof:

wherein Q is-OH, R₁Is H, R₂Is nitro, m is 1, and n is 4.

2. The imidazopyrimidine compound according to claim 1, a pharmaceutically acceptable salt thereof, or a deutero-derivative thereofThe deutero-derivative of the imidazopyrimidine compound is at least one R of the compound of the general formula 1₁Compounds substituted with deuterium.

3. The imidazopyrimidine compound, its pharmaceutically acceptable salt, or deutero-compound according to claim 1 or 2, wherein the methyl group in formula 1 is further substituted with at least one deuterium.

4. The imidazopyrimidine compound according to claim 1, a pharmaceutically acceptable salt or deutero-derivative thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate, undecanoate, sodium, calcium, potassium, ammonium, tetraethylammonium, methylammonium, dimethylammonium, and ethanolamine salts.

5. The imidazopyrimidine-based compound according to claim 1, which is represented by general formula 1-1:

，

q, R therein₁、R₂M and n are as defined for formula 1.

6. The imidazopyrimidine compound according to claim 1, a pharmaceutically acceptable salt or a deutero-derivative thereof, which is selected from the group consisting of:

compound HDLY001 compound 1-1,

the deuterons include compounds HDLY001 and compounds in which at least one H in compound 1-1 is substituted with deuterium.

7. A pharmaceutical composition comprising a therapeutically effective amount of the imidazopyrimidine-based compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a deutero-derivative thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition further comprises one or more additional therapeutic or prophylactic agents for hepatitis B.

9. The pharmaceutical composition of claim 8, wherein the additional therapeutic or prophylactic agent for hepatitis B comprises nitazoxanide, an interferon, and a nucleoside analog.

10. Use of a pharmaceutical composition according to any one of claims 7 to 9 in the manufacture of a medicament for the treatment of hepatitis b.