Nitrile compound and application thereof

Abstract

The invention relates to the technical field of medicine, in particular to a nitrile compound and application of the nitrile compound in disease treatment medicine, and the chemical structural formula of the nitrile compound is shown in the formula I in the specification. The invention also provides a pharmaceutical composition containing the compound. The invention finds that the compound with the nitrile structure shows an excellent TLR7 agonist effect and can be used for treating diseases related to TLR7.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a nitrile compound and application of the compound in disease treatment drugs. Background Art

[0002] The cyano group has strong electron-withdrawing properties and can be used to reduce the electron density of aromatic or heteroaromatic hydrocarbons, reduce the basicity of amines, or increase the polar surface area and solubility of lead compounds. The cyano group metabolism is very stable, and nitrile compounds are widely present in drugs. For example, the introduction of a cyano structure into the molecular structure of the following marketed drugs has achieved unexpected results in improving the drug-like properties of the drug molecules, enhancing the efficacy, and reducing toxic side effects.

[0003]

[0004] Toll-like receptors (TLRs) are a key class of protein molecules involved in nonspecific immunity (innate immunity) and serve as a bridge between nonspecific and specific immunity. TLRs are single, transmembrane, non-catalytic proteins that recognize molecules with conserved structures derived from microorganisms. When microorganisms breach the body's physical barriers, such as the skin and mucous membranes, TLRs recognize them and activate immune cell responses. TLRs monitor and recognize a variety of disease-associated molecular patterns and serve as the body's first line of defense against infectious diseases.

[0005] Although a series of TLR7 agonists have been disclosed in recent years, there is still a need to discover and develop new compounds with better efficacy, better selectivity, and better pharmacokinetic properties.

[0006] In view of this, the present invention is proposed. Summary of the Invention

[0007] The present invention provides a compound as shown in Formula I, its stereoisomers, tautomers or pharmaceutically acceptable salts. The present invention has found that the nitrile compound exhibits excellent TLR7 agonist effect;

[0008]

[0009] Wherein, X is a sulfur atom or NR 13 ;

[0010] Y is an oxygen atom or a sulfur atom;

[0011] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R7 、R 8 、R 9 、R 11 、R 12 independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl, wherein said alkyl, aryl, heteroaryl are independently optionally substituted with one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl;

[0012] R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl or alkenyl;

[0013] R 10 is hydrogen or is selected from the following structures:

[0014]

[0015] The present invention also provides a compound as shown in Formula II, its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0016]

[0017] Wherein, X is a sulfur atom or NR 13 ;

[0018] R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl, or alkenyl;

[0019] R 10 is hydrogen or is selected from the following structures:

[0020]

[0021] The present invention also provides a compound as shown in formula III, its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0022]

[0023] Where X is a sulfur atom, NR 13 ;

[0024] R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl, or alkenyl;

[0025] R 10 is hydrogen or is selected from the following structures:

[0026]

[0027] The present invention provides a pharmaceutical composition comprising a therapeutically effective dose of any one of the above compounds of the present invention or its stereoisomers, tautomers or pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

[0028] The present invention also provides the use of any of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for treating TLR7 (Toll-like Receptor 7, TLR7)-related diseases. TLR7-related diseases include tumors, hepatitis A virus disease, hepatitis B virus disease, hepatitis C virus disease, and hepatitis D virus disease.

[0029] The technical solution provided by the embodiment of the present invention has the following advantages compared with the existing technology:

[0030] The embodiments of the present invention provide a novel compound having an unsaturated alkane functional group, which has excellent TLR7 agonist effect, high biological activity, better efficacy, and better selectivity, and can be used as a TLR7 agonist to treat a variety of TLR7-related diseases. Detailed Description of the Invention

[0032] All technical and scientific terms used in this specification have the same meanings as commonly understood by those skilled in the art.

[0033] Table 1:

[0034]

[0035]

[0036] The term "alkyl" refers herein to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and further refers to a saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. The term includes straight and branched hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkyloxy, heterocyclooxy, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0037] The term "aryl" herein refers to a 6-10 membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system. The aryl group can be covalently attached to the defined chemical structure at any carbon atom that produces a stable structure. The aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0038] The term "heterocyclyl" refers to a ring system containing a nitrogen atom or an oxygen atom, and the ring system can be "parallel" to aromatic and non-aromatic ring systems, or linked to other ring systems through a "spiro carbon atom".

[0039] The term "heteroaryl" as used herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term can have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0040] The term "alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and at least one alkenyl unsaturated site in this article, and further refers to an alkenyl group having 2 to 6 carbon atoms and at least one alkenyl unsaturated site. Non-limiting examples of alkenyl include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc. Alkenyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfydryl, alkylthiol, deuterated alkylthiol, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0041] The term "alkynyl" herein refers to an alkyl group having 2 to 8 carbon atoms in which two adjacent carbon atoms are linked by a triple bond, and further refers to an alkynyl group having 2 to 6 carbon atoms and having at least one alkynyl unsaturation site, wherein the alkyl group is as defined herein. Alkynyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylthio, deuterated alkylthio, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, and ester.

[0042] The present invention provides a novel compound having an unsaturated alkane functional group, which has excellent TLR7 agonist activity. The chemical structure thereof is shown in Formula I, or its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0043]

[0044] Wherein, X is a sulfur atom or NR 13 ;

[0045] Y is an oxygen atom or a sulfur atom;

[0046] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 11 、R 12 independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl, wherein said alkyl, aryl, heteroaryl are independently optionally substituted with one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl;

[0047] R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl or alkenyl;

[0048] R10 is hydrogen or is selected from the following structures:

[0049]

[0050] As an improvement of the embodiment of the present invention, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 11 、R 12 Independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C3-C8 cycloalkyl, C3-C5 heterocyclyl, C3-C5 heterocyclyl substituted C1-C6 alkyl, C6-C10 aryl, C3-C9 heteroaryl, sulfone, phosphorus carbonyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein the alkyl, aryl, heteroaryl are independently optionally substituted by one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, C1-C6 alkylamino, di(C1-C6)alkylamino, trifluoromethyl.

[0051] As an improvement of the embodiment of the present invention, R 13 It can be hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkynyl or C2-C8 alkenyl, and can further be hydrogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C4 alkynyl or C2-C4 alkenyl.

[0052] As an improvement to the embodiment of the present invention, R 13 It may be propargyl.

[0053] As an improvement to the embodiment of the present invention, X may be a sulfur atom.

[0054] As an improvement to the embodiment of the present invention, Y may be an oxygen atom.

[0055] As an improvement of the embodiment of the present invention, R 1 、R 2 It can also be a hydrogen atom.

[0056] As an improvement of the embodiment of the present invention, R 4 It may be a hydrogen atom.

[0057] As an improvement of the embodiment of the present invention, R 7 、R 8 It can also be a hydrogen atom.

[0058] As an improvement of the embodiment of the present invention, R 9 It may be a hydrogen atom.

[0059] As an improvement of the embodiment of the present invention, R 11 、R 12 It can also be a hydrogen atom.

[0060] As an improvement of the embodiment of the present invention, the embodiment of the present invention provides a compound as shown in Formula II, its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0061]

[0062] Wherein, X is a sulfur atom or NR 13 ;

[0063] R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl, or alkenyl;

[0064] R 10 is hydrogen or is selected from the following structures:

[0065]

[0066] As an improvement to the embodiment of the present invention, X may be a sulfur atom.

[0067] As an improvement of the embodiment of the present invention, R 13 It can be hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkynyl or C2-C8 alkenyl, and can further be hydrogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C4 alkynyl or C2-C4 alkenyl.

[0068] As an improvement of the embodiment of the present invention, R 13 It is propargyl.

[0069] As an improvement of the embodiment of the present invention, the embodiment of the present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts:

[0070]

[0071] As an improvement of the embodiment of the present invention, the embodiment of the present invention provides a compound as shown in Formula III, its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0072]

[0073] Wherein, X is a sulfur atom or NR 13 ;

[0074] R13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl, or alkenyl;

[0075] R 10 is hydrogen or is selected from the following structures:

[0076]

[0077]

[0078] As an improvement to the embodiment of the present invention, X may be a sulfur atom.

[0079] As an improvement of the embodiment of the present invention, R 13 It can be hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkynyl or C2-C8 alkenyl; it can further be hydrogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C4 alkynyl or C2-C4 alkenyl.

[0080] As an improvement of the embodiment of the present invention, R 13 It may be propargyl.

[0081] As an improvement of the embodiment of the present invention, the embodiment of the present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

[0082]

[0083] The present invention also provides a method for preparing the above-mentioned compound. For example, the intermediate IM-7 can be prepared first:

[0084]

[0085] Then, the oxirane group on the intermediate IM-7 and the cleavage of the fused [1,3]dioxolane ring on tetrahydrofuran are utilized to sequentially connect other groups, thereby obtaining the compound of the embodiment of the present invention.

[0086] In embodiments of the present invention, compounds of the present invention having the same molecular formula but different properties or sequences of their atomic bonds or different spatial arrangements of their atoms are referred to as "isomers". Isomers having different spatial arrangements of atoms are referred to as "stereoisomers". All isomers of the compounds described herein (e.g., cis-, trans-, or diastereomers) alone or in any mixture thereof are encompassed within the scope of the embodiments of the present invention. All of these forms include enantiomers, diastereomers, cis, trans, syn, anti, tautomers, and mixtures thereof. Stereoisomeric mixtures (e.g., mixtures of diastereomers) can be separated into their corresponding isomers using suitable separation methods in a known manner.

[0087] In embodiments of the present invention, the pharmaceutically acceptable salts of Formula I, Formula II, and Formula III compounds can include acid addition salts and basic salts. Suitable acid addition salts are formed by the acid that can form non-toxic salts. For example, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, sucrose salt, stearate, succinate, tannate, tartrate. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0088] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the above-mentioned compound or its stereoisomers, tautomers or pharmaceutically acceptable salts and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be prepared by methods known in the art. The pharmaceutical composition used in the present invention can be formulated according to conventional methods using one or more pharmaceutically acceptable carriers, which include excipients and adjuvants, which facilitate processing of the active compound into a pharmaceutically usable preparation. Suitable formulations depend on the selected route of administration. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore encompassed by the scope of the present invention. The pharmaceutical composition of the embodiments of the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the compounds of the embodiments of the present invention can be present in suitable solid or liquid carriers or diluents. The pharmaceutical composition of the present invention can also be stored in suitable sterile equipment for injection or infusion. Generally, the amount of active ingredient in the pharmaceutical composition is 0.01% to 99% by weight of the pharmaceutical composition.

[0089] The compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered clinically to mammals (including humans) via oral, nasal, dermal, pulmonary, or gastrointestinal routes. The preferred route of administration is oral. The preferred daily dose is 0.5 to 200 mg / kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for each individual should be determined based on the specific treatment. Typically, a low dose is started and the dose is gradually increased until the most appropriate dose is found. The effective dose of the active ingredient used may vary depending on the compound used, the mode of administration, and the severity of the disease being treated. However, satisfactory results are generally achieved when the compounds of the present invention are administered at a dose of about 1 to 300 mg / kg of animal body weight per day, preferably in 1 to 3 divided doses per day, or in a sustained-release form. For most large mammals, the total daily dose is about 5 to 1000 mg, preferably about 10 to 500 mg. Dosage forms suitable for oral administration contain about 1 to 200 mg of the active compound intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as required by the exigencies of the therapeutic situation.

[0090] The present invention also provides the use of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating diseases associated with TLR7 (Toll-like Receptor 7, TLR7). The compound of the present invention can be used as a TLR7 agonist to treat a variety of TLR7-related diseases, such as tumors, hepatitis A, hepatitis B, hepatitis C, and hepatitis D.

[0091] The embodiments of the present invention also provide methods for treating or preventing a disease or condition, which include administering an effective amount of a compound comprising an embodiment of the present invention or a pharmaceutically acceptable salt thereof to an individual. The compound of the present invention or its pharmaceutical composition can be administered orally, parenterally, topically, rectally, mucosally or intestinally. Parenteral administration includes indirect injection to produce a systemic effect or direct injection to the affected site. Topical administration includes treatment of the skin or organs (such as eyes or ears) that can be easily reached by topical application. Transdermal delivery is also included to produce a systemic effect. Rectal administration includes the form of suppositories. Preferred routes of administration are oral and parenteral. DETAILED DESCRIPTION

[0092] The present invention is further illustrated by the following examples, but the present invention is not limited thereto. Throughout this application, various examples of the compounds and methods of the present invention are mentioned herein. The present invention is not limited to these examples. The following examples are merely provided to provide methods for practicing the present invention and are not intended to limit the scope of the present invention in any way.

[0093] The compounds provided herein can be prepared by standard synthetic methods known in the art, and this specification provides general methods for preparing the compounds of the present invention. Starting materials can generally be obtained commercially or prepared by methods well known to those skilled in the art.

[0094] The compounds of the present invention and corresponding preparation methods are further explained and listed below by way of examples and preparations. It should be understood that although typical or preferred reaction conditions are given in the specific examples, other reaction conditions may also be used by those skilled in the art. Optimum reaction conditions may vary with the specific reaction used.

[0095] Intermediate preparation

[0096]

[0097] first step:

[0098] IM-1 (20.0 g), pyridine (12.1 g), and toluene (200 mL) were added to a reaction flask, cooled to 0-10°C, and trifluoromethanesulfonic anhydride (26.0 g) was slowly added dropwise. After the addition, stirring was continued at 0-10°C for 4 hours. Water (60 mL) was slowly added to the reaction solution at 0-10°C to quench the reaction. The layers were separated, and the organic phase was washed with 10% aqueous acetic acid (80 mL × 3), saturated aqueous sodium bicarbonate (80 mL × 2), and water (60 mL). It was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with toluene. The combined organic phases (referred to as solution A) were used directly in the next step.

[0099] Step 2:

[0100] Tetrabutylammonium borohydride (39.5 g) and toluene (80 mL) were added to a reaction flask, heated to 65°C, and then Solution A was added. After the addition was complete, the reaction was allowed to react at 65°C for 5 hours. The temperature was then lowered to 0-10°C, and water (200 mL) was added to the reaction solution, which was stirred for 1 hour. The top organic phase was separated, and the middle and lower layers were washed with 1:1 toluene / n-heptane (200 mL x 2). The combined organic phases were washed with 20% aqueous sodium chloride solution (70 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 15 g of a white solid, IM-3.

[0101] Step 3:

[0102] IM-3 (13.0 g) and 50% aqueous acetic acid (65 mL) were added to a reaction flask and reacted at 30°C for 6 hours. The reaction solution was concentrated to dryness under reduced pressure at 45°C and washed twice with toluene. The crude product was purified by flash chromatography (1:1 petroleum ether / acetone) to yield 4.27 g of an off-white solid. Acetonitrile (4.3 mL) was added to the product and the temperature was raised to 65°C. Once dissolved, the mixture was stirred for 5 minutes. The mixture was then cooled to room temperature and stirred in an ice-water bath for 30 minutes to allow crystallization. The mixture was filtered, rinsed with cold acetonitrile, and dried at 30°C to yield 3.5 g of IM-4 as a white solid. 1 H NMR (CDCl3, 600MHz), δ: 6.116~6.108 (d, J=4.8Hz, 1H), 5.282~5.262 (t, J=6Hz, 1H), 4.868~4.830 (dt, J=3Hz, J=9.6Hz 1H), 4.575~4.543 (m, 1H), 4.477~4.447 (dd, J=4.2Hz, J=13.8Hz, 1H), 4.316~4.283 (dd, J=6Hz, J=1 3.8Hz,1H),3.861(br,1H),3.264~3.206(m,2H),3.115~3.082(m,1H),2.690(s,3H),2.504(s,3H).

[0103] Step 4:

[0104] Anhydrous pyridine (74 mL) was added to IM-4 (10.2 g). The mixture was cooled to 0-5°C in an ice bath. A solution of benzoyl chloride (7.03 g) in dichloromethane (15 mL) was added dropwise. After the addition was complete, the mixture was naturally warmed to room temperature and stirred overnight. The reaction mixture was poured into ice water (120 mL) and stirred for 0.5 h. The mixture was extracted with dichloromethane (120 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no fractions remained. Toluene was added and the mixture was concentrated again until no fractions remained. This process was repeated once. Dichloromethane and silica gel were added, the mixture was concentrated, and the mixture was purified by flash chromatography (silica gel column, 20% petroleum ether in ethyl acetate) to obtain 11.1 g of a light yellow oil, IM-5. 1H NMR (DMSO-d6, 600MHz), δ: 6.902~6.886(d,J=9.6Hz,2H), 6.645~6.015(t,J =9.0Hz,1H),6.542~6.512(m,2H),5.054~5.046(d,J=4.8Hz,1H),4.620~4. 609(d,J=6.6Hz,1H),4.306(m,1H),3.949~3.864(m,2H),3.741~3.631(m,2 H),2.262~2.205(m,1H),2.116~2.077(m,1H),1.681(s,3H),1.508(s,3H).

[0105] Step 5:

[0106] To IM-5 (11.1 g) was added dichloromethane (360 mL), and the mixture was cooled to 0-5°C in an ice bath. Triethylamine (10.92 g) was then added, and methanesulfonic anhydride (10.04 g) was added portionwise while maintaining the temperature below 10°C. The reaction was maintained at this temperature for 40 min. The mixture was concentrated under reduced pressure at 40°C until no fraction remained. Dichloromethane and silica gel were added, and the mixture was concentrated and mixed. Purification by flash chromatography (silica gel column, 30% petroleum ether in ethyl acetate) afforded 13 g of IM-6 as a white solid. 1 H NMR (DMSO-d6, 600MHz), δ: 6.920~6.903 (m, 2H), 6.658~6.628 (t, J=9.0Hz, 1H), 6.549~6. 518(t,J=9.0Hz,2H),5.180~5.173(d,J=4.2Hz,1H),4.591~4.555(m,1H),4.391~4.373(t J=5.4Hz 1H), 4.203~4.173 (dd, J=3.0Hz, J=15Hz, 1H), 4.049~3.996 (m, 2H), 3.101 (s, 3H), 2.360 ~2.362 (m, 1H), 2.266 ~ 2.232 (dd, J = 3.0Hz, J = 17.4Hz, 1H), 1.719 (s, 3H), 1.520 (s, 3H).

[0107] Step 6:

[0108] Methanol (337 mL) was added to IM-6 (13 g). Potassium tert-butoxide (7.4 g) was added portionwise at room temperature. The mixture was exothermed to 30°C, and the solution gradually dissolved. The reaction was allowed to react at room temperature overnight. The mixture was cooled to 5°C, and ice water (235 mL) was added dropwise. Ethyl acetate (500 mL) and saturated sodium chloride (150 mL) were added. The mixture was stirred to separate the layers, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (250 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After purification by flash chromatography (silica gel column, 12% petroleum ether in ethyl acetate), 3.7 g of IM-7 was obtained as a yellow oil, which solidified to a solid at room temperature. 1 H NMR (CDCl3, 600MHz), δ: 6.116~6.109 (d, J=4.2Hz, 1H), 5.282~5.263 (dd, J=5.4Hz ,J=6.6Hz,1H),4.475~4.439(dt,J=9.6Hz,J=2.4Hz,1H),4.111~4.083(m,1H),3. 754~3.737(t,J=5.4Hz,1H),3.588~3.573(dd,J=3.0Hz,J=6.0Hz,1H),3.342~3.3 10(dd,J=2.4Hz,J=16.8Hz,1H),3.267~3.210(m,1H),2.705(s,3H),2.518(s,3H).

[0109] Compound preparation

[0110] Example 1:

[0111] The preparation method of compound 3-1 is as follows:

[0112]

[0113] first step:

[0114] To SM-1 (2.4 g) was added ultra-dry tetrahydrofuran (31 mL), followed by trimethylsilyl cyanide (TMSCN) (1.92 g) at room temperature, followed by tetrabutylammonium fluoride (TBAF) (1 M in THF, 19.35 mL) to give a light yellow clear solution. The reaction was carried out at 60°C for 6 h. The temperature was lowered to room temperature, ethyl acetate (25 mL) and saturated sodium chloride (5 mL) were added, and the mixture was stirred at room temperature for 5 min. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (5 mL), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and washed with a small amount of ethyl acetate. The filtrate was concentrated at 40°C until no fraction was obtained, yielding 10 g of a light yellow oil. After purification by flash chromatography (silica gel column, 28% petroleum ether ethyl acetate system), 2 g of a white needle-shaped solid, the intermediate IM-1-1, was obtained. 1H NMR (CDCl3, 600MHz), δ: 5.837~5.833 (d, J=2.4Hz, 1H), 4.786 (s, 1H), 4.263~4.239 (t, J=7.2Hz, 1H), 4.055~4.039 (t, J=4.8Hz, 1H), 3.275~ 3.270(d,J=3.0Hz,1H),2.646~2.547(ddd,J=6.0Hz,2H),2.358~2.309(m,1H),2.124~2.100(d,J=14.4Hz,1H),1.562(s,3H),1.333(s,3H).

[0115] Step 2:

[0116] IM-1-1 (2 g), dichloromethane (20 mL), triethylamine (5.7 g), 4-dimethylaminopyridine (DMAP) (0.23 g), and acetic anhydride (4.3 g) were added to a round-bottom flask and stirred at room temperature for 1 h. Saturated sodium bicarbonate was added dropwise under ice to quench the mixture. The organic layer was separated and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic layers were washed with saturated sodium chloride (10 mL) and concentrated at 40°C until free of fractions, yielding 2.4 g of a yellow oil. Flash chromatography (silica gel column, 18% petroleum ether in ethyl acetate) afforded 2.3 g of a colorless oil, which formed colorless prismatic crystals upon freezing, i.e., IM-1-2.

[0117] Step 3:

[0118] Add dichloromethane (11.5 mL) to IM-1-2 (2.3 g) to obtain a colorless, clear solution at room temperature. Add acetic acid (5.4 g) dropwise to a low-energy release. Add acetic anhydride (4.6 g) dropwise to a low-energy release. Add concentrated sulfuric acid (57.5 μL) dropwise to a low-energy release, reaching a maximum of 8°C. Remove the ice bath and allow to react at 25°C for 6 h. Add saturated sodium bicarbonate dropwise to a low-energy release. Adjust the pH to 6 using approximately 110 mL of saturated sodium bicarbonate. Separate the organic layer, extract the aqueous layer with dichloromethane (20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter, and rinse with a small amount of dichloromethane. Purify by flash chromatography (silica gel column, 18% petroleum ether / ethyl acetate) to obtain 1.5 g of a colorless oil, which partially solidifies upon freezing, i.e., intermediate IM-1-3. 1H NMR (CDCl3, 600MHz), δ: 6.228 (s, 1H), 5.222~5.193 (m, 2H), 4.535~4.504 (m, 1H), 2.833~2.726 (m, 2H), 2. 614~2.563(m,1H),2.162(s,3H),2.106(s,3H),2.084(s,3H),1.886~1.853(dd,J=14.4Hz,J=4.8Hz,1H).

[0119] Step 4:

[0120] To 5-aminothiazolo[4,5-d]pyrimidin-2(3H)-one (105 mg) was added xylene (2 mL) and stirred at 70°C for 10 min. The solution was concentrated at 70°C to remove approximately 10% of the solvent. BSA (490 μL) was added dropwise at 60°C over approximately 15 min. The solution was stirred at 60°C for 1 h. The solution was concentrated at 40-60°C to remove approximately 50% of the solvent. Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (120 μL) was added dropwise at 60°C, gradually turning the solution into a tan, clear solution over approximately 10 min. A xylene solution (0.5 mL) of the intermediate IM-1-3 (198 mg) was then added. The reaction was stirred at 65°C for 1 h. The temperature was lowered to 30°C, and isopropyl acetate (4 mL) was added. Saturated sodium bicarbonate (approximately 3 mL) was added dropwise until the pH reached 7-8. Bubbling and a slight exotherm were observed during the reaction. The organic layer was separated, and the aqueous layer was extracted with isopropyl acetate (3 mL), emulsified, passed through celite, and rinsed with isopropyl acetate. The filtrate was separated into an organic layer. The brown oil in the filter cake was dissolved in approximately 2 mL each of dichloromethane and methanol. The oil and the organic layer were combined and purified by flash chromatography (silica gel column, 3% dichloromethane and methanol) to obtain 98 mg of a yellow foamy solid, IM-1-4. m / z: 408.15 (M+H), 406.10 (MH).

[0121] Steps 5 and 6:

[0122] IM-1-4 (80 mg), potassium carbonate powder (54.6 mg), PEG-400 (8 μL), methanol (64 μL), and 2-methyltetrahydrofuran (320 μL) were added to a reaction flask and reacted at 20°C for 2.5 h. Potassium carbonate powder (27.3 mg) was added and the reaction was continued at 20°C for 1 h. The mixture was filtered, rinsed with methanol, and the filtrate was concentrated and purified by flash chromatography (silica gel column, 6% dichloromethane in methanol) to obtain 16 mg of compound 3-1 as a light orange solid. m / z: 324.05 (M+H), 322.15 (MH). 1H NMR (DMSO-d6, 600MHz), δ: 8.326 (s, 1H), 6.834 (s, 2H), 5.876~5.866 (d, J=6.6Hz, 1H), 5.623~5.608 (d, J=9.0Hz, 1H), 5.482~5.470 (d, J=7.2Hz ,1H),5.049(m,1H),4.341~4.318(m,1H),3.688(m,1H),2.601~2.538( m, 2H), 2.426 ~ 2.364 (m, 1H), 1.857 ~ 1.783 (dd, J = 9.0Hz, J = 29.4Hz, 1H).

[0123] Example 2:

[0124] The preparation method of compound 2-2 is as follows:

[0125]

[0126] first step:

[0127] To IM-7 (1.8 g) was added ultra-dry tetrahydrofuran (23.4 mL). Trimethylsilyl cyanide (TMSCN, 1.82 mL) was added at room temperature, followed by tetrabutylammonium fluoride (TBAF, 1 M in THF, 14.6 mL) to yield a light yellow, clear solution. The reaction was incubated at 60°C for 3 h. The temperature was lowered to room temperature, and ethyl acetate (20 mL) and saturated sodium chloride (4 mL) were added. The mixture was stirred at room temperature for 5 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (4 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and washed with a small amount of ethyl acetate. The filtrate was concentrated at 40°C until no fractions remained, yielding 7.5 g of a light yellow oil. Silica gel (8 g, 100-200 mesh) was added, and the mixture was concentrated and mixed at 40°C. Purification by flash chromatography (silica gel column, 35% ethyl acetate in petroleum ether) afforded 2 g of a light yellow oil, IM-2-1.

[0128] Step 2:

[0129] IM-2-1 (2 g), dichloromethane (20 mL), triethylamine (5.7 g), p-dimethylaminopyridine (DMAP, 0.23 g), and acetic anhydride (4.3 g) were added in one pot and stirred at room temperature for 0.5 h. Saturated sodium bicarbonate was added dropwise under ice to quench the mixture and adjust the pH to 7-8 (a significant initial exotherm, reaching a maximum of 30°C, was used, using 20 mL of saturated sodium bicarbonate). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were washed with saturated sodium chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and rinsed with a small amount of dichloromethane. The filtrate was concentrated at 40°C until no fractions remained, yielding 2.5 g of a yellow oil. 3 g of silica gel (100-200 mesh) was added, and the sample was concentrated and mixed at 40°C. Purification was performed on a flash column (silica gel column, 15-18% ethyl acetate in petroleum ether) to yield 2 g of a light yellow oil, IM-2-2.

[0130] Step 3:

[0131] Add dichloromethane (9.5 mL) to IM-2-2 (1.9 g) to obtain a colorless, clear solution at room temperature. Ice-bath to 0-10°C, add acetic acid (4.25 mL) dropwise, and exotherm is not obvious. Add acetic anhydride (5.25 mL) dropwise, and exotherm is not obvious. Add concentrated sulfuric acid (47.5 μL) dropwise, and exotherm is slight. Remove the ice bath and keep at 25°C for 4 h. Ice-bath to 0-10°C, add saturated sodium bicarbonate dropwise, and exotherm is not obvious. Adjust the pH to 6, using approximately 100 mL of saturated sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, rinsed with a small amount of dichloromethane, and silica gel (5 g, 100-200 mesh) was added. The sample was concentrated and mixed at 40°C. After purification by flash chromatography (silica gel column, 23% ethyl acetate petroleum ether system), 1.7 g of a colorless oil was obtained, namely IM-2-3. 1 HNMR (CDCl3, 600MHz), δ: 6.425 (s, 1H), 5.579~5.568 (d, J=6.6Hz, 1H), 5.463~5.427 (m, 1H), 5.002~4.961 (td, J=4.2Hz, J=10.2Hz, 1H), 3.741~ 3.712(dd,J=5.4Hz,J=11.4Hz,2H),3.509~3.451(m,1H),3.165(s,3H),3.133(s,3H),3.116(s,3H),3.002~2.967(dd,J=3.6Hz,J=17.4Hz,1H).

[0132] Step 4:

[0133] Acetonitrile (4 mL) was added to 5-amino-3,4-dihydro-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione (184 mg). BSA (1.54 g) was added with stirring at room temperature, followed by stirring at 70°C until the starting material was essentially dissolved. The mixture was cooled to room temperature, and IM-2-3 (150 mg) and trimethylsilyl trifluoromethanesulfonate (TMSOTf, 1.66 g) were added with stirring. After complete addition, the mixture was stirred at 70°C for 1 hour. The reaction mixture was vortexed at 45°C until no liquid was added. Ethyl acetate (10 mL) and saturated sodium bicarbonate (6 mL) were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated on silica gel at 40°C. The sample was purified by flash chromatography (silica gel column, 8% methanol in dichloromethane) to obtain 164 mg of a white solid, intermediate IM-2-4. m / z: 424.10(M+H), 422.10(MH).

[0134] Steps 5 and 6:

[0135] IM-2-4 (164 mg) and methanol (9.84 mL) were added to a reaction flask, followed by potassium carbonate powder (107 mg). The mixture was allowed to react at room temperature for 10 minutes. Three drops of acetic acid were added to the reaction solution to adjust the pH to 7. Silica gel was added and the sample was mixed. Flash chromatography (silica gel column, 13% methanol in dichloromethane) was performed to yield 110 mg of an off-white solid. The solid was dissolved in DMSO and purified by preparative HPLC (0.1% formic acid, acetonitrile, 20% acetonitrile isocratic elution). The product was lyophilized to yield 65 mg of compound 2-2 as a white solid. m / z: 340.05 (M+H), 338.10 (MH). 1 H NMR (CD3OD, 600MHz), δ: 5.997~5.990 (d, J=4.2Hz, 1H), 5.120~5.090 (td, J=4.2Hz, J=7.2Hz, 1H), 4.453~4.417 (m, 1H), 3.87 3~3.843(td,J=3.6Hz,J=7.2Hz,1H), 2.753~2.699(m,2H), 2.571~2.530(dd,1J=7.2Hz,J=16.8Hz,1H), 2.004~1.927(m,1H).

[0136] Example 3:

[0137] The preparation method of compound 3-3 is as follows:

[0138]

[0139] first step:

[0140] IM-2-3 (110 mg) and toluene (2.1 mL) were added to a reaction flask and stirred at 110°C for 20 min. The system was concentrated under reduced pressure until no solvent flowed out. Toluene (1.1 mL) and BSA (0.5 mL) were added and stirred at 80°C for 2 h. TMSOTf (12.6 μL) was added, and intermediate 9 (200 mg) was dissolved in toluene (0.67 mL) and added to the system. The system became brown and clear, and the reaction was continued at 80°C for 3 h. After the reaction was complete, the temperature was lowered to 0-10°C. Water (1.9 mL) was added dropwise at 0-10°C to quench the reaction. Isopropyl acetate (2 mL) and saturated sodium chloride solution (2 mL) were added, and the mixture was stirred for 5 min. The mixture was filtered through celite and rinsed with isopropyl acetate (2 mL). The filtrate was separated and the organic layer was separated. The aqueous layer was extracted with isopropyl acetate (2 mL x 1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The mixture was dissolved in dichloromethane and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain 130 mg of a yellow solid, intermediate IM-3-4. m / z: 397.10 (M+H), 395.10 (MH).

[0141] Step 2:

[0142] Intermediate IM-3-4 (40 mg), potassium carbonate powder (14 mg), and 2-methyltetrahydrofuran (160 μL) were added to a reaction flask. PEG-400 (4 μL) and methanol (32 μL) were added with stirring at room temperature. The mixture was allowed to react at room temperature for 2.5 h. The mixture was filtered through a 0.45 μm filter, and the filtrate was purified by preparative thin layer chromatography (dichloromethane:methanol = 10:1) to afford 13 mg of compound 3-3 as a colorless oil. m / z: 355.10 (M+H), 353.10 (MH). 1 H NMR (DMSO-d6, 600MHz) δ = 7.180 (s, 1H), 6.018 (s, 2H), 5.175 ~ 5.166 (d, J = 5.4Hz, 1H), 4.917 ~ 4.907 (d, J = 6.0Hz, 1 H), 4.564~4.514(m,1H), 4.405~4.372(m,1H), 4.063~4.042(t,J=6.0Hz,1H), 2.150(s,3H), 2.060~1.350(m,4H). 13 C NMR (DMSO-d6, 600MHz) δ = 175.20, 144.46, 144.06, 137.69, 132.90, 129.47, 80.32, 73.27, 68.06, 56.41, 29.74, 26.84, 25.09.

[0143] Experimental Example 1

[0144] This experimental example is used to illustrate the agonistic activity of the compounds of the present invention on human TLR7:

[0145] Test method: Take HEK-Blue test powder, add 50mL of endotoxin-free water to dissolve, then place in a 37℃ incubator and sterile filter for a few minutes. Prepare the compound into a stock solution, then dilute it with pure DMSO, and then dilute it in a series of 10 points; dilute the compound 20 times with culture medium, and then add the diluted compound to each well. TM hTL7 cells, first remove the supernatant, add preheated PBS, place in the incubator for 1-2 minutes, gently pipette the cells, and count with trypan blue staining. Resuspend the cells in HEK-Blue detection medium to adjust the concentration to 2.2×10 5 Cells were added to the 96-well cell culture plate containing the drug and cultured at 37°C for 16 h. The corresponding optical density (OD) value was obtained by microplate reader at a wavelength of 620 nm. The EC value of the drug was calculated using Graphpad Prism. 50 The test results are shown in Table 2:

[0146] Table 2: EC of the compounds of the present invention on human TLR7 50 value

[0147] Example Compound No. <![CDATA[EC of TLR7 50 (μM)]]> 2-2 12

[0148] The above data show that compound 2-2 of the present invention has a good activation effect on human TLR7.

[0149] Experimental Example 2

[0150] This experimental example is used to illustrate the prodrug release of the compound of the present invention by liver enzyme incubation:

[0151] The human liver microsome incubation system consisted of the following components: buffer (176 μL), NADPH (solution A, 20 μL), NADPH (solution B, 4 μL), and human liver microsomes (10 μL).

[0152] Test Method: Prepare the human liver microsome incubation system. First, add compound 3-3 (1 mg) and place in an ice bath. Preheat to 37.5°C for 5 minutes. Add human liver microsomes and immediately add 200 μL of cold acetonitrile to quench the 0-min system. Transfer to an ice bath. Shake the remaining samples on a shaker. Then, at the time points indicated in Table 3, add 200 μL of cold acetonitrile to quench the system. Transfer to an ice bath.

[0153] Table 3:

[0154]

[0155] After the experiment, the samples were centrifuged at 10,000 rpm for 5 min, and the supernatant was injected into LC-MS / MS for detection.

[0156] Experimental results: Compound 2-1 was detected at all time points, indicating that compound 3-3 could be further metabolized into active compound 2-1 under the action of human liver microsomes.

[0157] Experimental Example 3

[0158] This experimental example is used to illustrate the preliminary safety experiment of the compound of the present invention:

[0159] Test sample: Compound 3-3;

[0160] Animal species and number: Balb / c mice; 6 mice per group (half male and half female);

[0161] Administration: oral gavage;

[0162] Animal grouping and administration dosage: vehicle blank group, compound 3-3, administered according to the time and dosage shown in Table 4.

[0163] Dosage frequency: once a day for 5 consecutive days.

[0164] Table 4:

[0165]

[0166]

[0167] Experimental results: During the dosing period of compound 3-3, animals in all dose groups had normal water and food intake, normal activity, and normal body weight, with no obvious abnormalities. This preliminarily suggests that the maximum tolerated dose of compound 3-3 is greater than 160 mg / kg.

[0168] Experimental Example 4

[0169] This experimental example is used to illustrate the capsule preparation product of the compound of the present invention:

[0170] The formula composition is shown in Table 5:

[0171] Table 5

[0172] Element effect Dosage per tablet (mg) Compound 3-3 Main drug 10 Mannitol diluent 80 starch slurry Adhesives appropriate amount Sodium starch glycolate disintegrants 20 magnesium stearate lubricant 2 Gelatin empty capsules capsule 1 pill

[0173] The capsule preparation method is as follows:

[0174] Wet granulate and mix the weighed compound 3-3, mannitol, and sodium starch glycolate. While stirring with purified water, slowly add an appropriate amount of starch and stir to disperse the mixture to obtain a starch slurry as a binder. A soft material is prepared by a wet process, followed by stirring and then slowly adding the starch slurry and stirring. The prepared soft material is granulated using a nylon sieve. The wet granules are placed on a tray and dried in a constant temperature oven to obtain dry granules. The dried granules are sieved and sized, and the granules are weighed. Magnesium stearate is added to the granules and mixed to obtain a mixed granule. Using a manual capsule filling plate, the mixed granules are filled into empty gelatin capsules, and qualified capsules are screened to prepare capsules for packaging.

[0175] A capsule sample with a neat appearance was obtained. The capsule product was tested for content uniformity and dissolution in accordance with the "Pharmacopoeia of the People's Republic of China (2020 Edition)".

[0176] The experimental results show that the content uniformity of the capsule meets the requirements; in a dissolution medium with a pH of 2.0, the cumulative dissolution rate within 1 hour is greater than 75%.

[0177] The foregoing description is intended only to provide specific embodiments of the present invention, which will enable those skilled in the art to understand and implement the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not intended to be limited to the embodiments described herein, but is to be construed in the widest manner consistent with the principles and novel features disclosed herein.

Claims

1. A compound as shown in formula I, its stereoisomers, tautomers or pharmaceutically acceptable salts, in, X is a sulfur atom or NR 13 ; Y is an oxygen atom or a sulfur atom; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 11 、R 12 independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl, wherein said alkyl, aryl, heteroaryl are independently optionally substituted with one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl; R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl or alkenyl; R 10 is hydrogen or is selected from the following structures:

2. The compound according to claim 1, its stereoisomers, tautomers or pharmaceutically acceptable salts, characterized in that R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 11 、R 12 independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkane, C3-C8 cycloalkyl, C3-C5 heterocyclyl, C3-C5 heterocyclyl-substituted C1-C6 alkyl, C6-C10 aryl, C3-C9 heteroaryl, sulfone, phosphorus carbonyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein said alkyl, aryl, heteroaryl are independently optionally substituted with one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, C1-C6 alkylamino, di(C1-C6)alkylamino, trifluoromethyl; Optionally, R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkynyl or C2-C8 alkenyl; Optionally, R 13 is propargyl; Alternatively, X is a sulfur atom; Optionally, Y is an oxygen atom; Optional, R 1 、R 2 is a hydrogen atom; Optional, R 4 is a hydrogen atom; Optional, R 7 、R 8 is a hydrogen atom; Optional, R 9 is a hydrogen atom; Optional, R 11 、R 12 A hydrogen atom.

3. A compound of formula II, its stereoisomers, tautomers or pharmaceutically acceptable salts, in, X is a sulfur atom or NR 13 ; R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl, or alkenyl; R 10 is hydrogen or is selected from the following structures:

4. The compound according to claim 3, its stereoisomers, tautomers or pharmaceutically acceptable salts, characterized in that X is a sulfur atom; Optionally, R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkynyl or C2-C8 alkenyl; Optionally, R 13 It is propargyl.

5. A compound of formula III, its stereoisomers, tautomers or pharmaceutically acceptable salts, in, X is a sulfur atom or NR 13 ; R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, alkynyl, or alkenyl; R 10 is hydrogen or is selected from the following structures:

6. The compound according to claim 5, its stereoisomers, tautomers or pharmaceutically acceptable salts, characterized in that X is a sulfur atom; Optionally, R 13 is hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkynyl or C2-C8 alkenyl; Optionally, R 13 It is propargyl.

7. The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts, 8. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 7 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9. A TLR7 agonist comprising the compound according to any one of claims 1 to 7 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

10. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for TLR7-related diseases; Optionally, the TLR7-related diseases include tumors, hepatitis A virus disease, hepatitis B virus disease, hepatitis C virus disease and hepatitis D virus disease.

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