Telomerase-targeting nucleoside analogue and application thereof

Abstract

The invention provides a nucleoside analogue as shown in a formula (I), a preparation method and a pharmaceutical composition thereof. The invention also discloses application of the compound or the pharmaceutical composition thereof in preparation of anti-cancer drugs.

Description

A class of nucleoside analogs targeting telomerase and their applications Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a class of nucleoside analogs with telomerase inhibitory activity and a preparation method thereof, as well as the use of such compounds in preventing and treating tumors. Background Art

[0002] Telomeres, located at the ends of chromosomes, are composed of 3-15kb repeating sequences called TTAGGG. They act like caps on either end of chromosomes, protecting their integrity and stability and preventing degradation, fusion, and recombination. Telomere length decreases with the number of cell divisions. As telomeres shorten, the genome within the cell cannot maintain a stable state, leading to cell aging and death. Telomerase, a reverse transcriptase found in eukaryotic cells, can extend shortened telomeres and plays a crucial role in maintaining telomere stability, genome integrity, long-term cell activity, and potential for continued proliferation. Telomerase activity is tightly regulated in normal human tissues. Numerous studies have shown that the immortalization of tumor cells is closely associated with telomerase activity, with tumor cells displaying elevated telomerase activity.

[0003] 6-Mercapto-2′-deoxyguanosine (6-thio-dG) is a nucleoside analog. Studies have found that it can inhibit telomerase activity and activate tumor-specific T cells through the STING / IFN-I pathway, thereby exerting an immune anti-tumor effect. Its metabolite is 6-thioguanine (6TG).

[0004] Maia Biotech's 6-thio-dG combination has entered Phase II clinical trials. No 6-thio-dG or its derivatives have yet entered clinical trials. The present invention provides a new class of 6-thio-dG derivatives that exhibit superior anticancer activity and lower toxicity compared to 6-thio-dG.

[0005] Summary of the Invention

[0006] The first aspect of the present invention relates to a class of small molecule inhibitors with anti-cancer activity, specifically to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0007] Among them, R 1 、R 2 、R 3 or R 4 each independently hydrogen or deuterium;

[0008] R 5 -OH, or -OC(=O)C 1-5 Alkyl; wherein, when R 5 When it is -OH, R 1 、R 2 、R 3 or R 4 Not simultaneously hydrogen;

[0009] R 6 for

[0010] R 7 or R 8 Each independently represents -OH, -OC 1-5 Alkyl, -NR a R b or -OAr, the -OC 1-5 The alkyl group is optionally substituted with one or more -OC(=O)C 1-5 Alkyl substituted, Ar is a 5-6 membered aromatic group;

[0011] R a or R b Each is independently -H or -C 1-5 Alkyl, the -C 1-5 The alkyl group is optionally substituted with one or more -C(=O)OC 1-5 Alkyl substitution;

[0012] L is a bond, -S-, -O-, -C 1-3 Alkylene-, -SC 1-3 Alkylene- or -OC 1-3 Alkylene-, the-C 1- 3-alkylene-, -SC 1-3 Alkylene- or -OC 1-3 Alkylene-optionally substituted with one or more -C 1-3 Alkyl substitution;

[0013] R 9 -C 2-6 Alkenyl or 5-6 membered aryl, the -C 2-6 The alkenyl or 5-6 membered aryl group is optionally substituted with one or more -OC(=O)C 1-5 Alkyl or -C(=O)C 1-5 Alkyl substitution;

[0014] R 10 H or -C(=O)C 1-5 alkyl.

[0015] In some embodiments of the present invention, R 1or R 2 For deuterium.

[0016] In some embodiments of the present invention, R 3 For deuterium.

[0017] In some embodiments of the present invention, R 4 For deuterium.

[0018] In some embodiments of the present invention, when R 1 or R 2 When it is deuterium, R 3 and R 4 are all hydrogen; or when R 3 or R 4 When it is deuterium, R 1 and R 2 All are hydrogen.

[0019] In some embodiments of the present invention, R 5 -OH, or -OC(=O)C 1-4 Alkyl; preferably, R5 is -OH,

[0020] In some embodiments of the present invention, R 7 or R 8 Each independently -OC 1-3 Alkyl, -NR a R b or -OAr, the -C 1-3 The alkyl group is optionally substituted with one or more -OC(=O)C 1-5 Alkyl substituted, Ar is a 6-membered aromatic group; preferably, R 7 or R 8 Each independently -NR a R b or -OPh.

[0021] In some embodiments of the present invention, R a or R b Each is independently -H or -C 1-3 Alkyl, the -C 1-3 The alkyl group is optionally substituted with one or more -C(=O)OC 1-3 Alkyl substituted; preferably, R a or R b Each independently is -H or

[0022] In some embodiments of the present invention, R 10 H or -C(=O)C 1-3 Alkyl, preferably, R10 For H.

[0023] In some embodiments of the present invention, L is a bond, -S-, -C 1-3 Alkylene- or -SC 1-3 Alkylene, the -C 1-3 Alkylene- or -SC 1-3 The alkylene group is optionally substituted with one or more -C 1-3 Alkyl substituted; preferably, L is a bond, -S-, -C 1-3 Alkylene- or -SC 1-3 Alkylene; more preferably, L is a bond, -S-, -CH2- or -S-CH2-.

[0024] In some embodiments of the present invention, R 9 -C 2-4 Alkenyl or 6-membered aryl, the -C 2-4 The alkenyl or 6-membered aryl group is optionally substituted with one or more -OC(=O)C 1-3 Alkyl or -C(=O)C 1-3 Alkyl substituted; preferably, R 9 is vinyl or phenyl, said vinyl or phenyl being optionally substituted by one or more -OC(=O)C 1-3 Alkyl or -C(=O)C 1-3 Alkyl substituted; more preferably, R 9 For vinyl, In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure shown in formula (I-1),

[0025] Among them, R 1 、R 2 、R 3 or R 4 each independently hydrogen or deuterium;

[0026] R 5 -OH or -OC(=O)C 1-5 Alkyl; when R 5 When it is -OH, R 1 、R 2 、R 3 or R 4 Not hydrogen at the same time.

[0027] In some embodiments of the present invention, R 5 -OH or -OC(=O)C 1-3 Alkyl, preferably, R5 is -OH or

[0028] In some embodiments of the present invention, the compounds of the present invention or pharmaceutically acceptable salts thereof include the following compounds:

[0029] In some embodiments of the present invention, the compounds according to the present invention or pharmaceutically acceptable salts thereof include the following compounds:

[0030] In some embodiments of the present invention, the pharmaceutically acceptable salts of the compounds of the present invention are acid addition salts.

[0031] Another aspect of the present invention provides a pharmaceutical composition comprising the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers or additives.

[0032] The present invention also provides a use of the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the present invention in the preparation of an anticancer drug.

[0033] In some embodiments of the present invention, the cancer of the use of the present invention includes gastric cancer, colorectal cancer, breast cancer, sarcoma, melanoma, lymphoma, pancreatic cancer, lung cancer or brain cancer.

[0034] Definition and Description

[0035] Unless defined otherwise, 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 belongs.

[0036] Unless otherwise indicated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR and pharmacological methods, are adopted. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthesis chemistry and medicine and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, preparation and delivery, and in the treatment of patients. For example, the instructions for use of the manufacturer's test kit can be utilized, or reaction and purification can be implemented according to a manner well known in the art or the description of the present invention. Conventionally, the above-mentioned techniques and methods can be implemented according to conventional methods well known in the art, based on the description of a plurality of summaries and more specific documents cited and discussed in this specification.

[0037] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a designated atom or group with the selection of a designated group, provided that the normal valence of the designated atom is not exceeded. When the substituent is an oxo or keto group (i.e., =O), then two hydrogen atoms on the atom are replaced.

[0038] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.A stable compound or structure is one that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and subsequent formulation into an efficacious therapeutic agent.

[0039] In the present invention, "optional" or "optionally" means that the subsequently described event or situation may or may not occur, and the description includes both cases where the event or situation occurs and cases where it does not occur. "Optionally substituted" refers to a group having 0, 1, 2 or more substituents. It will be understood by those skilled in the art that for any group containing one or more substituents, these groups do not introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible and / or inherently unstable. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

[0040] The term "C n -C m "With C n-m Used interchangeably to mean having n to m carbon atoms.

[0041] The term "alkyl" or "alkylene" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. 1-10 "Alkyl" refers to a straight or branched saturated alkyl group containing 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, n-hexyl, n-heptyl, isoheptyl, n-octyl, n-nonyl, n-decyl, etc., preferably methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl or tert-butyl. The term "C 1-3 The term "alkyl" refers to a straight or branched chain saturated alkyl group containing 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl.

[0042] The terms "comprising" or "including" may be open, semi-closed or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0043] The pharmaceutically acceptable salts of the present invention can be prepared by reacting with corresponding organic or inorganic acids in an organic solvent such as acetonitrile or tetrahydrofuran. Typical organic acids include oxalic acid, tartaric acid, maleic acid, succinic acid, methanesulfonic acid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid, aminosulfonic acid, citric acid, glutamic acid, pyroglutamic acid, aspartic acid, glucuronic acid, naphthalenesulfonic acid, glutaric acid, acetic acid, trifluoroacetic acid, malic acid, fumaric acid, salicylic acid, 4-aminosalicylic acid, lactic acid, palmitate, stearic acid, lauric acid, cinnamic acid, alginic acid, and ascorbate. Typical inorganic acids include nitric acid, hydrochloric acid, sulfuric acid, and phosphoric acid.

[0044] The term "aryl" or "aromatic ring" includes 5- and 6-membered monocyclic aromatic groups that may contain 0-4 heteroatoms, such as benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine; in addition, the term "aryl" also includes polycyclic aromatic groups, such as tricyclic and bicyclic groups, such as naphthalene, benzoxazole, benzodiazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine or indolizine.

[0045] The compounds of this invention can exist in the following form: tautomer, optically pure enantiomer, pure diastereomer, enantiomeric mixture, diastereomer mixture, enantiomeric racemic mixture, racemate or racemate mixture.All possible isomers (including but not limited to tautomer, enantiomer, diastereomer, stereoisomer) and its mixture of the compound of formula (I) are also within the scope of the present invention.

[0046] The compounds of the present invention may exist in different hydrogen attachment points, known as tautomers. For example,

[0047] When compounds of the present invention contain olefinic double bonds, unless specified otherwise, these double bonds are intended to encompass both E and Z geometric isomers.

[0048] The pharmaceutical compositions provided by the present invention can be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained-release preparations of the active ingredients, wherein examples of capsules include hard or soft gelatin capsules, and granules and powders can be non-effervescent or effervescent forms.

[0049] The pharmaceutical composition of the present invention may further include one or more pharmaceutically or physiologically acceptable carriers, which are suitably formulated for ease of administration. For example, the pharmaceutically or physiologically acceptable carrier may be one or more of saline, autoclaved water, Ringer's solution, buffered saline, glucose, alcohol, honey, mannitol, sorbitol, dextrin, lactose, caramel, gelatin, calcium sulfate, magnesium stearate, talc, kaolin, glycerol, Tween, agar, calcium carbonate, calcium bicarbonate, surfactants, cyclodextrin and its derivatives, phospholipids, phosphates, starch and its derivatives, silicon derivatives, cellulose and its derivatives, pyrrolidones, polyethylene glycols, acrylic resins, phthalates, acrylic acid copolymers, and trimellitic acid esters.

[0050] The pharmaceutical composition of the present invention may further include pharmaceutically or physiologically acceptable additives, such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, dispersants, surfactants, solvents, coating agents, foaming agents, or fragrances.

[0051] Examples of diluents that may be used include, but are not limited to, lactose, sucrose, starch, salt, mannitol, and dicalcium phosphate; examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium, and stearic acid; examples of binders include, but are not limited to, microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste; examples of glidants include, but are not limited to, colloidal silicon dioxide; examples of disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, and glutamic acid. Starch, bentonite, methylcellulose, agar and carboxymethylcellulose; examples of sweeteners include, but are not limited to, sucrose, lactose, mannitol and artificial sweeteners such as sodium cyclamate and saccharin, and any number of spray-dried flavors; examples of flavors include, but are not limited to, natural flavors extracted from plants, such as fruits, and flavorful compounds such as, but not limited to, mint and methyl salicylate; examples of wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

[0052] The pharmaceutical compositions of the present invention can be administered by various routes according to conventional methods, including oral, intravenous, intraarterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular, and subcutaneous administration. Pharmacological experiments have demonstrated that the compounds or pharmaceutical compositions provided by the present invention can be used to treat cancers, including but not limited to gastric cancer, colorectal cancer, breast cancer, sarcoma, melanoma, lymphoma, pancreatic cancer, lung cancer, and brain cancer.

[0053] The abbreviations used in the present invention have the conventional meanings in the art. For example, the following abbreviations have the following meanings:

[0054] Compound Preparation Examples

[0055] Example 1:

[0056] Synthesis of 2-amino-9-((4S,5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-5,9-dihydro-6H-purine-6-thione (1)

[0057] Step 1: Synthesis of (2R, 3S)-5-methoxy-2-((tributoxy)methyl)tetrahydrofuran-3-ol (1b)

[0058] To a 500 mL three-necked flask were added 1a (20.09 g, 135.60 mmol), CH2Cl2 (300 mL), Et3N (16.53 g, 163.36 mmol), and TrCl (41.87 g, 150.19 mmol) in sequence. The mixture was stirred at room temperature for about 24 h. The reaction solution was washed twice with 100 mL×2 water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was used directly in the next reaction without purification.

[0059] LCMS (ESI-MS) m / z: 391.2 (M+H + ).

[0060] Step 2 Synthesis of (2R, 3S)-5-methoxy-3-(naphthalen-2-ylmethoxy)-2-((tributoxy)methyl)tetrahydrofuran (1c)

[0061] To the crude compound obtained in the first step, dry DMF (300 mL) was added, and NaH (mass fraction 60%, 5.45 g, 136.25 mmol) was added under ice-water bath cooling, and finally NapBr (33.15 g, 149.26 mmol) was slowly added. The ice-water bath was maintained and the reaction was continued with stirring for about 2 h. TLC detection (ethyl acetate: petroleum ether = 1:6) showed that the reaction was complete. The reaction solution was poured into 2 L of water, and the aqueous layer was extracted twice with ethyl acetate (500 mL, 100 mL). The obtained organic phase was washed with 150 mL of brine, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The obtained crude compound was used directly in the next reaction without purification.

[0062] LCMS (ESI-MS) m / z: 531.1 (M+H + ).

[0063] Step 3 Synthesis of ((2R,3S)-5-methoxy-3-(naphthalen-2-ylmethoxy)tetrahydrofuran-2-yl)methanol (1d)

[0064] To the crude compound obtained in the second step, CH2Cl2 (250 mL), methanol (50 mL), and p-toluenesulfonic acid monohydrate (2.1 g) were added, and the reaction was stirred at room temperature for about 24 h. The reaction solution was washed with 100 mL of brine, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by column chromatography to obtain compound 1d (33 g).

[0065] LCMS (ESI-MS) m / z: 289.1 (M+H + ).

[0066] Step 4: Synthesis of (2S, 3S)-5-methoxy-3-(naphthalen-2-ylmethoxy)tetrahydrofuran-2-carboxylic acid (1e)

[0067] To a 1L three-necked flask, 1d (32.06 g, 111.19 mmol), CH2Cl2 (300 mL), NaBr (0.8 g, 7.77 mmol, dissolved in 1 mL of water), and TEMPO (0.894 g, 5.72 mmol) were added sequentially and cooled in an ice-water bath. A 10% aqueous NaClO solution (210 g) was weighed and adjusted to pH 8-9 with saturated sodium bicarbonate solution. The solution was then slowly added to the reaction mixture. The reaction was stirred in an ice-water bath for approximately 5 h. TLC analysis (ethyl acetate:petroleum ether = 1:3; dichloromethane:methanol = 10:1) indicated the reaction was complete. The reaction solution was allowed to stand for separation, and the aqueous layer was washed twice with CH2Cl2 (100 mL×2), and the pH of the aqueous layer was adjusted to 3-4 with dilute aqueous hydrochloric acid. The aqueous layer was then extracted three times with tert-methyl ether (300 mL, 100 mL, 100 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 1e (33.56 g).

[0068] LCMS (ESI-MS) m / z: 303.2 (M+H + ).

[0069] Step 5: Synthesis of ((2R, 3S)-5-methoxy-3-(naphthalen-2-ylmethoxy)tetrahydrofuran-2-yl)methane-d2-ol (1f)

[0070] To a 1L three-necked flask, 1e (33.56 g, 111.0 mmol) and dry THF (300 mL) were added sequentially. The mixture was cooled in an ice-water bath, followed by the addition of LiAlD4 (6.37 g, 151.74 mmol). The mixture was stirred and reacted in an ice-water bath for approximately 4 h. TLC (dichloromethane:methanol = 10:1) indicated the reaction was complete. Aqueous sodium hydroxide solution (10 g NaOH in 100 mL water) was slowly added dropwise to the reaction solution, followed by the addition of 400 mL of saturated brine. The mixture was stirred for 15 min and filtered. The filtrate was separated, and the aqueous layer was extracted twice with ethyl acetate (100 mL x 2). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to yield 1f (25.91 g).

[0071] LCMS (ESI-MS) m / z: 291.2 (M+H + ).

[0072] Step 6 Synthesis of (2R, 3S)-2-(hydroxymethyl-d2)-5-methoxytetrahydrofuran-3-ol (1g)

[0073] To a 100 mL single-necked flask, 1f (3.55 g, 12.22 mmol), methanol (40 mL), and 10% Pd / C (420 mg) were added sequentially. The mixture was stirred at room temperature under atmospheric H₂ pressure for approximately 72 h. TLC analysis (dichloromethane:methanol = 10:1) indicated the reaction was complete. The palladium on carbon was removed by filtration, and the methanol was removed by concentration below 40°C. The crude product was used directly in the next step without purification.

[0074] LCMS (ESI-MS) m / z: 151.1 (M+H + ).

[0075] Step 7: Synthesis of ((2R, 3S)-3-(benzoyloxy)-5-methoxytetrahydrofuran-2-yl)methyl-d2benzoate (1h)

[0076] To a 100 mL three-necked flask were added the crude compound from the previous step, CH2Cl2 (20 mL), triethylamine (3.20 g, 31.62 mmol), and 4-dimethylaminopyridine (catalytic amount) in sequence. Benzoyl chloride (3.83 g, 27.25 mmol) was slowly added under ice-water cooling. The mixture was stirred in an ice-water bath and allowed to react. The mixture was slowly allowed to warm to room temperature and continued to stir for approximately 19 h. The reaction mixture was washed with 30 mL of water and allowed to stand for stratification. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by column chromatography to obtain 1h (3.0 g).

[0077] LCMS (ESI-MS) m / z: 359.1 (M+H + ).

[0078] Step 8 Synthesis of (2R, 3S)-5-(2-amino-6-thioxy-5,6-dihydro-9H-purin-9-yl)-2-((benzoyloxy)methyl-d2)tetrahydrofuran-3-ylbenzoate (1k)

[0079] To a 100 mL three-necked flask were added 1i (2.0 g, 11.98 mmol), 1h (2.8 g, 7.9 mmol), N,O-bis(trimethylsilyl)acetamide (4.8 g, 24 mmol), and anhydrous toluene (80 mL). The reaction mixture was nitrogen-purged three times, heated to 80°C (internal temperature), stirred for 20 h, then cooled to an internal temperature of approximately 65°C. Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (2.5 g, 12.3 mmol) was added dropwise. The reaction mixture was allowed to react for 3 h. A sample was taken and sent for MS analysis, indicating that the reaction was complete. The reaction mixture was cooled to room temperature, DCM (150 mL) was added, and then a saturated NaHCO3 solution (100 mL) was added. If emulsification occurred, the mixture was filtered and separated. The organic phase was washed once with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to obtain 1k (1.0 g).

[0080] LCMS (ESI-MS) m / z: 494.1 (M+H + ).

[0081] Step 9 Synthesis of 2-amino-9-((4S,5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-5,9-dihydro-6H-purine-6-thione (1)

[0082] To a 100 mL single-necked flask, add 1k (1.0 g, 2 mmol) obtained in the previous step and ammonia methanol solution (30 mL, 7 M) and stir at room temperature overnight. The solvent was concentrated to dryness, and the resulting crude product was purified by column chromatography to obtain compound 1 (0.46 g, a mixture of α and β configurations).

[0083] LCMS (ESI-MS) m / z: 286.1 (M+H + ).

[0084] Example 2:

[0085] (2R,3S,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl-d2)tetrahydrofuran-3-yl isobutyrate (2)

[0086] Step 1: Synthesis of 2-amino-9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (2b)

[0087] Compound 2a (300 mg, 1.06 mmol) was dissolved in DMF (5 mL), and imidazole (360 mg, 5.3 mmol) and TBSCl (479 mg, 3.18 mmol) were added. The reaction solution was stirred at room temperature overnight, precipitated by adding water, filtered, washed with methyl tert-butyl ether, and dried to obtain compound 2b (440 mg).

[0088] LCMS (ESI-MS) m / z: 496.2 [M+H] +

[0089] Step 2: Synthesis of N-(9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxymethyl)tetrahydrofuran-2-yl)-6-oxo-6,9-dihydro-1H-purin-2-yl)benzamide (2c)

[0090] Compound 2b (5.0 g, 10 mmol) was dissolved in pyridine (50 mL), and BzCl (2.8 g, 20 mmol) was added. The mixture was stirred at room temperature for one hour. The reaction mixture was slowly poured into ice water and stirred for 10 minutes. The precipitated solid was filtered, washed with water, and dried to obtain compound 2c (5.1 g).

[0091] LCMS (ESI-MS) m / z: 600.3 (M+H + ).

[0092] Step 3 Synthesis of N-(9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-6-oxo-6,9-dihydro-1H-purin-2-yl)benzamide (2d)

[0093] Compound 2c (5.1 g, 8.3 mmol) was dissolved in THF (100 mL), and TFA (10 mL) and water (10 mL) were added. The mixture was stirred in an ice-water bath for 4 hours. Aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with EA. The mixture was concentrated and passed through a flash column to afford product 2d (3.8 g).

[0094] LCMS (ESI-MS) m / z: 486.2 (M+H + ).

[0095] Step 4: Synthesis of (2S, 3S, 5R)-5-(2-benzylamino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-carboxylic acid (2e)

[0096] Compound 2d (3.8 g, 7.8 mmol) was dissolved in acetonitrile (50 mL), 50 mL of water was added, the temperature was lowered to about 0 degrees, sodium bicarbonate (1.4 g, 16.6 mmol) and iodophenyl diacetic acid (5.3 g, 16.6 mmol) were added, and TEMPO (249 mg, 1.6 mol) was slowly added. The mixture was stirred at room temperature for 2 hours until the reaction solution became clear. Sodium sulfite was added to quench the mixture, the acetonitrile was concentrated, and the precipitated compound was filtered, dried, and obtained compound 2e (3.5 g).

[0097] LCMS (ESI-MS) m / z: 500.2 (M+H + ).

[0098] Step 5: Synthesis of (2S, 3S, 5R)-5-(2-benzylamino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-carboxylic acid (2f)

[0099] Compound 2e (3.5 g, 7.0 mmol) was dissolved in methanol (50 mL), EDCI (2.5 g, 14.0 mmol) was added, and the mixture was stirred at room temperature. DMAP (244 mg, 2 mmol) was added and stirred at room temperature overnight. The mixture was concentrated, water was added, and the mixture was extracted with DCM. The mixture was concentrated and passed through a flash column to obtain compound 2f (3 g).

[0100] LCMS (ESI-MS) m / z: 514.2 (M+H + ).

[0101] Step 6: Synthesis of methyl (2S, 3S, 5R)-5-(2-benzylamino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-carboxylate (2 g)

[0102] Compound 2f (3.0 g, 5.8 mmol) was dissolved in THF / CD3OD / D2O (40 mL / 8 mL / 4 mL), cooled to 0°C, and NaBD4 (0.97 g, 23.4 mmol) was added. The mixture was stirred at room temperature for 4 h, quenched by adding aqueous ammonium chloride, extracted with DCM, concentrated, and passed through a flash column to obtain compound 2g (2.2 g).

[0103] LCMS (ESI-MS) m / z: 488.3 (M+H + ).

[0104] Step 7: Synthesis of methyl (2S, 3S, 5R)-5-(2-benzylamino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-carboxylate (2h)

[0105] Compound 2g (2.2g, 4.5mmol) was dissolved in THF (30mL). 3HF.Et3N (2.4g, 15.1mmol) and Et3N (1.5g, 15.1mmol) were added dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and reacted for 5 hours. LCMS showed complete reaction. The reaction mixture was poured into ice water and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. A large amount of compound precipitated, which was filtered and dried to obtain compound 2h (1.4g).

[0106] LCMS (ESI-MS) m / z: 374.3 (M+H + ).

[0107] Step 8 Synthesis of N-(9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-6-oxo-6,9-dihydro-1H-purin-2-yl)benzamide (2i)

[0108] Compound 2h (1.4 g, 3.7 mmol) was dissolved in anhydrous pyridine (20 mL), and imidazole (0.5 g, 7.5 mmol) was added. TBSCl (1.1 g, 7.5 mmol) was added portionwise at 0°C, and the reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was poured into ice water, whereupon a large amount of compound precipitated. The precipitate was filtered, and the filter cake was washed with water. The filter cake was collected and dried to obtain compound 2i (1.7 g).

[0109] LCMS (ESI-MS) m / z: 488.6 (M+H + ).

[0110] Step 9 Synthesis of 2-amino-9-((2R,4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl-d2)-4-hydroxytetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6-one (2j)

[0111] Compound 2i (1.7 g, 3.7 mmol) was dissolved in methanolic ammonia solution (40 mL), and aqueous ammonia (4 mL) was added. The mixture was heated at 50°C for 8 hours. The mixture was concentrated, THF was added three times, and the mixture was concentrated to dryness. The mixture was slurried with PE:EA = 2:1, filtered, and the filter cake was collected and dried to obtain compound 2j (1.4 g).

[0112] LCMS (ESI-MS) m / z: 384.6 (M+H+ ).

[0113] Step 10: Synthesis of (2R, 3S, 5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-((tert-butyldimethylsilyl)oxy)methyl-d2)tetrahydrofuran-3-yl isobutyrate (2k)

[0114] Compound 2j (1.4 g, 36.4 mmol) was dissolved in DMF (20 mL) and Et3N (1.1 g, 10.9 mmol). Isobutyric anhydride (1.2 g, 7.3 mmol) was then added dropwise. The reaction mixture was allowed to react at room temperature for 16 hours. LCMS showed that the starting material was essentially reacted. The reaction mixture was poured into ice water, where a large amount of compound precipitated. The filter cake was collected by filtration and dried to yield 2k (0.72 g).

[0115] LCMS (ESI-MS) m / z: 454.3 (M+H + ).

[0116] Step 11 Synthesis of (2R, 3S, 5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl-d2)tetrahydrofuran-3-yl isobutyrate (2l)

[0117] Compound 2k (0.72 g, 1.6 mmol) was dissolved in THF (10 mL). 3HF.Et3N (0.51 g, 3.2 mmol) was added dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and allowed to react for 16 hours. LCMS indicated complete reaction. The reaction mixture was poured into ice water and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. A large amount of compound precipitated, which was filtered, collected, and dried to yield 2l (0.4 g).

[0118] LCMS (ESI-MS) m / z: 340.2 (M+H + ).

[0119] Step 12 Synthesis of (2R, 3S, 5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-2-(hydroxymethyl-d2)tetrahydrofuran-3-ylisobutyric acid (2)

[0120] Compound 21 (100 mg, 0.29 mmol) was dissolved in pyridine (3 mL). Trifluoromethanesulfonic anhydride (618 mg, 2.9 mmol) was added dropwise at 0°C. The reaction mixture was allowed to react at room temperature for 1 hour. The temperature was then lowered to 0°C, and a solution of NaHS (243 mg, 4.35 mmol) in DMF (3 mL) was added dropwise. The reaction mixture was allowed to react at room temperature for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was directly purified by Prep-HPLC to yield compound 2 (70 mg).

[0121] LCMS (ESI-MS) m / z: 356.2 (M+H + ).

[0122] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.19(s,1H),6.84(s,2H),6.10(dd,J=8.8,5.8Hz,1H),5.36–5.24(m,1H),3.9 8(d,J=1.7Hz,1H),2.79(ddd,J=14.5,8.8,5.9Hz,1H),2.68–2.54(m,1H),2.44–2.34(m,1H),1.11(d,J=6.9Hz,6H).

[0123] Example 3:

[0124] 2-Amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (3)

[0125] Step 1 Synthesis of 2-amino-9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6-one (3a)

[0126] Compound 2g (1.5g, 3.0mmol) was dissolved in methanolic ammonia solution (30mL), and aqueous ammonia (3mL) was added. The mixture was heated at 50°C for 8 hours. The mixture was concentrated, THF was added, and the mixture was concentrated to dryness three times. The mixture was slurried in a PE:EA ratio of 2:1, filtered, and the filter cake was collected and dried to obtain 3a (0.8g).

[0127] LCMS (ESI-MS) m / z: 384.2 (M+H + ).

[0128] Step 2 Synthesis of 2-amino-9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (3b)

[0129] Compound 3a (200 mg, 0.52 mmol) was dissolved in pyridine (3 mL). Trifluoromethanesulfonic anhydride (1.1 g, 5.2 mmol) was added dropwise at 0°C. The reaction mixture was allowed to react at room temperature for 1 hour. The temperature was then lowered to 0°C, and a solution of NaHS (440 mg, 7.8 mmol) in DMF (3 mL) was added dropwise. The reaction mixture was allowed to react at room temperature for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was directly used for Prep-HPLC to yield compound 3b (100 mg).

[0130] LCMS (ESI-MS) m / z: 400.2 (M+H + ).

[0131] Step 3 Synthesis of 2-amino-9-((2R, 4S, 5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (3)

[0132] Compound 3b (100 mg, 0.25 mmol) was dissolved in THF (5 mL). 3HF.Et3N (95 mg, 0.5 mmol) was added dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and allowed to react for 5 hours. LCMS indicated complete reaction. The reaction mixture was poured into ice water and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. A large amount of compound precipitated, which was filtered and dried to yield 3 (40 mg).

[0133] LCMS (ESI-MS) m / z: 286.3 (M+H + ).

[0134] 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),8.09(s,1H),6.78(s,2H),6.09(dd,J=7.6,6.1Hz,1H),5.25(d,J=4.0Hz,1H),4 .87(s,1H),4.32(dq,J=6.5,3.3Hz,1H),3.79(d,J=2.9Hz,1H),2.55–2.50(m,1H),2.20(ddd,J=13.1,6.1,3.3Hz,1H).

[0135] Example 4:

[0136] 2-Amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl-2d)-1,9-dihydro-6-purine-6-thione (4) Step 1: Synthesis of methyl ((2R,3S)-3-(benzoyloxy)-5-oxotetrahydrofuran-2-yl)benzoate (4b)

[0137] To a three-necked flask, compound 4a (1.32 g, 10 mmol), pyridine (10 mL), DMAP (122 mg, 1 mmol) were added in sequence, and finally benzoyl chloride (2.9 mL, 25 mmol) was added. The reaction was allowed to proceed overnight at room temperature, and the system was evaporated to dryness. The product was purified by column chromatography to obtain 4b (2.7 g).

[0138] LCMS [M+H] + =341.20 358.20 (acetal)

[0139] Step 2 Synthesis of Bis(3-methylbutan-2-yl)borane-d(4d)

[0140] Take a three-necked flask and add BD3 (22 mL, 22 mmol) in sequence. Replace nitrogen at room temperature, cool to -10°C and add 4c (4.87 mL, 46 mmol) dropwise. After the addition is complete, react at 0°C for 2 h to obtain 4d, which is directly used in the next step.

[0141] Step 3: ((2R, 3S)-3-(benzoyloxy)-5-hydroxytetrahydrofuran-2-yl-5-d)methylbenzoate (4e)

[0142] To the reaction mixture from the previous step, 4b (1.9 g, 5.5 mmol) in DCM (10 mL) was added dropwise. The temperature was slowly raised and the reaction was allowed to react overnight at room temperature. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered, and evaporated to dryness. Purification by column chromatography afforded 4e (1.05 g).

[0143] LCMS (ESI-MS) m / z: 366.2 [M+Na] +

[0144] Step 4: Synthesis of methyl ((2R, 3S)-3-(benzoyloxy)-5-methoxytetrahydrofuran-2-yl-5-d)methylbenzoate (4f)

[0145] To a single-necked flask, add methanol (50 mL), replace the atmosphere with nitrogen, cool to 10°C, add acetyl chloride (1 mL), and stir for 10 min to obtain Solution A. To another single-necked flask, add methanol (90 mL) and compound 4e (5 g, 14.5 mmol) sequentially. Replace the atmosphere with nitrogen, cool to 10°C, add Solution A (10 mL) first, maintain the temperature for 1.5 h, add more Solution A (10 mL), and continue the reaction until the reaction is complete. Remove the methanol by distillation at 30°C, add dichloromethane, adjust the mixture to neutral with saturated sodium bicarbonate solution, extract with dichloromethane, combine the organic phases, dry over anhydrous Na2SO4, filter, and concentrate. Purify by column chromatography to obtain compound 4f (4.4 g).

[0146] LCMS (ESI-MS) m / z: 380.2 [M+Na] +

[0147] Step 5 Synthesis of 6-chloro-N, N, 9-tris(trimethylsilyl)-9H-purine-2-amine (4h)

[0148] In a single-necked flask, crude compound 4g (1.9 g, 11.2 mmol), HDMS (13.5 mL, 62 mmol), DCE (30 mL), and ammonium sulfate (22 mg, 0.168 mmol) were added sequentially. The atmosphere was replaced with nitrogen three times at room temperature. The reaction solution was refluxed at 110°C until transparent and clear for 8 h. Compound 4h was obtained and used directly in the next step.

[0149] Step 6 Synthesis of (2R, 3S)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-((benzoyloxy)methyl)tetrahydrofuran-3-yl-5-benzoate (4i)

[0150] The reaction mixture from step 4h was cooled to room temperature, and compound 4f (1 g, 2.8 mmol) was added, followed by TMSOTf (0.8 mL, 4.2 mmol). The atmosphere was replaced with nitrogen three times, and the reaction was continued at 95°C for 1 h, followed by 24 h at room temperature. Water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography afforded 4i (1.0 g).

[0151] LCMS (ESI-MS) m / z: 495.2 [M+H] +

[0152] Step 7 Synthesis of (2R, 3S)-5-(2-amino-6-mercapto-9H-purin-9-yl)-2-((benzoyloxy)methyl)tetrahydrofuran-3-yl-5-benzoate (4j)

[0153] To a single-necked flask, add NaHS (994 mg, 17.7 mmol) and DMF (10 mL) sequentially. Replace the atmosphere with nitrogen three times at room temperature and stir for 30 minutes. Add 4i (1.46 g, 2.95 mmol) at 0°C and allow to react overnight. Water was added to the system, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to afford 4j (270 mg).

[0154] LCMS (ESI-MS) m / z: 493.2 [M+H] +

[0155] Step 8 Synthesis of 2-amino-9-((2R, 4S, 5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl-2d)-1,9-dihydro-6-purine-6-thione (4)

[0156] In a single-necked flask, 4j (110 mg, 0.22 mmol) and methanol (10 mL) were placed under nitrogen three times at room temperature. A methanol solution of sodium methoxide (0.8 mL, 4.3 mmol) was added to the suspension at 0°C and allowed to react at room temperature. Acetic acid was added, the mixture was adjusted to neutrality, and the mixture was concentrated. Purification by column chromatography afforded 4 (46 mg).

[0157] LCMS (ESI-MS) m / z: 285.10 [M+H] +

[0158] 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),8.08(s,1H),6.79(s,2H),5.26(d,J=3.8Hz,1H),4.93(s,1H),4.32( d,J=5.5Hz,1H),3.81-3.78(m,1H),3.58–3.45(m,2H),2.52(d,J=5.8Hz,1H),2.19(dd,J=13.2,3.3Hz,1H).

[0159] Example 5:

[0160] 2-Amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl-5d)-1,9-dihydro-6H-purine-6-thione (5)

[0161] Step 1 Synthesis of (2S,3S,5R)-5-(2-benzylamino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methyltetrahydrofuran-2-carboxamide (5a)

[0162] To a three-necked flask, compound 2e (1 g, 2 mmol), N-methoxy-N-methylamide hydrochloride (234 mg, 2.4 mmol), DMF (10 mL), and DIEA (520 mg, 4 mmol) were added sequentially. HATU (836 mg, 2.2 mmol) was added at room temperature and allowed to react for 5 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to obtain 5a (1 g).

[0163] LCMS (ESI-MS) m / z: 543.5 [M+H] +

[0164] Step 2 Synthesis of N-(9-((2R,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-formyltetrahydrofuran-2-yl)-6-oxo-6,9-dihydro-1H-purin-2-yl)benzamide (5b)

[0165] To a three-necked flask, add 5a (1.08 g, 2 mmol) and tetrahydrofuran (10 mL) sequentially. Displace the nitrogen atmosphere at room temperature, cool to -78°C, and add 2.5N lithium aluminum tetrahydride solution (1.6 mL, 4 mmol) dropwise. Reaction is continued at the same temperature for 1 h. Methanol is added to quench the reaction, and the mixture is evaporated to dryness. Purification by column chromatography affords 5b (1.4 g).

[0166] LCMS (ESI-MS) m / z: 484.2 [M+H] +

[0167] Step 3: Synthesis of N-(9-((2R, 4S, 5S)-4-((tert-butyldimethylsilyl)oxy)-5-formyltetrahydrofuran-2-yl-5d)-6-oxo-6,9-dihydro-1H-purin-2-yl)benzamide (5c)

[0168] To a sealed tube, add anhydrous pyridine (10 mL), deuterated water (10 mL), and 5b (1.4 g, 2.89 mmol) in sequence. Displace nitrogen from the system and react at 95°C for 15 min, followed by 15 h at room temperature. Repeat this temperature cycle three times. Concentrate to obtain crude 5c, which is used directly in the next step.

[0169] LCMS (ESI-MS) m / z: 485.2 [M+H] +

[0170] Step 4: Synthesis of N-(9-((2R,4S,5R)-4-(((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl-5d)-6-oxo-6,9-dihydro-1H-purin-2-yl)benzamide (5d)

[0171] In a single-necked flask, compound 5c (crude, 2.89 mmol) and anhydrous methanol (5 mL) were added sequentially. The atmosphere was replaced with nitrogen three times. Sodium borohydride (547 mg, 14.4 mmol) was added under an ice-water bath. The reaction was continued at room temperature for 1 h. The system was concentrated and purified by column chromatography to afford compound 5d (800 mg).

[0172] LCMS (ESI-MS) m / z: 487 [M+H] +

[0173] Step 5 Synthesis of 2-amino-9-((2R, 4S, 5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl-5d)-1,9-dihydro-6H-purin-6-one (5e)

[0174] To a sealed tube, compound 5d (800 mg, 1.64 mmol), anhydrous methanol (5 mL), and aqueous ammonia (5 mL) were added sequentially and reacted at 50°C for 5 h. The system was concentrated and purified by column chromatography to afford compound 5e (420 mg).

[0175] LCMS (ESI-MS) m / z: 383.20 [M+H] +

[0176] Step 6 Synthesis of 2-amino-9-((2R, 4S, 5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-2-yl-5d)-1,9-dihydro-6-purine-6-thione (5f)

[0177] Take a single-necked bottle and add pyridine / DMF (6 mL, v / v = 1:1) and sodium hydrosulfide (840 mg, 15 mmol) in sequence. Replace the atmosphere with nitrogen at room temperature and stir for 1 h to obtain intermediate B for later use.

[0178] In a separate single-necked flask, 5e (382 mg, 1 mmol) and pyridine (3 mL) were added sequentially. The atmosphere was replaced with nitrogen at room temperature. Trifluoroacetic anhydride (210 mg, 10 mmol) was added dropwise in an ice-water bath. The reaction was allowed to proceed for 1 h at room temperature. The mixture was then added to Intermediate B and allowed to react for 1 h at room temperature. Acetic acid (15 mmol) was added, and the pyridine was evaporated. Purification by preparative chromatography afforded 5f (50 mg).

[0179] LCMS (ESI-MS) m / z: 399.20 [M+H] +

[0180] Step 7 Synthesis of 2-amino-9-((2R, 4S, 5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl-5d)-1,9-dihydro-6H-purine-6-thione (5)

[0181] In a single-necked bottle, compound 5f (50 mg, 0.16 mmol), DCM (3 mL), and tetrabutylammonium fluoride (83 mg, 0.32 mmol) were added in sequence. The mixture was reacted at room temperature for 1 h, evaporated to dryness, and purified by column chromatography to obtain 5 (25 mg).

[0182] LCMS (ESI-MS) m / z: 285.10 [M+H] +

[0183] 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.03-8.02(md,1H),6.76(s,2H),6.03 (t,J=6.8Hz,1H),5.21(s,1H),4.87(s,1H),4.26–4.25(m,1H),3.49-3.40(m, 2H),2.47–2.45(m,1H),2.16-2.10(m,1H).

[0184] Example 6:

[0185] (2R,3S,5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-2-((S)-hydroxymethyl-d)tetrahydrofuran-3-yl isobutyrate (6)

[0186] Step 1: Synthesis of 2-amino-9-((2R,4S,5R)-5-((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxytetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6-one (6a)

[0187] Compound 2a (8 g, 29.9 mmol) was dissolved in DMF (100 mL), and imidazole (8.13 g, 119.6 mmol) was added. TBSCl (4.96 g, 32.9 mmol) was added portionwise at 0°C, and the reaction mixture was allowed to react at room temperature for 16 hours. LCMS indicated some starting material remained, so additional TBSCl (4.5 g, 29.9 mmol) was added, and the reaction mixture was stirred at room temperature for another 6 hours. LCMS indicated that the starting material had reacted substantially completely. The reaction mixture was poured into ice water, where a large amount of compound precipitated. The mixture was filtered, and the filter cake was washed with water. The filter cake was collected and dried to yield compound 6a (7.0 g).

[0188] LCMS (ESI-MS) m / z: 382.3 (M+H+ ).

[0189] Step 2: Synthesis of (2R, 3S, 5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-3-yl isobutyrate (6b)

[0190] Compound 6a (5.0 g, 13.1 mmol) was dissolved in acetonitrile (100 mL), and DMAP (0.16 g, 1.31 mmol) and Et3N (3.96 g, 39.3 mmol) were added dropwise. Isobutyric anhydride (3.1 g, 19.7 mmol) was then added dropwise. The reaction mixture was allowed to react at room temperature for 16 hours. LCMS showed that the starting materials were essentially reacted. The reaction mixture was poured into ice water, where a large amount of compound precipitated. The filter cake was collected by filtration and dried to yield compound 6b (4.6 g).

[0191] LCMS (ESI-MS) m / z: 452.3 (M+H + ).

[0192] Step 3: Synthesis of (2R, 3S, 5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate (6c)

[0193] Compound 6b (1.7 g, 3.77 mmol) was dissolved in THF (30 mL). 3HF.Et3N (2.4 g, 15.1 mmol) and Et3N (1.5 g, 15.1 mmol) were added dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and reacted for 5 hours. LCMS showed complete reaction. The reaction mixture was poured into ice water and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. A large amount of compound precipitated, which was filtered, collected, and dried to yield compound 6c (1.2 g).

[0194] LCMS (ESI-MS) m / z: 338.2 (M+H + ).

[0195] Step 4: Synthesis of (2S, 3S, 5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-formyltetrahydrofuran-3-ylisobutyric acid (6d)

[0196] Compound 6c (0.95 g, 2.82 mmol) was dissolved in DMSO / THF (40 mL / 40 mL). Dess-Martin periodinane (2.4 g, 5.64 mmol) was added portionwise at 0°C. The reaction mixture was slowly warmed to room temperature and reacted for 1.5 hours. LCMS indicated a small amount of residual starting material. The reaction mixture was poured into ice water and adjusted to pH 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with DCM / MeOH (10 / 1) (150 mL x 3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC to afford compound 6d (300 mg).

[0197] LCMS (ESI-MS) m / z: 336.2 (M+H + ).354.2(M+H + H2O) +

[0198] Step 5: Synthesis of (2R, 3S, 5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-((S)-hydroxymethyl-d)tetrahydrofuran-3-yl isobutyrate (6e)

[0199] Compound 6d (200 mg, 0.6 mmol) was dissolved in MeOH (6 mL), and sodium deuterated borohydride (76 mg, 1.8 mmol) was added portionwise. The reaction mixture was allowed to react at room temperature for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride solution, and water (30 mL) was added. The organic phases were combined with DCM / MeOH = 10 / 1 (60 mL x 3), washed with saturated brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was spin-dried to afford crude compound 6e (90 mg).

[0200] LCMS (ESI-MS) m / z: 339.2 (M+H + ).

[0201] Step 6: Synthesis of (2R, 3S, 5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-2-((S)-hydroxymethyl-d)tetrahydrofuran-3-yl isobutyrate (6)

[0202] Compound 6e (90 mg, 0.27 mmol) was dissolved in pyridine (3 mL). Trifluoromethanesulfonic anhydride (567 mg, 2.7 mmol) was added dropwise at 0°C. The reaction mixture was allowed to react at room temperature for 1 hour. The temperature was then lowered to 0°C, and a solution of NaHS (227 mg, 4.05 mmol) in DMF (3 mL) was added dropwise. The reaction mixture was allowed to react at room temperature for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was directly purified by Prep-HPLC to yield compound 6 (16 mg).

[0203] LCMS (ESI-MS) m / z: 355.2 (M+H + ).

[0204] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.20(s,1H),6.84(s,2H),6.11(dd,J=8. 7,5.8Hz,1H),5.29(d,J=5.8Hz,1H),4.0–3.98(m,1H),3.58–3.54(m,1H),2.83 -2.75(m,1H),2.61–2.54(m,1H),2.41–2.36(m,1H),1.12(d,J=7.0Hz,6H).

[0205] Example 7:

[0206] 4-((2-amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)methyl)phenyl acetate (7)

[0207] Step 1: Synthesis of 2-amino-9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-((tert-butyldimethylsilyl)oxymethyl-d2)tetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (7a)

[0208] Compound 3 (600 mg, 2.1 mmol) was dissolved in DMF (10 mL), and imidazole (720 mg, 10.6 mmol) and TBSCl (960 mg, 6.4 mmol) were added. The reaction solution was stirred at room temperature overnight, precipitated by adding water, filtered, washed with methyl tert-butyl ether, and dried to obtain compound 7a (810 mg).

[0209] LCMS m / z(ESI):514[M+H] +

[0210] Step 2: Synthesis of 4-((2-amino-9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilylalkyl)oxy)methyl-d2)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)methyl)phenyl acetate (7c)

[0211] Compound 7a (880 mg, 1.7 mmol) and DIPEA (670 mg, 5.2 mmol) were dissolved in DMF (10 mL). Compound 7b (628 mg, 3.4 mmol) was added to the reaction solution under nitrogen atmosphere at room temperature. The mixture was stirred at room temperature overnight, quenched with water, extracted with ethyl acetate, concentrated, and passed through a flash column to obtain compound 7c (1.0 g).

[0212] LCMS m / z(ESI):662.4[M+H] +

[0213] Step 3: Synthesis of 4-((2-amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)methyl)phenyl acetate (7)

[0214] Compound 7c (560 mg, 0.85 mmol), TEA (172 mg, 1.7 mmol), and TEA·3HF (274 mg, 1.7 mmol) were dissolved in THF (4 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was concentrated and purified by prep-HPLC to obtain compound 7 (91 mg).

[0215] LCMS m / z(ESI):434.2[M+H] +

[0216] Example 8:

[0217] 4-((2-amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)but-3-en-2-one (8)

[0218] Step 1: Synthesis of 4-((2-amino-9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-((tert-butyldimethylsilylalkyl)oxymethyl-d2)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)but-3-en-2-one (8b)

[0219] Dissolve 7a (130 mg, 0.25 mmol) and sodium acetate (6.6 mg, 0.08 mmol) in tetrahydrofuran / water (5 mL / 1 mL). Add 3-butyn-2-one (8a) (30.6 mg, 0.45 mmol) dropwise under ice. Stir at room temperature for 1 hour. The mixture is concentrated, and the crude product is flash purified to afford compound 8b (140 mg).

[0220] LCMS (ESI-MS) m / z: 582.40 [M+H] + .

[0221] Step 2 Synthesis of 4-((2-amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl-d2)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)but-3-en-2-one (8)

[0222] 8b (100 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL). Et3N(HF)3 (177.3 mg, 1.10 mmol) was added under ice-cooling conditions. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC to yield compound 8 (20 mg).

[0223] LCMS (ESI-MS) m / z: 354.20 [M+H] + .

[0224] Example 9:

[0225] (2R,3S,5S)-5-(6-(allyldisulfanyl)-2-amino-9H-purin-9-yl)-2-(hydroxymethyl-d2)tetrahydrofuran-3-ol (9)

[0226] Compound 3 (400 mg, 1.4 mmol) was dissolved in ethanol (50 mL), and allicin 9a (1.1 g, 7.0 mmol) and phosphate buffer (100 mL) were added sequentially. The mixture was stirred at room temperature for 48 h, concentrated, extracted with DCM, concentrated, and subjected to preparative HPLC to obtain compound 9 (50 mg).

[0227] LCMS (ESI-MS) m / z: 358.2 (M+H + ).

[0228] Example 10:

[0229] (2R,3S,5R)-5-(2-amino-6-thioxy-1H-purin-9-yl)-2-[dideuterio(hydroxy)methyl]tetrahydrofuran-3-yl bis{[(2,2-dimethylpropionyl)oxy]methyl}phosphate (10)

[0230] Step 1: Synthesis of 2-amino-9-((2R,4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl-d2)-4-hydroxytetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (10a)

[0231] Compound 3 (2.9 g, 10.0 mmol) and imidazole (680 mg, 10.0 mmol) were dissolved in DMF (50 mL). TBSCl (1.7 mg, 11.0 mmol) was added. The reaction mixture was stirred in an ice bath, allowed to warm to room temperature, and stirred for 4 hours. The reaction solution was added dropwise to stirred ice water (200 mL). The compound precipitated, was filtered, and dried under reduced pressure to obtain compound 10a (2.8 g).

[0232] MS m / z(ESI):400.2[M+1] +

[0233] Step 2: Synthesis of (2R,3S,5R)-5-(2-amino-6-thioxy-1H-purin-9-yl)-2-(1,1-dideuterio-3,3,4,4-tetramethyl-2-oxo-3-silapentan-1-yl)tetrahydrofuran-3-yl bis{[(2,2-dimethylpropionyl)oxy]methyl}phosphate (10c)

[0234] Compound 10a (1.0 g, 2.5 mmol) was dissolved in pyridine (20 mL), and 10b (1.1 g, 3.3 mmol) and BOPCl (0.97 g, 3.8 mmol) were added sequentially. The mixture was allowed to react at room temperature overnight. After evaporation of most of the pyridine, the mixture was diluted with water, extracted with dichloromethane, concentrated, and purified on a flash column to afford compound 10c (88 mg).

[0235] MS m / z(ESI):708.2[M+1] +

[0236] Step 3: (2R, 3S, 5R)-5-(2-amino-6-thioxy-1H-purin-9-yl)-2-[dideuterio(hydroxy)methyl]tetrahydrofuran-3-ylbis{[(2,2-dimethylpropionyl)oxy]methyl}phosphate (10)

[0237] Compound 10c (88 mg, 0.12 mmol) was dissolved in THF (8 mL). 3HF.Et3N (77 mg, 0.48 mmol) and Et3N (49 mg, 0.48 mmol) were added dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and reacted for 5 hours. LCMS showed complete reaction. The reaction mixture was poured into water and adjusted to pH 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, concentrated, and purified by preparative column chromatography to afford the desired product 10 (21 mg).

[0238] LCMS (ESI-MS) m / z: 594.2 (M+H+).

[0239] Example 11:

[0240] Isopropyl (((2R,3S,5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl-d2)tetrahydrofuran-3-yl)oxy)(phenoxy)phosphoryl)-L-alaninate (11)

[0241] Step 1: Synthesis of isopropyl (((2R,3S,5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl-d2)tetrahydrofuran-3-yl)oxy(phenoxy)phosphoryl)-L-alaninate (11b)

[0242] 10a (500 mg, 1.3 mmol) was dissolved in anhydrous THF-NMP (10 mL, 1:1 v / v). A 1.0 M solution of tert-butylmagnesium chloride in THF (2.9 mL, 2.9 mmol) was slowly added dropwise under ice-water cooling. After the addition was complete, the mixture was warmed to room temperature and stirred for 30 minutes. A solution of 11a (0.73 g, 1.6 mmol) in THF was then added, and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. Compound 11b (330 mg) was obtained by flash column purification.

[0243] MS m / z(ESI):669.2[M+1] +

[0244] Step 2: Synthesis of isopropyl (((2R,3S,5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl-d2)tetrahydrofuran-3-yl)oxy)(phenoxy)phosphoryl)-L-alaninate (11)

[0245] Compound 11c (330 mg, 0.49 mmol) was dissolved in THF (8 mL). 3HF.Et3N (322 mg, 2.0 mmol) and Et3N (200 mg, 2.0 mmol) were added dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and allowed to react for 5 hours. LCMS indicated complete reaction. The reaction mixture was poured into water and adjusted to pH 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, concentrated, and purified by preparative column chromatography to afford the desired product 11 (87 mg).

[0246] LCMS (ESI-MS) m / z: 555.2 (M+H+).

[0247] Biological activity test

[0248] Example 1: In vivo efficacy experiment of the compound of the example in mice (I)

[0249] 1. Dosage regimen

[0250] Under sterile conditions, MC38 mouse colon cancer cells in the logarithmic growth phase were digested into single cells and then transplanted subcutaneously on the right side of the back of C57BL / 6 mice. Each mouse was inoculated with 1×10 6 After inoculation, the tumor was grown to 100 mm3. 3 ), the mice were randomly divided into two groups, each with 8 mice for drug efficacy experiments, and the negative control group was given an equal amount of solvent for a total of 14 days of observation. The specific design is shown in Table 1.

[0251] Table 1: In vivo efficacy experimental plan of compounds

[0252] 2. Experimental Animals

[0253] C57BL / 6 mice, SPF grade, 6-8 weeks old, female, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., license number SCXK (Shanghai) 2017-0011.

[0254] 3. Trial Drugs

[0255] Example Compound 1.

[0256] 4. Drug configuration

[0257] An appropriate amount of compound was weighed, dissolved in 5% dimethyl sulfoxide (DMSO), vortexed and sonicated, and then added with normal saline for injection and sonicated to prepare a 0.3 mg / mL solution.

[0258] 5. Medication

[0259] The specific administration is carried out according to the administration plan.

[0260] 6. Experimental results and conclusions

[0261] The tumor growth inhibition rate of Example Compound 1 at a dosage of 3 mg / kg was greater than 80%. The results showed that the Example of the present invention could effectively inhibit tumor growth in the mouse colon cancer MC38 model.

[0262] Example 2: In vivo efficacy experiment of the compound of the example in mice (II)

[0263] 1. Dosage regimen

[0264] Under sterile conditions, human lung cancer A549 cells in the logarithmic growth phase were digested into single cells and then transplanted subcutaneously on the right side of the back of Balb / c nude mice. Each mouse was inoculated with 1×10 7 After inoculation, the tumor was grown to 80 mm3. 3 ), the mice were randomly divided into two groups, each with 8 mice for the efficacy test, and the negative control group was given an equal amount of solvent for a total of 21 days of observation. The specific design is shown in Table 2.

[0265] Table 2: In vivo efficacy experimental plan of compounds

[0266] 2. Experimental Animals

[0267] Balb / c nude mice, SPF grade, 6-8 weeks old, female, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., license number SCXK (Shanghai) 2017-0011.

[0268] 3. Trial Drugs

[0269] Example Compound 1.

[0270] 4. Drug configuration

[0271] An appropriate amount of compound was weighed, dissolved in 5% dimethyl sulfoxide (DMSO), vortexed and sonicated, and then added with normal saline for injection and sonicated to prepare a 0.5 mg / mL solution.

[0272] 5. Medication

[0273] The specific administration is carried out according to the administration plan.

[0274] 6. Experimental results and conclusions

[0275] The tumor growth inhibition rate of Example Compound 1 at a dosage of 5 mg / kg was greater than 70%. The results showed that the Example of the present invention had a good tumor inhibition effect on the A549 human lung cancer model.

[0276] Example 3: In vivo efficacy experiment of the compound of the example in mice (III)

[0277] 1. Dosage regimen

[0278] Under sterile conditions, human lung cancer PC9 cells in logarithmic growth phase were digested into single cells and then transplanted subcutaneously on the right side of the back of Balb / c nude mice. Each mouse was inoculated with 1×10 7 After inoculation, the tumor was grown to 50 mm3. 3 ), the mice were randomly divided into two groups, each with 8 mice for drug efficacy experiments, and the negative control group was given an equal amount of vehicle for observation for a total of 14 days. The specific design is shown in Table 3.

[0279] Table 3: In vivo efficacy experimental plan of compounds

[0280] 2. Experimental Animals

[0281] Balb / c nude mice, SPF grade, 6-8 weeks old, female, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., license number SCXK (Shanghai) 2017-0011.

[0282] 3. Trial Drugs

[0283] Example Compound 1.

[0284] 4. Drug configuration

[0285] An appropriate amount of Example Compound 1 was weighed and dissolved in 5% dimethyl sulfoxide (DMSO) and vortexed and sonicated. Then, physiological saline for injection was added and sonicated to prepare a 0.5 mg / mL solution.

[0286] 5. Medication

[0287] The specific administration is carried out according to the administration plan.

[0288] 6. Experimental results and conclusions

[0289] The tumor growth inhibition rate of Example Compound 1 at a dosage of 5 mg / kg was greater than 80%. The results showed that the Example of the present invention had a good tumor inhibition effect on the PC9 human lung cancer model.

[0290] Example 4: Pharmacokinetic study of the compound of the example in mice

[0291] 1. Experimental Animals

[0292] ICR mice, SPF grade, were purchased from Hunan Slake Jingda (weight 29-37 g, sex: male)

[0293] 2. Preparation of dosing solution

[0294] Preparation of intravenous administration solution of Example Compound 3: Example Compound 3 was weighed and dissolved in dimethyl sulfoxide to prepare a stock solution, which was then diluted with phosphate buffer containing 10% PEG400 to prepare the desired concentration for administration.

[0295] The intravenous administration solution of Example Compound 4 was prepared in the same manner.

[0296] 3. Operation process

[0297] Male ICR mice were randomly divided into groups of 3. Mice were intravenously administered with 15 μM / kg of the example compound. Orbital blood was collected 2, 5, 10, 30, and 60 minutes after administration. After pretreatment, the plasma concentrations of the example compound and 6-thio-dG metabolite 6-TG were determined by LC-MS / MS.

[0298] The data were processed using the non-compartmental model of WinNonlin 8.3 software to calculate the pharmacokinetic parameters of mice after administration, including the maximum plasma concentration (C max , using the measured value); time to reach the maximum plasma concentration (T max , using the measured value); area under the curve (AUC, calculated using the trapezoidal method), AUC 0-∞ =AUC 0- t +C t / k e , C t is the blood drug concentration at the last measurable time point, k e is the elimination rate constant; elimination half-life t 1 / 2 =0.693 / k e .

[0299] Excel software was used to calculate the mean and standard deviation of the blood drug concentration of each sample.

[0300] 4. Experimental results and conclusions

[0301] After a single intravenous administration of 15 μM / kg of Example Compound 3, Example Compound 4, and 6-thio-dG, the pharmacokinetic parameters of their metabolite 6TG were determined, as shown below.

[0302] All documents mentioned herein are incorporated by reference as if each were individually incorporated by reference. Furthermore, it should be understood that the preferred embodiments described above are merely illustrative of the technical concepts and features of the present invention, intended to facilitate understanding of the present invention by those skilled in the art, and are not intended to limit the scope of the present invention. Any equivalent variations or modifications made in accordance with the spirit and substance of the present invention are intended to fall within the spirit and scope of this disclosure.

Claims

1. A compound having a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof, It is characterized in that R 1 , R 2 , R 3 or R 4 each independently is hydrogen or deuterium; R 5 is -OH, or -OC(=O)C 1-5 Alkyl; wherein, when R 5 When it is -OH, R 1 , R 2 , R 3 or R 4 Not at the same time hydrogen; R 6 for R 7 or R 8 Each independently represents -OH, -OC 1-5 Alkyl, -NR a R b or -OAr, the -OC 1-5 The alkyl group is optionally substituted with one or more -OC(=O)C 1-5 Alkyl substituted, Ar is a 5-6 membered aromatic group; R a or R b Each is independently -H or -C 1-5 Alkyl, the -C 1-5 The alkyl group is optionally substituted with one or more -C(=O)OC 1-5 Alkyl substitution; L is a bond, -S-, -O-, -C 1-3 Alkylene-, -SC 1-3 Alkylene- or -OC 1-3 Alkylene-, the-C 1- 3 Alkylene-, -SC 1-3 Alkylene- or -OC 1-3 Alkylene-optionally substituted with one or more -C 1-3 Alkyl substitution; R 9 For -C 2-6 alkenyl or 5-6 membered aryl, the -C 2-6 The alkenyl or 5-6 membered aryl group is optionally substituted with one or more -OC(=O)C 1-5 Alkyl or -C(=O)C 1-5 Alkyl substitution; R 10 H or -C(=O)C 1-5 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 or R 2 is deuterium; or R 3 is deuterium; or R 4 for deuterium; Preferably, when R 1 or R 2 When it is deuterium, R 3 and R 4 are hydrogen; or when R 3 or R 4 When it is deuterium, R 1 and R 2 All are hydrogen.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: R 5 is -OH, or -OC(=O)C 1-4 Alkyl; preferably, R5 is -OH, R 7 or R 8 Each independently is -OC 1-3 Alkyl, -NR a R b or -OAr, the -C 1-3 The alkyl group is optionally substituted with one or more -OC(=O)C 1-5 alkyl substituted, Ar is a 6-membered aromatic group; preferably, R 7 or R 8 Each independently -NR a R b or -OPh; or R a or R b Each is independently -H or -C 1-3 Alkyl, the -C 1-3 The alkyl group is optionally substituted with one or more -C(=O)OC 1-3 Alkyl substituted; preferably, R a or R b Each independently is -H or 4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that: R 10 H or -C(=O)C 1-3 Alkyl, preferably, R 10 is H; or L is a bond, -S-, -C 1-3 Alkylene- or -SC 1-3 Alkylene, the -C 1-3 Alkylene- or -SC 1-3 The alkylene group is optionally substituted with one or more -C 1-3 Alkyl substituted; preferably, L is a bond, -S-, -C 1-3 Alkylene- or -SC 1-3 Alkylene; more preferably, L is a bond, -S-, -CH2- or -S-CH2-.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: R 9 For -C 2-4 alkenyl or 6-membered aryl, the -C 2-4 The alkenyl or 6-membered aryl group is optionally substituted with one or more -OC(=O)C 1-3 Alkyl or -C(=O)C 1-3 Alkyl substituted; preferably, R 9 is vinyl or phenyl, the vinyl or phenyl being optionally substituted by one or more -OC(=O)C 1-3 Alkyl or -C(=O)C 1-3 Alkyl substituted; more preferably, R 9 for 6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that: It has a structure shown in formula (I-1), Among them, R 1 , R 2 , R 3 or R 4 each independently is hydrogen or deuterium; R 5 -OH or -OC(=O)C 1-5 Alkyl, preferably, R 5 -OH or -OC(=O)C 1-3 Alkyl, more preferably, R5 is -OH or When R 5 When it is -OH, R 1 , R 2 , R 3 or R 4 Not at the same time as hydrogen.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following compounds:

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following compounds:

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is an acid addition salt of the compound represented by formula (I).

10. A pharmaceutical composition, characterized in that It comprises the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or additives.

11. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 10 in the preparation of an anticancer drug; preferably, the cancer includes gastric cancer, colorectal cancer, breast cancer, sarcoma, melanoma, lymphoma, pancreatic cancer, lung cancer or brain cancer.

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