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 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 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 compound having a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0007] R 1 is hydroxyl or -OC(=O)R 3 ;

[0008] R 7 is hydroxyl or -OC(=O)R 2 ;

[0009] R 2 and R 3 Each independently is -C 1-10 Alkyl, the -C 1-10 Alkyl is optionally substituted with one or more -NH2;

[0010] R 8 for

[0011] 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;

[0012] 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;

[0013] R 10 -H, -C 1-10 Alkyl or -C(=O)-C 1-10 alkyl;

[0014] X 1 and X 2 are independently hydrogen or halogen; when R 7 When X is hydroxyl, 1 and X 2 Not at the same time it is F.

[0015] In some embodiments of the present invention, R 2 and R 3 Each independently CR 4 R 5 R 6 , R 4 、R 5 and R 6 are independently -H, -C 1-3 Alkyl or -NH2, preferably, R 4 、R 5 and R 6 Each independently is -H, methyl, isopropyl or -NH2, more preferably, R 2 and R3 are each independently isopropyl, tert-butyl or

[0016] 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-.

[0017] 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,

[0018] In some embodiments of the present invention, R 10 -H or -C(=O)-C 1-5 Alkyl, preferably, R 10 is -H.

[0019] In some embodiments of the present invention, X 1 and X 2 Each independently is -H or -F, preferably, X 1 and X 2 All are -H; or X 1 and X 2 All are -F; or X 1 -H,X 2 is -F.

[0020] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof has a structure of formula (I-1).

[0021] where R 1is hydroxyl or -OC(=O)R 3 ;

[0022] R 2 and R 3 Each independently is -C 1-10 alkyl.

[0023] In some embodiments of the present invention, R 2 and R 3 Each is independently -CHR 4 R 5 , R 4 、R 5 are each independently -H or -C 1-3 alkyl.

[0024] In some embodiments of the present invention, R 4 and R 5 All -C 1-3 alkyl.

[0025] In some embodiments of the present invention, R 4 and R 5 All are methyl.

[0026] In some embodiments of the present invention, the compounds of the present invention or pharmaceutically acceptable salts thereof include the following compounds or pharmaceutically acceptable salts thereof:

[0027] In some embodiments of the present invention, the pharmaceutically acceptable salts of the compounds of the present invention are acid addition salts.

[0028] The second aspect of the present invention provides a pharmaceutical composition comprising the compound of the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or additives.

[0029] The present invention also provides a use of the compound of the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect of the present invention 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.

[0030] Definition and Description

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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."

[0037] Unless otherwise specified, the compounds herein encompass within their scope the compound, its pharmaceutically acceptable salts, and its isotopic derivatives. The compounds of the present invention also encompass within their scope stereoisomers, polymorphs, solvates, and prodrugs.

[0038] The compounds of the present invention may exist with different points of hydrogen attachment, termed tautomers.

[0039] 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.

[0040] The compounds of the present invention can exist in the form of optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, racemates or mixtures of racemates. All possible isomers, stereoisomers and mixtures thereof of the compounds of formula (I) are also within the scope of the present invention.

[0041] The term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are replaced by an isotope thereof (an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature). Examples of isotopes include, but are not limited to, isotopes of hydrogen (e.g. 2 H. 3 H), carbon isotopes (e.g. 11 C. 13 C and 14 C), isotopes of fluorine (e.g. 18 F), nitrogen isotopes (e.g. 13 N and 15 N), oxygen isotopes (e.g. 15 O. 17 O and 18 O). The compounds of the present invention include isotopic derivatives of the compounds of the present invention.

[0042] The term "C n -C m "With C n-m Used interchangeably to mean having n to m carbon atoms.

[0043] 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.

[0044] The term "halo" or "halogen" refers to chlorine, bromine, fluorine and iodine.

[0045] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and typically having 2 to 20 carbon atoms. For example, "C 2-8 "Alkenyl" contains 2-8 carbon atoms. Alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0046] The term "alkylacyl" refers to -C(=O)-alkyl, for example, methylacyl, ethylacyl, etc. The term "C 1- 3 alkylacyl" refers to -C(=O)-C 1-3 alkyl.

[0047] The term "carboxylate" refers to -C(O)O-alkyl, -C(O)O-cycloalkyl, alkyl-C(O)O- or cycloalkylC(O)O-, wherein alkyl and cycloalkyl are as defined above. 1-3 "Carboxylate" refers to -C(O)OC 1- 3 alkyl or -C 1-3 Alkyl-C(O)O-.

[0048] 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.

[0049] The aromatic ring of "aryl" or "heteroaryl" can be substituted at one or more ring positions with substituents as described above, such as halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, hydroxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, cyano, amino (including alkylamino, dialkylamino) and alkylamino. The invention also includes but is not limited to: alkyl, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, hydroxythiocarbonyl, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl, or aromatic or heteroaromatic groups, wherein the aryl group can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic rings (e.g., tetralin).

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to a conventional non-toxic salt formed by reacting the active compound of the present invention with an inorganic acid or an organic acid.

[0051] The pharmaceutically acceptable salts of the present invention can be prepared by reacting with the 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] The pharmaceutical composition 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.

[0057] Pharmacological experiments have shown that the compounds or pharmaceutical compositions provided by the present invention can be used to treat cancer, including but not limited to gastric cancer, colorectal cancer, breast cancer, sarcoma, melanoma, lymphoma, pancreatic cancer, lung cancer, and brain cancer.

[0058] The abbreviations used in the present invention have the conventional meanings in the art. For example, the following abbreviations have the following meanings: DETAILED DESCRIPTION

[0059] Compound Preparation Examples

[0060] Example 1:

[0061] Synthesis of (2R,3S,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl isobutyrate (1)

[0062] Compound 1a (500 mg, 1.77 mmol) was dissolved in acetonitrile (10 mL). TEA (550 μL, 3.89 mmol), isobutyric anhydride (650 μL, 3.89 mmol), and DMAP (24 mg, 0.2 mmol) were added sequentially at room temperature and stirred overnight. LCMS indicated the formation of product. The reaction was quenched with MeOH and dried under reduced pressure. The residue was purified by RP-HPLC to yield compound 1 (60 mg).

[0063] LCMS (ESI-MS) m / z: 424.0 (M+H + ).

[0064] 1 H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.09(s,1H),6.85(s,2H),6.16– 6.12(m,1H),5.34–5.31(m,1H),4.28–4.16(m,3H),2.98–2.90(m,1H),2.63–2.44(m,3H),1.13–1.05(m,12H).

[0065] Example 2:

[0066] Synthesis of (2R,3S,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate (2)

[0067] Compound 1 (150 mg, 0.35 mmol) was suspended in acetonitrile (3 mL) / H₂O (0.5 mL) and cooled to 0°C. DIEA (184 μL, 1.06 mmol) and LiBr (92 mg, 1.06 mmol) were added sequentially, and the mixture was stirred at room temperature for 4 days. LCMS indicated the formation of product. The reaction solution was directly subjected to RP-HPLC to obtain compound 2 (15 mg).

[0068] LCMS (ESI-MS) m / z: 353.9 (M+H + ).

[0069] 1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.13(s,1H),6.91(s,2H),6.13–6.09(m,1H),5.31–5.30(m,1H),5.16(brs,1H) ,4.01–3.98(m,1H),3.59–3.58(m,2H),2.82–2.78(m,1H),2.60–2.55(m,1H),2.42–2.37(m,1H),1.13–1.11(m,6H).

[0070] Example 3:

[0071] Synthesis of (2R,3S,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl pivalate (3)

[0072] Step 1: Synthesis of 2-amino-9-((2R,4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxytetrahydrofuran-2-yl)-1,9-dihydro-6-purine-6-thione (3a)

[0073] Compound 1a (283 mg, 1.0 mmol) and imidazole (68 mg, 1.0 mmol) were dissolved in DMF (3 mL). TBSCl (165 mg, 1.1 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 then added dropwise to stirred ice water (20 g). A solid precipitated, which was filtered and dried under reduced pressure to obtain compound 3a (281 mg).

[0074] MS m / z(ESI):398.2[M+1] +

[0075] Step 2: Synthesis of (2R,3S,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-3-yl pivalate (3c)

[0076] Compound 3a (281 mg, 0.71 mmol) and DMAP (32 mg, 0.28 mmol) were dissolved in DMF (3 mL), and compound 3b (528 mg, 2.84 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction solution was added dropwise to ice water (20 g). A solid precipitated and was filtered. The filter cake was washed with petroleum ether (3 mL x 3) and dried under reduced pressure to obtain compound 3c (225 mg).

[0077] MS m / z(ESI):482.3[M+1] +

[0078] Step 3: Synthesis of (2R,3S,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl pivalate (3)

[0079] Compound 3c (225 mg, 0.47 mmol) was mixed with THF (4 mL), followed by the addition of triethylamine hydrofluoride (193 mg, 1.17 mmol), and the resulting mixture was stirred at room temperature overnight. The resulting reaction solution was directly separated by preparative HPLC and lyophilized to obtain compound 3 (108.1 mg).

[0080] MS m / z(ESI):368.2[M+1] +

[0081] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.18(s,1H),6.84(s,2H),6.13–6.07(m,1H),5.30–5.26( m,1H),3.99–3.96(m,1H),3.59–3.56(m,3H),2.84–2.77(m,1H),2.42–2.34(m,1H),1.17(s,9H).

[0082] Example 4:

[0083] Synthesis of 4-((2-amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)methyl)phenyl acetate (4)

[0084] 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 (4a)

[0085] Compound 1a (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 mixture was stirred at room temperature overnight. Water was added to precipitate a solid, which was filtered, washed with methyl tert-butyl ether, and dried to obtain compound 4a (440 mg).

[0086] LCMS m / z(ESI):512[M+H] +

[0087] Step 2: Synthesis of 4-(((2-amino-9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)methyl)phenyl acetate (4c)

[0088] Compound 4a (440 mg, 0.86 mmol) and DIPEA (336 mg, 2.58 mmol) were dissolved in DMF (10 mL). Compound 4b (317 mg, 1.72 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 EA, concentrated, and passed through a flash column to obtain compound 4c (560 mg).

[0089] LCMS m / z(ESI):660.4[M+H] +

[0090] Step 3: Synthesis of 4-(((2-amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)methyl)phenylacetate (4)

[0091] Compound 4c (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 4 (75 mg).

[0092] LCMS m / z(ESI):432.2[M+H] +

[0093] 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.52–7.45(m,2H),7.05–6.98(m,2H),6.60(s,2H),6.22–6.15(m,1H),5.24(d,J=4.0Hz,1H),4.92(t,J=5.6 Hz,1H),4.58–4.49(m,2H),4.33(dt,J=6.5,3.2Hz,1H),3.83–3.77(m,1H ),3.59–3.43(m,2H),2.61-2.54(m,1H),2.23(s,3H),2.21–2.17(m,1H).

[0094] Example 5:

[0095] Synthesis of 4-((2-amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)but-3-en-2-one (5)

[0096] Step 1: Synthesis of 4-((2-amino-9-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)but-3-en-2-one (5b)

[0097] Dissolve 4a (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 (5a) (30.6 mg, 0.45 mmol) dropwise under ice-cooling. Stir at room temperature for 1 hour. The mixture is concentrated, and the crude product is flash purified to afford 5b (130 mg).

[0098] LCMS (ESI-MS) m / z: 580.40 [M+H] + .

[0099] Step 2 Synthesis of 4-((2-amino-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)thio)but-3-en-2-one (5)

[0100] 5b (130 mg, 0.22 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 was concentrated, and the crude product was purified by preparative HPLC to yield 5 (30 mg, a mixture of Z and E configurations).

[0101] LCMS (ESI-MS) m / z: 352.20 [M+H] + .

[0102] 1H NMR (400MHz, DMSO-d6) δ8.87(d,J=16.4Hz,1H),8.29(s,1H),6.86(s,2H),6.65(d,J=16.4Hz,1H),6.23(t,J=6.8Hz,1H),5.32(s,1H),4.9 7(s,1H),4.37(dt,J=6.0,3.2Hz,1H),3.83(td,J=4.4,2.8Hz,1H),3.60–3.49(m,2H),2.65–2.57(m,1H),2.30(s,3H),2.27–2.25(m,1H).

[0103] Example 6:

[0104] Synthesis of (2R,3S,5S)-5-(6-(allyldisulfanyl)-2-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol (6)

[0105] Compound 1a (200 mg, 0.7 mmol) was dissolved in ethanol (50 mL), and allicin 6a (567 mg, 3.5 mmol) and phosphate buffer (50 mL) were added sequentially. The mixture was stirred at room temperature for 48 h, concentrated, extracted with DCM, concentrated, and prepared by HPLC to give compound 6 (30 mg).

[0106] LCMS (ESI-MS) m / z: 356.2 (M+H + ).

[0107] 1 H NMR(400MHz, DMSO-d6)δ8.21(s,1H),6.67(s,2H),6.21(dd,J=7.6,6.1Hz,1H),5.92–5.80(m,1H),5.26(s,1H),5.16–5.06(m,2H),4.92(s,1 H),4.35(dd,J=5.9,3.0Hz,1H),3.81(td,J=4.6,2.8Hz,1H),3.61(d,J=7.4Hz,2H),3.58–3.46(m,2H),2.56-2.63(m,1H),2.19-2.25(m,1H).

[0108] Example 7:

[0109] ((2R,3S,5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methyl isobutyrate (7)

[0110] Compound 1 (0.8 g, 1.9 mmol) was dissolved in ACN (16 mL) / H₂O (4 mL), followed by the addition of DIEA (1.0 mL, 5.7 mmol) and LiBr (500 mg, 5.7 mmol). After stirring at room temperature for 4 days, LCMS indicated the formation of product. The reaction solution was directly subjected to RP-HPLC and lyophilized to afford compound 7 (30 mg).

[0111] LCMS (ESI-MS) m / z: 354.2 (M+H + ).

[0112] 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.03(s,1H),7.04(brs,2H),6.11(m,1H),5.62(m,1H),4.39(m,1H),4 .23–4.09(m,2H),3.95(m,1H),2.65–2.58(m,1H),2.30–2.26(m,1H),2.00–1.95(m,1H),1.27–1.03(m,6H).

[0113] Example 9:

[0114] 2-Amino-9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,9-dihydro-6-purine-6-thione (9d) and (2R,3R,4R,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate (9)

[0115] Step 1: Synthesis of 2-amino-9-((2R, 3R, 4R, 5R)-4-((tert-butyldimethylsilyl)oxy)-5-((tert-butyldimethylsilyl)oxymethyl)-3-fluorotetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6-one (9b)

[0116] Compound 9a (500 mg, 1.7 mmol) was dissolved in DMF (5 mL), followed by the addition of imidazole (1.2 g, 17 mmol) and TBSCl (1.3 g, 8.5 mmol). The reaction was allowed to react overnight at room temperature. LCMS indicated the product as the primary product. The reaction solution was diluted with EA and washed three times with a saturated aqueous NaCl solution. The organic phase was dried over anhydrous NaSO, filtered, and the filtrate was directly spin-dried. The crude product was used directly in the next reaction.

[0117] LCMS (ESI-MS) m / z: 514.4 (M+H + ).

[0118] Step 2: Synthesis of 2-amino-9-((2R, 3R, 4R, 5R)-4-((tert-butyldimethylsilyl)oxy)-5-((tert-butyldimethylsilyl)oxymethyl)-3-fluorotetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (9c)

[0119] Compound 9b (crude, 1.7 mmol) was dispersed in toluene (34 mL), and 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphino-2,4-sulfide (824 mg, 2.0 mmol) was added. The mixture was reacted at 100°C for 4 h. LCMS showed the product as the primary product. The reaction solution was directly dried and purified by column chromatography to obtain compound 9c (700 mg).

[0120] LCMS (ESI-MS) m / z: 530.4 (M+H + ).

[0121] Step 3 Synthesis of 2-amino-9-((2R, 3R, 4R, 5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,9-dihydro-6-purine-6-thione (9d)

[0122] Compound 9c (0.7 g, 1.3 mmol) was dissolved in DCM (20 mL), followed by the addition of TREAT-HF (1.3 mL, 7.9 mmol) and Et3N (1.1 mL, 7.9 mmol). The mixture was stirred at room temperature overnight. LCMS indicated the formation of product. The reaction mixture was spin-dried and directly subjected to RP-HPLC preparation and lyophilized to afford compound 9d (100 mg).

[0123] LCMS (ESI-MS) m / z: 302.1 (M+H + ).

[0124] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.13(s,1H),6.88(brs,2H),6.03–5.98(m,1H),5.68–5.66(m,1H),5.33 –5.18(m,1H),5.16–5.13(m,1H),4.40–4.34(m,1H),3.94–3.92(m,1H),3.77–3.73(m,1H),3.62–3.56(m,1H).

[0125] Step 4: Synthesis of 2-amino-9-((2R, 3R, 4R, 5R)-5-((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)-1,9-dihydro-6-purine-6-thione (9e)

[0126] Compound 9d (90 mg, 0.3 mmol) was dissolved in DMF (2 mL), followed by the addition of imidazole (24 mg, 0.36 mmol) and TBSCl (45 mg, 0.3 mmol). The mixture was allowed to react at room temperature for 3 h. LCMS indicated the product as the primary product. The reaction solution was diluted with EA and washed three times with brine. The organic phase was dried over anhydrous NaSO, filtered, and the filtrate was directly spin-dried. The crude product was used directly in the next reaction.

[0127] LCMS (ESI-MS) m / z: 416.3 (M+H + ).

[0128] Step 5: Synthesis of (2R, 3R, 4R, 5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-2-((tert-butyldimethylsilyl)oxy)methyl)-4-fluorotetrahydrofuran-3-yl isobutyrate (9f)

[0129] Compound 9e (83 mg, 0.2 mmol) was dispersed in ACN (5 mL), followed by the addition of TEA (28 μL, 0.2 mmol), isobutyric anhydride (33 μL, 0.2 mmol), and DMAP (1.2 mg, 0.01 mmol). The reaction was allowed to react overnight at room temperature. LCMS showed the product as the primary product. The reaction solution was quenched with MeOH and then directly spin-dried to dryness. The crude product was used directly in the next reaction.

[0130] LCMS (ESI-MS) m / z: 486.3 (M+H + ).

[0131] Step 6: Synthesis of (2R, 3R, 4R, 5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate (9)

[0132] Compound 9f (crude, 0.2 mmol) was dissolved in DCM (5 mL), followed by the addition of TREAT-HF (98 μL, 0.6 mmol) and Et3N (83 μL, 0.6 mmol). The mixture was stirred at room temperature overnight. LCMS indicated the formation of product. The reaction mixture was spin-dried and directly subjected to RP-HPLC preparation and lyophilized to afford compound 9 (17 mg).

[0133] LCMS (ESI-MS) m / z: 372.2 (M+H + ).

[0134] 1 H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.16(s,1H),6.91(brs,2H),6.09–6.04(m,1H),5.75–5.60(m,1H),5.43 –5.38(m,1H),5.33–5.30(m,1H),4.22–4.19(m,1H),3.72–3.59(m,2H),2.70–2.73(m,1H),1.14–1.13(m,6H).

[0135] Example 10:

[0136] 2-Amino-9-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (10f) and (2R,3R,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate (10)

[0137] Step 1: Synthesis of 6-chloro-N,N,9-tris(trimethylsilyl)-9H-purin-2-amine (10b)

[0138] Compound 10a (7 g, 41 mmol) was dissolved in DCE (40 mL), and (NH4)2SO4 (80 mg, 0.6 mmol) and HMDS (48 mL, 230 mmol) were added in sequence. The mixture was reacted at 100°C for 16 h, then cooled to room temperature and used directly in the next step.

[0139] LCMS (ESI-MS) m / z: 386.2 (M+H + ).

[0140] Step 2 Synthesis of (2R, 3R, 5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-((benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-ylbenzoate (10d)

[0141] To a solution of compound 10b (crude, 41 mmol) in DCE (40 mL) were added 10c (7.8 g, 17.1 mmol) and TMSOTf (6 mL, 33.2 mmol) in sequence. The mixture was reacted at 100°C for 8 h. LCMS indicated the formation of the product. The reaction was quenched with a saturated aqueous solution of NaHCO₃. After stirring for 30 min, the mixture was filtered and the filtrate was extracted with EA. The organic phase was dried and spin-dried. The product was then washed off with PE / EA (9:1 to 7:3) and spin-dried to afford compound 10d (1.1 g).

[0142] LCMS (ESI-MS) m / z: 530.2 (M+H + ).

[0143] Step 3 Synthesis of (2R, 3R, 5R)-5-(2-amino-6-thioxy-1,6-dihydro-9H-purin-9-yl)-2-(benzoyloxy)methyl)-4,4-difluorotetrahydrofuran-3-ylbenzoate (10e)

[0144] Compound 10d (550 mg, 1 mmol) was dissolved in DMF (10 mL), cooled to 0°C, and NaSH (340 mg, 6 mmol) was added. The reaction was allowed to react at 0°C for 2 h. LCMS showed the product as the primary product. The reaction was neutralized with 10% HOAc and directly subjected to RP-HPLC preparation. Freeze-dried to afford compound 10e (200 mg).

[0145] LCMS (ESI-MS) m / z: 528.2 (M+H + ).

[0146] Step 4 Synthesis of 2-amino-9-((2R, 4R, 5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-thione (10f)

[0147] Compound 10e (400 mg, 0.4 mmol) was dispersed in MeOH (40 mL) and MeONa solution (1.6 mL, 1 M, 1.6 mmol) was added dropwise at room temperature. The mixture was allowed to react for 1.5 h. LCMS indicated the product as the primary product. The reaction mixture was neutralized with 10% HOAc, dried by vortexing, and used directly in the next step.

[0148] LCMS (ESI-MS) m / z: 320.1 (M+H + ).

[0149] 1H NMR (400MHz, DMSO-d6) δ12.21(s,1H), δ8.61(s,1H),7.72–7.69(m,1H),6.67( brs,2H),6.43(brs,1H),5.43(brs,1H),4.41–4.33(m,1H),3.89–3.65(m,3H).

[0150] Step 5: Synthesis of 2-amino-9-((2R, 4R, 5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluoro-4-hydroxytetrahydrofuran-2-yl)-1,9-dihydro-6-purine-6-thione (10 g)

[0151] Compound 10f (crude, 0.8 mmol) was dissolved in DMF (6 mL), followed by the addition of imidazole (62 mg, 0.9 mmol) and TBSCl (120 mg, 0.8 mmol). The reaction was allowed to react overnight at room temperature. LCMS indicated the product as the primary product. The reaction solution was diluted with EA and washed three times with brine. The organic phase was dried over anhydrous NaSO, filtered, and the filtrate was directly spin-dried. The crude product was used directly in the next reaction.

[0152] LCMS (ESI-MS) m / z: 434.3 (M+H + ).

[0153] Step 6: Synthesis of (2R, 3R, 5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4,4-difluorotetrahydrofuran-3-yl isobutyrate (10h)

[0154] Compound 10f (crude, 0.8 mmol) was dispersed in ACN (20 mL), followed by the addition of TEA (111 μL, 0.8 mmol), isobutyric anhydride (133 μL, 0.8 mmol), and DMAP (5 mg, 0.04 mmol). The mixture was allowed to react at room temperature for 4 h. LCMS showed the product as the primary product. The reaction solution was quenched with MeOH and then directly spin-dried to dryness. The crude product was used directly in the next reaction.

[0155] LCMS (ESI-MS) m / z: 504.3 (M+H + ).

[0156] Step 7: Synthesis of (2R, 3R, 5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate (10)

[0157] Compound 10h (crude, 0.8 mmol) was dissolved in DCM (20 mL), followed by the addition of TREAT-HF (400 μL, 2.4 mmol) and Et3N (350 μL, 2.4 mmol). The mixture was stirred at room temperature overnight. LCMS indicated the formation of product. The reaction mixture was spin-dried and directly subjected to RP-HPLC. Freeze-dried to afford compound 10 (150 mg).

[0158] LCMS (ESI-MS) m / z: 390.2 (M+H + ).

[0159] 1 H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.62(m,1H),7.85–7.81(m,1H),6.68(brs,2H),5.53–5.47(m,1H),5.41 –5.38(m,1H),4.25–4.22(m,1H),3.83–3.77(m,1H),3.69–3.63(m,1H),2.75–2.68(m,1H),1.17–1.13(m,6H).

[0160] Example 11:

[0161] (2R,3S,5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl L-valine (11)

[0162] Step 1 Synthesis of (2R, 3S, 5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl(tert-butyloxycarbonyl)-L-valine (11b)

[0163] Compound 1a (1 g, 3.54 mmol) was dissolved in DMF (20 mL), followed by the addition of DIEA (616 μL, 3.54 mmol), HOBT (478 mg, 3.54 mmol), 11a (770 mg, 3.54 mmol), and DCC (800 mg, 3.88 mmol). The mixture was allowed to react overnight at room temperature. LCMS analysis indicated the formation of the desired product. The reaction solution was directly subjected to RP-HPLC and lyophilized to afford compound 11b (260 mg).

[0164] LCMS (ESI-MS) m / z: 483.3 (M+H + ).

[0165] Step 2 Synthesis of (2R, 3S, 5R)-5-(2-amino-6-thioxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl L-valine (11)

[0166] Compound 11b (260 mg, 0.54 mmol) was dispersed in DCM (30 mL), cooled to 0°C, and TBSOTf (200 μL, 0.8 mmol) was added dropwise. After incubation for 4 days, LCMS indicated the formation of product. The reaction solution was directly subjected to RP-HPLC and lyophilized to afford compound 11 (18 mg).

[0167] LCMS (ESI-MS) m / z: 383.2 (M+H + ).

[0168] 1 H NMR(400MHz,DMSO-d6)δ8.15(s,1H),6.87(brs,2H),6.14–6.09(m,1H),5.35–5.31(m,1H),5.13(brs,1H),4.01–3.99(m ,1H),3.60–3.59(m,2H),3.17–3.16(m,1H),2.85–2.78(m,1H),2.45–2.40(m,1H),2.03–1.84(m,1H),0.92–0.81(m,6H).

[0169] Biological activity test

[0170] Example 1: Pharmacokinetic study in mice

[0171] 1. Experimental Animals

[0172] ICR mice, SPF grade, were purchased from Hunan Slake Jingda (weight 29-37 g, sex: male)

[0173] 2. Preparation of dosing solution

[0174] Preparation of test compound intravenous administration solution: Example compound 4, Example compound 5, and Example compound 6 were weighed separately, first dissolved in dimethyl sulfoxide to prepare a stock solution, and then diluted with phosphate buffer containing 10% PEG400 to prepare the required concentration for administration.

[0175] 3. Operation process

[0176] Male ICR mice were randomly divided into groups of 3. Mice were intravenously administered with 15 μM / kg of the test compound. Orbital blood was collected 2, 5, 10, 30, and 60 minutes after administration and pretreated, followed by LC-MS / MS analysis of the test metabolite 6TG.

[0177] 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 .

[0178] Excel software was used to calculate the mean and standard deviation of the blood drug concentration of each sample.

[0179] 4. Experimental results and conclusions

[0180] The pharmacokinetic parameters of the metabolites 6-thio-dG and 6-thio-dG of the example compounds were shown in Table 1 after a single intravenous administration of 15 μM / kg of the test compounds Example 4, Example 5, Example 6 and 6-thio-dG.

[0181] Table 1: Pharmacokinetic parameters of the compounds

[0182] Example 2: In vivo pharmacodynamic study in tumor-bearing mice

[0183] 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 6 groups, each with 8 mice for the efficacy test, and the negative control group was given the same amount of solvent for a total of 14 days of observation. The specific design is shown in Table 2.

[0184] Table 2: In vivo efficacy experimental plan of compounds

[0185] 2. Experimental Animals

[0186] 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.

[0187] 3. Trial Drugs

[0188] Example Compound 1, Example Compound 2, Example Compound 3, Example Compound 5, Example Compound 6.

[0189] 4. Drug configuration

[0190] An appropriate amount of compound was weighed, dissolved in 10% dimethyl sulfoxide (DMSO), vortexed and sonicated, and then added with normal saline for injection and sonicated to prepare a 0.5 mg / mL solution.

[0191] 5. Medication

[0192] The specific administration is carried out according to the administration plan.

[0193] 6. Experimental results and conclusions

[0194] The tumor growth inhibition rates of Example Compound 1, Example Compound 2, Example Compound 3, Example Compound 5, and Example Compound 6 at a dosage concentration of 5 mg / kg were 87%, 58%, 24%, 25%, and 11%, respectively. The results showed that the example compounds of the present invention can effectively inhibit tumor growth in the mouse colon cancer MC38 model.

[0195] 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 is hydroxyl or -OC(=O)R 3 ; R 7 is hydroxyl or -OC(=O)R 2 ; R 2 and R 3 Each independently is -C 1-10 Alkyl, the -C 1-10 The alkyl group is optionally substituted with one or more -NH 2 replace; R 8 for 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, -C 1-10 Alkyl or -C(=O)-C 1-10 alkyl; X 1 and X 2 are each independently hydrogen or halogen; when R 7 When X is hydroxyl, 1 and X 2 Not at the same time it is F.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that R 2 and R 3 Each independently is CR 4 R 5 R 6 , R 4 , R 5 and R 6 are independently hydrogen, -C 1-3 Alkyl or -NH 2 , preferably, R 4 , R 5 and R 6 Each is independently -H, methyl, isopropyl or -NH 2 , more preferably, R 2 and R 3 are each independently isopropyl, tert-butyl or 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, It is characterized in that 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 More preferably, L is a bond, -S-, -CH 2 -or-S-CH 2 -.

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, It is 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 vinyl, R 10 is -H or -C(=O)-C 1-5 Alkyl, preferably, R 10 is -H.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, It is characterized in that X 1 and X 2 Each independently is -H or -F, preferably, X 1 and X 2 All are -H; or X 1 and X 2 All are -F; or X 1 -H,X 2 is -F.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, It is characterized in that It has the structure of formula (I-1), It is characterized in that R 1 is hydroxyl or -OC(=O)R 3 ; R 2 and R 3 Each independently is -C 1-10 alkyl; Preferably, R 2 and R 3 Each independently is -CHR 4 R 5 , R 4 , R 5 Each is independently -H or -C 1-3 More preferably, R 4 and R 5 All -C 1-3 Alkyl; More preferably, R 4 and R 5 All are methyl.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, It is characterized in that The compound is selected from the following compounds:

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, It is characterized in that The pharmaceutically acceptable salt is an acid addition salt.

9. A pharmaceutical composition, It is 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.

10. 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 9 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.

Images