Fluorine-containing parthenolide derivative as well as preparation method and application thereof

Abstract

The invention provides a fluorine-containing parthenolide derivative compound as shown in a formula (I), a deuterated substance, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and the fluorine-containing parthenolide derivative compound has a better tumor inhibition effect and can be used for preventing and / or treating cancers. The preparation method provided by the invention is simple to operate, and fluorine-containing parthenolide molecules can be efficiently and quickly constructed. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to fluorine-containing parthenolide derivatives, and preparation methods and uses thereof. Background Art

[0002] Parthenolide ((-)-Parthenolide, abbreviated as PTL) is a natural sesquiterpene lactone and a secondary metabolite of the Compositae and Magnoliaceae families. Initially, this type of compound was first isolated from the Western plant feverfew in 1965, and later it was found to be present in relatively high amounts in Magnolia denudata. Parthenolide has excellent anti-inflammatory and anti-tumor activities. More importantly, parthenolide is active against tumor cells with little effect on normal cells. In addition, parthenolide is the first small molecule drug found to be able to selectively induce apoptosis of cancer stem cells.

[0003] The potential mechanism of the anti-inflammatory effect of parthenolide may be to attenuate the production of inflammatory mediators by inhibiting the activation of the Akt, mTOR, and NF-κB pathways mediated by toll-like receptor 4. Recent studies have shown that parthenolide may act as a potential drug to induce apoptosis in a variety of human cancer cells, including colorectal cancer (CRC), chronic myeloid leukemia (CML), pancreatic cancer, osteosarcoma, and breast cancer. Parthenolide can not only induce apoptosis in tumor cells but also has an anti-proliferative effect on tumor cells. For example, parthenolide may inhibit lung cancer growth by inhibiting the PI3K / Akt / FoxO3α signaling pathway mediated by IGF-1R and inhibit the development of non-small cell lung cancer cells through the B-Raf / MAPK / Erk pathway. In addition, parthenolide can inhibit the growth of colorectal cancer cells by inhibiting the ubiquitin-specific peptidase 7 (USP7 / Wnt) signaling pathway. Although parthenolide has unique biological activities, poor water solubility and structural instability limit the clinical application of parthenolide. The Michael addition products of parthenolide can not only overcome the disadvantage of poor water solubility but also increase the bioavailability of the drug. For example, the dimethylamine addition product of parthenolide (DMAPT) has entered clinical trials for cancer treatment. It is necessary to further develop parthenolide compounds with medicinal value that are easy to synthesize and produce. Summary of the Invention

[0004] The present invention provides a compound represented by formula (I), its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug:

[0005]

[0006] Wherein:

[0007] X is selected from unsubstituted or optionally substituted by one, two, or more Rx The following substituted groups: OH, SH, C 1-10 alkyl;

[0008] Y is selected from H, unsubstituted or optionally substituted by one, two or more R y The following substituted groups: OH, SH, C 1-10 alkyl;

[0009] Each R x and R y are the same or different and are independently selected from H, OH, deuterium, halogen, CN, C 1-10 alkyl, C 1-10 alkyloxy, halo C 1-10 alkyl, halo C 1-10 alkyloxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl;

[0010] R1 is selected from hydrogen or deuterium;

[0011] R2 is selected from unsubstituted or optionally substituted by one, two or more R 21 substituted

[0012] or is selected from unsubstituted or optionally substituted by one or two R 22 substituted

[0013] R3 and R4 are the same or different and are independently selected from H, unsubstituted or optionally substituted by one, two or more R 31 substituted groups: C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl; or, R3 and R4 together with the N to which they are attached form an unsubstituted or optionally substituted by one, two or more R 32 substituted 3- to 10-membered heterocyclic group;

[0014] Each R 21 , R 22 , R 31 and R 32 are the same or different and are independently selected from H, OH, deuterium, halogen, CN, C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl.

[0015] According to an embodiment of the present invention, X is selected from unsubstituted or optionally substituted by one, two or more Rx Substituted with the following groups: OH, SH, C 1-6 alkyl;

[0016] According to an embodiment of the present invention, X is selected from unsubstituted or optionally substituted with one, two or more R x Substituted with the following groups: OH, SH, methyl.

[0017] According to an embodiment of the present invention, each R x is the same or different and independently selected from H, halogen, CN, C 1-6 alkyl, halo C 1-6 alkyl;

[0018] According to an embodiment of the present invention, each R x is the same or different and independently selected from H, F, CN, CF3.

[0019] According to an embodiment of the present invention, X is selected from CF3, OCF3, SCF3, SCN.

[0020] According to an embodiment of the present invention, Y is selected from H.

[0021] According to an embodiment of the present invention, R1 is hydrogen.

[0022] According to an embodiment of the present invention, R2 is selected from R3 and R4 are the same or different and independently selected from H, C 1-6 alkyl; or, R3 and R4 together with the N to which they are attached form an unsubstituted or optionally substituted with one, two or more R 32 substituted 5-8 membered heterocyclic group;

[0023] According to an embodiment of the present invention, R3 and R4 are the same or different and independently selected from H, methyl, ethyl, propyl; or, R3 and R4 together with the N to which they are attached form an unsubstituted or optionally substituted with one, two or more R 32 substituted pyrrolidinyl, piperazinyl, piperidinyl;

[0024] According to an embodiment of the present invention, each R 32 is the same or different and independently selected from H, OH, C 1-6 alkyl;

[0025] According to an embodiment of the present invention, each R 32 is the same or different and independently selected from H, OH, methyl;

[0026] According to an embodiment of the present invention, R2 is selected from

[0027] According to an embodiment of the present invention, For

[0028] According to an embodiment of the present invention, the pharmaceutically acceptable salt is a pharmaceutically acceptable salt formed by the compound shown in formula (I) and an inorganic acid or an organic acid, including a quaternary ammonium salt formed with the compound shown in formula (I), and the inorganic acid or organic acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, phosphorous acid, sulfurous acid, carbonic acid, boric acid, phosphomolybdic acid, selenous acid, methanesulfonic acid, substituted methanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acid, fumaric acid, citric acid, maleic acid, tartaric acid, oxalic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-lactic acid, formic acid, substituted formic acid, acetic acid, propionic acid, butyric acid, valeric acid, oleic acid, lauric acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, phthalic acid, malonic acid, succinic acid, glycolic acid, thioglycolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinic acid, dichloroacetic acid, benzoic acid, substituted benzoic acid.

[0029] According to an embodiment of the present invention, the compound of formula (I) has the following structure:

[0030]

[0031] Wherein, X, Y, R1, and R2 have the definitions described in the present invention.

[0032] According to an embodiment of the present invention, the compound of formula (I) has the following structure:

[0033]

[0034] Wherein, X, R3, and R4 have the definitions described in the present invention.

[0035] According to an embodiment of the present invention, the compound shown in formula (I) is selected from the following structures:

[0036]

[0037] According to an embodiment of the present invention, the pharmaceutically acceptable salt of the compound shown in formula (I) is selected from the following structures:

[0038]

[0039]

[0040] The present invention also provides a method for preparing the compound shown in formula (I), comprising the following steps: adding triphenylphosphine and a haloalkane to a solution of compound a, and then adding Cu and a trifluoromethylating agent to obtain the compound shown in formula (I);

[0041]

[0042] Among them, X, Y, R1, and R2 have the definitions described in the present invention;

[0043] According to an embodiment of the present invention, the haloalkane is, for example, a dihaloalkane, preferably methyl iodide, ethyl iodide, diiodomethane, or diiodoethane;

[0044] According to an embodiment of the present invention, the trifluoromethylation reagent is, for example, methyl fluorosulfonyldifluoroacetate (FSO2CF2CO2Me).

[0045] According to an embodiment of the present invention, when in formula (I) is the preparation method further includes the following steps: reacting compound (I') with compound NH(R3)(R4) to obtain compound (I");

[0046]

[0047] Among them, X, Y, R3, and R4 have the definitions described in the present invention; when in formula (I) is it is denoted as (I'), and when in formula (I) is it is denoted as (I").

[0048] The present invention also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by formula (I), including the following steps: reacting the compound represented by formula (I) with an acid to obtain a pharmaceutically acceptable salt of the compound represented by formula (I);

[0049] According to an embodiment of the present invention, the acid is selected from inorganic acids or organic acids, and the inorganic acids or organic acids are selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, phosphorous acid, sulfurous acid, carbonic acid, boric acid, phosphomolybdic acid, selenous acid, methanesulfonic acid, substituted methanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acid, fumaric acid, citric acid, maleic acid, tartaric acid, oxalic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-lactic acid, formic acid, substituted formic acid, acetic acid, propionic acid, butyric acid, valeric acid, oleic acid, lauric acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, phthalic acid, malonic acid, succinic acid, glycolic acid, thioglycolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinic acid, dichloroacetic acid, benzoic acid, substituted benzoic acid.

[0050] The present invention also provides a pharmaceutical composition, including the compound represented by formula (I), its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug.

[0051] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0052] According to an embodiment of the present invention, the pharmaceutical composition further comprises other anti-cancer drugs.

[0053] The present invention also provides the use of the compound represented by formula (I), its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug in the preparation of a drug.

[0054] According to an embodiment of the present invention, the drug is an anti-cancer drug.

[0055] According to an embodiment of the present invention, the cancer includes: leukemia, breast cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, rectocolon cancer, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer, blood cancer, bone cancer, brain cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, genital cancer, urogenital cancer, head cancer, laryngeal cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, testicular cancer.

[0056] The present invention also provides a compound represented by formula (I), its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug or the pharmaceutical composition for preventing and / or treating cancer.

[0057] The present invention also provides a method for preventing and / or treating cancer, comprising administering to a patient a therapeutically effective amount of at least one of the compound represented by formula (I), its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug or the pharmaceutical composition.

[0058] According to an embodiment of the present invention, the cancer includes: leukemia, breast cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, rectocolon cancer, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer, blood cancer, bone cancer, brain cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, genital cancer, urogenital cancer, head cancer, laryngeal cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, testicular cancer.

[0059] According to an embodiment of the present invention, the carrier is one or more solid, semi-solid, liquid preparations and pharmaceutical product adjuvants. The drugs of the present invention can be administered in two forms: injection and oral administration. Injection can be intravenous injection and intramuscular injection, and oral dosage forms can be tablets and capsules.

[0060] When preparing the drugs of the present invention, the active compound is combined or formulated with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into preparations in solid, semi-solid, liquid or gas forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. The administration methods include oral, intraperitoneal, transdermal, subcutaneous, intravenous or intramuscular injection, inhalation, topical, intralesional, infusion; liposome-mediated delivery; local, intrathecal, gingival pocket, rectal, intratracheal, nasal, transmucosal, intestinal, ophthalmic or otic delivery, or any other method known in the art, and all can achieve the treatment of tumors;

[0061] The therapeutically effective amount or dose of the present invention will vary according to several factors, including the selected administration route, the formulation of the composition, the patient's response, the severity of the condition, the weight of the subject, and the judgment of the prescribing doctor. For example, it is 1 - 200 mg / kg, 40 - 150 mg / kg, such as 50 mg / kg. The dose can be increased or decreased over time, as needed for individual patients. In some cases, patients are initially given a low dose and then increased to an effective dose that the patient can tolerate. In addition, patients can be given multiple doses over a determined period of time, especially at time intervals (such as daily, weekly, bi-weekly, monthly, quarterly, biennially or the like).

[0062] Beneficial effects

[0063] The present invention provides a fluorinated parthenolide derivative compound represented by formula (I), its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, which has good tumor inhibitory effects and can be used for the prevention and / or treatment of cancer. The preparation method provided by the present invention has simple operation and can efficiently and rapidly construct fluorinated parthenolide molecules. Description of the drawings

[0064] Appendix Figure 1 Release curve of Compound 4 in buffer solution.

[0065] Appendix Figure 2 Plasma concentration curves after single intragastric administration and intravenous injection of Compound 4.

[0066] Appendix Figure 3 It is the 1H NMR spectrum of Compound 1;

[0067] Appendix Figure 4It is the carbon NMR spectrum of Compound 1;

[0068] Attached Figure 5 It is the fluorine NMR spectrum of Compound 1;

[0069] Attached Figure 6 It is the hydrogen NMR spectrum of Compound 2;

[0070] Attached Figure 7 It is the carbon NMR spectrum of Compound 2;

[0071] Attached Figure 8 It is the fluorine NMR spectrum of Compound 2;

[0072] Attached Figure 9 It is the hydrogen NMR spectrum of Compound 3;

[0073] Attached Figure 10 It is the carbon NMR spectrum of Compound 3;

[0074] Attached Figure 11 It is the fluorine NMR spectrum of Compound 3;

[0075] Attached Figure 12 It is the hydrogen NMR spectrum of Compound 4;

[0076] Attached Figure 13 It is the carbon NMR spectrum of Compound 4;

[0077] Attached Figure 14 It is the fluorine NMR spectrum of Compound 4;

[0078] Attached Figure 15 It is the hydrogen NMR spectrum of Compound 5;

[0079] Attached Figure 16 It is the carbon NMR spectrum of Compound 5;

[0080] Attached Figure 17 It is the fluorine NMR spectrum of Compound 5;

[0081] Attached Figure 18 It is the hydrogen NMR spectrum of Compound 6;

[0082] Attached Figure 19 It is the carbon NMR spectrum of Compound 6;

[0083] Attached Figure 20 It is the fluorine NMR spectrum of Compound 6;

[0084] Attached Figure 21 It is the hydrogen NMR spectrum of Compound 7;

[0085] Attached Figure 22 It is the carbon NMR spectrum of Compound 7;

[0086] Attached Figure 23 It is the fluorine NMR spectrum of Compound 7;

[0087] Attachment Figure 24 is the 1H NMR spectrum of Compound 8;

[0088] Attachment Figure 25 is the 13C NMR spectrum of Compound 8;

[0089] Attachment Figure 26 is the 19F NMR spectrum of Compound 8;

[0090] Attachment Figure 27 is the 1H NMR spectrum of Compound 9;

[0091] Attachment Figure 28 is the 13C NMR spectrum of Compound 9;

[0092] Attachment Figure 29 is the 19F NMR spectrum of Compound 9;

[0093] Attachment Figure 30 is the 1H NMR spectrum of Compound 10;

[0094] Attachment Figure 31 is the 13C NMR spectrum of Compound 10;

[0095] Attachment Figure 32 is the 19F NMR spectrum of Compound 10;

[0096] Attachment Figure 33 is the 1H NMR spectrum of Compound 11;

[0097] Attachment Figure 34 is the 13C NMR spectrum of Compound 11;

[0098] Attachment Figure 35 is the 19F NMR spectrum of Compound 11;

[0099] Attachment Figure 36 is the 1H NMR spectrum of Compound 12;

[0100] Attachment Figure 37 is the 13C NMR spectrum of Compound 12;

[0101] Attachment Figure 38 is the 19F NMR spectrum of Compound 12;

[0102] Attachment Figure 39 is the 1H NMR spectrum of Compound 13;

[0103] Attachment Figure 40 is the 13C NMR spectrum of Compound 13;

[0104] Attachment Figure 41 is the 19F NMR spectrum of Compound 13;

[0105] Attachment Figure 42 is the 1H NMR spectrum of Compound 14;

[0106] Attached Figure 43 is the carbon NMR spectrum of Compound 14;

[0107] Term Definitions and Explanations

[0108] Unless otherwise specified, the group and term definitions described in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should be understood to be within the scope described in the specification and / or claims of this application.

[0109] It should be understood that when describing one, two, or more, "more" should mean greater than 2, for example, an integer greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9, or 10.

[0110] The term "C 1-10 alkyl" means a straight-chain or branched-chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C 1-10 alkyl includes C 1-3 alkyl, C 1-6 alkyl, C 3-6 alkyl, etc. "C 1-10 alkyl" means a straight-chain and branched-chain alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and "C 1-8 alkyl" means a straight-chain and branched-chain alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and "C 1-6 alkyl" means a straight-chain and branched-chain alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc. or their isomers.

[0111] The term "C 3-10 cycloalkyl" means a saturated monovalent monocyclic, bicyclic (such as fused rings, bridged rings, spiro rings) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C 3-10 cycloalkyl includes C 3-8 cycloalkyl, C3-5 Naphthenyl, C 6-8 Naphthenyl, C 3-4 Naphthenyl, C 5-6 Naphthenyl, C6 naphthenyl, etc. The C 3-10 Naphthenyl may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0112] The term "3- to 10-membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S, and N. The heterocyclic group may be attached to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group may include fused or bridged rings as well as spiro rings. In particular, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example but not limited to 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or, it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.

[0113] The term "C 6-14 aryl" should preferably be understood to represent a monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms that is aromatic or partially aromatic ("C 6-14"Aryl"), especially a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthryl. When the C 6-20 aryl is substituted, it can be mono-substituted or multi-substituted. And there is no restriction on the substitution site, for example, it can be ortho-substituted, para-substituted or meta-substituted.

[0114] The term "5- to 14-membered heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and the ring atoms of which contain 1-5 heteroatoms independently selected from N, O and S. The bicyclic and tricyclic aromatic ring systems can be fused rings, spiro rings or bridged rings. The number of heteroatoms in the 5- to 14-membered heteroaryl is 1-5, preferably 1-3. Additionally, in each case, the 5- to 14-membered heteroaryl can be benzo-fused. The 5- to 14-membered heteroaryl includes 5- to 8-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, 6-membered heteroaryl, etc. Examples of heteroaryl include, but are not limited to: 5-membered rings, such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazole, imidazolyl, etc.; 6-membered rings, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclic group can be bicyclic, including but not limited to: 5,5-membered rings, such as tetrahydrocyclopentanopyrazole; 5,6-membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuranopyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6-membered rings, such as tetrahydroquinoline; 5,7-membered rings, such as tetrahydrocycloheptathiazole, tetrahydrocycloheptafuran. The heterocyclic group can be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5- to 14-membered heteroaryl is substituted, it can be mono-substituted or multi-substituted. And there is no restriction on the substitution site, for example, the hydrogen atom connected to a carbon atom on the heteroaryl ring can be substituted, or the hydrogen atom connected to a heteroatom on the heteroaryl ring can be substituted.

[0115] The term "spiro ring" means a ring system in which two rings share 1 ring-forming atom.

[0116] The term "fused ring" means a ring system in which two rings share 2 ring-forming atoms.

[0117] The term "bridged ring" refers to a ring system in which two rings share more than three ring-forming atoms.

[0118] The term "halogen" means fluorine, chlorine, bromine and iodine.

[0119] "Halogenated" means substituted by one or more halogens.

[0120] The term "halo-C 1-10 alkyl" means an alkyl group as defined above, which is substituted by one or more halogens as defined above. The haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.

[0121] The term "C 1-10 alkyloxy" means the group -O-R X , where R X is an alkyl group as defined above. Detailed embodiments

[0122] The technical solutions of the present disclosure will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only for illustrative and explanatory purposes of the present disclosure, and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are covered within the scope of protection intended by the present disclosure.

[0123] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products, or can be prepared by known methods.

[0124] Synthesis of compounds:

[0125] Example 1 Preparation of compound 1:

[0126]

[0127] Add MMB (132.0 mg, 0.5 mmol), Ph3P (157.4 mg, 0.6 mmol) and ICH2CH2I (169.1 mg, 0.6 mmol) to a Schlenk tube, introduce nitrogen, and then add DMF (5 mL). After stirring at room temperature until completely dissolved, add Cu (31.8 mg, 0.5 mmol) and FSO2CF2CO2Me (480.2 mg, 2.5 mmol) in sequence. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a sintered funnel. The filtrate was concentrated, and the obtained crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 8:1) to obtain compound 1 as a white solid. Yield: 50 mg, 32%. Melting point: 230 - 231 °C.1 1H NMR (400 MHz, DMSO-d6): δ = 6.07 (d, J = 3.5 Hz, 1H), 5.80 (d, J = 3.2 Hz, 1H), 5.58 (t, J = 8 Hz, 1H), 4.08 (t, J = 9.3 Hz, 1H), 3.09–2.89 (m, 2H), 2.86 (d, J = 9.5 Hz, 1H), 2.82–2.72 (m, 1H), 2.45–2.23 (m, 3H), 2.20–1.98 (m, 3H), 1.76–1.60 (m, 1H), 1.47 (s, 3H), 0.96 (m, 1H). 13 13C NMR (100 MHz, DMSO-d6): δ = 169.4, 139.2, 133.1, 129.8, 120.0, 80.7, 62.4, 59.9, 41.5, 37.3 (q, J = 37.15 Hz), 36.3, 25.1, 24.4, 23.7, 17.4. 19 19F NMR (376 MHz, DMSO-d6) δ = -63.49 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for: C 16 H 20 F3O3: 317.1359; found: 317.1354.

[0128] Preparation of Compound 2 in Example 2:

[0129]

[0130] Compound 1 (316.1 mg, 1 mmol), Me2NH·HCl (652.4 mg, 8 mmol) and potassium carbonate (2073.2 mg, 15 mmol) were added to a round-bottom flask, and then CH2Cl2 (10 mL) was added. The reaction was carried out at room temperature for 2 h. The reaction mixture was filtered through a sintered funnel and then diluted with 50 mL of dichloromethane. The organic phase was washed with brine and then dried over anhydrous Na2SO4. The crude product obtained by concentrating the organic phase was purified on a silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain a white solid compound. Yield: 325.0 mg, 90%. Melting point: 102 - 103 °C. 11H NMR (400 MHz, CDCl3) δ = 5.54 (t, J = 8.0 Hz, 1H), 3.83 (t, J = 9.6 Hz, 1H), 3.31–3.19 (m, 1H), 2.79–2.64 (m, 3H), 2.64–2.51 (m, 2H), 2.51–2.27 (m, 4H), 2.24–2.09 (m, 10H), 1.63–1.54 (m, 1H), 1.52 (s, 3H), 1.07 (t, J = 12.5 Hz, 1H). 13 13C NMR (100 MHz, CDCl3): δ = 176.8, 132.6, 131.0 (q, J = 3 Hz), 127.6, 81.3, 64.0, 59.7, 57.9, 45.5, 43.9, 42.2, 38.6 (q, J = 28 Hz), 36.9, 26.6, 25.6, 24.1, 17.9. 19 19F NMR (376 MHz, CDCl3) δ = -64.78 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for: C 18 H 27 F3NO3: 362.1938; found: 362.1934.

[0131] Preparation of Compound 3 in Example 3:

[0132]

[0133] Compound 2 (361.2 mg, 1 mmol) and citric acid (192.13 mg, 1 mmol) were separately added to a round-bottom flask, and then acetone (10 mL) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was concentrated to obtain a white solid. Yield: 525.5 mg, 95%. Melting point: 69 - 70 °C. 1 1H NMR (400 MHz, DMSO-d6) δ = 5.57 (t, J = 8.0 Hz, 1H), 4.06 (t, J = 9.5 Hz, 1H), 3.15–3.01 (m, 1H), 2.98–2.91 (m, 2H), 2.86 (dd, J = 14.3, 9.0 Hz, 1H), 2.75–2.67 (m, 4H), 2.61 (d, J = 15.3 Hz, 3H), 2.47 (m, 5H), 2.40–2.19 (m, 3H), 2.18–1.99 (m, 5H), 1.74–1.64 (m, 1H), 1.47 (s, 3H), 1.01–0.87 (m, 1H). 13¹³C NMR (100 MHz, DMSO-d₆): δ = 176.8, 175.6, 171.4, 132.8, 130.3, 126.8 (d, J = 276 Hz), 80.9, 72.1, 62.9, 59.8, 56.5, 44.4, 43.4, 42.4, 41.8, 37.5, 36.5, 25.4, 25.2, 23.6, 17.4. 19 ¹⁹F NMR (376 MHz, DMSO-d₆) δ = -63.48 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for: C 18 H 27 F₃NO₃: 362.1938; found: 362.1934.

[0134] Preparation of Compound 4 in Example 4:

[0135]

[0136] Compound 2 (361.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were separately added to a round-bottom flask, and then acetone (10 mL) was added. The reaction was carried out at 50 °C for 0.5 h. The reaction solution was concentrated to obtain a white solid. Yield: 453.3 mg, 95%. Melting point: 213 - 214 °C. ¹H NMR (400 MHz, DMSO-d₆) δ = 6.60 (s, 2H), 5.56 (t, J = 8 Hz, 1H), 4.03 (t, J = 8 Hz, 1H), 3.24–3.07 (m, 1H), 2.97–2.90 (m, 1H), 2.75 - 2.66 (m, 4H), 2.47–2.22 (m, 8H), 2.17–2.01 (m, 3H), 1.71–1.65 (m, 1H), 1.47 (s, 3H), 1.02–0.87 (m, 1H). 13 ¹³C NMR (100 MHz, DMSO-d₆): δ = 176.9, 166.4, 134.2, 132.6, 130.5, 126.8 (d, J = 277 Hz), 80.6, 63.2, 59.7, 57.4, 44.8, 42.7, 41.9, 37.5 (q, J = 28 Hz), 36.5, 25.3, 23.6, 17.4. 19 ¹⁹F NMR (376 MHz, DMSO-d₆) δ = -63.53 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for: C 18 H 27 F₃NO₃: 362.1938; found: 362.1932.

[0137] Preparation of Compound 5 in Example 5

[0138]

[0139] Add MMB (132.0 mg, 0.5 mmol), Ph3P (183.6 mg, 0.7 mmol) and ICH2CH2I (197.3 mg, 0.7 mmol) into a Schlenk tube, purge with nitrogen, and then add DMF (3 mL). After stirring at room temperature until completely dissolved, add successively n Bu4N + I - (277 mg, 0.75 mmol) and AgSCF3 (314.9 mg, 1.5 mmol) dissolved in acetonitrile (1.5 mL). The reaction mixture was stirred at 80 °C for 15 minutes. The reaction mixture was cooled to room temperature and filtered through a sintered funnel. The filtrate was concentrated, and the obtained crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 8:1) to obtain Compound 1 as a white solid. Yield: 52 mg, 30%. Melting point: 82 - 83 °C. 1 1H NMR (400 MHz, CDCl3): δ = 6.28 (d, J = 3.5 Hz, 1H), 5.70 (t, J = 8.1 Hz, 1H), 5.55 (d, J = 3.2 Hz, 1H), 3.85 (t, J = 9.3 Hz, 1H), 3.72 (d, J = 13.1 Hz, 1H), 3.41 (d, J = 13.1 Hz, 1H), 2.82 (d, J = 9.4 Hz, 1H), 2.78–2.64 (m, 1H), 2.57–2.37 (m, 2H), 2.37–2.10 (m, 4H), 1.78–1.67 (m, 1H), 1.56 (m, 3H), 1.11 (t, J = 12.3 Hz, 1H). 13 13C NMR (100 MHz, CDCl3): δ = 169.1, 138.5, 133.7, 131.5, 120.4, 80.9, 63.3, 59.9, 42.5, 36.6, 35.0, 25.0, 24.1, 23.6, 17.9; 19 19F NMR (376 MHz, CDCl3) δ = -41.13 (s, 3F). HRMS (ESI): m / z [M + H] + calcd for: C 16 H 20 F3O3S: 349.1080; found: 349.1074.

[0140] Preparation of Compound 6 in Example 6:

[0141]

[0142] In a round-bottom flask, compound 1 (316.1 mg, 1 mmol), N-methyl-n-propylamine (87.8 mg, 1.2 mmol), and potassium carbonate (165.9 mg, 1.2 mmol) were added respectively. Subsequently, MeOH (10 mL) was added, and the reaction was carried out at room temperature for 2 h. The reaction mixture was filtered through a sintered funnel, and then diluted with 50 mL of dichloromethane. The organic phase was washed with brine and then dried over anhydrous Na2SO4. The crude product obtained by concentrating the organic phase was purified on a silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain a yellow oily compound. Yield: 268.5 mg, 69%. 1 1H NMR (400 MHz, CDCl3): δ = 5.60–5.49 (m, 1H), 3.83 (t, J = 9.6 Hz, 1H), 3.25 - 3.18 (m, 1H), 2.85–2.62 (m, 4H), 2.54–2.40 (m, 3H), 2.37–2.23 (m, 4H), 2.23–2.03 (m, 6H), 1.64–1.55 (m, 1H), 1.53 (s, 3H), 1.47 (m, 2H), 1.08 (t, J = 12.5 Hz, 1H), 0.87 (t, J = 7.4 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ = 176.9, 132.8, 130.9, 81.1, 63.8, 60.1, 59.8, 56.7, 44.0, 42.5, 41.8, 38.9 (q, J = 38.7 Hz), 36.8, 26.7, 25.6, 24.0, 20.0, 17.8, 14.1, 11.8. 19 19F NMR (376 MHz, CDCl3): δ = -64.79 (s, 3F). HRMS (ESI): m / z [M + H] + calcd for: C 20 H 31 F3NO3: 390.2251; found: 390.2247.

[0143] Preparation of compound 7 in Example 7:

[0144]

[0145] Compound 6 (389.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were separately added into a round-bottom flask, and then acetone (10 mL) was added. The reaction was carried out at 50 °C for 1 h. The solid obtained by concentrating the reaction solution was washed with ethyl acetate and filtered to obtain a white solid. Yield: 252.7 mg, 50%. Melting point: 187 - 188 °C. 1 H NMR (400 MHz, DMSO-d6): δ=6.59 (s, 2H), 5.60–5.53 (m, 1H), 4.01 (t, J=9.6 Hz, 1H), 3.20–3.05 (m, 1H), 3.01–2.88 (m, 1H), 2.78–2.58 (m, 4H), 2.43–2.16 (m, 5H), 2.13 (s, 3H), 2.08 (m, 4H), 1.69 - 1.62 (m, 1H), 1.47 (s, 3H), 1.46–1.37 (m, 2H), 0.93 (dd, J=20.9, 9.5 Hz, 1H), 0.83 (t, J=7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6): δ=177.2, 166.7, 134.4, 132.8, 130.4, 80.5, 63.1, 59.8, 59.6, 56.8, 42.9, 42.3, 41.5, 37.8 (q, J=28 Hz), 36.5, 25.5 (d, J=15 Hz), 23.6, 19.6, 17.4, 11.7. 19 F NMR (376 MHz, DMSO-d6): δ=-63.56 (s, 3F). HRMS (ESI): m / z [M + H] + calcd for: C 20 H 31 F3NO3: 390.2251; found: 390.2247.

[0146] Preparation of Compound 8 in Example 8:

[0147]

[0148] Compound 1 (316.1 mg, 1 mmol) and pyrrolidine (85.3 mg, 1.2 mmol) were separately added into a round-bottom flask, and then DCM (10 mL) was added. The reaction was carried out at room temperature for 2 h. The reaction mixture was filtered through a sintered funnel and then diluted with 50 mL of dichloromethane. The organic phase was washed with brine and then dried over anhydrous Na2SO4. The crude product obtained by concentrating the organic phase was purified on a silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain a white solid compound. Yield: 375.6 mg, 97%. Melting point: 172 - 173 °C. 11H NMR (400 MHz, CDCl3): δ = 5.53 (t, J = 8 Hz, 1H), 3.84 (t, J = 8 Hz, 1H), 3.29 (m, 1H), 2.99–2.87 (m, 1H), 2.81 - 2.76 (m, 1H), 2.71 (d, J = 9.3 Hz, 1H), 2.68–2.57 (m, 1H), 2.54–2.28 (m, 8H), 2.16 (m, 4H), 1.72 (s, 4H), 1.63 - 1.59 (m, 1H), 1.52 (s, 3H), 1.11 - 1.04 (m, 1H). 13 13C NMR (100 MHz, CDCl3): δ = 176.8, 132.7, 131.1, 81.3, 64.0, 59.7, 54.1, 53.6, 44.6, 41.8, 38.8 (q, J = 29 Hz), 36.9, 26.4, 25.5, 24.0, 23.4, 17.8. 19 19F NMR (376 MHz, CDCl3): δ = -64.83 (s, 3F). HRMS (ESI): m / z [M + H] + calcd for: C 20 H 29 F3NO3: 388.2094; found: 388.2088.

[0149] Example 9 Preparation of Compound 9:

[0150]

[0151] Compound 8 (387.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were added to a round-bottom flask, followed by the addition of acetone (10 mL). The reaction was carried out at 50 °C for 1 h. The solid obtained by concentrating the reaction solution was washed with ethyl acetate and filtered to obtain a white solid. Yield: 387.5 mg, 77%. Melting point: 216 - 217 °C. 1 1H NMR (400 MHz, DMSO-d6): δ = 6.59 (s, 2H), 5.59–5.53 (m, 1H), 4.04 (t, J = 9.6 Hz, 1H), 3.23 - 3.17 (m, 1H), 2.97–2.82 (m, 3H), 2.71 (dd, J = 11.9, 7.7 Hz, 2H), 2.59 - 2.54 (m, 4H), 2.43–2.18 (m, 3H), 2.15–2.02 (m, 4H), 1.73 - 1.68 (m, 5H), 1.47 (s, 3H), 1.04–0.87 (m, 1H). 1313C NMR (100 MHz, DMSO-d6): δ = 176.9, 166.6, 134.3, 132.7, 130.5, 80.7, 63.3, 59.7, 53.6, 53.0, 44.7, 43.6, 41.4, 37.7 (q, J = 27 Hz), 36.6, 25.2 (q, J = 5 Hz), 23.6, 23.0, 17.4. 19 19F NMR (376 MHz, DMSO-d6): δ = -63.60. HRMS (ESI): m / z [M+H] + calcd for: C 20 H 29 F3NO3: 388.2094; found: 388.2091.

[0152] Preparation of the compound 10 in Example 10:

[0153]

[0154] Add compound 1 (316.1 mg, 1 mmol), N-methylpiperazine (120.2 mg, 1.2 mmol), and potassium carbonate (165.9 mg, 1.2 mmol) into a round-bottom flask respectively, then add MeOH (10 mL), and react at room temperature for 2 h. The reaction mixture was filtered through a sintered funnel and then diluted with 50 mL of dichloromethane. The organic phase was washed with brine and then dried over anhydrous Na2SO4. The concentrated crude product was purified on a silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain a white solid compound. Yield: 398.6 mg, 96%. Melting point: 110 - 112 °C. 1 1H NMR (400 MHz, CDCl3): δ = 5.65–5.51 (m, 1H), 3.86 - 3.81 (m, 1H), 3.32–3.18 (m, 1H), 2.85 - 2.80 (m, 1H), 2.76–2.68 (m, 2H), 2.66 - 2.61 (m, 1H), 2.59–2.27 (m, 11H), 2.25 - 2.19 (m, 3H), 2.19–2.03 (m, 4H), 1.64–1.54 (m, 1H), 1.52 (s, 3H), 1.12 - 1.04 (m, 1H). 13 13C NMR (100 MHz, CDCl3): δ = 176.7, 133.0, 130.8, 81.1, 68.0, 63.8, 59.8, 57.5, 54.6, 46.6, 45.9, 43.1, 42.8, 39.7, 36.8, 26.8, 25.6, 24.0, 17.8. 1919F NMR (376 MHz, CDCl3): δ = -64.21 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for: C 21 H 32 F3N2O3: 417.2360; found: 417.2352.

[0155] Preparation of Compound 11 in Example 11:

[0156]

[0157] Compound 10 (416.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were separately added to a round-bottom flask, and then acetone (10 mL) was added. The reaction was carried out at 50 °C for 1 h. The concentrated solid was washed with ethyl acetate and filtered to obtain a white solid. Yield: 319.4 mg, 60%. Melting point: 225 - 226 °C. 1 1H NMR (400 MHz, DMSO-d6): δ = 6.59 (s, 2H), 5.65 - 5.50 (m, 1H), 4.03 (t, J = 9.5 Hz, 1H), 3.22 - 3.11 (m, 1H), 3.08–2.94 (m, 1H), 2.82–2.62 (m, 7H), 2.62–2.19 (m, 11H), 2.19–2.02 (m, 4H), 1.67 (t, J = 11.0 Hz, 1H), 1.48 (s, 3H), 0.95 (t, J = 12.3 Hz, 1H). 13 13C NMR (100 MHz, DMSO-d6): δ = 177.6, 167.2, 134.9, 133.3, 130.9, 127.3 (q, J = 276 Hz), 81.1, 63.6, 60.3, 56.4, 53.5, 51.4, 44.0, 42.9, 42.1, 38.5 (q, J = 10 Hz), 37.0, 26.0, 25.8, 24.1, 17.9. 19 19F NMR (376 MHz, DMSO-d6): δ = -63.06 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for: C 21 H 32 F3N2O3: 417.2360; found: 417.2357.

[0158] Preparation of Compound 12 in Example 12:

[0159]

[0160] In a round-bottom flask, add compound 1 (316.1 mg, 1 mmol), 4-hydroxypiperidine (121.4 mg, 1.2 mmol), and potassium carbonate (165.9 mg, 1.2 mmol) respectively. Then add MeOH (10 mL) and react at room temperature for 2 h. The reaction mixture is filtered through a sintered funnel and then diluted with 50 mL of dichloromethane. The organic phase is washed with brine and then dried over anhydrous Na2SO4. The organic layer is concentrated under reduced pressure to obtain a white solid compound. Yield: 375.5 mg, 90%. Melting point: 123 - 124 °C. 1 1H NMR (400 MHz, CDCl3): δ = 5.56 (t, J = 8 Hz, 1H), 3.84 (t, J = 9.5 Hz, 1H), 3.73 - 3.63 (m, 1H), 3.35–3.12 (m, 1H), 2.85–2.71 (m, 4H), 2.66–2.57 (m, 2H), 2.51 - 2.43 (m, 3H), 2.37–2.06 (m, 8H), 1.91–1.81 (m, 2H), 1.75 - 1.67 (m, 1H), 1.62 - 1.59 (m, 1H), 1.54 - 1.53 (m, 3H), 1.51–1.46 (m, 1H), 1.08 (t, J = 12 Hz, 1H). 13 13C NMR (100 MHz, CDCl3): δ = 176.9, 133.0, 130.8, 81.2, 63.8, 59.9, 57.2, 51.1, 46.6, 43.4, 42.6, 39.2 (q, J = 29 Hz), 36.8, 34.1, 34.0, 26.8, 25.6, 24.1, 17.9. 19 19F NMR (376 MHz, CDCl3): δ = -64.40 (s, 3F). HRMS (ESI): m / z [M + H] + calcd for: C 21 H 31 F3NO4: 418.2200; found: 418.2198.

[0161] Preparation of Compound 13 in Example 13:

[0162]

[0163] In a round-bottom flask, add compound 12 (417.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) respectively. Then add acetone (10 mL) and react at 50 °C for 1 h. The solid obtained by concentrating the reaction solution is washed with ethyl acetate and filtered to obtain a white solid. Yield: 320.0 mg, 60%. Melting point: 198 - 199 °C. 11H NMR (400 MHz, DMSO-d6): δ = 6.59 (s, 2H), 5.58 (t, J = 8 Hz, 1H), 4.02 (t, J = 8 Hz, 1H), 3.47 (s, 1H), 3.27 - 3.21 (m, 1H), 3.01–2.89 (m, 1H), 2.74 - 2.70 (m, 3H), 2.65 - 2.64 (m, 3H), 2.41 - 2.27 (m, 3H), 2.21–1.91 (m, 7H), 1.75 - 1.65 (m, 3H), 1.47 (s, 3H), 1.43–1.28 (m, 2H), 0.95 (t, J = 12.3 Hz, 1H). 13 13C NMR (100 MHz, DMSO-d6): δ = 177.3, 166.8, 134.5, 132.9, 130.6, 126.2 (d, J = 277 Hz), 80.6, 63.3, 59.9, 57.1, 50.7, 42.4, 42.2, 38.1 (q, J = 27 Hz), 36.5, 34.0, 33.8, 25.6, 25.4, 23.7, 17.5. 19 19F NMR (376 MHz, DMSO-d6) δ = -63.28 (s, 3F). HRMS (ESI): m / z [M + H] + calcd for: C 21 H 31 F3NO4: 418.2200; found: 418.2196.

[0164] Preparation of Compound 14 in Example 14:

[0165]

[0166] Add CuSCN (243.24 mg, 2.0 mmol), cesium fluoride (379.8 mg, 2.5 mmol), DMF (2 mL) and TMSCF2H (186.3 mg, 1.5 mmol) to a Schlenk tube. Stir the resulting mixture at 40 °C for 60 min, then cool to room temperature.

[0167] Add MMB (132.0 mg, 0.5 mmol), Ph3P (157.4 mg, 0.6 mmol) and ICH2CH2I (169.1 mg, 0.6 mmol) into the Schlenk tube, introduce nitrogen, and then add DMF (3 mL). Stir at room temperature until completely dissolved, then add it to the reaction mixture obtained in the previous step and stir at room temperature for 12 hours. Filter the reaction mixture through a sintered funnel. Concentrate the filtrate, and purify the obtained crude product on a silica gel column (petroleum ether:ethyl acetate = 4:1) to obtain Compound 14 as a yellow solid. Yield: 45.8 mg, 30%. Melting point: 155 - 157 °C. 1 1H NMR (400 MHz, CDCl3): δ = 6.24 (d, J = 4 Hz, 1H), 5.76 (t, J = 8 Hz, 1H), 5.56 (d, J = 4 Hz, 1H), 3.84 (t, J = 8 Hz, 1H), 3.76 (d, J = 12 Hz, 1H), 3.44 (d, J = 12 Hz, 1H), 2.82 (d, J = 12 Hz, 1H), 2.75–2.65 (m, 1H), 2.58–2.41 (m, 2H), 2.40–2.25 (m, 3H), 2.20 - 2.15 (m, 1H), 1.80–1.70 (m, 1H), 1.54 (s, 3H), 1.15 - 1.07 (m, 1H). 13 13C NMR (100 MHz, CDCl3): δ = 169.1, 138.3, 133.8, 133.3, 120.5, 111.4, 80.8, 63.1, 59.9, 42.3, 39.3, 36.4, 24.9, 24.1, 23.1, 17.9; HRMS (ESI): m / z [M+H] + calcd for: C 16 H 20 NO3S: 306.1158; found: 306.1158.

[0168] Test Example 1 Anticancer Activity Test

[0169] Take cells in the logarithmic growth phase, digest, centrifuge and count them, and make up the volume to 1500 - 3500 cells / well, 95 μL per well, and inoculate them into a 96-well plate.

[0170] Continue to culture overnight, then add drugs at different concentrations, 6 replicates for each concentration, add 10 μL of the drug to each well, after incubating for 72 h, add 10 μL of CCK-8 solution to each well (note that no bubbles should be generated in the wells as they will affect the OD value reading), incubate in the incubator for 1 - 4 h, and measure the OD value at 450 nm with an enzyme-linked immunosorbent assay reader. The experiment on the effect of each drug on each cell line at different times is repeated three times.

[0171] The data was processed with EXCEL software to solve the inhibition rates at different concentrations, and the IC50 values were fitted with SPSS. The average value and standard deviation of the IC50 values were solved three times with EXCEL. Inhibition rate % = {1 - (OD value of drug well - OD value of blank well) / (OD value of control well - OD value of blank well)} * 100%.

[0172] Table 1-1 Activity of Compounds in Inhibiting Cancer Cells

[0173]

[0174] Table 1-2 Activity of Compounds in Inhibiting PANC-1 Cells

[0175] Compound IC50 (μM) PTL 6.156±0.141 Compound 6 7.199±0.224 Compound 7 5.059±0.619 Compound 8 4.132±1.121 Compound 9 6.574±1.732 Compound 10 24.422±1.804 Compound 11 16.772±4.203 Compound 12 4.058±0.621 Compound 13 3.865±0.095

[0176] Note: PTL is parthenolide, and its structure is shown as follows:

[0177]

[0178] Conclusion: The compounds have certain effects on glioma, lung cancer, colon cancer, liver cancer, and pancreatic cancer

[0179] Test Example 2 Experimental Study on the Release of Compound 4 in Buffer Solution

[0180] Take Compound 4 and prepare a test solution of about 10 μg / ml with 0.01M HEPES buffer solution (pH = 7.4). Incubate it in a water bath at 37°C. Take appropriate amounts at 0 h, 0.5 h, 1 h, 2 h, and 4 h, and analyze the concentrations of Compound 4 and its degradation products by HPLC to investigate the release rate of Compound 4. The results are shown in Figure 1 。

[0181] Conclusion: In buffer solution (pH = 7.4), Compound 4 can slowly release the active substance Compound 1

[0182] Test Example 3 Pharmacokinetics of Compound 4 and Distribution Experiment in Tissues Such as the Brain

[0183] (1) Take 48 healthy Bar b / c mice weighing about 20 g and divide them into 3 groups. Blank control group (6 mice), intragastric administration group (Compound 4 dosage 50 mg / kg, 21 mice), and tail vein injection administration group (Compound 4 dosage 10 mg / kg, 21 mice)

[0184] (2) Blood samples were collected from the intragastric administration group at 5 min, 15 min, 30 min, 1 h, 3 h, 8 h, and 24 h after administration. Blood samples were collected from the intravenous injection group at 2 min, 5 min, 15 min, 30 min, 1 h, 3 h, 8 h, and 24 h after administration. Blood was collected from the mice by eye enucleation and placed in an anticoagulant tube containing sodium heparin. It was quickly centrifuged at 5000 rpm at low temperature (4°C) for 10 min to obtain plasma samples. The samples were stored in a -80°C refrigerator waiting for detection. Three mice were used at each time point.

[0185] (3) The mice were fixed on a foam board. After lifting the chest skin with forceps, the skin and ribs of the chest cavity were cut open with scissors to expose the heart and liver, and the auricle was cut open. The syringe needle was inserted into the left ventricle of the mouse, and normal saline was perfused for 1 min (10 - 20 ml of normal saline) until the limbs, liver, and tongue of the mouse turned white. Brain extraction from the mouse: Cut open the head skin to expose the white skull, cut open the cartilage, carefully remove the skull cap to expose the white brain, and dissect the whole brain. At the same time, tissues such as pancreas, liver, lung, and rectum were collected. The samples were stored in a -80°C refrigerator waiting for detection.

[0186] (4) LC / MS was used to detect the contents of Compound 4 and Compound 1 in peripheral blood and tissues.

[0187] MS / MS information

[0188]

[0189] Note: Tolbutamide is the internal standard for peak area ratio calculation. Compound 1 is quantified using [M+NH -4 + peak quantification.

[0190] The results are as follows:

[0191] Table 2 Plasma concentration of Compound 4 after single intragastric administration and intravenous injection (ng / mL)

[0192]

[0193] Note: The lower limit of quantification is 3 ng / mL; "-" indicates not estimable; "*" indicates the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0194] Table 3 Plasma concentration of Compound 1, the active substance released after single intragastric administration and intravenous injection of Compound 4 (ng / mL)

[0195]

[0196]

[0197] ​Note: The lower limit of quantification is 3 ng / mL; "-" indicates not estimable; "*" indicates the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0198] Table 4 Concentrations (ng / g) of Compound 4 in Brain Tissue after Single Oral and Intravenous Administrations

[0199]

[0200] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates not estimable; "*" indicates the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0201] Table 5 Concentrations (ng / g) of Compound 4 in Pancreatic Tissue after Single Oral and Intravenous Administrations

[0202]

[0203] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates not estimable; "*" indicates the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0204] Table 6 Concentrations (ng / g) of Compound 4 in Rectum after Single Oral and Intravenous Administrations

[0205]

[0206] Note:: The lower limit of quantification is 13.5 ng / g; "-" indicates not estimable; "*" indicates the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0207] Table 7 Concentrations (ng / g) of Compound 4 in Liver after Single Oral and Intravenous Administrations

[0208]

[0209] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates not estimable; "*" indicates the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0210] Table 8 Concentrations (ng / g) of Compound 4 in Lung after Single Oral and Intravenous Administrations

[0211]

[0212] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates not estimable; "*" indicates the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0213] Table 9 Concentrations of Compound 1 in Brain Tissue after Single Oral Gavage and Intravenous Injection of Compound 4 (ng / g)

[0214]

[0215] Note: The lower limit of quantification is 20 ng / g; "-" indicates non - estimable; "*" indicates that the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0216] Table 10 Concentrations of Compound 1 in Pancreatic Tissue after Single Oral Gavage and Intravenous Injection of Compound 4 (ng / g)

[0217]

[0218]

[0219] Note: The lower limit of quantification is 20 ng / g; "-" indicates non - estimable; "*" indicates that the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0220] Table 11 Concentrations of Compound 1 in Rectum after Single Oral Gavage and Intravenous Injection of Compound 4 (ng / g)

[0221]

[0222] Note: The lower limit of quantification is 20 ng / g; "-" indicates non - estimable; "*" indicates that the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0223] Table 12 Concentrations of Compound 1 in Liver after Single Oral Gavage and Intravenous Injection of Compound 4 (ng / g)

[0224]

[0225] Note: The lower limit of quantification is 20 ng / g; "-" indicates non - estimable; "*" indicates that the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0226] Table 13 Concentrations of Compound 1 in Lung after Single Oral Gavage and Intravenous Injection of Compound 4 (ng / g)

[0227]

[0228] Note: The lower limit of quantification is 20 ng / g; "-" indicates non - estimable; "*" indicates that the value is an estimate; "NA" indicates not applicable. "NS" indicates no sample

[0229] Table 14 Comparison of Exposure in Plasma and Tissues after Single Oral Gavage and Intravenous Injection of Compound 4

[0230]

[0231] The results show that the compounds of the present invention have a higher concentration distribution in various tissues (especially liver tissue).

[0232] The above has given an exemplary description of the implementation manners of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above implementation manners. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included within the protection scope of the claims of this application.

Claims

1. A compound of formula (I), its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: Wherein: X is selected from the group consisting of unsubstituted or optionally substituted by one, two or more R x substituted with the following groups: OH, SH, C 1-10 alkyl; Y is selected from H, the following groups which are unsubstituted or optionally substituted by one, two or more Rs y : OH, SH, C 1-10 alkyl; Each R x and R y are the same or different and are each independently selected from H, OH, deuterium, halogen, CN, C 1-10 alkyl, C 1-10 alkyloxy, halo-C 1-10 alkyl, halo-C 1-10 alkyloxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl; R1 is selected from hydrogen or deuterium; R2 is selected from unsubstituted or optionally substituted by one, two or more R 21 substituted or selected from unsubstituted or optionally substituted by one or two R 22 substituted R3 and R4 are the same or different and are each independently selected from H, an unsubstituted or optionally substituted by one, two or more R 31 substituted with the following groups: C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl; or, R3 and R4 together with the N to which they are attached form an unsubstituted or optionally substituted by one, two or more R 32 substituted 3- to 10-membered heterocyclic group; Each R 21 , R 22 , R 31 and R 32 are the same or different and are each independently selected from H, OH, deuterium, halogen, CN, C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl, 5- to 14-membered heteroaryl.

2. The compound according to claim 1, its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that, X is selected from the following groups which are unsubstituted or optionally substituted by one, two or more Rs x : OH, SH, C 1-6 alkyl; Preferably, X is selected from the following groups which are unsubstituted or optionally substituted by one, two or more Rs x substituted: OH, SH, methyl; Preferably, each R x is the same or different and is independently selected from H, halogen, CN, C 1-6 alkyl, halo-C 1-6 alkyl; Preferably, each R x is the same or different and is independently selected from H, F, CN, CF3; Preferably, X is selected from CF3, OCF3, SCF3, SCN.

3. The compound, deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 1 or 2, characterized in that, Y is selected from H; Preferably, R1 is hydrogen; Preferably, R2 is selected from R3 and R4 are the same or different and are each independently selected from H, C 1-6 alkyl; alternatively, R3 and R4 together with the N to which they are attached form an unsubstituted or optionally substituted by one, two or more R 32 substituted 5- to 8-membered heterocyclic group; Preferably, R3 and R4 are the same or different and independently selected from H, methyl, ethyl, propyl; or, R3 and R4 together with the N to which they are attached form an unsubstituted or optionally substituted tetrahydropyrrolyl, piperazinyl, piperidinyl group by one, two or more R 32 substituted tetrahydropyrrolyl, piperazinyl, piperidinyl; Preferably, each R 32 is the same or different and is independently selected from H, OH, C 1-6 alkyl; Preferably, each R 32 is the same or different and is independently selected from H, OH, and methyl; Preferably, R2 is selected from Preferably, is 4. The compound, its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to any one of claims 1-3, characterized in that, The pharmaceutically acceptable salt is a pharmaceutically acceptable salt formed by the compound of formula (I) and an inorganic acid or an organic acid, including a quaternary ammonium salt formed with the compound of formula (I), and the inorganic acid or organic acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, phosphorous acid, sulfurous acid, carbonic acid, boric acid, phosphomolybdic acid, selenious acid, methanesulfonic acid, substituted methanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acid, fumaric acid, citric acid, maleic acid, tartaric acid, oxalic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-lactic acid, formic acid, substituted formic acid, acetic acid, propionic acid, butyric acid, valeric acid, oleic acid, lauric acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, phthalic acid, malonic acid, succinic acid, glycolic acid, thioglycolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinic acid, dichloroacetic acid, benzoic acid, substituted benzoic acid.

5. A compound, a deuterated compound, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug according to any one of claims 1-4, characterized in that, The compound of formula (I) has the following structure: Wherein, X, Y, R1, R2 have the definitions described in any one of claims 1-4; Preferably, the compound of formula (I) has the following structure: Wherein, X, R3, R4 have the definitions described in any one of claims 1-4.

6. The compound, deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to any one of claims 1-5, characterized in that, The compound of formula (I) is selected from the following structures: The pharmaceutically acceptable salt of the compound of formula (I) is selected from the following structures:

7. A method for preparing the compound according to any one of claims 1-6, its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, comprising the following steps: Adding triphenylphosphine and a haloalkane to a solution of compound a, and then adding Cu and a trifluoromethylating reagent to obtain the compound of formula (I); Wherein, X, Y, R1, R2 have the definitions described in any one of claims 1-6; The haloalkane is, for example, a dihaloalkane, preferably methyl iodide, ethyl iodide, diiodomethane, diiodoethane; The trifluoromethylating reagent is, for example, methyl fluorosulfonyldifluoroacetate; Preferably, when in formula (I) is , the preparation method further comprises the following steps: reacting compound (I') with compound NH(R3)(R4) to obtain compound (I"); wherein, X, Y, R3, and R4 have the definitions described in any one of claims 1-6; when in formula (I) is it is denoted as (I'), and when in formula (I) is it is denoted as (I").

8. The preparation method according to claim 7, wherein Comprising the following steps: Reacting the compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of the compound of formula (I); The acid is selected from an inorganic acid or an organic acid, and the inorganic acid or organic acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, phosphorous acid, sulfurous acid, carbonic acid, boric acid, phosphomolybdic acid, selenious acid, methanesulfonic acid, substituted methanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acid, fumaric acid, citric acid, maleic acid, tartaric acid, oxalic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-lactic acid, formic acid, substituted formic acid, acetic acid, propionic acid, butyric acid, valeric acid, oleic acid, lauric acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, phthalic acid, malonic acid, succinic acid, glycolic acid, thioglycolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinic acid, dichloroacetic acid, benzoic acid, substituted benzoic acid.

9. A pharmaceutical composition comprising the compound according to any one of claims 1-6, its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; and / or, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; and / or, the pharmaceutical composition further comprises other anti-cancer drugs.

10. The present invention also provides the use of the compound represented by formula (I), its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug in the preparation of a drug; Preferably, the drug is an anti-cancer drug; Preferably, the cancer includes: Leukemia, breast cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, rectal colon cancer, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer, blood cancer, bone cancer, brain cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, genital cancer, urogenital cancer, head cancer, laryngeal cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, testicular cancer.

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