Fluorine-containing parthenolide derivative, preparation method therefor and use thereof

Abstract

The present invention provides a fluorine-containing parthenolide derivative compound as shown in formula (I), and a deuterated form, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrugs thereof, which have good tumor inhibitory activity, and can be used for the prevention and / or treatment of cancer. The preparation method provided by the present invention is simple to operate, and can efficiently and rapidly construct fluorine-containing parthenolide molecules.

Description

Fluorine-containing parthenolide derivatives and preparation methods and uses thereof

[0001] This application claims the benefit of priority to a prior application filed by the applicant with the State Intellectual Property Office of China on January 12, 2024, entitled "Fluorinated Parthenolide Derivatives, Preparation Methods, and Uses Thereof," with patent application number 202410049665.5. The entire text of that prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a fluorine-containing parthenolide derivative and a preparation method and application thereof. Background Art

[0003] (-)-Parthenolide (PTL) is a natural sesquiterpene lactone and a secondary metabolite of the Asteraceae and Magnoliaceae families. Initially, this compound was first isolated from the Western plant feverfew in 1965 and was later found to be present in higher concentrations in magnolia. Parthenolide has excellent anti-inflammatory and anti-tumor activity. More importantly, parthenolide is active against tumor cells while having little effect on normal cells. Furthermore, parthenolide is the first small molecule drug discovered to selectively induce apoptosis in cancer stem cells.

[0004] The potential mechanism of parthenolide's anti-inflammatory effects may be through inhibiting toll-like receptor 4-mediated activation of the Akt, mTOR, and NF-κB pathways, thereby attenuating the production of inflammatory mediators. Recent studies have suggested that parthenolide may be a potential agent for inducing apoptosis in various human cancer cells, including colorectal cancer (CRC), chronic myeloid leukemia (CML), pancreatic cancer, osteosarcoma, and breast cancer. Parthenolide not only induces apoptosis but also exhibits antiproliferative effects on tumor cells. For example, parthenolide may inhibit lung cancer growth by inhibiting the IGF-1R-mediated PI3K / Akt / FoxO3α signaling pathway and inhibit the development of non-small cell lung cancer cells through the B-Raf / MAPK / Erk pathway. Furthermore, parthenolide may inhibit the growth of colorectal cancer cells by inhibiting ubiquitin-specific peptidase 7 (USP7 / Wnt) signaling. Despite its unique biological activities, parthenolide's poor water solubility and unstable structure limit its clinical application. Michael addition products of parthenolide not only overcome the disadvantage of poor water solubility but also increase the bioavailability of drugs. For example, dimethylamine addition product of parthenolide (DMAPT) has entered clinical trials for cancer treatment. There is a need to further develop pharmaceutically valuable parthenolide compounds that are easily synthesized and produced. Summary of the Invention

[0005] The present invention provides a compound represented by formula (I), its deuterated form, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0006] in:

[0007] X is selected from unsubstituted or optionally substituted with one, two or more R x Substituted with the following groups: OH, SH, C 1-10 alkyl;

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

[0009] Each R x and R y the same or different, independently selected from H, OH, deuterium, halogen, CN, C 1-10 Alkyl, C 1-10 Alkyloxy, halogenated C 1- 10 Alkyl, halogenated C 1-10 Alkyloxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl;

[0010] R1 is selected from hydrogen or deuterium;

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

[0012] or Selected from unsubstituted or optionally substituted by one or two R 22 Replaced

[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 with the following groups: C 1- 10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl; or, R3 and R4 and the N to which they are attached form an unsubstituted or optionally substituted group with one, two or more R 32 substituted 3-10 membered heterocyclic group;

[0014] Each R 21 、R 22 、R31 and R 32 the same or different, independently selected from H, OH, deuterium, halogen, CN, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl.

[0015] 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, 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 The same or different, independently selected from H, halogen, CN, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0018] According to an embodiment of the present invention, each R x The same or different, 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 are independently selected from H, C 1-6 Alkyl; or, R3 and R4 and the N to which they are attached form an unsubstituted or optionally substituted group 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 are independently selected from H, methyl, ethyl, propyl; or, R3 and R4 and the N to which they are connected form an unsubstituted or optionally substituted group with one, two or more R 32 substituted tetrahydropyrrolyl, piperazinyl, piperidinyl;

[0024] According to an embodiment of the present invention, each R 32 The same or different, independently selected from H, OH, C1-6 alkyl;

[0025] According to an embodiment of the present invention, each R 32 The same or different, 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 represented by formula (I) and an inorganic acid or an organic acid, including a quaternary ammonium salt formed with the compound represented by formula (I), wherein 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, phenylsulfonic acid, substituted phenylsulfonic 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, mercaptan 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] Wherein, X, Y, R1 and R2 have the definitions described in the present invention.

[0031] According to an embodiment of the present invention, the compound of formula (I) has the following structure:

[0032] wherein X, R3, and R4 have the definitions described in the present invention.

[0033] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the following structures:

[0034] According to an embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is selected from the following structures:

[0035] The present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps: adding triphenylphosphine and a halogenated alkane to a solution of compound a, and then adding Cu and a trifluoromethylating agent to obtain the compound represented by formula (I);

[0036] Wherein, X, Y, R1, and R2 have the definitions described in the present invention;

[0037] According to an embodiment of the present invention, the halogenated alkane is, for example, a dihalogenated alkane, preferably methyl iodide, ethyl iodide, dimethyl iodide, or diethyl iodide;

[0038] According to an embodiment of the present invention, the trifluoromethylation agent is, for example, methyl fluorosulfonyldifluoroacetate (FSO2CF2CO2Me).

[0039] According to an embodiment of the present invention, when in formula (I) for When the compound (I') is NH(R3)(R4), the preparation method further comprises the following steps: reacting the compound (I') with the compound NH(R3)(R4) to obtain the compound (I");

[0040] Wherein, X, Y, R3, and R4 have the definitions described in the present invention; when in formula (I) for When , recorded as (I'), when formula (I) for When , it is recorded as (I”).

[0041] The present invention also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by formula (I), comprising 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);

[0042] According to an embodiment of the present invention, 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, phenylsulfonic acid, substituted phenylsulfonic 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, mercaptic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picoline acid, isonicotinic acid, dichloroacetic acid, benzoic acid, and substituted benzoic acid.

[0043] The present invention also provides a pharmaceutical composition comprising a compound represented by formula (I), a deuterated substance, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.

[0044] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0045] According to an embodiment of the present invention, the pharmaceutical composition further comprises other drugs for treating cancer.

[0046] The present invention also provides the use of the compound represented by formula (I), its deuterated product, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug in the preparation of medicines.

[0047] According to an embodiment of the present invention, the drug is a drug for treating cancer.

[0048] 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, colorectal 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, external genital cancer, genitourinary tract cancer, head cancer, laryngeal cancer, muscle tissue cancer, neck cancer, oral or nasal mucosal cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, testicular cancer.

[0049] The present invention also provides a compound of formula (I), its deuterated form, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug or pharmaceutical composition for preventing and / or treating cancer.

[0050] 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 form, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug, or pharmaceutical composition.

[0051] 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, colorectal 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, external genital cancer, genitourinary tract cancer, head cancer, laryngeal cancer, muscle tissue cancer, neck cancer, oral or nasal mucosal cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, testicular cancer.

[0052] According to an embodiment of the present invention, the carrier is one or more solid, semi-solid, liquid preparations and pharmaceutical product adjuvants. The drug of the present invention can be administered in two forms: injection and oral administration. The injection can be intravenous injection and intramuscular injection, and the oral dosage form can be tablets and capsules.

[0053] When preparing the medicament of the present invention, the active compound is combined or formulated with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into a solid, semi-solid, liquid or gaseous preparation, 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; topical, intrathecal, gingival pocket, rectal, intrabronchial, nasal, transmucosal, intestinal, ocular or aural delivery, or any other method known in the art, all of which can achieve the treatment of tumors.

[0054] The therapeutically effective amount or dosage of the present invention will vary according to several factors, including the selected route of administration, the formulation of the composition, the patient's response, the severity of the condition, the subject's weight, and the judgment of the prescribing physician, for example, 1-200 mg / kg, 40-150 mg / kg, such as 50 mg / kg. The dosage can be increased or decreased over time as needed by the individual patient. In some cases, the patient is initially given a low dose, which is then increased to an effective dose that the patient can tolerate. In addition, the patient can be given multiple doses over a defined time period, particularly in increments of time (such as daily, weekly, biweekly, monthly, quarterly, biennially, or the like). Beneficial effects

[0055] The present invention provides a fluorine-containing parthenolide derivative compound represented by formula (I), its deuterated derivatives, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, which exhibit potent tumor-suppressing effects and can be used to prevent and / or treat cancer. The preparation method provided by the present invention is simple to operate and enables efficient and rapid construction of the fluorine-containing parthenolide molecule. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 shows the release curve of compound 4 in buffer solution.

[0057] Figure 2 shows the blood concentration curves of compound 4 after single oral gavage and intravenous injection.

[0058] Figure 3 is a 1H NMR spectrum of compound 1;

[0059] Figure 4 is a carbon nuclear magnetic spectrum of compound 1;

[0060] Figure 5 is a fluorine NMR spectrum of compound 1;

[0061] Figure 6 is a 1H NMR spectrum of compound 2;

[0062] Figure 7 is a carbon NMR spectrum of compound 2;

[0063] Figure 8 is a fluorine NMR spectrum of compound 2;

[0064] Figure 9 is a 1H NMR spectrum of compound 3;

[0065] Figure 10 is a carbon NMR spectrum of compound 3;

[0066] Figure 11 is a fluorine NMR spectrum of compound 3;

[0067] Figure 12 is a 1H NMR spectrum of compound 4;

[0068] Figure 13 is a carbon NMR spectrum of compound 4;

[0069] Figure 14 is a fluorine NMR spectrum of compound 4;

[0070] Figure 15 is a 1H NMR spectrum of compound 5;

[0071] Figure 16 is a carbon NMR spectrum of compound 5;

[0072] Figure 17 is a fluorine NMR spectrum of compound 5;

[0073] Figure 18 is a 1H NMR spectrum of compound 6;

[0074] Figure 19 is a carbon NMR spectrum of compound 6;

[0075] Figure 20 is a fluorine NMR spectrum of compound 6;

[0076] Figure 21 is a 1H NMR spectrum of compound 7;

[0077] Figure 22 is a carbon NMR spectrum of compound 7;

[0078] Figure 23 is a fluorine NMR spectrum of compound 7;

[0079] Figure 24 is a 1H NMR spectrum of compound 8;

[0080] Figure 25 is a carbon NMR spectrum of compound 8;

[0081] Figure 26 is a fluorine NMR spectrum of compound 8;

[0082] Figure 27 is a 1H NMR spectrum of compound 9;

[0083] Figure 28 is a carbon NMR spectrum of compound 9;

[0084] Figure 29 is a fluorine NMR spectrum of compound 9;

[0085] Figure 30 is a 1H NMR spectrum of compound 10;

[0086] Figure 31 is a carbon NMR spectrum of compound 10;

[0087] Figure 32 is a fluorine NMR spectrum of compound 10;

[0088] Figure 33 is a 1H NMR spectrum of compound 11;

[0089] Figure 34 is a carbon NMR spectrum of compound 11;

[0090] Figure 35 is a fluorine NMR spectrum of compound 11;

[0091] Figure 36 is a 1H NMR spectrum of compound 12;

[0092] Figure 37 is a carbon NMR spectrum of compound 12;

[0093] Figure 38 is a fluorine NMR spectrum of compound 12;

[0094] Figure 39 is a 1H NMR spectrum of compound 13;

[0095] Figure 40 is a carbon NMR spectrum of compound 13;

[0096] Figure 41 is a fluorine NMR spectrum of compound 13;

[0097] Figure 42 is a 1H NMR spectrum of compound 14;

[0098] Figure 43 is a carbon NMR spectrum of compound 14;

[0099] Definitions and Explanations of Terms

[0100] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0101] It should be understood that herein, when describing one, two or more, "more" should refer to an integer greater than 2, for example, greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0102] The term "C 1-10 "Alkyl" means a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.1- 10 Alkyl groups include C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Alkyl, etc. "C 1-10 "Alkyl" means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group 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, or the like or isomers thereof.

[0103] The term "C 3-10 "Cycloalkyl" refers to a saturated monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 Cycloalkyl groups include C 3-8 Cycloalkyl, C 3-5 Cycloalkyl, C 6-8 Cycloalkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C6 cycloalkyl, etc. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, 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.

[0104] The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl can be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The heterocyclyl can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclyl can include, but is not limited to, 4-membered rings such as azetidinyl, oxetane; 5-membered rings such as tetrahydrofuranyl, dioxolyl, 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 heterocyclyl can be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a 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, for example, 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, for example, but not limited to, dihydroisoquinolinyl.

[0105] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example 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 anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0106] The term "5-14 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 include 1-5 heteroatoms independently selected from N, O and S. The bicyclic and tricyclic aromatic ring systems can be fused, spirocyclic or bridged. The 5-14 membered heteroaryl group contains 1-5 heteroatoms, preferably 1-3 heteroatoms. In addition, the 5-14 membered heteroaryl group can be benzo-fused in each case. The 5-14 membered heteroaryl group includes 5-8 membered heteroaryl, 5-9 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, 6 membered heteroaryl, etc. Examples of heteroaryl groups 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 may be bicyclic, including, but not limited to, 5,5-membered rings such as tetrahydrocyclopentapyrazole; 5,6-membered rings such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuropyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6-membered rings such as tetrahydroquinoline; 5,7-membered rings such as tetrahydrocycloheptathiazole and tetrahydrocycloheptafuran. The heterocyclic group may 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 group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site; for example, a hydrogen atom attached to a carbon atom on the heteroaryl ring may be substituted, or a hydrogen atom attached to a heteroatom on the heteroaryl ring may be substituted.

[0107] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0108] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0109] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0110] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0111] "Halo" means substituted with one or more halogens.

[0112] The term "halogenated C 1-10 "Alkyl" refers to an alkyl group as defined above, which is substituted by one or more halogen groups as defined above. Such 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.

[0113] The term "C 1-10 "Alkyloxy" refers to the group -OR X , where R X is an alkyl group as defined above. DETAILED DESCRIPTION

[0114] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations 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 included within the scope of protection intended by the present disclosure.

[0115] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0116] Synthesis of compounds:

[0117] Example 1 Preparation of Compound 1:

[0118] MMB (132.0 mg, 0.5 mmol), Ph3P (157.4 mg, 0.6 mmol), and ICH2CH2I (169.1 mg, 0.6 mmol) were added to a Schlenk tube and purged with nitrogen. DMF (5 mL) was then added. After stirring at room temperature until completely dissolved, Cu (31.8 mg, 0.5 mmol) and FSO2CF2CO2Me (480.2 mg, 2.5 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a fritted funnel. The filtrate was concentrated, and the 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 H NMR (400MHz, DMSO-d6): δ = 6.07 (d, J = 3.5Hz, 1H), 5.80 (d, J = 3.2Hz, 1H), 5.58 (t, J = 8Hz, 1H), 4.08 (t, J = 9.3Hz, 1H), 3.09–2.89 (m, 2H),2.86(d,J=9.5Hz,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). 13CNMR (100MHz, 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 = 37.15Hz), 36.3, 25.1, 24.4, 23.7, 17.4. 19 F NMR(376MHz, 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.

[0119] Example 2 Preparation of Compound 2:

[0120] 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, followed by CH2Cl2 (10 mL). The reaction mixture was allowed to react at room temperature for 2 h. The reaction mixture was filtered through a fritted funnel and diluted with 50 mL of dichloromethane. The organic phase was washed with brine and then dried over anhydrous Na2SO4. The crude product obtained by concentration of the organic phase was purified on a silica gel column (petroleum ether:ethyl acetate = 4:1) to obtain the compound as a white solid. Yield: 325.0 mg, 90%. Melting point: 102-103°C. 1 H NMR(400MHz, CDCl3)δ=5.54(t,J=8.0Hz,1H),3.83(t,J=9.6Hz,1H),3.31–3.19(m,1H),2.79–2.64(m,3H),2.6 4–2.51(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=12.5Hz,1H). 13 C NMR (100MHz, CDCl3): δ = 176.8, 132.6, 131.0 (q, J = 3Hz), 127.6, 81.3, 64.0, 5 9.7,57.9,45.5,43.9,42.2,38.6(q,J=28Hz),36.9,26.6,25.6,24.1,17.9. 19 F NMR (376MHz, CDCl3) δ = -64.78 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for:C18 H 27 F3NO3:362.1938; found:362.1934.

[0121] Example 3 Preparation of Compound 3:

[0122] To a round-bottom flask, compound 2 (361.2 mg, 1 mmol) and citric acid (192.13 mg, 1 mmol) were added, followed by acetone (10 mL). The mixture was allowed to react at room temperature for 0.5 h. The reaction mixture was concentrated to afford a white solid. Yield: 525.5 mg, 95%. Melting point: 69-70°C. 1 H NMR (400MHz, DMSO-d6) δ = 5.57 (t, J = 8.0Hz, 1H), 4.06 (t, J = 9.5Hz, 1H), 3.15–3.01 (m, 1H), 2.98–2.91 (m, 2H), 2.86 (dd, J = 14.3, 9.0Hz, 1H), 2.7 5–2.67(m,4H),2.61(d,J=15.3Hz,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). 13 C NMR (100MHz, DMSO-d6): δ = 176.8, 175.6, 171.4, 132.8, 130.3, 126.8 (d, J = 276Hz), 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 F NMR(376MHz, 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.

[0123] Example 4 Preparation of Compound 4:

[0124] To a round-bottom flask, compound 2 (361.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were added, followed by acetone (10 mL). The mixture was allowed to react at 50°C for 0.5 h. The reaction mixture was concentrated to afford a white solid. Yield: 453.3 mg, 95%. Melting point: 213-214°C. H NMR (400MHz, DMSO-d6) δ = 6.60 (s, 2H), 5.56 (t, J = 8Hz, 1H), 4.03 (t, J = 8Hz, 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 C NMR (100MHz, DMSO-d6): δ = 176.9, 166.4, 134.2, 132.6, 130.5, 126.8 (d, J = 277Hz), 80.6,63.2,59.7,57.4,44.8,42.7,41.9,37.5(q,J=28Hz),36.5,25.3,23.6,17.4. 19 F NMR(376MHz, 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.

[0125] Example 5 Preparation of Compound 5

[0126] Add MMB (132.0 mg, 0.5 mmol), Ph3P (183.6 mg, 0.7 mmol) and ICH2CH2I (197.3 mg, 0.7 mmol) to a Schlenk tube, introduce nitrogen, and then add DMF (3 mL). Stir at room temperature until completely dissolved, then add n Bu4N + I - (277 mg, 0.75 mmol) and acetonitrile (1.5 mL) dissolved in AgSCF3 (314.9 mg, 1.5 mmol). The reaction mixture was stirred at 80°C for 15 minutes. The reaction mixture was cooled to room temperature and filtered through a fritted funnel. The filtrate was concentrated, and the 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 H NMR (400MHz, CDCl3): δ=6.28 (d, J=3.5Hz, 1H), 5.70 (t, J=8.1Hz, 1H), 5.55 (d, J=3.2Hz, 1H), 3.85 (t, J=9.3Hz, 1H), 3.72 (d, J=13.1Hz, 1H), 3.41 (d, J= 13.1Hz,1H),2.82(d,J=9.4Hz,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=12.3Hz,1H). 13 C NMR (100MHz, 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 F NMR (376MHz, CDCl3) δ = -41.13 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for:C 16 H 20 F3O3S:349.1080; found:349.1074.

[0127] Example 6 Preparation of Compound 6:

[0128] Compound 1 (316.1 mg, 1 mmol), N-methylpropylamine (87.8 mg, 1.2 mmol), and potassium carbonate (165.9 mg, 1.2 mmol) were added to a round-bottom flask, followed by MeOH (10 mL) and allowed to react at room temperature for 2 h. The reaction mixture was filtered through a fritted funnel and 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%. 1H NMR (400MHz, CDCl3): δ=5.60–5.49(m,1H),3.83(t,J=9.6Hz,1H),3.25-3.18(m,1H),2.85–2.62(m,4H),2.54–2.40(m,3H),2.3 7–2.23(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=12.5Hz,1H),0.87(t,J=7.4Hz,3H). 13 C NMR (100MHz, 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=38.7Hz),36.8,26.7,25.6,24.0,20.0,17.8,14.1,11.8. 19 F NMR (376MHz, CDCl3): δ = -64.79 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for:C 20 H 31 F3NO3:390.2251; found:390.2247.

[0129] Example 7 Preparation of Compound 7:

[0130] To a round-bottom flask, compound 6 (389.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were added, followed by acetone (10 mL). The mixture was allowed to react at 50°C for 1 h. The resulting solid was concentrated, washed with ethyl acetate, and filtered to afford a white solid. Yield: 252.7 mg, 50%. Melting point: 187-188°C. 1 H NMR (400MHz, DMSO-d6): δ = 6.59 (s, 2H), 5.60–5.53 (m, 1H), 4.01 (t, J = 9.6Hz, 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=20.9,9.5Hz,1H),0.83(t,J=7.4Hz,3H). 13C NMR (100MHz, DMSO-d6): δ=177.2,166.7,134.4,132.8,130.4,80.5,63.1,59.8,59.6,5 6.8,42.9,42.3,41.5,37.8(q,J=28Hz),36.5,25.5(d,J=15Hz),23.6,19.6,17.4,11.7. 19 F NMR (376MHz, 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.

[0131] Example 8 Preparation of Compound 8:

[0132] Compound 1 (316.1 mg, 1 mmol) and tetrahydropyrrole (85.3 mg, 1.2 mmol) were added to a round-bottom flask, followed by DCM (10 mL). The reaction mixture was allowed to react at room temperature for 2 h. The reaction mixture was filtered through a fritted funnel and diluted with 50 mL of dichloromethane. The organic phase was washed with brine and then dried over anhydrous Na2SO4. The crude product obtained by concentration of the organic phase was purified on a silica gel column (petroleum ether:ethyl acetate = 4:1) to obtain the compound as a white solid. Yield: 375.6 mg, 97%. Melting point: 172-173°C. 1 H NMR (400MHz, CDCl3): δ=5.53(t,J=8Hz,1H),3.84(t,J=8Hz,1H),3.29(m,1H),2.99–2.87(m,1H),2.81-2.76(m,1H),2.71(d,J= 9.3Hz,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 C NMR (100MHz, 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 = 29Hz), 36.9, 26.4, 25.5, 24.0, 23.4, 17.8. 19 F NMR (376MHz, CDCl3): δ = -64.83 (s, 3F). HRMS (ESI): m / z [M+H]+ calcd for:C 20 H 29 F3NO3:388.2094; found:388.2088.

[0133] Example 9 Preparation of Compound 9:

[0134] To a round-bottom flask, compound 8 (387.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were added, followed by acetone (10 mL). The mixture was allowed to react at 50°C for 1 h. The resulting solid was concentrated, washed with ethyl acetate, and filtered to afford a white solid. Yield: 387.5 mg, 77%. Melting point: 216-217°C. 1 H NMR (400MHz, DMSO-d6): δ=6.59(s,2H),5.59–5.53(m,1H),4.04(t,J=9.6Hz,1H),3.23-3.17(m,1H),2.97–2.82(m,3H),2.71(dd, J=11.9,7.7Hz,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). 13 C NMR (100MHz, 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=27Hz),36.6,25.2(q,J=5Hz),23.6,23.0,17.4. 19 F NMR (376MHz, DMSO-d6): δ = -63.60.HRMS (ESI): m / z [M+H] + calcd for:C 20 H 29 F3NO3:388.2094; found:388.2091.

[0135] Example 10 Preparation of Compound 10:

[0136] Compound 1 (316.1 mg, 1 mmol), N-methylpiperazine (120.2 mg, 1.2 mmol), and potassium carbonate (165.9 mg, 1.2 mmol) were added to a round-bottom flask, followed by MeOH (10 mL) and allowed to react at room temperature for 2 h. The reaction mixture was filtered through a fritted funnel and diluted with 50 mL of dichloromethane. The organic phase was washed with brine and then dried over anhydrous Na2SO4. The crude product was concentrated and 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 H NMR (400MHz, 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 C NMR (100MHz, 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. 19 F NMR (376MHz, CDCl3): δ = -64.21 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for:C 21 H 32 F3N2O3:417.2360; found:417.2352.

[0137] Example 11 Preparation of Compound 11:

[0138] To a round-bottom flask, compound 10 (416.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were added, followed by acetone (10 mL). The mixture was reacted at 50°C for 1 h. The resulting solid was washed with ethyl acetate and filtered to afford a white solid. Yield: 319.4 mg, 60%. Melting point: 225-226°C. 1H NMR (400MHz, DMSO-d6): δ = 6.59 (s, 2H), 5.65-5.50 (m, 1H), 4.03 (t, J = 9.5Hz, 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=11.0Hz,1H),1.48(s,3H),0.95(t,J=12.3Hz,1H). 13 C NMR (100MHz, DMSO-d6): δ = 177.6, 167.2, 134.9, 133.3, 130.9, 127.3 (q, J = 276Hz), 81.1, 63. 6,60.3,56.4,53.5,51.4,44.0,42.9,42.1,38.5(q,J=10Hz),37.0,26.0,25.8,24.1,17.9. 19 F NMR (376MHz, 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.

[0139] Example 12 Preparation of Compound 12:

[0140] Compound 1 (316.1 mg, 1 mmol), 4-hydroxypiperidine (121.4 mg, 1.2 mmol), and potassium carbonate (165.9 mg, 1.2 mmol) were added to a round-bottom flask, followed by MeOH (10 mL). The reaction mixture was allowed to react at room temperature for 2 h. The reaction mixture was filtered through a fritted funnel and diluted with 50 mL of dichloromethane. The organic phase was washed with brine and then dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to yield the compound as a white solid. Yield: 375.5 mg, 90%. Melting point: 123-124°C. 1H NMR (400MHz, CDCl3): δ = 5.56 (t, J = 8Hz, 1H), 3.84 (t, J = 9.5Hz, 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),1.6 2-1.59(m,1H),1.54-1.53(m,3H),1.51–1.46(m,1H),1.08(t,J=12Hz,1H). 13 C NMR (100MHz, CDCl3): δ=176.9,133.0,130.8,81.2,63.8,59.9,57.2,51.1,4 6.6, 43.4, 42.6, 39.2 (q, J = 29Hz), 36.8, 34.1, 34.0, 26.8, 25.6, 24.1, 17.9. 19 F NMR (376MHz, CDCl3): δ = -64.40 (s, 3F). HRMS (ESI): m / z [M+H] + calcd for:C 21 H 31 F3NO4:418.2200; found:418.2198.

[0141] Example 13 Preparation of Compound 13:

[0142] To a round-bottom flask, compound 12 (417.2 mg, 1 mmol) and fumaric acid (116.1 mg, 1 mmol) were added, followed by acetone (10 mL). The mixture was allowed to react at 50°C for 1 h. The resulting solid was concentrated, washed with ethyl acetate, and filtered to afford a white solid. Yield: 320.0 mg, 60%. Melting point: 198-199°C. 1 H NMR (400MHz, DMSO-d6): δ = 6.59 (s, 2H), 5.58 (t, J = 8Hz, 1H), 4.02 (t, J = 8Hz, 1H), 3.47 (s, 1H), 3.27-3.21 (m, 1H), 3.01–2.89 (m, 1H), 2.74-2.7 0(m,3H),2.65-2.64(m,3H),2.41-2.27(m,3H),2.21–1.91(m,7H),1.7 5-1.65(m,3H),1.47(s,3H),1.43–1.28(m,2H),0.95(t,J=12.3Hz,1H).13 C NMR (100MHz, DMSO-d6): δ = 177.3, 166.8, 134.5, 132.9, 130.6, 126.2 (d, J = 277Hz), 80.6, 63. 3,59.9,57.1,50.7,42.4,42.2,38.1(q,J=27Hz),36.5,34.0,33.8,25.6,25.4,23.7,17.5. 19 F NMR(376MHz,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.

[0143] Example 14 Preparation of Compound 14:

[0144] 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) were added to a Schronck tube and the resulting mixture was stirred at 40° C. for 60 min and then cooled to room temperature.

[0145] MMB (132.0 mg, 0.5 mmol), Ph3P (157.4 mg, 0.6 mmol), and ICH2CH2I (169.1 mg, 0.6 mmol) were added to a Schlenk tube, purged with nitrogen, and then DMF (3 mL) was added. After stirring at room temperature until completely dissolved, the mixture was added to the reaction mixture obtained in the previous step and stirred at room temperature for 12 hours. The reaction mixture was filtered through a fritted funnel. The filtrate was concentrated, and the crude product was purified 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. 1H NMR (400MHz, CDCl3): δ = 6.24 (d, J = 4Hz, 1H), 5.76 (t, J = 8Hz, 1H), 5.56 (d, J = 4Hz, 1H), 3.84 (t, J = 8Hz, 1H), 3.76 (d, J = 12Hz, 1H), 3.44 (d, J = 12Hz, 1H), 2.82(d,J=12Hz,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 C NMR (100MHz, 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.

[0146] Test Example 1 Anticancer Activity Test

[0147] Cells in the logarithmic growth phase were taken, digested, centrifuged and counted, and the volume was adjusted to 1500-3500 cells / well, 95 μL per well, and inoculated into a 96-well plate.

[0148] After continuing to incubate overnight, different concentrations of drug were added, with 10 μL of drug added to each well in replicates of six. After 72 hours of incubation, 10 μL of CCK-8 solution was added to each well (be careful not to create bubbles in the wells, as these will affect the OD reading). The cells were incubated in an incubator for 1-4 hours, and the OD at 450 nm was measured using a microplate reader. The effects of each drug on each cell line were repeated three times at different times.

[0149] Data were processed using Excel to determine the inhibition rate at different concentrations, and SPSS was used to fit the IC50 values. The mean and standard deviation of the three IC50 values ​​were calculated using Excel. Inhibition rate (%) = {1 - (OD value of the drug well - OD value of the blank well) / (OD value of the control well - OD value of the blank well)} * 100%.

[0150] Table 1-1 Compounds' activity in inhibiting cancer cells

[0151] Table 1-2 Compounds inhibit the activity of PANC-1 cells

[0152] Note: PTL is parthenolide, and its structure is as follows:

[0153] Conclusion: The compound has certain effects on brain glioma, lung cancer, colon cancer, liver cancer and pancreatic cancer

[0154] Test Example 2: Experimental study on the release of compound 4 in buffer solution

[0155] Compound 4 was prepared into a test solution of approximately 10 μg / ml using 0.01 M HEPES buffer solution (pH = 7.4). The solution was incubated in a 37°C water bath. Appropriate amounts were removed at 0 h, 0.5 h, 1 h, 2 h, and 4 h. The concentrations of compound 4 and its degradation products were analyzed by HPLC to investigate the release rate of compound 4. The results are shown in Figure 1.

[0156] Conclusion: Compound 4 can slowly release the active substance Compound 1 in a buffer solution (pH = 7.4)

[0157] Test Example 3 Pharmacokinetics and distribution experiments of compound 4 in brain and other tissues

[0158] (1) 48 healthy Bar b / c mice weighing approximately 20 g were divided into three groups: blank control group (6 mice), oral administration group (Compound 4 dosed at 50 mg / kg, 21 mice), and tail vein injection group (Compound 4 dosed at 10 mg / kg, 21 mice).

[0159] (2) Blood samples were collected from the oral gavage 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 mouse eyeballs and placed in an anticoagulant tube containing sodium heparin. The blood was quickly centrifuged at 5000 rpm (4°C) for 10 min to obtain plasma samples. The samples were stored in a -80°C refrigerator and awaited testing. Three mice were included at each time point.

[0160] (3) Fix the mouse on a foam board, pull up the chest skin with tweezers, and use scissors to cut the chest skin and ribs to expose the heart and liver, and cut open the heart and ears. Insert the syringe needle into the left ventricle of the mouse and perfuse with normal saline for 1 minute (10-20 ml) of normal saline until the mouse's limbs, liver, and tongue turn white. Remove the mouse brain: Cut the skin on the head to expose the white skull, cut the cartilage, carefully open the skull cap to expose the white brain, and peel out the brain completely. At the same time, take the pancreas, liver, lungs, rectum and other tissues. Store in a -80℃ refrigerator and wait for detection.

[0161] (4) LC / MS was used to detect the contents of compound 4 and compound 1 in peripheral blood and tissues.

[0162] MS / MS Information

[0163] Note: Tolbutamide is the internal standard for peak area ratio calculation. -4 ] + Peak quantification.

[0164] Here are the results:

[0165] Table 2 Blood concentrations of compound 4 after single oral gavage and intravenous injection (ng / mL)

[0166] Note: The lower limit of quantification is 3 ng / mL; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample.

[0167] Table 3 Blood concentration of active substance Compound 1 after single oral gavage and intravenous injection of Compound 4 (ng / mL)

[0168] Note: The lower limit of quantification is 3 ng / mL; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample.

[0169] Table 4 Concentration of compound 4 in brain tissue after single oral gavage and intravenous injection (ng / g)

[0170] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0171] Table 5 Concentration of compound 4 in pancreatic tissue after single oral gavage and intravenous injection (ng / g)

[0172] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0173] Table 6 Concentration of Compound 4 in the rectum after single oral gavage and intravenous injection (ng / g)

[0174] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that no sample was found.

[0175] Table 7 Concentration of Compound 4 in the liver after single oral gavage and intravenous injection (ng / g)

[0176] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0177] Table 8 Concentration of Compound 4 in the lung after single oral gavage and intravenous injection (ng / g)

[0178] Note: The lower limit of quantification is 13.5 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0179] Table 9 Concentration of compound 1 in brain tissue after single oral gavage and intravenous injection of compound 4 (ng / g)

[0180] Note: The lower limit of quantification is 20 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0181] Table 10 Concentration of compound 1 in pancreatic tissue after single oral gavage and intravenous injection of compound 4 (ng / g)

[0182] Note: The lower limit of quantification is 20 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0183] Table 11 Concentration of Compound 1 in the rectum after single oral gavage and intravenous injection of Compound 4 (ng / g)

[0184] Note: The lower limit of quantification is 20 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0185] Table 12 Concentration of Compound 1 in the liver after single oral gavage and intravenous injection of Compound 4 (ng / g)

[0186] Note: The lower limit of quantification is 20 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0187] Table 13 Concentration of Compound 1 in the lung after single oral gavage and intravenous injection of Compound 4 (ng / g)

[0188] Note: The lower limit of quantification is 20 ng / g; "-" indicates that the value cannot be estimated; "*" indicates that the value is estimated; "NA" indicates not applicable. "NS" indicates that there is no sample

[0189] Table 14 Comparison of exposure levels in plasma and tissues after single oral gavage and intravenous injection of compound 4

[0190] The results showed that the compound of the present invention has a higher concentration distribution in various tissues (especially liver tissue).

[0191] The above is an exemplary description of the implementation methods of the technical solutions disclosed herein. It should be understood that the scope of protection of the present disclosure is not limited to the above-mentioned implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the scope of protection 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 with 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, 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 unsubstituted or optionally substituted by one, two or more Rs x substituted groups: 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 5- to 8-membered heterocyclic group by one, two or more R 32 substituted; Preferably, R3 and R4 are the same or different and are independently selected from H, methyl, ethyl, propyl; alternatively, 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 groups; Preferably, each R 32 is the same or different and 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, For 4. The compound according to any one of claims 1-3, its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, 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 by the compound of formula (I), and the inorganic acid or the 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. The compound, deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or 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, and 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, and 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 shown in formula (I) is selected from the following structures: The pharmaceutically acceptable salts of the compound represented by formula (I) are 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: Add triphenylphosphine and haloalkane to a solution of compound a, and then add Cu and a trifluoromethylating reagent to obtain the compound shown in formula (I); Wherein, X, Y, R1, and R2 have the definitions described in any one of claims 1-6; The haloalkane is, for example, a dihaloalkane, preferably iodomethane, iodoethane, diiodomethane, diiodoethane; The trifluoromethylation reagent is, for example, methyl fluorosulfonyldifluoroacetate; Preferably, when in formula (I) For When, 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) For When it is, it is denoted as (I'), when in formula (I) For When it 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 the 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. Use of the compound according to any one of claims 1-6, its deuterated compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to claim 9 in the preparation of a drug; Preferably, the drug is a drug for treating cancer; 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, external 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.

Images