Nitrogen-containing heterocyclic ring compound containing unsaturated ketone structure as well as pharmaceutical composition and application of nitrogen-containing heterocyclic ring compound

Abstract

The invention provides a nitrogen-containing heterocyclic ring compound containing an unsaturated ketone structure, or a pharmaceutically acceptable salt or a stereoisomer or a prodrug molecule thereof, and a pharmaceutical composition and application thereof. The nitrogen-containing heterocyclic ring compound has a structure as shown in a formula (I) or a formula (II). The compound provided by the invention can effectively degrade RIOK2 protein, and has good inhibitory activity on various tumor cells. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly relates to nitrogen-containing heterocyclic compounds containing an unsaturated ketone structure, their pharmaceutical compositions and uses. Background Art

[0002] Malignant tumors (cancers) are a major category of serious diseases and have become the most lethal "killers" of humans. Conventional treatment methods for cancer, including radiotherapy, chemotherapy, surgical resection, various other treatment approaches, and drug discovery, etc., although bring hope to cancer patients, often have many drawbacks, including large side effects, poor treatment effects, recurrence of tumors after prognosis, metastasis, etc. Therefore, there is an urgent need for new treatment technologies to solve such bottleneck problems. Individualized treatment and targeted therapy are regarded as the hope for breaking through the current bottleneck of cancer treatment in recent years.

[0003] Targeted protein degradation provides a solution for traditionally undruggable pathogenic proteins. Currently, there are mainly two medicinal chemistry strategies for targeted protein degradation: heterobifunctional proteolysis-targeting chimeras (PROTACs) and monovalent molecular glue degraders. Both of these methods can induce the proximity of E3 ubiquitin ligase to the target protein, resulting in the ubiquitination of the protein and degrading the target protein in a proteasome-dependent manner. The design of PROTAC is relatively modular, which is composed of a target protein-targeting ligand linked to an E3 ubiquitin ligase ligand through a "Linker". The discovery of new molecular glue degraders mostly comes from the contingency of phenotypic screening or through specific and well-characterized E3 ligase-targeting ligands (such as Cereblon). By rational medicinal chemistry design principles, the protein-targeting ligand is transformed into a degrader to achieve protein degradation.

[0004] RIOK protein kinases (RIOKs) are a class of evolutionarily conserved atypical protein kinases that are widely present in all eukaryotes, as well as most archaea and prokaryotes. Currently, three subtypes have been discovered. Among them, RIOK1 and RIOK2 are found in all eukaryotes, while in some higher eukaryotes, RIOK3 also exists. These kinases are components of the 40S ribosomal precursor and play different functions at different stages during the generation of 40S ribosomes. For example, the deletion of RIOK1 or RIOK2 will prevent the maturation of 40S ribosomes. Although RIOKs have a protein kinase domain, they lack the substrate-binding regions present in other eukaryotic protein kinases, including the activation loop. Studies have shown that the main function of RIOKs is to act as ATP hydrolases. RIOK2 is highly expressed in various types of cancers. In patients with non-small cell lung cancer, the high expression of RIOK2 is significantly correlated with the malignancy of the final outcome. The normal progression of the cell cycle depends on protein translation, but whether RIOK2 simply enhances ribosome assembly ability through high expression to promote protein synthesis or has obtained other oncogenic functions to promote ribosome assembly remains to be further studied. Currently, there is some evidence indicating that RIOK1 and RIOK2 can promote cell proliferation and survival, and their expression is related to the oncogenic AKT signaling pathway. RIOK1 and RIOK2 may also play roles in downstream signaling pathways such as PI3Ks kinases and receptor tyrosine kinases including EGFR.

[0005] Given the high expression of RIOK2 in various types of cancers, the development of small molecule inhibitors against RIOK2 helps to understand the functions of the RIOK family in cells and is expected to develop new targeted anti-tumor drugs. In 2019, researchers from the University of Oxford, Eli Lilly and Company, and the Federal University of Ceará collaborated to report the crystal structure of a small molecule inhibitor binding to human RIOK2. This laid the foundation for the development of selective small molecule inhibitors of RIOK2. However, the small molecule inhibitors they reported have relatively weak inhibitory activity against RIOK2. At the same time, there is no report on the degraders of RIOK2 kinase, so the development of relevant kinase degraders is of great significance. Summary of the Invention

[0006] To address the above problems, the present invention provides a series of nitrogen-containing heterocyclic compounds with a carbonyl structure at the end. This series of compounds can effectively degrade RIOK2 protein and have good inhibitory activity against various tumor cells.

[0007] The present invention includes the following technical solutions.

[0008] A nitrogen-containing heterocyclic compound containing an unsaturated ketone structure having the structure shown in formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof:

[0009]

[0010] Wherein D is N or CR7;

[0011] X1 and X2 are each independently selected from: N, CR8;

[0012] X3, X4, X5, X6, X7, X8, X9 are each independently selected from: N, CR9;

[0013] n is selected from: 0, 1, 2, 3, 4;

[0014] R1 is selected from: H, One or more R 11 Substituted or unsubstituted C1-C 18 Alkyl, one or more R 11 Substituted or unsubstituted C3-C 18 Cycloalkyl, one or more R 11 Substituted or unsubstituted C6-C 18 Aryl, one or more R 11 Substituted or unsubstituted 5- to 18-membered heteroaryl;

[0015] R'1 is selected from: H, one or more R 11 Substituted or unsubstituted C1-C 18 Alkyl; or R1 and R'1 are linked together to form a saturated or unsaturated C3-C 18 Cycloalkyl;

[0016] The dashed line between R1 and R'1 represents a carbon-carbon single bond or none;

[0017] R2 is selected from: H, halogen, C1-C 18 Alkyl, halogen-substituted C1-C 18 Alkyl, C3-C 18 Cycloalkyl, 3- to 18-membered heterocycloalkyl, C1-C 18 Alkoxy, C3-C8 cycloalkylalkoxy, C1-C 18 Alkylamino, C3-C8 cycloalkylalkylamino, amino, hydroxy, cyano, nitro, ester group, amide group, sulfonyl group, sulfonamido group, C6-C 18 Aryl, C6-C 18 Aryl-substituted C1-C 18 Alkyl, 5- to 18-membered heteroaryl;

[0018] R3 and R4 are each independently selected from: H, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C1-C8 alkyl acyl; or R3, R4 and the N atom to which they are attached together form R 12 A substituted or unsubstituted 4-8 membered heteroalkyl;

[0019] R5 is selected from: H, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl; or R5 and R3 are joined to form a 3-8 membered heteroalkyl; or R5 and R4 are joined to form a 3-8 membered heteroalkyl; or R5 and R 12 Are joined to form a 3-8 membered heteroalkyl;

[0020] R6 is selected from: H, halogen, C1-C 18 Alkyl, C3-C 10 Cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 Alkoxy, halogen substituted C1-C 18 Alkoxy, C3-C8 cycloalkylalkoxy, C1-C 18 Alkylamino, C3-C8 cycloalkylalkylamino, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, 5-18 membered heteroaryl;

[0021] Each R7 is independently selected from: H, halogen, C1-C 18 Alkyl, C3-C 18 Cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 Alkoxy, C1-C 18 Alkylamino, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 Aryl, C6-C 18 Aryl substituted C1-C 18 Alkyl, 5-18 membered heteroaryl;

[0022] Each R8 is independently selected from: H, halogen, C1-C 18 Alkyl, C3-C 18 Cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 Alkoxy, C1-C 18 Alkylamino, halogen substituted C1-C 18 Alkyl, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 Aryl, C6-C 18 Aryl substituted C1-C 18 Alkyl, 5-18 membered heteroaryl;

[0023] Each R9 is independently selected from: H, halogen, C1-C 18alkyl, C3-C 18 cycloalkyl, 3- to 18-membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, halogen-substituted C1-C 18 alkyl, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, 5- to 18-membered heteroaryl;

[0024] R 10 selected from: H, one or more R 11 substituted or unsubstituted C1-C 18 alkyl, one or more R 11 substituted or unsubstituted C3-C 18 cycloalkyl, one or more R 11 substituted or unsubstituted 3- to 18-membered heteroalkyl, one or more R 11 substituted or unsubstituted C6-C 18 aryl, one or more R 11 substituted or unsubstituted 5- to 18-membered heteroaryl;

[0025] each R 11 independently selected from: H, halogen, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3- to 18-membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, halogen-substituted C1-C 18 alkyl, halogen-substituted C1-C 18 alkoxy, amino, hydroxy, cyano, nitro;

[0026] each R 12 independently selected from: H, C1-C 18 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heteroalkyl, C1-C8 alkyl acyl, sulfonyl, C6-C 18 aryl-substituted C1-C8 alkyl.

[0027] In some embodiments, R1 is selected from: H, R 11 substituted or unsubstituted C1-C6 alkyl, R 11 substituted or unsubstituted C3-C8 cycloalkyl, R 11 substituted or unsubstituted C6-C 10 aryl, R 11 substituted or unsubstituted 5- to 10-membered heteroaryl;

[0028] R’1 is selected from: H, R 11 substituted or unsubstituted C1-C6 alkyl; or R1 and R’1 are linked together to form a saturated or unsaturated C3-C8 cycloalkyl.

[0029] In some embodiments, R1 is selected from: H, R 11 substituted or unsubstituted phenyl, R 11 substituted or unsubstituted naphthyl, R 11 substituted or unsubstituted 5-6 membered heteroaryl;

[0030] R’1 is selected from: H, R 11 substituted or unsubstituted C1-C3 alkyl; or R1 and R’1 are linked together to form a saturated or unsaturated C5-C8 cycloalkyl.

[0031] In some embodiments, R1 and R’1 are linked together to form a saturated or unsaturated C5-C6 cycloalkyl.

[0032] In some embodiments, the nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure has the structure shown in formula (III) or formula (IV):

[0033]

[0034] In some embodiments, X1 is selected from: N, CR8; X2 is CR8; X3 is N; X4 and X5 are each independently selected from: N, CR9; X6 is CR9; X7, X8, and X9 are each independently selected from: CR9.

[0035] In some embodiments, X1 is CH; X2 is CR8; X3 is N; X4, X5, X6, X7, X8, and X9 are all CH.

[0036] In some embodiments, the nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure has the structure shown in formula (V) or formula (VI):

[0037]

[0038] wherein, D is N or CR7.

[0039] In some embodiments, R3 and R4 are each independently selected from: H, C1-C3 alkyl, C1-C3 alkyl acyl; or R3, R4 and the N atom connected thereto together form R 12 substituted or unsubstituted 5-6 membered heterocycloalkyl.

[0040] In some embodiments, R5 is selected from: H, C1-C3 alkyl; or R5 and R3 are connected to form a 5-6 membered heteroalkyl ring; or R5 and R4 are connected to form a 5-6 membered heteroalkyl ring; or R5 and R 12 are connected to form a 5-6 membered heteroalkyl ring.

[0041] In some embodiments, R5 and R3 are connected to form a 5-6 membered heteroalkyl ring, and R4 is selected from: H, C1-C3 alkyl.

[0042] In some embodiments, the nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure has the structure shown in formula (VII) or formula (VIII):

[0043] Wherein, R5 is preferably selected from: H, C1-C3 alkyl.

[0044] In some embodiments, the nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure has the structure shown in formula (IX) or formula (X):

[0045]

[0046] Preferably, R4 is selected from: H, C1-C3 alkyl.

[0047] In some embodiments, R 10 is selected from: H, one or more R 11 substituted or unsubstituted C1-C6 alkyl, one or more R 11 substituted or unsubstituted C3-C8 cycloalkyl, one or more R 11 substituted or unsubstituted 3-8 membered heteroalkyl, one or more R 11 substituted or unsubstituted C6-C 10 aryl, one or more R 11 substituted or unsubstituted 5-10 membered heteroaryl.

[0048] In some embodiments, R 10 is selected from: H, one or more R 11 substituted or unsubstituted phenyl, one or more R 11 substituted or unsubstituted naphthyl, one or more R 11 substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl is preferably selected from: pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, pyridazinyl.

[0049] In some embodiments, R 10 is selected from: one or more R 11 substituted or unsubstituted phenyl, one or more R11 Substituted or unsubstituted furyl group.

[0050] In some embodiments, R 10 is selected from: Furyl group.

[0051] In some embodiments, each R 11 is independently: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, amino, hydroxy, cyano, nitro.

[0052] In some embodiments, each R 11 is independently: H, halogen, C1-C3 alkyl, C5-C8 cycloalkyl, 5-8 membered heterocycloalkyl, methoxy, ethoxy, n-propoxy, isopropoxy, C1-C3 alkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, amino, hydroxy, cyano, nitro.

[0053] In some embodiments, each R 11 is independently: H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl, cyclohexyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, monofluoromethoxy, monofluoroethoxy, amino, hydroxy, cyano, nitro.

[0054] In some embodiments, each R 12 is independently selected from: H, C1-C6 alkyl, C5-C8 cycloalkyl, 5-8 membered heterocycloalkyl, C1-C6 alkyl acyl, sulfonyl, phenyl-substituted C1-C6 alkyl.

[0055] In some embodiments, each R 12 is independently selected from: H, C1-C3 alkyl.

[0056] In some embodiments, R2 is selected from: H, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, preferably methoxy.

[0057] In some embodiments, R6 is selected from: H, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, preferably methoxy.

[0058] In some of these embodiments, each R7 is independently selected from: H, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy.

[0059] In some of these embodiments, each R8 is independently selected from: H, fluorine, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, amino, hydroxyl, cyano, nitro, phenyl.

[0060] In some of these embodiments, each R8 is independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, fluoromethyl, fluoroethyl, cyclohexyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, fluoromethoxy, fluoroethoxy, amino, hydroxyl, cyano, nitro.

[0061] In some of these embodiments, each R9 is independently selected from: H, halogen, C1-C3 alkyl.

[0062] The present invention also provides the use of the nitrogen-containing heterocyclic compounds containing an unsaturated ketone structure as described above, including the following:

[0063] Use of the nitrogen-containing heterocyclic compounds containing an unsaturated ketone structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof as described in the present invention in the preparation of an RIOK2 inhibitor or an RIOK2 degrader.

[0064] Use of the nitrogen-containing heterocyclic compounds containing an unsaturated ketone structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof as described in the present invention in the preparation of a drug for preventing and / or treating a disease associated with high expression of RIOK2.

[0065] In some of these embodiments, the disease associated with high expression of RIOK2 is a tumor.

[0066] Use of the nitrogen-containing heterocyclic compounds containing an unsaturated ketone structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof as described in the present invention in the preparation of a drug for preventing and / or treating a tumor.

[0067] In some of these embodiments, the tumor is: non-small cell lung cancer, colon cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, skin squamous cell carcinoma, ovarian cancer.

[0068] The present invention also provides a pharmaceutical composition for treating and / or preventing tumors, which is prepared from an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient includes the nitrogen-containing heterocyclic compound containing an unsaturated ketone structure described in the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof.

[0069] The nitrogen-containing heterocyclic compound with a carbonyl structure at the end provided by the present invention has a good inhibitory or degradative effect on RIOK2 protein, and can highly actively inhibit the proliferation of various tumor cells. In particular, the compound with an unsaturated 1,4-dicarbonyl group at the end has better activity. Moreover, the compounds of the present invention have good pharmacokinetic properties, good cell and in vivo activities, and high bioavailability, and are expected to become small molecule anti-tumor drugs with development prospects. Description of the Drawings

[0070] Figure 1 It is the test result that compound 4 effectively induces the degradation of RIOK2 protein in MOLT4 cells and reduces the half-life. Detailed Embodiments

[0071] In the compounds of the present invention, when any variable (such as R8, R9, etc.) appears more than once in any component, its definition each time is independent of the definition of each other occurrence. Similarly, combinations of substituents and variables are allowed, as long as such combinations render the compound stable. The line drawn from a substituent into the ring system indicates that the bond referred to can be attached to any ring atom capable of being substituted. If the ring system is polycyclic, it means that such a bond is only attached to any appropriate carbon atom of the adjacent ring. It is to be understood that those of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention to provide compounds that are chemically stable and can be easily synthesized from readily available starting materials by the techniques of the art and the methods presented below. If a substituent itself is substituted by more than one group, it is to be understood that these groups can be on the same carbon atom or different carbon atoms, as long as the structure is stable.

[0072] As used herein, the term "alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, the definition of "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight-chain or branched-chain manner. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0073] As used herein, the term "cycloalkyl" means a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon group whose ring atoms are composed of carbon atoms, and bicyclic or polycyclic includes spiro rings, fused rings, and bridged rings. For example: "cycloalkyl" includes, but is not limited to, the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0074] As used herein, the term "alkoxy" refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0075] As used herein, the term "heterocycloalkyl" or "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring substituent (including spiro, bridged, fused, annulated, etc.), wherein one or more ring atoms are heteroatoms selected from N, O or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Bicyclic or polycyclic rings include spiro, fused and bridged rings. For example: morpholinyl, piperidinyl, pyrrolidinyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and their N-oxides. The connection of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom.

[0076] As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S, and the aromatic ring can be monocyclic, bicyclic or polycyclic. For example, but not limited to: quinolinyl, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, etc.; "heteroaryl" is also understood to include any N-oxide derivative of a heteroaryl containing nitrogen. The connection of the heteroaryl can be achieved through a carbon atom or through a heteroatom.

[0077] As will be understood by those skilled in the art, "halo" or "halogen" as used herein means chlorine, fluorine, bromine and iodine.

[0078] The present invention includes free forms of compounds of Formulae I-X, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to amine compounds in non-salt form. The pharmaceutically acceptable salts included herein not only include the exemplary salts of the specific compounds described herein, but also include typical pharmaceutically acceptable salts of all free forms of compounds of Formulae I-X. The free forms of the specific salts of the compounds can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free form differs somewhat from its respective salt form in certain physical properties such as solubility in polar solvents, but for the purposes of the invention, such acid and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0079] The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired salt form of an inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0080] Accordingly, the pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reaction of the basic compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, trifluoroacetic acid, etc.

[0081] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared with pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, said bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, pyrrolidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0082] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. ’1977:66:1-19 more particularly describes the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0083] Since under physiological conditions the deprotonated acidic moiety in the compound, such as a carboxyl group, can be anionic, and this resulting charge can then be balanced and counteracted by a protonated or alkylated basic moiety bearing a cation internally, such as a quaternary nitrogen atom, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.

[0084] In one embodiment, the present invention provides a method for treating hyperproliferative diseases or conditions such as tumors in humans or other mammals using a compound of formula I-X and its pharmaceutically acceptable salts.

[0085] In one embodiment, the compounds of the present invention and their pharmaceutically acceptable salts can be used for treating or controlling hyperproliferative diseases such as non-small cell lung cancer, colon cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, skin squamous cell carcinoma, ovarian cancer, etc.

[0086] The present invention also provides a pharmaceutical composition which comprises an active ingredient in a safe and effective amount range, and a pharmaceutically acceptable carrier or excipient.

[0087] The "active ingredient" as described in the present invention refers to the compound of formula I-X described in the present invention, or its pharmaceutically acceptable salt, or its stereoisomer.

[0088] The "active ingredient" and pharmaceutical composition of the present invention can be used to prepare drugs for preventing and / or treating tumors.

[0089] "Safe and effective amount" means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0090] "Pharmaceutically acceptable carrier or excipient" means one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0091] "Compatibility" here means that the components in the composition can be mixed with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0092] Some examples of pharmaceutically acceptable carriers or excipients are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0093] In another preferred embodiment, the compounds of formula I-X of the present invention can form complexes with macromolecules or polymers through non-bonding interactions. In another preferred embodiment, the compounds of formula I-X of the present invention, as small molecules, can also be connected to macromolecules or polymers through chemical bonds. The macromolecules can be biological macromolecules such as polysaccharides, proteins, nucleic acids, polypeptides, etc.

[0094] There is no particular limitation on the administration mode of the active ingredient or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0095] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0096] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or is mixed with the following components:

[0097] (a) Fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0098] (b) Binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic;

[0099] (c) Humectants, such as glycerol;

[0100] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0101] (e) Sustained-release agents, such as paraffin wax;

[0102] (f) Absorption accelerators, such as quaternary ammonium compounds;

[0103] (g) Wetting agents, such as cetyl alcohol and glycerol monostearate;

[0104] (h) Adsorbents, such as kaolin; and

[0105] (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0106] The solid dosage forms described above can also be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax substances.

[0107] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0108] In addition to the active ingredient, suspensions may contain suspending agents, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar, or mixtures of these substances.

[0109] Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0110] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0111] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for illustrative purposes only.

[0112] The reagents used in the following examples are all commercially available.

[0113] Example 1

[0114] (E)-1-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-(p-tolyl)but-2-ene-1,4-dione (Compound 1)

[0115]

[0116] Synthesis of Compound 1-2a: In a 250 ml reaction flask, Compound 1-1a (2.25 g, 10 mmol), anhydrous piperazine (1.29 g, 15 mmol) and K2CO3 (2.76 g, 20 mmol) were added to 20 ml of DMSO, protected by Ar, and stirred at 80 °C for 4 h. After the reaction was completed, it was cooled to room temperature, 100 ml of water was added, and it was extracted with ethyl acetate (100 ml × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 2.36 g of a yellow solid, with a yield of 86%.

[0117] Synthesis of Compound 1-3a: In a 100 ml reaction flask, dissolve Compound 1-2a (2.75 g, 10 mmol) in 10 ml of THF, then add triethylamine (1.67 ml, 12 mmol). After 10 min, add acetic anhydride (1.13 ml, 12 mmol), and stir the reaction at room temperature for 2 h. Extract with dichloromethane (100 ml × 3), wash with water and saturated sodium chloride, combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which is directly used for the next reaction.

[0118] Synthesis of Compound 1-4a: In a 250 ml reaction flask, dissolve Compound 1-3a (3.17 g, 10 mmol), iron powder (2.78 g, 50 mmol), and ammonium chloride (4.28 g, 80 mmol) in 50 ml of EtOH / H2O (4:1), and reflux at 80 °C overnight. After the reaction is completed, filter through diatomaceous earth, add water, and adjust the pH to alkaline with sodium carbonate. Extract with dichloromethane (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, rotary evaporate under reduced pressure to obtain the crude product, and recrystallize to obtain 2.32 g of a light yellow solid with a yield of 81%. 1 HNMR(400MHz,DMSO-d 6 )δ7.08(d,J=8.4Hz,1H),6.89(d,J=2.8Hz,1H),6.77(dd,J=8.4Hz,2.8Hz,1H),3.88-3.97(m,2H),3.68(brs,2H),3.39-3.52(m,2H),2.74-2.79(m,4H),2.10(s,3H);ESI-MS:m / z 288.1[M+H] + .

[0119] Synthesis of Compound 1-5a: At 0 °C, dissolve Compound 1-4a (2.00 g, 7 mmol) in 15 ml of HCl, then add 10 ml of water and stir until dissolved; then, at 0 °C, dropwise add an aqueous solution of 5 ml of NaNO2 (0.68 g, 9.8 mmol) to the mixture, and continue the reaction at 0 °C for 1 h; finally, at 0 °C, dropwise add an aqueous solution of 5 ml of NaN3 (0.64 g, 9.8 mmol) to the mixture, and continue to stir the reaction for 0.5 h. After the reaction is completed, neutralize with an aqueous solution of K2CO3, extract with ethyl acetate (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate at 45 °C under reduced pressure to obtain the crude product, which is purified by column chromatography (dichloromethane:methanol = 50:1 (V / V)) to obtain 1.82 g of a light brown solid with a yield of 83%.

[0120] Synthesis of Compound 1-7a: Compound 1-6a (4.70 g, 10 mmol), Compound 1-5a (3.44 g, 11 mmol), CuI (0.19 g, 1 mmol) and K2CO3 (2.76 g, 20 mmol) were added into a 25 ml reaction flask, protected by Ar, and 20 ml of DMSO was added under heating at 110 °C, followed by stirring the reaction for 4 h. After the reaction was completed, it was cooled to room temperature, quenched with 2 ml of ammonia water, extracted with dichloromethane (50 ml × 3), washed with saturated sodium chloride and water, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate) to obtain 3.41 g of a white solid with a yield of 52%. 1 H NMR(400MHz,DMSO-d 6 )δ7.93(d,J=2.4Hz,1H),7.84(dd,J=8.4Hz,2.4Hz,1H),7.61(d,J=8.4Hz,1H),7.55(dd,J=9.2Hz,J=2.4Hz,1H),7.43(d,J=2.0Hz,1H),7.34(d,J=9.2Hz,1H),7.17(d,J=8.8Hz,2H),6.82(d,J=8.8Hz,2H),3.79-3.94(m,2H),3.75(s,3H),3.67-3.70(m,2H),3.06-3.11(m,4H),2.17(s,3H); ESI-MS: m / z 655.1[M+H] + .

[0121] Synthesis of Compound 1-8a: In a 25 ml reaction flask, Compound 1-7a (3.27 g, 5 mmol) was added to 5 ml of ethanol and 10 ml of concentrated hydrochloric acid, and the reaction was refluxed at 120 °C overnight. After the reaction was completed, water was added, and the mixture was filtered by suction. The filter cake was dried in an oven to obtain the crude product, which was directly used for the next step of the reaction.

[0122] Synthesis of Compound 1-9a: In a 25 ml reaction flask, Compound 1-8a (3.06 g, 5 mmol) was dissolved in TFA (200 mmol) and TfOH (25 mmol), and the mixture was stirred at room temperature overnight. After the reaction was completed, it was quenched with water, and the pH was adjusted to alkaline with saturated sodium bicarbonate. The mixture was filtered by suction, and the filter cake was dried in an oven to obtain the crude product, which was directly used for the next step of the reaction.

[0123] Synthesis of compound CQ-211: Compound 1-9a (0.49 g, 1 mmol), compound 1-10a (0.23 g, 1.5 mmol), (PPh3)4Pd (23 mg, 0.02 mmol) and Cs2CO3 (0.65 g, 2 mmol) were added to a 25 ml reaction flask. Protected by Ar, 20 ml of DMF / H2O (3:1) was then added, and the mixture was refluxed at 80 °C overnight. After the reaction was completed, the reaction was quenched with water, and suction filtration was carried out. The filter cake was purified by column chromatography (methylene chloride: methanol: triethylamine = 100:10:1) to obtain 0.35 g of a white solid with a yield of 67%. 1 H NMR(400MHz,DMSO-d 6 )δ8.31(d,J=2.4Hz,1H),8.20(dd,J=8.4Hz,2.4Hz,1H),8.08(d,J=2.4Hz,1H),7.87-7.94(m,2H),7.56-7.64(m,2H),7.07(d,J=2.0Hz,1H),6.82(d,J=8.4Hz,1H),3.85(s,3H),3.15-3.17(m,8H);ESI-MS:m / z 522.1[M+H] + .

[0124] Synthesis of compound 1: In a 100 ml reaction flask, compound CQ-211 (156.3 mg, 0.3 mmol), compound 1-11a (62.7 mg, 0.33 mmol) and HATU (228 mg, 0.6 mmol) were dissolved in 10 ml of DMF. The solution was cooled to 0 °C, and DIPEA (155 mg, 1.2 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction was quenched with water, and suction filtration was carried out. The filter cake was purified by column chromatography (methylene chloride: methanol: triethylamine = 50:1:1) to obtain 124 mg of a white solid with a yield of 60%. 1 H NMR(400MHz,DMSO-d 6)δ12.05(s,1H),8.33(s,1H),8.20(d,J=8.0Hz,1H),8.10(s,1H),7.98(m,3H),7.92(d,J=8.4Hz,1H),7.83(d,J=15.2Hz,1H),7.65(d,J=8.0Hz,1H),7.59(d,J=8.4Hz,1H),7.51(d,J=15.2Hz,1H),7.41(d,J=6.8Hz,2H),7.09(s,1H),6.85(d,J=7.2Hz,1H),3.84(s,3H),3.83(m,4H),3.11(m,4H),2.42(s,3H); ESI-MS: m / z 694.2 [M+H] + .

[0125] Example 2

[0126] (E)-1-(4-chlorophenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 2)

[0127]

[0128] The synthesis method was referred to Example 1. 150 mg of white solid was obtained with a yield of 72%.

[0129] 1 H NMR (400 MHz, DMSO-d 6 )δ12.04(s,1H),8.32(s,1H),8.20(d,J=7.6Hz,1H),8.09(m,3H),7.98(d,J=8.0Hz,1H),7.92(d,J=8.8Hz,1H),7.80(d,J=15.2Hz,1H),7.66(m,3H),7.59(d,J=8.4Hz,1H),7.53(d,J=15.2Hz,1H),7.09(s,1H),6.85(d,J=7.6Hz,1H),3.84(s,3H),3.82(m,4H),3.11(m,4H); ESI-MS: m / z 714.2 [M+H] + .

[0130] Example 3

[0131] (E)-1-(4-(4-(8-(6-Methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-(4-(trifluoromethyl)phenyl)but-2-ene-1,4-dione (Compound 3)

[0132]

[0133] The synthesis method was referred to Example 1. 150 mg of white solid was obtained with a yield of 72%.

[0134] 1 H NMR(400MHz,DMSO-d 6 )δ12.05(s,1H),8.33(d,J=2.0Hz,1H),8.25(d,J=8.0Hz,2H),8.21(dd,J=8.4,2.4Hz,1H),8.10(d,J=2.4Hz,1H),7.99-7.95(m,3H),7.92(dd,J=8.4,1.6Hz,1H),7.81(d,J=15.2Hz,1H),7.64(dd,J=8.8,2.4Hz,1H),7.59(d,J=8.8Hz,1H),7.56(d,J=15.2Hz,1H),7.10(d,J=2.0Hz,1H),6.85(d,J=8.8Hz,1H),3.85(s,3H),3.83(m,4H),3.11(m,4H); ESI-MS: m / z 748.2[M+H] + .

[0135] Example 4

[0136] (E)-1-(4-Fluorophenyl)-4-(4-(4-(8-(6-Methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 4)

[0137]

[0138] The synthesis method was referred to Example 1. 132 mg of white solid was obtained with a yield of 75%.

[0139] 1 H NMR(400MHz,DMSO-d 6)δ12.04(s,1H),8.32(d,J=2.4Hz,1H),8.24-8.13(m,3H),8.10(d,J=2.4Hz,1H),7.98(d,J=8.8Hz,1H),7.91(dd,J=8.8,2.0Hz,1H),7.83(d,J=15.6Hz,1H),7.64(dd,J=8.4,2.4Hz,1H),7.59(d,J=8.8Hz,1H),7.52(d,J=15.6Hz,1H),7.42(t,J=8.8Hz,2H),7.09(d,J=1.6Hz,1H),6.85(d,J=8.8Hz,1H),3.85(s,3H),3.82(m,4H),3.11(m,4H);ESI-MS:m / z 698.2[M+H] + .

[0140] Example 5

[0141] (E)-1-(3-methoxyphenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 5)

[0142]

[0143] The synthesis method was referred to Example 1. 136 mg of white solid was obtained with a yield of 69%.

[0144] 1 H NMR(400MHz,DMSO-d 6 )δ12.04(s,1H),8.33(d,J=2.4Hz,1H),8.20(dd,J=8.4,2.4Hz,1H),8.10(d,J=2.4Hz,1H),7.98(d,J=8.4Hz,1H),7.91(dd,J=8.4,1.6Hz,1H),7.81(d,J=15.2Hz,1H),7.69-7.62(m,2H),7.58(d,J=8.8Hz,1H),7.55-7.48(m,3H),7.29(dd,J=8.0,2.0Hz,1H),7.09(d,J=2.0Hz,1H),6.85(d,J=8.4Hz,1H),3.86(s,3H),3.85(s,3H),3.82(m,4H),3.11(m,4H);ESI-MS:m / z 710.2[M+H] + .

[0145] Example 6

[0146] (E)-1-(2-Methoxyphenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 6)

[0147]

[0148] The synthesis method was referred to Example 1. 127 mg of white solid was obtained with a yield of 73%.

[0149] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.04 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.8, 2.4 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.8, 2.0 Hz, 1H), 7.64 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 - 7.57 (m, 3H), 7.52 (d, J = 15.2 Hz, 1H), 7.35 (d, J = 15.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.80 (m, 4H), 3.11 (m, 4H); ESI-MS: m / z 710.2 [M+H] + .

[0150] Example 7

[0151] 1-(4-(4-Acryloylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(6-methoxypyridin-3-yl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (Compound 7)

[0152]

[0153] The synthesis method was referred to Example 1. 137 mg of white solid was obtained with a yield of 73%.

[0154] 1 H NMR (400 MHz, DMSO-d 6)δ12.05(s,1H),8.32(d,J=2.0Hz,1H),8.19(d,J=8.4Hz,1H),8.09(d,J=2.0Hz,1H),7.98(d,J=8.8Hz,1H),7.92(dd,J=8.4,2.4Hz,1H),7.66(dd,J=8.4,2.4Hz,1H),7.59(d,J=8.8Hz,1H),7.09(d,J=1.6Hz,1H),6.95 - 6.79(m,2H),6.18(dd,J=16.4,2.0Hz,1H),5.75(dd,J=10.4,2.4Hz,1H),3.87(s,3H),3.77(m,4H),3.06(m,4H); ESI-MS: m / z 576.2[M + H] + .

[0155] Example 8

[0156] (E)-1-(4-(4-(8-(6 - methoxypyridin - 3 - yl)-4 - oxo - 4,5 - dihydro - 1H - [1,2,3]triazolo[4,5 - c]quinolin - 1 - yl)-2-(trifluoromethyl)phenyl)piperazin - 1 - yl)-4-(3-(trifluoromethyl)phenyl)but - 2 - en - 1,4 - dione (Compound 8)

[0157]

[0158] The synthesis method was referred to Example 1. 119 mg of white solid was obtained with a yield of 72%.

[0159] 1 H NMR(400MHz, DMSO - d 6 )δ12.04(s,1H),8.37(d,J=8.0Hz,1H),8.33(d,J=2.4Hz,1H),8.31(s,1H),8.20(dd,J=8.4,2.4Hz,1H),8.11 - 8.08(m,2H),7.98(d,J=8.4Hz,1H),7.92(dd,J=8.8,2.0Hz,1H),7.88(d,J=9.0Hz,1H),7.84(d,J=8.4Hz,1H),7.65(dd,J=8.8,2.4Hz,1H),7.60(d,J=8.4Hz,1H),7.56(d,J=15.2Hz,1H),7.10(d,J=1.6Hz,1H),6.85(d,J=8.4Hz,1H),3.85(s,3H),3.83(m,4H),3.11(m,4H); ESI - MS: m / z748.2[M + H] +.

[0160] Example 9

[0161] (E)-1-(Furan-2-yl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 9)

[0162]

[0163] The synthesis method refers to Example 1. 138 mg of white solid was obtained with a yield of 72%.

[0164] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.20 (dd, J = 8.5, 2.2 Hz, 1H), 8.14 (d, J = 1.1 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = 8.7, 2.0 Hz, 1H), 7.82 (d, J = 3.6 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.60 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.82 (dd, J = 3.6, 1.7 Hz, 1H), 3.85 (s, 3H), 3.82 (m, 4H), 3.11 (m, 4H); ESI-MS: m / z 670.2 [M + H] + .

[0165] Example 10

[0166] (E)-1-(4-Bromophenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 10)

[0167]

[0168] The synthesis method refers to Example 1. 119 mg of white solid was obtained with a yield of 72%.

[0169] 1 H NMR (400 MHz, DMSO-d6 )δ12.05(s,1H),8.33(d,J=2.4Hz,1H),8.20(dd,J=8.8,2.4Hz,1H),8.10(d,J=2.4Hz,1H),8.01 - 7.97(m,3H),7.91(dd,J=8.8,2.0Hz,1H),7.84 - 7.76(m,3H),7.64(dd,J=8.4,2.4Hz,1H),7.58(d,J=8.8Hz,1H),7.53(d,J=15.2Hz,1H),7.09(d,J=1.6Hz,1H),6.85(d,J=8.8Hz,1H),3.85(s,3H),3.82(m,4H),3.11(m,4H); ESI - MS: m / z 758.1[M + H] + .

[0170] Example 11

[0171] 1 - (4 - (4 - (Cyclopent - 1 - ene - 1 - carbonyl)piperazin - 1 - yl)-3 - (trifluoromethyl)phenyl)-8 - (6 - methoxypyridin - 3 - yl)-1,5 - dihydro - 4H - [1,2,3]triazolo[4,5 - c]quinolin - 4 - one (Compound 11)

[0172]

[0173] The synthesis method was referred to Example 1. 115 mg of white solid was obtained with a yield of 61%.

[0174] 1 H NMR(400MHz, DMSO - d 6 )δ12.05(s,1H),8.32(d,J=2.4Hz,1H),8.20(dd,J=8.4,2.4Hz,1H),8.08(d,J=2.4Hz,1H),7.98(d,J=8.8Hz,1H),7.91(dd,J=8.8,2.0Hz,1H),7.66(dd,J=8.4,2.4Hz,1H),7.58(d,J=8.8Hz,1H),7.07(d,J=2.0Hz,1H),6.85(d,J=8.8Hz,1H),6.00 - 5.92(m,1H),3.86(s,3H),3.72(m,4H),3.12 - 2.97(m,4H),2.56 - 2.54(m,2H),2.47 - 2.45(m,2H),1.97 - 1.80(m,2H); ESI - MS: m / z 616.2[M + H] + .

[0175] Example 12

[0176] (E)-1-(3,4-Dimethoxyphenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 12)

[0177]

[0178] The synthesis method was referred to Example 1. 120 mg of white solid was obtained with a yield of 63%.

[0179] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.21 (dd, J = 8.8, 2.4 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.95 - 7.91 (m, 1H), 7.88 (d, J = 15.2 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 (dd, J = 8.8, 2.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 15.2 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.83 (m, 4H), 3.11 (m, 4H); ESI-MS: m / z 740.2 [M + H] + .

[0180] Example 13

[0181] (E)-1-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-(4-nitrophenyl)but-2-ene-1,4-dione (Compound 13)

[0182]

[0183] The synthesis method was referred to Example 1. 119 mg of white solid was obtained with a yield of 63%.

[0184] 11H NMR (400 MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 8.40 - 8.35 (m, 2H), 8.33 (d, J = 2.0 Hz, 1H), 8.30 - 8.27 (m, 2H), 8.23 - 8.17 (m, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.82 (d, J = 15.2 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.61 - 7.54 (m, 2H), 7.10 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H), 3.83 (m, 4H), 3.11 (m, 4H); ESI-MS: m / z 725.2 [M + H] + .

[0185] Example 14

[0186] 1-(4-Methoxyphenyl)-4-(4-(4-(8-(6-Methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)butane-1,4-dione (Compound 14)

[0187]

[0188] The synthesis method was referred to Example 1. 131 mg of white solid was obtained with a yield of 76%.

[0189] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.8, 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.01 - 7.96 (m, 3H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.66 (dd, J = 8.4, 2.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 3.86 (s, 6H), 3.75 - 3.66 (m, 4H), 3.24 (t, J = 6.0 Hz, 2H), 3.12 - 3.02 (m, 4H), 2.78 (t, J = 6.0 Hz, 2H); ESI-MS: m / z 712.2 [M + H] + .

[0190] Example 15

[0191] (E)-1-(4-Ethoxyphenyl)-4-(4-(4-(8-(6-Methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 15)

[0192]

[0193] The synthesis method was referred to Example 1. 118 mg of white solid was obtained with a yield of 71%.

[0194] 1 H NMR(400MHz,DMSO-d 6 )δ12.05(s,1H),8.33(s,1H),8.20(d,J = 9.2Hz,1H),8.10(d,J = 2.0Hz,1H),8.06(d,J = 8.4Hz,2H),7.98(d,J = 8.8Hz,1H),7.92(d,J = 8.8Hz,1H),7.85(d,J = 15.2Hz,1H),7.64(dd,J = 8.4,2.4Hz,1H),7.59(d,J = 8.4Hz,1H),7.49(d,J = 15.2Hz,1H),7.14 - 7.02(m,3H),6.85(d,J = 8.8Hz,1H),4.16(q,J = 6.8Hz,2H),3.85(s,3H),3.82(m,4H),3.11(m,4H),1.37(t,J = 7.2Hz,3H); ESI-MS: m / z 724.2[M + H] + .

[0195] Example 16

[0196] (E)-1-(3,4-Difluorophenyl)-4-(4-(4-(8-(6-Methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 16)

[0197]

[0198] The synthesis method was referred to Example 1. 119 mg of white solid was obtained with a yield of 63%.

[0199] 11H NMR (400 MHz, DMSO-d 6 ) δ 12.04 (s, 1H), 8.33 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.15 - 8.10 (m, 2H), 7.98 - 7.96 (m, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 15.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.59 - 7.52 (m, 2H), 7.09 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.82 (m, 4H), 3.11 (m, 4H); ESI-MS: m / z 716.2 [M+H] + .

[0200] Example 17

[0201] (E)-1-(4-Methoxyphenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 17)

[0202]

[0203] The synthesis method was referred to Example 1. 131 mg of white solid was obtained, with a yield of 72%.

[0204] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.4, 2.0 Hz, 1H), 8.14 - 8.04 (m, 3H), 7.98 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.85 (d, J = 15.2 Hz, 1H), 7.64 (dd, J = 8.4, 2.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 15.2 Hz, 1H), 7.15 - 7.04 (m, 3H), 6.85 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.84 - 3.78 (m, 2H), 3.15 - 3.06 (m, 6H); ESI-MS: m / z 710.2 [M+H] + .

[0205] Example 18

[0206] (E)-1-(4-(4-(8-(6-Methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-phenylbut-2-ene-1,4-dione (Compound 18)

[0207]

[0208] The synthesis method was referred to Example 1. 125 mg of white solid was obtained with a yield of 73%.

[0209] 1 H NMR(400MHz,DMSO-d 6 )δ12.03(s,1H),8.32(d,J=2.4Hz,1H),8.20(dd,J=8.4,2.0Hz,1H),8.10 - 8.05(m,3H),7.98(d,J=8.4Hz,1H),7.90(dd,J=8.4,2.0Hz,1H),7.83(d,J=15.6Hz,1H),7.75 - 7.66(m,1H),7.65 - 7.50(m,5H),7.08(d,J=1.2Hz,1H),6.84(d,J=8.8Hz,1H),3.95 - 3.70(m,7H),3.15 - 3.05(m,4H); ESI-MS: m / z 680.2[M+H] + .

[0210] Example 19

[0211] (E)-1-(4-(4-(6-Methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-(4-(trifluoromethoxy)phenyl)but-2-ene-1,4-dione (Compound 19)

[0212]

[0213] The synthesis method was referred to Example 1. 119 mg of white solid was obtained with a yield of 73%.

[0214] 1 H NMR(400MHz,DMSO-d 6)δ12.05(s,1H),8.33(d,J=2.4Hz,1H),8.22-8.20(m,3H),8.10(d,J=2.4Hz,1H),7.98(d,J=8.8Hz,1H),7.91(dd,J=8.8,2.0Hz,1H),7.82(d,J=15.2Hz,1H),7.64(dd,J=8.8,2.4Hz,1H),7.61-7.50(m,4H),7.09(d,J=1.6Hz,1H),6.85(d,J=8.8Hz,1H),3.84(s,3H),3.83(m,4H),3.11(m,4H); ESI-MS: m / z 764.2[M+H] + .

[0215] Example 20

[0216] (E)-1-(4-(Difluoromethoxy)phenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 20)

[0217]

[0218] The synthesis method was referred to Example 1. 121 mg of white solid was obtained with a yield of 61%.

[0219] 1 H NMR (400 MHz, DMSO-d 6 )δ12.04(s,1H),8.33(d,J=2.4Hz,1H),8.20(dd,J=8.4,2.4Hz,1H),8.18-8.14(m,2H),8.09(d,J=2.4Hz,1H),7.98(d,J=8.8Hz,1H),7.91(dd,J=8.8,2.0Hz,1H),7.84(d,J=15.2Hz,1H),7.64(s,0.25H),7.63(dd,J=6.7,1.9Hz,1H),7.58(d,J=8.7Hz,1H),7.53(d,J=15.2Hz,1H),7.45(s,0.45H),7.36(d,J=8.7Hz,2H),7.27(s,0.25H),7.09(d,J=1.9Hz,1H),6.85(d,J=8.6Hz,1H),3.84(s,3H),3.83(m,4H),3.11(m,4H); ESI-MS: m / z 746.2[M+H]+ .

[0220] Example 21

[0221] (E)-1-(4-Isopropoxyphenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 21)

[0222]

[0223] The synthesis method was referred to Example 1. 119 mg of white solid was obtained with a yield of 63%.

[0224] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.04 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.4, 2.0 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.8, 2.0 Hz, 1H), 7.84 (d, J = 15.2 Hz, 1H), 7.64 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 15.2 Hz, 1H), 7.09 - 7.06 (m, 3H), 6.85 (d, J = 8.8 Hz, 1H), 4.79 (dt, J = 12.0, 6.0 Hz, 1H), 3.85 (s, 3H), 3.83 (m, 4H), 3.11 (m, 4H), 1.31 (d, J = 6.0 Hz, 6H); ESI-MS: m / z 738.3 [M + H] + .

[0225] Example 22

[0226] (E)-1-(2-Fluorophenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 22)

[0227]

[0228] The synthesis method was referred to Example 1. 115 mg of white solid was obtained with a yield of 63%.

[0229] 1 H NMR(400 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.4, 2.4 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 8.8, 2.0 Hz, 1H), 7.84 (td, J = 7.6, 2.0 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.65 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 4.4, 2.0 Hz, 2H), 7.42 (ddd, J = 12.4, 9.6, 5.6 Hz, 2H), 7.09 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H), 3.81 (m, 4H), 3.10 (m, 4H); ESI-MS: m / z 698.2 [M + H] + .

[0230] Example 23

[0231] (E)-1-(2-Ethoxyphenyl)-4-(4-(4-(8-(6-Methoxypyridin-3-yl)-6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 23)

[0232]

[0233] The synthesis method was referred to Example 1. 119 mg of white solid was obtained with a yield of 65%.

[0234] 1 H NMR(400 MHz, DMSO-d 6)δ12.05(s,1H),8.33(d,J=2.4Hz,1H),8.20(dd,J=8.4,2.4Hz,1H),8.10(d,J=2.4Hz,1H),7.97(d,J=8.8Hz,1H),7.92(dd,J=8.8,2.0Hz,1H),7.68 - 7.63(m,1H),7.63 - 7.53(m,4H),7.36(d,J=15.2Hz,1H),7.21(d,J=8.4Hz,1H),7.08(dd,J=9.2,4.4Hz,2H),6.86(d,J=8.8Hz,1H),4.19(q,J=7.2Hz,2H),3.85(s,3H),3.80(m,4H),3.10(m,4H),1.38(t,J=7.0Hz,3H); ESI-MS: m / z 724.2 [M + H] + .

[0235] Example 24

[0236] (E)-1-(4-(2-Chloro-4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)phenyl)piperazin-1-yl)-4-(4-fluorophenyl)but-2-ene-1,4-dione (Compound 24)

[0237]

[0238] The synthesis method was referred to Example 1. A white solid of 123 mg was obtained with a yield of 69%.

[0239] 1 H NMR(400MHz, DMSO-d 6 )δ12.03(s,1H),8.18 - 8.16(m,2H),8.13 - 8.07(m,2H),7.90(d,J = 8.0Hz,1H),7.87 - 7.79(m,2H),7.73 - 7.65(m,1H),7.61 - 7.50(m,3H),7.42(t,J = 8.8Hz,2H),7.17(s,1H),6.88(d,J = 8.4Hz,1H),3.86(m,4H),3.84(s,3H),3.22(m,4H); ESI-MS: m / z 664.2 [M + H] + .

[0240] Example 25

[0241] (E)-1-(4-Fluorophenyl)-4-(4-(2-methoxy-4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 25)

[0242]

[0243] The synthesis method was referred to Example 1. 121 mg of white solid was obtained with a yield of 65%.

[0244] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.98 (s, 1H), 8.21 - 8.12 (m, 2H), 8.07 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 15.2 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.58 - 7.38 (m, 5H), 7.36 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.13 (s, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.83 (d, J = 7.2 Hz, 10H), 3.20 (s, 4H); ESI-MS: m / z 660.2 [M+H] + .

[0245] Example 26

[0246] (E)-1-(4-Fluorophenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-methylphenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 26)

[0247]

[0248] The synthesis method was referred to Example 1. 119 mg of white solid was obtained with a yield of 63%.

[0249] 1 H NMR (400 MHz, DMSO-d 6)δ11.98(s,1H),8.21 - 8.12(m,2H),8.07(s,1H),7.88(d,J=8.8Hz,1H),7.82(d,J=15.2Hz,1H),7.67(d,J=8.8Hz,1H),7.58 - 7.38(m,5H),7.36(d,J=8.4Hz,1H),7.26(d,J=8.4Hz,1H),7.13(s,1H),6.85(d,J=8.8Hz,1H),3.86(m,4H),3.84(s,3H),3.22(m,4H),2.14(s,3H); ESI-MS: m / z 644.2 [M + H] + .

[0250] Example 27

[0251] (E)-1-(4-(2-Fluoro-4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)phenyl)piperazin-1-yl)-4-(4-fluorophenyl)but-2-ene-1,4-dione (Compound 27)

[0252]

[0253] The synthesis method was referred to Example 1. 121 mg of white solid was obtained with a yield of 73%.

[0254] 1 H NMR(400MHz, DMSO-d 6 )δ12.05(s,1H),8.20 - 8.18(m,2H),8.15 - 8.09(m,2H),7.92(d,J=8.0Hz,1H),7.89 - 7.81(m,2H),7.75 - 7.67(m,1H),7.63 - 7.52(m,3H),7.44(t,J=8.8Hz,2H),7.19(s,1H),6.90(d,J=8.4Hz,1H),3.88(m,4H),3.86(s,3H),3.20(m,4H); ESI-MS: m / z 648.2 [M + H] + .

[0255] Example 28

[0256] (R,E)-1-(4-Fluorophenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)but-2-ene-1,4-dione (Compound 28)

[0257]

[0258] The synthesis method was referred to Example 1. 117 mg of white solid was obtained with a yield of 63%.

[0259] 1 H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.0 Hz, 1H), 8.12 - 8.09 (m, 4H), 8.04 - 7.92 (m, 2H), 7.87 (dd, J = 8.4, 1.6 Hz, 1H), 7.71 - 7.50 (m, 4H), 7.22 (t, J = 8.4 Hz, 2H), 6.79 (d, J = 8.8 Hz, 1H), 4.37 (s, 3H), 3.99 (s, 3H), 3.06 - 2.90 (m, 3H), 2.60 - 2.55 (m, 3H), 1.63 (s, 3H); ESI-MS: m / z 726.2 [M + H] + .

[0260] Example 29

[0261] (E)-1-(4-(4-(3-(4-Methoxyphenyl)acryloyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(6-methoxypyridin-3-yl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (Compound 29)

[0262]

[0263] The synthesis method was referred to Example 1. 119 mg of white solid was obtained with a yield of 65%.

[0264] 1 H NMR (400 MHz, DMSO-d 6)δ 12.05 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 8.4, 2.0 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.66 (dd, J = 8.8, 2.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 15.2 Hz, 1H), 7.21 (d, J = 15.2 Hz, 1H), 7.10 (d, J = 1.2 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 3.93 (m, 4H), 3.85 (s, 3H), 3.81 (s, 3H), 3.09 (m, 4H); ESI-MS: m / z 682.2 [M+H] + .

[0265] Example 30

[0266] (E)-1-(4-(4-(4-Methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-(4-methoxyphenyl)but-2-ene-1,4-dione (Compound 30)

[0267]

[0268] Synthesis of Compound 30-3a: In a 250 ml reaction flask, dissolve Compound 30-1a (4.39 g, 13.8 mmol) in 40 ml of DMF, then add Compound 30-2a (4.52 g, 13.09 mmol) and triethylamine (1.59 g, 15.71 mmol), and react at room temperature for 4 hours. After the reaction is completed, cool to room temperature, add 100 ml of water, extract with dichloromethane (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the product, which is directly used for the next step.

[0269] Synthesis of Compound 30-4a: In a 100 ml reaction flask, dissolve anhydrous methanol (5.1 mg, 1.58 mmol) in 15 ml of dry tetrahydrofuran, add NaH (127 mg, 3.18 mmol) and react for 10 minutes, then add Compound 30-3a (500 mg, 0.79 mmol) and react at room temperature for 4 h. After the reaction is completed, add 20 ml of saturated NaHCO3, extract with dichloromethane (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the product, which is directly used for the next step.

[0270] Synthesis of Compound 30-5a: In a 100 ml reaction flask, dissolve Compound 30-4a (427 mg, 0.68 mmol) in 20 ml of acetic acid, then add iron powder (209 mg, 3.74 mmol), and react at 60 °C for 4 hours. After the reaction is completed, filter with diatomaceous earth while it is hot, wash the diatomaceous earth layer with DCM / MeOH = 50 ml:50 ml, rotary evaporate the filtrate, add 100 ml of DCM, adjust the pH to alkaline with saturated Na2CO3 solution, extract with dichloromethane (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the product, which is directly used for the next step.

[0271] Synthesis of Compound 30-6a: Dissolve Compound 30-5a (200 mg, 0.33 mmol) in 5 ml of acetic acid, then add sodium nitrite (22.7 mg, 0.33 mmol) and react at room temperature for 4 h. After the reaction is completed, add 30 ml of water, filter by suction, and dry the filter cake to obtain the product.

[0272] Synthesis of Compound 30-7a: In a 100 ml reaction flask, dissolve Compound 30-6a (149 mg, 0.24 mmol) in 5 ml of DCM, then add trifluoroacetic acid (2.8 g, 24.6 mmol) and react at room temperature for 4 h. After the reaction is completed, adjust the pH to alkaline with saturated Na2CO3 solution, extract with dichloromethane (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the product.

[0273] Synthesis of Compound 30-9a: Add Compound 30-7a (111 mg, 0.19 mmol), Compound 30-8a (51 mg, 0.33 mmol), (PPh3)4Pd (5 mg, 0.0044 mmol), and Cs2CO3 (215 mg, 0.66 mmol) to a 25 ml reaction flask, protect with argon, then add 20 ml of DMF / H2O (volume ratio 3:1), and reflux at 80 °C overnight. After the reaction is completed, quench with water, filter by suction, and purify the filter cake by column chromatography (dichloromethane:methanol:triethylamine = 100:10:1) to obtain 103 mg of a white solid with a yield of 88%. 1 H NMR (400 MHz, DMSO-d 6)δ8.32(d,J=2.4Hz,1H),8.25-8.16(m,2H),8.09-7.99(m,2H),7.90(d,J=8.4Hz,1H),7.75(dd,J=8.8,2.8Hz,1H),7.41(d,J=1.6Hz,1H),6.85(d,J=8.4Hz,1H),4.26(s,3H),3.88(s,3H),3.11-2.91(m,8H);ESI-MS:m / z 536.2[M+H] + .

[0274] Synthesis of Compound 30: In a 100 ml reaction flask, dissolve Compound 30-9a (156.3 mg, 0.3 mmol), Compound 30-10a (68 mg, 0.33 mmol) and HATU (228 mg, 0.6 mmol) in 10 ml of DMF, cool to 0 °C, add DIPEA (155 mg, 1.2 mmol), and react at room temperature for 4 h. After the reaction is completed, quench with water, filter by suction, and purify the filter cake by column chromatography (dichloromethane:methanol:triethylamine = 50:1:1) to obtain 121 mg of a white solid with a yield of 60%. 1 H NMR(400MHz,DMSO-d 6 )δ8.23(d,J=2.4Hz,1H),8.12-8.08(m,4H),8.04(d,J=14.8Hz,1H),7.95(dd,J=8.8,2.4Hz,1H),7.87(dd,J=8.8,2.0Hz,1H),7.67-7.62(m,3H),7.56(d,J=14.8Hz,1H),7.04-6.99(m,2H),6.80(d,J=8.8Hz,1H),4.37(s,3H),4.04-4.00(m,2H),3.99(s,3H),3.93(s,3H),3.92-3.88(m,2H),3.20-3.12(m,4H);ESI-MS:m / z 724.2[M+H] + .

[0275] Example 31

[0276] (E)-1-(4-Fluorophenyl)-4-(4-(4-(4-Methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 31)

[0277]

[0278] Synthesis of Compound 31-2a: In a 100 ml reaction flask, dissolve Compound 30-5a (377 mg, 0.63 mmol) and PPTS (1.6 mg, 0.0063 mmol) in 5 ml of 31-1a, and react at 105 °C overnight. After the reaction is completed, cool to room temperature, add 20 ml of n-hexane, filter by suction, and rotary evaporate the filter residue to obtain the product. 1 H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.8, 2.8 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.30 (d, J = 2.0 Hz, 1H), 4.28 (s, 3H), 3.74 - 3.56 (m, 4H), 3.04 (m, 4H), 1.51 (s, 9H).

[0279] Synthesis of Compound 31-3a: In a 100 ml reaction flask, dissolve Compound 31-2a (100 mg, 0.16 mmol) in 5 ml of DCM, then add trifluoroacetic acid (1.9 g, 16.5 mmol) and react at room temperature for 4 h. After the reaction is completed, adjust the pH to alkaline with saturated Na2CO3 solution, extract with dichloromethane (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the product.

[0280] Synthesis of Compound 31-5a: Add Compound 31-3a (89 mg, 0.17 mmol), Compound 31-4a (40 mg, 0.255 mmol), (PPh3)4Pd (4 mg, 0.034 mmol) and Cs2CO3 (166 mg, 0.51 mmol) to a 25 ml reaction flask, protect with argon, then add 20 ml of DMF / H2O (volume ratio 3:1), and reflux at 80 °C overnight. After the reaction is completed, quench with water, filter by suction, and purify the filter cake by column chromatography (dichloromethane:methanol:triethylamine = 100:10:1) to obtain 80 mg of a white solid with a yield of 88%. 1 HNMR (400 MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 8.08 (dd, J = 8.4, 2.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.96 - 7.80 (m, 2H), 7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.18 (s, 3H), 3.86 (s, 3H), 3.08 - 2.90 (m, 8H).

[0281] Synthesis of Compound 31: In a 100 ml reaction flask, compound 31-5a (160.3 mg, 0.3 mmol), compound 31-6a (64 mg, 0.33 mmol) and HATU (228 mg, 0.6 mmol) were dissolved in 10 ml of DMF. The mixture was cooled to 0 °C, and DIPEA (155 mg, 1.2 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction was quenched with water, and filtration was performed by suction. The filter cake was purified by column chromatography (methylene chloride: methanol: triethylamine = 50:1:1) to obtain 127 mg of a white solid with a yield of 60%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.22 (s, 1H), 8.18 - 8.14 (m, 2H), 8.12 - 8.10 (m, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 15.2 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 15.2 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H), 7.15 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.17 (s, 3H), 3.85 (s, 3H), 3.82 (m, 4H), 3.08 (m, 4H); ESI-MS: m / z 711.2 [M + H] + .

[0282] Example 32

[0283] (E)-1-(4-methoxyphenyl)-4-(4-(4-(8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 32)

[0284]

[0285] Synthesis of Compound 32-2a: In a 100 ml reaction flask, compound 32-1a (5 g, 18.59 mmol) was dissolved in 20 ml of POCl3. The mixture was refluxed at 150 °C for 4 hours. After the reaction was completed, it was cooled to room temperature and then quenched with ice water. The pH was adjusted to alkaline with sodium bicarbonate solution, 100 ml of water was added, and extraction was performed with ethyl acetate (100 ml × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was directly used in the next step.

[0286] Synthesis of Compound 32-4a: In a 100 ml reaction flask, dissolve Compound 32-2a (3.9 g, 13.56 mmol) and Compound 32-3a (3.9 g, 13.56 mmol) in 60 ml of acetic acid, and react overnight at room temperature. After the reaction is completed, add 100 ml of water, extract with dichloromethane (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which is directly used for the next step.

[0287] Synthesis of Compound 32-5a: In a 100 ml reaction flask, dissolve Compound 32-4a (5.39 g, 10 mmol), iron powder (2.79 g, 50 mmol), and ammonium chloride (4.28 g, 80 mmol) in 200 ml of EtOH / H2O (4:1), and reflux at 80 °C overnight. After the reaction is completed, filter through diatomaceous earth, add water, then adjust the pH to alkaline with sodium carbonate, extract with dichloromethane (100 ml × 3), combine the organic layers, dry over anhydrous sodium sulfate, rotary evaporate under reduced pressure to obtain the crude product, and recrystallize to obtain 4 g of a light yellow solid with a yield of 78%.

[0288] Synthesis of Compound 32-6a: Under the condition of 0 °C, dissolve Compound 32-5a (253 mg, 0.5 mmol) in 3M HCl (20 ml). After 10 minutes, add an aqueous solution of 1.2M NaNO2 (5 ml) and react at 45 °C for 1 hour. After the reaction is completed, adjust the pH to alkaline with 1M NaOH, then filter, and the obtained solid is directly used for the next step.

[0289] Synthesis of Compound 32-7a: Dissolve Compound 32-6a (100 mg, 0.19 mmol) in 2 ml of hydrochloric acid and 2 ml of ethanol, and reflux at 120 °C for 4 h. After the reaction is completed, rotary evaporate the ethanol, then adjust the pH to neutral with 1M NaOH solution, then filter, and dry in an oven. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.37 (d, J = 1.2 Hz, 1H), 8.29 - 8.16 (m, 2H), 8.05 (dd, J = 8.8, 1.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 3.25 (m, 8H).

[0290] Synthesis of Compound 32-9a: Under argon protection, compound 32-7a (87 mg, 0.18 mmol), compound 32-8a (42 mg, 0.27 mmol), (Ph3P)4Pd (4.2 mg, 0.004 mmol), and Cs2CO3 (179 mg, 0.55 mmol) were dissolved in 8 ml of DMF and 2 ml of water, and the mixture was stirred at 80 °C for 3 h. After the reaction was completed, it was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol = 5:1) to obtain 70 mg of a yellow solid with a yield of 77%. 1 H NMR(400MHz,DMSO-d 6 )δ9.68(s,1H),8.37-8.35(m,2H),8.31(d,J=2.4Hz,1H),8.23-8.20(m,2H),7.90(d,J=8.8Hz,1H),7.83(d,J=8.8,2.8Hz,1H)7.61(d,J=2.0Hz,1H),6.89(d,J=8.8Hz,1H),3.89(s,3H),3.02-2.94(m,8H);ESI-MS:m / z 506.2[M+H] + .

[0291] Synthesis of Compound 32: In a 100 ml reaction flask, compound 32-9a (151.5 mg, 0.3 mmol), compound 32-10a (68 mg, 0.33 mmol), and HATU (228 mg, 0.6 mmol) were dissolved in 10 ml of DMF, cooled to 0 °C, and DIPEA (155 mg, 1.2 mmol) was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction was quenched with water, and the mixture was filtered by suction. The filter cake was purified by column chromatography (dichloromethane:methanol:triethylamine = 50:1:1) to obtain 124 mg of a white solid with a yield of 60%. 1 H NMR(400MHz,CDCl3)δ9.62(s,1H),8.41(d,J=8.4Hz,1H),8.26(s,1H),8.09-8.04(m,3H),8.00-7.94(m,3H),7.80(s,1H),7.68-7.64(m,2H),7.54(d,J=14.8Hz,1H),7.00(d,J=8.8Hz,2H),6.81(d,J=8.4Hz,1H),3.98(m,5H),3.90(m,5H),3.16(m,4H);ESI-MS:m / z 694.2[M+H] + .

[0292] Example 33

[0293] (E)-N-(1-(4-(4-Methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)-N-methyl-4-oxo-4-phenylbut-2-enamide (Compound 33)

[0294]

[0295] The synthesis method refers to Example 30. 40 mg of white solid was obtained with a yield of 68%.

[0296] 1 H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.7 Hz, 1H), 8.12 - 7.94 (m, 5H), 7.87 (ddd, J = 13.5, 8.5, 2.4 Hz, 2H), 7.63 (tdd, J = 14.6, 7.1, 3.7 Hz, 4H), 7.56 - 7.49 (m, 3H), 6.76 (d, J = 8.5 Hz, 1H), 4.35 (s, 3H), 3.95 (d, J = 5.7 Hz, 3H), 3.35 (d, J = 11.6 Hz, 2H), 3.17 - 2.96 (m, 5H), 2.30 - 2.12 (m, 1H), 2.03 (qd, J = 12.1, 4.1 Hz, 2H), 1.85 (s, 2H), 1.61 (s, 6H). ESI-MS: m / z 721.4 [M + H] + .

[0297] Example 34

[0298] (E)-4-(4-Fluorophenyl)-N-(1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)-N-methyl-4-oxobut-2-enamide (Compound 34)

[0299]

[0300] The synthesis method refers to Example 30. 70 mg of white solid was obtained with a yield of 70%.

[0301] 11H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.7 Hz, 1H), 8.12 - 7.94 (m, 5H), 7.87 (ddd, J = 13.5, 8.5, 2.4 Hz, 2H), 7.63 (tdd, J = 14.6, 7.1, 3.7 Hz, 4H), 7.56 - 7.49 (m, 3H), 6.76 (d, J = 8.5 Hz, 1H), 4.35 (s, 3H), 3.95 (d, J = 5.7 Hz, 3H), 3.35 (d, J = 11.6 Hz, 2H), 3.17 - 2.96 (m, 5H), 2.30 - 2.12 (m, 1H), 2.03 (qd, J = 12.1, 4.1 Hz, 2H), 1.85 (s, 2H), 1.61 (s, 6H). ESI-MS: m / z 721.4 [M+H] + .

[0302] Example 35

[0303] (E)-N-(1-(4-(4-Methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)-4-(4-methoxyphenyl)-N-methyl-4-oxobut-2-enamide (Compound 35)

[0304]

[0305] The synthesis method refers to Example 30. 63 mg of white solid was obtained with a yield of 76%.

[0306] 1 1H NMR (400 MHz, CDCl3) δ δ 8.23 (t, J = 3.2 Hz, 1H), 8.14 - 7.95 (m, 5H), 7.94 - 7.80 (m, 2H), 7.72 - 7.45 (m, 4H), 6.99 (d, J = 8.5 Hz, 2H), 6.76 (dd, J = 8.4, 2.0 Hz, 1H), 4.80 (tt, J = 12.3, 4.2 Hz, 1H), 4.34 (s, 3H), 3.95 (d, J = 8.6 Hz, 3H), 3.90 (s, 3H), 3.35 (d, J = 11.3 Hz, 2H), 2.32 - 2.09 (m, 1H), 2.03 (qd, J = 11.9, 3.9 Hz, 1H), 1.85 (t, J = 12.8 Hz, 2H). ESI-MS: m / z 751.7 [M+H] + .

[0307] Example 36

[0308] (E)-4-(4-Ethoxyphenyl)-N-(1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)-N-methyl-4-oxobut-2-enamide (Compound 36)

[0309]

[0310] The synthesis method was referred to Example 30. 104 mg of white solid was obtained with a yield of 79%.

[0311] 1 H NMR (400 MHz, CDCl3) δ 8.25 (t, J = 3.1 Hz, 1H), 8.16 - 7.97 (m, 5H), 7.95 - 7.82 (m, 2H), 7.73 - 7.49 (m, 4H), 6.99 (d, J = 8.5 Hz, 2H), 6.78 (dd, J = 8.4, 2.1 Hz, 1H), 4.82 (tt, J = 12.4, 4.3 Hz, 1H), 4.36 (s, 3H), 4.15 (q, J = 7.0 Hz, 2H), 3.97 (d, J = 8.5 Hz, 3H), 3.37 (d, J = 11.2 Hz, 2H), 3.15 (s, 2H), 3.13 - 3.02 (m, 3H), 2.30 - 2.16 (m, 1H), 2.05 (qd, J = 12.0, 3.8 Hz, 1H), 1.87 (t, J = 13.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H). ESI-MS: m / z 765.9 [M + H] + .

[0312] Example 37

[0313] (E)-N-(1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)-4-(2-methoxyphenyl)-N-methyl-4-oxobut-2-enamide (Compound 37)

[0314]

[0315] The synthesis method was referred to Example 30. 80 mg of white solid was obtained with a yield of 83%.

[0316] 11H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.6 Hz, 1H), 8.12 - 7.98 (m, 2H), 7.94 - 7.78 (m, 3H), 7.76 - 7.35 (m, 6H), 7.10 - 6.96 (m, 2H), 6.76 (dd, J = 8.7, 3.7 Hz, 1H), 4.86 - 4.71 (m, 1H), 4.35 (s, 3H), 3.95 (d, J = 5.6 Hz, 6H), 3.35 (d, J = 11.4 Hz, 2H), 3.08 (d, J = 26.8 Hz, 5H), 2.19 (d, J = 12.1 Hz, 1H), 2.10 - 1.93 (m, 2H), 1.83 (d, J = 12.7 Hz, 2H). ESI-MS: m / z 751.7 [M+H] + .

[0317] Example 38

[0318] (E)-1-(4-Fluorophenyl)-4-(4-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)but-2-ene-1,4-dione (Compound 38)

[0319]

[0320] The synthesis method refers to Example 30. 76 mg of white solid was obtained with a yield of 82%.

[0321] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.25 (d, J = 2.4 Hz, 1H), 8.13 - 8.07 (m, 4H), 8.04 (d, J = 14.8 Hz, 1H), 7.95 (dd, J = 8.8, 2.4 Hz, 1H), 7.87 (dd, J = 8.8, 2.0 Hz, 1H), 7.67 - 7.62 (m, 3H), 7.56 (d, J = 14.8 Hz, 1H), 7.06 - 7.03 (m, 2H), 6.80 (d, J = 8.8 Hz, 1H), 4.38 (s, 3H), 4.04 - 4.00 (m, 2H), 3.99 (s, 3H), 3.92 - 3.88 (m, 2H), 3.20 - 3.12 (m, 4H); ESI-MS: m / z 712.2 [M+H] + .

[0322] Example 39

[0323] (S,E)-1-(4-Fluorophenyl)-4-(4-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)but-2-ene-1,4-dione (Compound 39)

[0324]

[0325] The synthesis method was referred to Example 30. 73 mg of white solid was obtained with a yield of 81%.

[0326] 1 H NMR(400MHz,DMSO-d 6 )δ8.24(d,J = 2.4Hz,1H),8.13 - 8.07(m,4H),8.04(d,J = 14.8Hz,1H),7.95(dd,J = 8.8,2.4Hz,1H),7.88(dd,J = 8.8,2.0Hz,1H),7.67 - 7.62(m,3H),7.56(d,J = 14.8Hz,1H),7.06 - 7.03(m,2H),6.80(d,J = 8.8Hz,1H),4.38(s,3H),4.04 - 4.00(m,2H),3.99(s,3H),3.95 - 3.88(m,1H),3.20 - 3.12(m,4H),1.05(d,J = 6.4Hz,3H); ESI-MS: m / z 726.2[M+H] + .

[0327] Example 40

[0328] (S,E)-1-(2-Ethyl-4-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-(4-fluorophenyl)but-2-ene-1,4-dione (Compound 40)

[0329]

[0330] The synthesis method was referred to Example 30. 73 mg of white solid was obtained with a yield of 79%.

[0331] 1 H NMR(400MHz,DMSO-d 6)δ8.25(d, J = 2.4 Hz, 1H), 8.13 - 8.07(m, 4H), 8.04(d, J = 14.8 Hz, 1H), 7.95(dd, J = 8.8, 2.4 Hz, 1H), 7.87(dd, J = 8.8, 2.0 Hz, 1H), 7.67 - 7.62(m, 3H), 7.56(d, J = 14.8 Hz, 1H), 7.06 - 7.03(m, 2H), 6.80(d, J = 8.8 Hz, 1H), 4.38(s, 3H), 4.04 - 4.00(m, 2H), 3.99(s, 3H), 3.95 - 3.88(m, 1H), 3.20 - 3.12(m, 4H), 1.59 - 1.43(m, 2H), 1.02(t, J = 7.2 Hz, 3H); ESI-MS: m / z 740.3 [M + H] + .

[0332] Example 41

[0333] (E)-4-(4-Fluorophenyl)-N-(2-((4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)(methyl)amino)ethyl)-N-methyl-4-oxobut-2-enamide (Compound 41)

[0334]

[0335] The synthesis method was referred to Example 30. 73 mg of white solid was obtained with a yield of 84%.

[0336] 1 H NMR(400 MHz, DMSO-d 6 )δ8.25(d, J = 2.4 Hz, 1H), 8.13 - 8.07(m, 4H), 8.04(d, J = 14.8 Hz, 1H), 7.95(dd, J = 8.8, 2.4 Hz, 1H), 7.87(dd, J = 8.8, 2.0 Hz, 1H), 7.67 - 7.62(m, 3H), 7.56(d, J = 14.8 Hz, 1H), 7.06 - 7.03(m, 2H), 6.80(d, J = 8.8 Hz, 1H), 4.38(s, 3H), 3.99(s, 3H), 3.29(d, J = 6.0 Hz, 2H), 2.88(s, 3H), 2.82(t, J = 6.0 Hz, 2H), 2.47(s, 3H); ESI-MS: m / z714.2 [M + H] + .

[0337] Example 42

[0338] (S,E)-1-(4-Fluorophenyl)-4-(4-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)but-2-ene-1,4-dione (Compound 42)

[0339]

[0340] The synthesis method was referred to Example 31. 73 mg of white solid was obtained with a yield of 84%.

[0341] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.22 (s, 1H), 8.18 - 8.14 (m, 2H), 8.12 - 8.10 (m, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 15.2 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 15.2 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H), 7.15 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.17 (s, 3H), 3.85 (s, 3H), 3.82 (m, 2H), 3.75 - 3.68 (m, 1H), 3.08 (m, 4H); 1.05 (d, J = 6.4 Hz, 3H); ESI-MS: m / z 725.2 [M+H] + .

[0342] Example 43

[0343] (E)-1-(4-(4-(4-Methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-1-yl)-4-(4-methoxyphenyl)but-2-ene-1,4-dione (Compound 43)

[0344]

[0345] The synthesis method was referred to Example 31. 73 mg of white solid was obtained with a yield of 84%.

[0346] 1 H NMR (400 MHz, DMSO-d 6)δ8.53(s,1H),8.21(s,1H),8.17 - 8.14(m,2H),8.12 - 8.10(m,2H),7.96(d,J=8.8Hz,2H),7.88(d,J=8.8Hz,1H),7.83(d,J=15.2Hz,1H),7.71(d,J=8.8Hz,1H),7.52(d,J=15.2Hz,1H),7.42(t,J=8.8Hz,2H),7.15(s,1H),6.84(d,J=8.8Hz,1H),4.17(s,3H),3.85(s,3H),3.83(s,3H),3.82(m,2H),3.75 - 3.68(m,1H),3.08(m,4H);1.05(d,J=6.4Hz,3H);ESI-MS:m / z 723.2[M + H] + .

[0347] Example 44

[0348] (S,E)-1-(2-Ethyl-4-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-trifluoromethyl)phenyl)piperazin-1-yl)-4-(4-fluorophenyl)but-2-ene-1,4-dione (Compound 44)

[0349]

[0350] The synthesis method was referred to Example 31. 73 mg of white solid was obtained with a yield of 84%.

[0351] 1 H NMR(400MHz,DMSO-d 6 )δ8.54(s,1H),8.22(s,1H),8.18 - 8.14(m,2H),8.12 - 8.10(m,2H),7.96(d,J=8.8Hz,2H),7.88(d,J=8.8Hz,1H),7.83(d,J=15.2Hz,1H),7.71(d,J=8.8Hz,1H),7.52(d,J=15.2Hz,1H),7.42(t,J=8.8Hz,2H),7.15(s,1H),6.84(d,J=8.8Hz,1H),4.17(s,3H),3.85(s,3H),3.82(m,2H),3.75 - 3.68(m,1H),3.08(m,4H),1.59 - 1.43(m,2H),1.05(d,J=6.4Hz,3H);ESI-MS:m / z 739.2[M + H] + .

[0352] Example 45

[0353] In vitro antitumor activity of the compound: The cells used in this experiment, MOLT-4 (human acute lymphoblastic leukemia cells), K562 (human chronic myelogenous leukemia cells), COLO205 (human colon cancer cells), U937 (human histiocytic lymphoma cells), Ocily3 (human diffuse large B-cell lymphoma cells), and MV4-11 (human myelomonocytic leukemia cells), were all from the Cell Bank of the Typical Culture Collection Committee of the Chinese Academy of Sciences. 3000 - 10000 cells per well of the above cells were seeded into 96-well plates. After overnight incubation, different concentrations of the compound (0 - 30 μM) were added and continuously treated for 72 hours. Then, CCK8 reagent was added, and the incubation continued for 1 - 3 hours. Subsequently, the absorbance values at 450 nm and 650 nm were measured using a microplate reader. The half maximal inhibitory concentration (IC 50 ) was calculated using GrapPad prism 5.0 software.

[0354] It was found that the nitrogen-containing heterocyclic compounds containing unsaturated ketones of the present invention could significantly inhibit the proliferation of related tumor cells. The specific data are shown in Table 1 and Table 2.

[0355] Table 1 Inhibitory activity of the compound against MOLT-4 cells (μM)

[0356]

[0357]

[0358] Table 2 Inhibitory activity of compound 4 against tumor cells (μM)

[0359] Number K562 COLO205 U937 Ocily3 MV4-11 Compound 4 4.184 2.624 1.599 1.098 0.7671

[0360] Example 46

[0361] In this example, a pharmacokinetic study was conducted on compound 4. Six SPF-grade SD rats, male, were randomly divided into 2 groups according to body weight, with 3 rats in the intravenous injection group and 3 rats in the intraperitoneal injection group. The dosing doses were 5 mg / kg and 10 mg / kg respectively. Blood samples were collected from the orbital venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after intravenous and intraperitoneal injection. The blood samples were temporarily stored in an ice box and centrifuged at 4500 rpm for 10 min at 4°C to separate plasma. The drug concentration in plasma was determined by LC-MS method.

[0362] The results are shown in Table 3 below. First, after intravenous injection of 5 mg / kg of Compound 4 into SFP-grade SD rats, its clearance rate (CL) was 4154.39 mL / h / kg, and its half-life was 0.56 h. When administered intraperitoneally at a dose of 10 mg / kg, its max C was 90.57 ng / mL, the half-life was 8.09 h, and the bioavailability was 49.65%. This indicates that the compound has good pharmacokinetic properties when administered intraperitoneally.

[0363] Table 3 Pharmacokinetic results of Compound CQ627 in SD rats

[0364]

[0365] Example 47

[0366] In this example, Western Blot technology was used to test the degradation activity of Compound 4 on RIOK2 protein in leukemia cell MOLT-4, and protein immunoblot analysis was performed according to the method recommended by Cell Signaling Technology (CST, USA). Briefly, after culturing the cells for 12 hours, the cells were treated with the specified compound within the specified time period (see the compound, its concentration, and time in Figure 1)。Then, the cells were lysed in 1× SDS loading buffer (62.5 mM Tris-HCl, pH 6.8, 2% w / v SDS, 10% glycerol, 50 mM DTT, 0.01% w / v bromophenol blue, recommended by CST), the cell lysate was boiled and centrifuged, and the supernatant was loaded onto an SDS-PAGE gel to separate proteins by electrophoresis. Then the separated proteins were electrotransferred onto a PVDF membrane. The PVDF membrane was incubated with the primary antibody overnight at 4 °C (or incubated for 2 hours at room temperature), and then incubated with the secondary antibody for 1 - 4 hours at room temperature. According to the manufacturer's instructions, the protein bands were observed using an ECL Western Blotting Detection Kit (Thermo Scientific, Waltham, MA, USA), and the chemiluminescence signal was detected using an Amersham Imager 600 system (GE, Boston, MA, USA). Image gray-scale analysis was performed using ImageJ. The degradation rate (DR) was calculated using the formula: DR = (Gb - Gd) / Gb × 100% (G: gray-scale value, Gb: gray-scale value of the control group, Gd: gray-scale value of the experimental group). The antibodies used in the experiment were purchased from Cell Signaling Technology (CST, Boston, MA, USA) as follows: anti-pan-akt (#4685), anti-phospho-akt (Thr308) #13038), GAPDH (#2118), enzyme-linked anti-rabbit IgG (#7074), enzyme-linked anti-mouse Ig (#7076). Some antibodies were purchased from abcam as follows: RIOK2 (#ab88485); Proteintech Group was purchased from Wuhan Sanying Biotechnology Co., Ltd.

[0367] The results showed that compound 4 could dose-dependently induce the degradation of RIOK2, while CQ211 could not induce the degradation of RIOK2 protein ( Figure 1 a) in Figure 1 ). Treatment of MOLT4 cells with 1 μM compound 4 significantly downregulated the RIOK2 protein level at 12 hours, and the degradation of RIOK2 reached 94.8% at 24 hours ( Figure 1 b) in

[0368] ). It can be seen that compound 4 caused the degradation of RIOK2 protein in a dose- and time-dependent manner and could reduce the half-life of RIOK2.The technical features of the above-described embodiments can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0369] The above-described embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent for the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several variations and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention shall be subject to the appended claims.

Claims

1. A nitrogen-containing heterocyclic compound containing an unsaturated ketone structure having the structure shown in formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof: Among them, D is N or CR7; X1 and X2 are each independently selected from: N, CR8; X3, X4, X5, X6, X7, X8, X9 are each independently selected from: N, CR9; n is selected from: 0, 1, 2, 3, 4; R1 is selected from: H, one or more Rs 11 substituted or unsubstituted C1-C 18 alkyl, one or more Rs 11 substituted or unsubstituted C3-C 18 cycloalkyl, one or more Rs 11 substituted or unsubstituted C6-C 18 aryl, one or more Rs 11 substituted or unsubstituted 5- to 18-membered heteroaryl; R’1 is selected from: H, one or more Rs 11 substituted or unsubstituted C1-C 18 alkyl; or R1 and R’1 are linked to form a saturated or unsaturated C3-C 18 cycloalkyl; The dashed line between R1 and R’1 represents a carbon-carbon single bond or none; R2 is selected from: H, halogen, C1-C 18 alkyl, halogen-substituted C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C3-C8 cycloalkylalkoxy, C1-C 18 alkylamino, C3-C8 cycloalkylalkylamino, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, 5-18 membered heteroaryl; R3 and R4 are each independently selected from: H, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C1-C8 alkyl acyl; or R3, R4 and the N atom to which they are attached together form R 12 substituted or unsubstituted 4-8 membered heteroalkyl; R5 is selected from: H, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl; or R5 is linked to R3 to form a 3-8 membered heteroalkyl; or R5 is linked to R4 to form a 3-8 membered heteroalkyl; or R5 is linked to R 12 to form a 3-8 membered heteroalkyl; R6 is selected from: H, halogen, C1-C 18 alkyl, C3-C 10 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, halogen-substituted C1-C 18 alkoxy, C3-C8 cycloalkylalkoxy, C1-C 18 alkylamino, C3-C8 cycloalkylalkylamino, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, 5-18 membered heteroaryl; Each R7 is independently selected from: H, halogen, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3- to 18-membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, 5- to 18-membered heteroaryl; Each R8 is independently selected from: H, halogen, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, halogen-substituted C1-C 18 alkyl, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, 5-18 membered heteroaryl; Each R9 is independently selected from: H, halogen, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heteroalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, halogen-substituted C1-C 18 alkyl, amino, hydroxy, cyano, nitro, ester, amide, sulfonyl, sulfonamido, C6-C 18 aryl, C6-C 18 aryl-substituted C1-C 18 alkyl, 5-18 membered heteroaryl; R 10 Selected from: H, one or more Rs 11 Substituted or unsubstituted C1-C 18 alkyl, one or more Rs 11 Substituted or unsubstituted C3-C 18 cycloalkyl, one or more Rs 11 Substituted or unsubstituted 3- to 18-membered heteroalkyl, one or more Rs 11 Substituted or unsubstituted C6-C 18 aryl, one or more Rs 11 Substituted or unsubstituted 5- to 18-membered heteroaryl; Each R 11 is independently selected from: H, halogen, C1-C 18 alkyl, C3-C 18 cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 alkoxy, C1-C 18 alkylamino, halogen-substituted C1-C 18 alkyl, halogen-substituted C1-C 18 alkoxy, amino, hydroxy, cyano, nitro; Each R 12 is independently selected from: H, C1-C 18 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C1-C8 alkyl acyl, sulfonyl, C6-C 18 aryl-substituted C1-C8 alkyl.

2. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein R1 is selected from: H, R 11 substituted or unsubstituted C1-C6 alkyl, R 11 substituted or unsubstituted C3-C8 cycloalkyl, R 11 substituted or unsubstituted C6-C 10 aryl, R 11 substituted or unsubstituted 5- to 10-membered heteroaryl; R’1 is selected from: H, R 11 substituted or unsubstituted C1-C6 alkyl; or R1 and R’1 are linked to form a saturated or unsaturated C3-C8 cycloalkyl; Preferably, R1 is selected from: H, R 11 substituted or unsubstituted phenyl, R 11 substituted or unsubstituted naphthyl, R 11 substituted or unsubstituted 5- to 6-membered heteroaryl; R'1 is selected from: H, R 11 substituted or unsubstituted C1-C3 alkyl; or R1 and R'1 are linked to form a saturated or unsaturated C5-C8 cycloalkyl, preferably a saturated or unsaturated C5-C6 cycloalkyl.

3. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that, The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure has the structure shown in formula (III) or formula (IV):

4. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein X1 is selected from: N, CR8, X2 is CR8, X3 is N, X4 and X5 are each independently selected from: N, CR9, X6 is CR9, X7, X8, X9 are each independently selected from: CR9; Preferably, X1 is CH, X2 is CR8, X3 is N, and X4, X5, X6, X7, X8, X9 are all CH.

5. The nitrogen-containing fused heterocyclic compound having an unsaturated ketone structure according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure has the structure shown in formula (V) or formula (VI):

6. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein R3 and R4 are each independently selected from: H, C1-C3 alkyl, C1-C3 alkyl acyl; or R3, R4 and the N atom to which they are attached together form R 12 Substituted or unsubstituted 5-6 membered heteroalkyl.

7. The nitrogen-containing heteroaromatic compound containing an unsaturated ketone structure according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein, R5 is selected from: H, C1-C3 alkyl; or R5 is linked to R3 to form a 5- to 6-membered heteroalkyl ring; or R5 is linked to R4 to form a 5- to 6-membered heteroalkyl ring; or R5 is linked to R 12 to form a 5- to 6-membered heteroalkyl ring; Preferably, R5 and R3 are connected to form a 5- to 6-membered heteroalkyl ring, and R4 is selected from: H, C1-C3 alkyl.

8. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure has the structure shown in formula (VII) or formula (VIII): Preferably, R5 is selected from: H, C1-C3 alkyl.

9. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that, The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure has the structure shown in formula (IX) or formula (X): Preferably, R4 is selected from: H, C1-C3 alkyl.

10. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein R 10 Selected from: H, one or more Rs 11 Substituted or unsubstituted C1-C6 alkyl, one or more Rs 11 Substituted or unsubstituted C3-C8 cycloalkyl, one or more Rs 11 Substituted or unsubstituted 3-8 membered heterocycloalkyl, one or more Rs 11 Substituted or unsubstituted C6-C 10 Aryl, one or more Rs 11 Substituted or unsubstituted 5-10 membered heteroaryl; Preferably, R 10 is selected from: H, one or more R 11 -substituted or unsubstituted phenyl, one or more R 11 -substituted or unsubstituted naphthyl, one or more R 11 -substituted or unsubstituted 5- to 6-membered heteroaryl; the 5- to 6-membered heteroaryl is preferably selected from: pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, pyridazinyl; Preferably, R 10 is selected from: one or more R 11 substituted or unsubstituted phenyl, one or more R 11 substituted or unsubstituted furyl; Preferably, R 10 is selected from: furanyl.

11. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to claim 10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein Each R 11 is independently selected from: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, C1-C6 alkoxy, C1-C6 alkylamino, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, amino, hydroxy, cyano, nitro; Preferably, each R 11 is independently selected from: H, halogen, C1-C3 alkyl, C5-C8 cycloalkyl, 5-8 membered heteroalkyl, methoxy, ethoxy, n-propoxy, isopropoxy, C1-C3 alkylamino, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, amino, hydroxy, cyano, nitro; Preferably, each R 11 is independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, fluoromethyl, fluoroethyl, cyclohexyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, fluoromethoxy, fluoroethoxy, amino, hydroxy, cyano, nitro.

12. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein Each R 12 is independently selected from: H, C1-C6 alkyl, C5-C8 cycloalkyl, 5-8 membered heteroalkyl, C1-C6 alkyl acyl, sulfonyl, phenyl-substituted C1-C6 alkyl; Preferably, each R 12 is independently selected from: H, C1-C3 alkyl.

13. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, wherein R2 is selected from: H, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, preferably methoxy.

14. The nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that R6 is selected from: H, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, preferably methoxy.

15. The nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that Each R7 is independently selected from: H, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy.

16. The nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that Each R8 is independently selected from: H, fluorine, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, amino, hydroxy, cyano, nitro, phenyl; Preferably, each R8 is independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl, cyclohexyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, monofluoromethoxy, monofluoroethoxy, amino, hydroxy, cyano, nitro.

17. The nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that Each R9 is independently selected from: H, halogen, C1-C3 alkyl.

18. The nitrogen-containing heterocyclic compound containing an unsaturated ketone structure according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that The nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure is selected from the following compounds:

19. Use of the nitrogen-containing fused heterocyclic compound containing an unsaturated ketone structure according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof in the preparation of an RIOK2 inhibitor or an RIOK2 degrader.

20. Use of a nitrogen-containing heterocyclic compound containing an unsaturated ketone structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof as claimed in any one of claims 1-18 in the preparation of a drug for preventing and / or treating a disease associated with high expression of RIOK2. Preferably, the disease associated with high expression of RIOK2 is a tumor, preferably: non-small cell lung cancer, colon cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, skin squamous cell carcinoma, ovarian cancer.

21. Use of a nitrogen-containing heterocyclic compound containing an unsaturated ketone structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof as claimed in any one of claims 1-18 in the preparation of a drug for preventing and / or treating a tumor; Preferably, the tumor is: non-small cell lung cancer, colon cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, skin squamous cell carcinoma, ovarian cancer.

22. A pharmaceutical composition for treating and / or preventing tumors, characterized in that, Prepared from an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises a nitrogen-containing heterocyclic compound containing an unsaturated ketone structure or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof as claimed in any one of claims 1-18.

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