Phthalazinone GSPT1 protein degrading agent and use thereof

Abstract

Disclosed is a compound as shown in general formula I or a pharmaceutically acceptable salt, tautomer, mesomer, racemate, enantiomer, and diastereomer thereof. The compound of the present invention significantly improves the degradation effect of GSPT1 protein and the anti-proliferative inhibition activity of AML and solid tumor cells. Therefore, the compound of the present invention can be used in the preparation of a medicament for treating or preventing diseases related to GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC or C-MYC protein mutation, expression imbalance, and allostery and functional abnormalities; in addition, said compound can be used to prepare a GSPT1 degrading agent.

Description

A phthalazinone GSPT1 protein degrader and its application Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a phthalazinone GSPT1 protein degrader and applications thereof. Background Art

[0002] Targeted protein degradation technology (TPD) is a new technology that interferes with protein function by utilizing the protein degradation mechanism inherent in eukaryotic cells that regulates protein homeostasis. The rise of this technology has, to a certain extent, solved the difficulties faced by small molecule inhibitors and gene interference technologies. TPD currently mainly degrades target proteins through ubiquitin proteasomes and lysosomes. Currently, the most mature and most studied in this field are proteolysis-targeting chimeras (PROTACs) and molecular glues (MGs) based on the ubiquitination-proteasome system. Targeted protein degradation technology has broad application prospects and development space in various disease areas such as malignant tumors, neurodegenerative diseases, and metabolic diseases.

[0003] Molecular glues are small molecules that induce proximity and enable precise temporal control of various biological processes, such as signal transduction, transcription, chromatin regulation, and protein folding, localization, and degradation. As chemical inducers of proximity, they can induce protein-protein interactions between E3 ubiquitin ligases and target proteins, leading to their degradation. Molecular glues can promote dimerization or colocalization of two proteins by forming ternary complexes, resulting in a variety of biological and pharmacological functions.

[0004] G1 to S phase transition 1 (GSPT1, also known as eRF3a) is a translation termination factor in vivo. Downregulation of GSPT1 can lead to aberrant expression of key proteins, inhibiting proliferation or inducing apoptosis in various tumor cells. Since the discovery of GSPT1 as a novel substrate of the E3 ubiquitin ligase CRBN, it has become a target for targeted degradation by molecular adhesive degraders. Currently, a variety of molecular adhesive degraders are in clinical and preclinical development, and these molecules are highly effective in treating hematologic malignancies and certain solid tumors. GSPT1 possesses multifunctional properties. In addition to acting as a second peptide chain release factor, involved in protein translation termination, it is also implicated in apoptosis, cell cycle regulation, and tumor development and progression. For example, during apoptosis, GSPT1 is proteolytically processed to form another isoform that contains a conserved N-terminal inhibitor of apoptosis protein binding domain. GSPT1 interacts with inhibitors of apoptosis proteins (IAPs) through this processed form, releasing the inhibition of IAPs and releasing caspases, thereby promoting cell apoptosis. The M domain of eRF3 interacts with Polya-binding protein (PABP), coupling translation termination and mRNA degradation.

[0005] Acute myeloid leukemia (AML) is a genetically and biologically heterogeneous myeloid malignancy characterized by the abnormal expansion of immature myeloid progenitor cells, which impairs normal hematopoiesis, leading to severe infections, anemia, and bleeding. It is characterized by low survival and high relapse rates. As a relatively rare malignancy, it has been designated an orphan disease by the US Food and Drug Administration. GSPT1, a novel substrate of the CRL4-CRBN-E3 ubiquitin ligase, plays a key role in the treatment of AML. Clinical drugs targeting GSPT1 for the treatment of AML, such as CC-90009 and BTX-1188, are under development. CC-90009 is primarily administered intravenously for the treatment of AML, while BTX-1188 is an oral drug used to treat AML and NHL. Further research has revealed that GSPT1 degradation is associated with upregulation of ATF3 and ATF4 gene expression, which are crucial for the integrated stress response pathway. The activation of the integrated stress response pathway is closely related to the phosphorylation of eRF2. When the integrated stress response pathway is activated, it will lead to acute cell apoptosis.

[0006] According to the World Health Organization, breast cancer is the leading cause of death from malignant tumors in women. In 2018, Wang et al. analyzed gene expression in total RNA extracted from breast cancer samples collected and identified five genes, including GSPT1, as potential therapeutic targets for triple-negative breast cancer. More recently, a study by Malta-Vacas et al. demonstrated that the longer GSPT1 allele, 12-GGC, is present in 5.1% of breast cancer patients. Furthermore, mRNA quantification experiments revealed that GSPT1 is overexpressed in tumor tissues of patients with the 12-GGC allele relative to adjacent normal tissue. Furthermore, Miri et al. conducted a study investigating the relationship between the GSPT1 gene and breast cancer susceptibility in breast cancer patients. The study found that GSPT1 expression was significantly elevated in breast cancer tissue, and that the presence of the longer 12-GGC allele in the GSPT1 exon increased the risk of breast cancer by threefold. Therefore, some researchers believe that the 12-GGC allele is linked to cancer progression by causing GSPT1 protein dysfunction through regulation of mRNA degradation or translation efficiency.

[0007] Gastric cancer is the leading cause of cancer-related death in developing countries. Malta-Vacas et al. found that GSPT1 expression levels were significantly higher in intestinal-type gastric tumors than in diffuse-type gastric tumors. Furthermore, they evaluated the relationship between GSPT1 and potential genetic susceptibility to gastric cancer and found that, regardless of genotype, patients with the 12-GGC allele had a 20-fold increased risk of gastric cancer compared to the general population. Tian et al. explored the potential impact of GSPT1 on gastric cancer development and found that GSPT1 expression levels were significantly increased in gastric cancer tissues. Some scholars believe that GSPT1 overexpression promotes tumor development by increasing the translation efficiency of specific oncogene mRNAs, while others believe that this is through other effects of GSPT1, such as regulating the cell cycle and apoptosis. Because GSPT1 is also involved in cytoskeleton formation and controlling chromosome segregation, the effects of GSPT1 on chromosome segregation and cytokinesis may also be a potential mechanism by which this gene affects gastric cancer development.

[0008] Liver cancer is a common tumor. Clinical data show that GSPT1 expression is generally higher in liver cancer tissue than in normal cells. Since one of GSPT1's primary functions is to regulate the transition of cells from the G1 phase to the S phase, some researchers have hypothesized that interfering with GSPT1 mRNA expression could alter the cell cycle, increasing the percentage of cells in the G1 phase and leading to decreased tumor cell viability and proliferation. Although GSPT1 has a pro-oncogenic effect during the development and progression of liver cancer, some researchers have found that GSPT1 may inhibit the progression of liver cancer by overexpressing and knocking down the GSPT1 gene in HepG2 cells.

[0009] Colorectal cancer is one of the most common malignancies of the digestive system. Research by Xiao et al. demonstrated that GSPT18 is overexpressed in human colorectal cancer HCT116 cells compared to normal control colorectal cells. Further experiments also showed that knocking down GSPT1 in colorectal cancer cells with high GSPT1 expression inhibited cell proliferation and migration. Research results indicate that GSPT1 inhibits cell cycle progression in HCT116 cells through the mTOR pathway. Activation of the mTOR pathway leads to increased translation of mRNA subtypes. Therefore, GSPT1 may play a role as an oncogene in the development and progression of colorectal cancer.

[0010] In summary, GSPT1 plays a crucial role in the development and progression of solid tumors. However, due to its diverse functions and complex regulatory mechanisms, it plays distinct roles in different tumors. It is generally accepted that GSPT1 is a proto-oncogene in most tumors and, in certain specific tumor types, acts as a tumor suppressor gene. While the mechanisms of GSPT1's action in tumors remain understudied, there is no doubt that GSPT1 has become a promising potential target for cancer treatment.

[0011] Summary of the Invention

[0012] Objective of the invention: One of the objectives of the present invention is to provide a phthalazinone compound of formula I or a pharmaceutically acceptable salt, tautomer, mesoform, racemate, enantiomer, diastereomer thereof:

[0013] in:

[0014] represents a single bond or a double bond;

[0015] X is selected from -CH2-, -NH-, -O-, -S- or -Se-;

[0016] Each R1 is independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a Rb 、-SR a 、-S(O)R a 、-S(O)2R a or 3-10 membered cycloalkyl, heterocyclyl, aryl and heteroaryl containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or optionally substituted with 1-3 R a replace;

[0017] Each R2 is independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or 3-10 membered cycloalkyl, heterocyclyl, aryl and heteroaryl containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or optionally substituted with 1-3 R a replace;

[0018] Each R3 is independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R aor 3-10 membered cycloalkyl, heterocyclyl, aryl and heteroaryl containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or optionally substituted with 1-3 R a replace;

[0019] R4 is selected from hydrogen, deuterium, C1-C 12 alkyl,

[0020] R5 is selected from hydrogen, deuterium, C1-C 12 alkyl;

[0021] R6, R7, R8, R9, R 10 、R 11 are independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or 3-10 membered cycloalkyl, heterocyclyl, aryl and heteroaryl containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are unsubstituted or optionally substituted with 1-3 R a replace;

[0022] R a 、R b are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, cyano, nitro, benzyl, -C(O)NR c R d 、-C(O)R c 、-C(O)OR c 、-OR c 、-OC(O)R c 、-OC(O)OR c 、-OC(O)NR c R d 、-NR c R d、-SR c 、-S(O)R c 、-S(O)2R c or a 3-10 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl group is unsubstituted or optionally substituted with 1-3 R c replace;

[0023] R c 、R d Each is independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl or halogenated C3-C6 cycloalkyl;

[0024] m, p, q, t, and n are each independently selected from 0, 1, 2, or 3.

[0025] In certain preferred embodiments, X is selected from -NH- or -O-.

[0026] In certain preferred embodiments, each R1 is independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C2-C6 alkynyl, halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C2-C6 alkoxy, C2-C6 alkynyl, halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1 ... 10 Aryl or -NR a R b ;

[0027] R a 、R b are independently selected from hydrogen, C1-C6 alkyl or -C(O)R c ;

[0028] R c is selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or C3-C6 cycloalkyl.

[0029] In certain more preferred embodiments, each R1 is independently selected from hydrogen, methyl, fluorine, chlorine, bromine, methoxy, trifluoromethyl, trifluoromethoxy, vinyl, tert-butyl, and phenyl.

[0030] In certain preferred embodiments, R2 and R3 are each independently selected from hydrogen.

[0031] In certain preferred embodiments, R4 and R5 are each independently selected from hydrogen.

[0032] In certain preferred embodiments, p, q, and n are each independently selected from 1.

[0033] In certain preferred embodiments, m is selected from 0, 1 or 2.

[0034] In certain preferred embodiments, t is selected from 0 or 1.

[0035] The compounds of the general formula I described above may also exist in the form of their salts, which are converted in vivo into compounds of the general formula I. For example, within the scope of the present invention, the compounds of the present invention may be converted into pharmaceutically acceptable salts according to processes known in the art and used in the form of salts.

[0036] In some preferred embodiments, the pharmaceutically acceptable salts include but are not limited to acid addition salts formed between the compound of formula I and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; and also include acid salts formed between the compound of formula I and inorganic bases.

[0037] In some more preferred embodiments, the pharmaceutically acceptable salts include, but are not limited to, basic metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.

[0038] The compounds of the general formula I of the present invention are preferably the following compounds:

[0039] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer, mesomer, racemate, enantiomer, diastereomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0040] The pharmaceutical compositions of the present invention can be administered in various known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical compositions of the present invention can be administered alone or in combination with other drugs. Oral compositions can be in any orally acceptable dosage form, including but not limited to tablets, capsules, emulsions, suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.

[0041] Sterile injectable compositions can be formulated using suitable dispersing agents or wetting agents and suspending agents according to techniques known in the art. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, and the like.

[0042] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors, including the activity of the specific compound of the present invention or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the specific composition employed, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific composition employed, the age, sex, weight, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0043] Another object of the present invention is to provide the use of a compound of formula I or a pharmaceutically acceptable salt, tautomer, mesomer, racemate, enantiomer, or diastereomer thereof in the preparation of a medicament for treating or preventing diseases associated with GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC, or C-MYC protein mutations, expression imbalances, allostery, and functional abnormalities.

[0044] The related disease is cancer, viral infection, aging, immune disease or neurological disease; wherein the cancer is selected from acute myeloid leukemia, liver cancer, acute lymphocytic leukemia, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor, head and neck cancer, Hodgkin's lymphoma, laryngeal cancer, lung cancer, melanoma, mesothelioma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, skin cancer, testicular cancer, pharyngeal cancer, thyroid cancer or uterine cancer. The lung cancer is non-small cell lung cancer.

[0045] The present invention also provides use of a compound of formula I or a pharmaceutically acceptable salt, tautomer, mesomer, racemate, enantiomer, or diastereomer thereof in the preparation of a GSPT1 degrading agent. Beneficial effects:

[0046] The phthalazinone compounds of the present invention demonstrate significant GSPT1 protein degradation and anti-proliferative activity in AML cells. Therefore, the phthalazinone compounds of the present invention can be used to prepare medicaments for treating or preventing diseases associated with mutations, expression imbalances, allosteric changes, and functional abnormalities in GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC, or C-MYC proteins; and can be used to prepare GSPT1 degraders.

[0047] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0048] The term "isomer" includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure. For example, the present application includes R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers, and enantiomeric, diastereomeric, and geometric (or conformational) isomer mixtures.

[0049] The term "pharmaceutically acceptable salt" refers to, for example, acid addition salts and / or base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts, such as hydrochlorides / chlorides. Suitable base salts are formed from bases that form non-toxic salts, such as calcium salts and sodium salts. Hemi-salts of acids and bases can also be formed, such as hemisulfate salts and hemicalcium salts.

[0050] The term "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats a specific disease, condition, or disorder; (ii) alleviates, relieves, or eliminates one or more symptoms of a specific disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein.

[0051] The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith.

[0052] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, and the present invention preferably has an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0053] The term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. The alkenyl groups of the present invention preferably have 2 to 6 carbon atoms. For example, the term "C 2-6 The term "alkenyl" includes straight or branched unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0054] The term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. The alkynyl groups of the present invention have 2 to 6 carbon atoms. For example, "C 2-6 "Alkynyl" includes straight or branched hydrocarbon chain alkynyl groups as defined above having 2 to 6 carbon atoms.

[0055] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0056] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The cycloalkyl groups of the present invention preferably contain 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0057] The term "spiroalkyl" refers to a polycyclic group sharing a carbon atom (claiming spiral atom) between 5 to 20 yuan of monocycles, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between ring and ring, spiroalkyl is divided into single spiral alkyl, double spiral alkyl or multiple spiral alkyl, preferably single spiral alkyl and double spiral alkyl, more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiral alkyl.

[0058] The term "fused cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicycloalkyl groups.

[0059] The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bicyclic, tricyclic, or tetracyclic is preferred, and bicyclic or tricyclic is more preferred.

[0060] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, or S(O)m (wherein m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 10 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. The limiting examples of monocyclic heterocyclic radical include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclic radical includes spiroheterocyclic radical, condensed heterocyclic radical and bridged heterocyclic radical.

[0061] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Spiroheterocyclyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multiple spiro heterocyclyl according to the number of shared spiro atoms between rings, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members single spiro heterocyclyl.

[0062] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups.

[0063] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

[0064] The heterocyclic group includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0065] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0066] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; examples include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, and pyridazinyl.

[0067] The heteroaryl group includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0068] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0069] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0070] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. DETAILED DESCRIPTION

[0071] The technical solution of the present invention is described in detail below through specific examples, but the scope of protection of the present invention is not limited to the examples. Synthesis of key intermediate-1:

[0072] Step 1: Dissolve 5-cyanophthalide (25.00 g, 157.20 mmol) in 400 mL of carbon tetrachloride, add N-bromosuccinimide (49.00 g, 282.96 mmol) and azobisisobutyronitrile (13.00 g, 78.60 mmol) in sequence, and heat to reflux and stir for 10 hours. After cooling to room temperature, filter and concentrate the filtrate. The residue is purified by silica gel chromatography to obtain white solid compound 2 (21.57 g, yield 57.90%). HRMS (ESI + ):(M+H) + The measured value is 237.9486.

[0073] Step 2: Dissolve 3-bromo-1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (21.57 g, 91.02 mmol) in 300 mL of water, heat to reflux and stir for 4 hours. Cool to room temperature and filter, then dry the filter cake to obtain compound 3 as a white solid (12.16 g, yield 76.3%). HRMS (ESI - ):(M+H) + The measured value is 174.0188.

[0074] Step 3: Dissolve 4-cyano-2-formylbenzoic acid (12.16 g, 69.44 mmol) in 50 mL of 95% ethanol, add 80% hydrazine hydrate (13.90 g, 347.24 mmol) dropwise, heat to 80°C and stir for 30 minutes. Cool to room temperature, filter, and dry to obtain a brown solid compound 4 (10.01 g, yield 84.3%). HRMS (ESI + ):(M+H) + The measured value is 172.0510.

[0075] Step 4: Dissolve 1-oxo-1,2-dihydrophthalazine-6-carbonitrile (10.01 g, 58.52 mmol) in 50 mL of N,N-dimethylformamide, add sodium hydrogen hydride (2.80 g, 117.07 mmol) under ice bath, stir at room temperature for 1 hour, add 3-bromopiperidine-2,6-dione (22.35 g, 117.07 mmol), heat to 100 ° C and stir for 48 hours. Cool to room temperature, pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine in turn, dry and concentrate, and purify the residue with silica gel chromatography to obtain white solid compound 5 (6.81 g, yield 41.3%). HRMS (ESI + ):(M+H) + The measured value is 283.0820.

[0076] Step 5: Dissolve 2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazine-6-carbonitrile (6.81 g, 24.17 mmol) in 30 mL of N,N-dimethylformamide, add di-tert-butyl dicarbonate (10.54 g, 48.34 mmol) and 15 mL of Raney nickel in sequence, and heat to 50 ° C and stir for 5 hours under full hydrogen replacement. Filter, pour the filtrate into water, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine in sequence, dry and concentrate to obtain yellow solid compound 6 (6.14 g, yield 65.8%). HRMS (ESI + ):(M+H) + The measured value is 387.1665.

[0077] Step 6: Dissolve tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)methylcarbamate (6.14 g, 15.90 mmol) in 30 mL of hydrochloric acid-dioxane solution (4 M) and stir at room temperature for 3 hours. Filter and dry the filter cake to obtain a white solid, which is Intermediate-1: 3-((6-aminomethyl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione hydrochloride (3.71 g, yield 72.4%). HRMS (ESI + ):(M+H) + The measured value is 287.1130.

[0078] Synthesis of key intermediate-2:

[0079] Step 1: Dissolve methyl 2-methyl-4-nitrobenzoate (10.00 g, 51.24 mmol) in 200 mL of 1,2-dichloroethane, add N-bromosuccinimide (13.68 g, 76.86 mmol) and benzoyl peroxide (3.26 g, 13.48 mmol) in sequence, and heat to reflux and stir for 3 hours. After cooling to room temperature, concentrate, and the residue is purified by silica gel chromatography to obtain white solid compound 8 (8.71 g, yield 62.0%). HRMS (ESI + ):(M+H) + The measured value is 273.9711.

[0080] Step 2: Dissolve methyl 2-bromomethyl-4-nitrobenzoate (8.71 g, 31.78 mmol) in 300 mL of dichloromethane, and add N-methylmorpholine oxide (8.55 g, 73.00 mmol) and a small amount of molecular sieves. The mixture was stirred at room temperature for 4 hours. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain white solid compound 9 (4.67 g, yield 70.2%). HRMS (ESI + ):Measured value 210.0388.

[0081] Step 3: Dissolve methyl 2-formyl-4-nitrobenzoate (4.67 g, 22.33 mmol) in 25 mL of tetrahydrofuran, add 5 M aqueous lithium hydroxide solution (25 mL), and stir at room temperature for 2 hours. Concentrate to remove the organic solvent, adjust the pH to 2-3 with 1N dilute hydrochloric acid at 0°C, filter, wash the filter cake with water, and dry to obtain white solid compound 10 (4.00 g, yield 91.9%). HRMS (ESI - ):(MH) - The measured value is 194.0087.

[0082] Step 4: Dissolve 2-formyl-4-nitrobenzoic acid (4.00 g, 20.50 mmol) in 40 mL of ethanol, add 80% hydrazine hydrate (6.41 g, 102.5 mmol), and stir at 80°C for 2 hours. Cool to room temperature, filter, and wash the filter cake with a small amount of ethanol and dry to obtain a yellow solid compound 11 (3.37 g, yield 85.9%). HRMS (ESI + ):(M+H) + The measured value is 192.0401.

[0083] Step 5: Dissolve 6-nitrophthalazine-1(2H)-one (3.37 g, 17.63 mmol) in 150 mL of N,N-dimethylformamide, add sodium hydrogen hydride (1.41 g, 35.26 mmol), and stir at room temperature for 1 hour under nitrogen protection. Add 3-bromopiperidine-2,6-dione (5.08 g, 26.45 mmol) and stir at 85°C for 12 hours. Cool to room temperature, filter, pour the filtrate into water, extract with ethyl acetate, combine the organic layers, wash with water and saturated brine in turn, dry and concentrate, and purify the residue using a silica gel column chromatography to obtain white solid compound 12 (2.14 g, yield 40.2%). HRMS (ESI + ):(M+H) + The measured value is 303.0711.

[0084] Step 6: Dissolve 3-(6-nitro-1-oxonaphthyridine-2(1H)-yl)piperidine-2,6-dione (2.14 g, 7.08 mmol) in 50 mL of methanol, add 10% Pd / C (1.00 g), and stir at room temperature under hydrogen for 8 hours. Filter and concentrate the filtrate in vacuo to obtain a white solid, which is Intermediate-2: 3-(6-amino-1-oxonaphthyridine-2(1H)-yl)piperidine-2,6-dione (1.55 g, yield 80.2%). HRMS (ESI + ):(M+H) + The measured value is 273.0972.

[0085] Synthesis of key intermediate-3:

[0086] Step 1: Dissolve 2-hydroxybenzaldehyde (2.00 g, 16.39 mmol) in 15 mL of acrylonitrile, add 1,4-diazidebicyclo[2.2.2]octane (1.84 g, 16.39 mmol), and after the addition, heat to reflux and stir for 3 hours under nitrogen protection. Pour the reaction solution into 30 mL of 10% sodium hydroxide aqueous solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry and concentrate to obtain yellow crystalline solid compound 14 (2.30 g, yield 90.2%). HRMS (ESI + ):(M+H) + The measured value is 158.0621.

[0087] Step 2: Dissolve 2H-chromene-3-carbonitrile (2.30 g, 14.73 mmol) in 40 mL of 10% aqueous sodium hydroxide solution, heat to 60°C and stir for 10 hours. Add dilute hydrochloric acid (2 M) to adjust the pH to 4-5, filter and dry to obtain yellow solid compound 15 (1.65 g, yield 63.7%). HRMS (ESI - ):(MH) - The measured value is 175.0400.

[0088] Step 3: Dissolve 2H-chromene-3-carboxylic acid (1.50 g, 8.52 mmol) in 20 mL of methanol, add 10% Pd / C (1.00 g), and stir at room temperature for 8 hours. Filter and concentrate the filtrate in vacuo to obtain a brown solid, Intermediate-3: chroman-3-carboxylic acid (0.76 g, yield 50.2%). HRMS (ESI - ):(MH) - The measured value is 177.0545.

[0089] Example 1: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-2H-chromene-3-carboxamide (Compound T-1)

[0090] Intermediate-1 (0.10 g, 0.31 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and compound 15 (0.07 g, 0.38 mmol) and HATU (0.18 g, 0.47 mmol) were added sequentially, and the mixture was stirred at room temperature for 1 hour. DIPEA (0.12 g, 0.94 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, filtered, and the filter cake was purified by silica gel chromatography to obtain a white solid, compound T-1 (0.10 g, yield 72.6%, purity 98.93%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.06 (s, 1H), 9.02 (s, 1H), 8.55 (s, 1H), 8.20 (d, J = 6.4Hz, 1H), 7.84 (s, 1H), 7.39 (s, 1H), 7.12-7.06 (m, 2H), 6.93 ( t,J=8.2Hz,1H),6.92-6.87(m,2H),5.95-5.83(m,1H),5.15(d,J=6.2Hz, 2H), 4.64 (s, 2H), 2.97-2.85 (m, 1H), 2.64 (d, J = 7.9Hz, 2H), 2.12 (s, 1H).

[0091] Example 2: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-5-fluoro-2H-chromene-3-carboxamide (Compound T-2)

[0092] Synthesis of 5-fluoro-2H-chromene-3-carboxylic acid: 6-fluorosalicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 52.4%. HRMS (ESI - ):(MH) - The measured value is 193.0318.

[0093] Synthesis of compound T-2: The raw material 5-fluoro-2H-chromene-3-carboxylic acid was used to prepare the compound according to the synthesis method of compound T-1 to obtain a white solid, namely compound T-2 (0.08 g, yield 55.8%, purity 96.93%). 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.06 (s, 1H), 9.05 (s, 1H), 8.52 (s, 1H), 8.25 (d, J = 7.4Hz, 1H), 7.84 (d, J = 9.5Hz, 2H), 7.32 (s, 1H), 7.16-7.0 6(m,2H),6.91-6.87(m,1H),5.85-5.79(m,1H),5.05(s,2H),4.61(d,J=5.2Hz,2H),2.99-2.87(m,1H),2.64(d,J=16.1Hz,2H),2.12(s,1H).

[0094] Example 3: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-fluoro-2H-chromene-3-carboxamide (Compound T-3)

[0095] Synthesis of 6-fluoro-2H-chromene-3-carboxylic acid: 5-fluorosalicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 62.1%. HRMS (ESI - ):(MH) - The measured value is 193.0310.

[0096] Synthesis of compound T-3: The raw material 6-fluoro-2H-chromene-3-carboxylic acid was used to prepare the compound according to the synthesis method of compound T-1 to obtain a white solid, namely T-3 (0.12 g, yield 83.7%, purity 97.63%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.08 (s, 1H), 9.05 (s, 1H), 8.50 (s, 1H), 8.26 (d, J = 7.8Hz, 1H), 7.84 (d, J = 9.5Hz, 2H), 7.32 (s, 1H), 7.16-7.06 (m ,2H),6.91-6.87(m,1H),5.85-5.79(m,1H),4.95(s,2H),4.61(d,J=5. 2Hz, 2H), 2.98-2.89 (m, 1H), 2.64 (d, J = 16.1Hz, 2H), 2.14-2.10 (m, 1H).

[0097] Example 4: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-7-fluoro-2H-chromene-3-carboxamide (Compound T-4)

[0098] Synthesis of 7-fluoro-2H-chromene-3-carboxylic acid: 4-fluorosalicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 56.8%. HRMS (ESI - ):(MH) - The measured value is 193.0321.

[0099] Synthesis of compound T-4: The raw material 7-fluoro-2H-chromene-3-carboxylic acid was used to prepare the compound according to the synthesis method of compound T-1 to obtain a white solid, namely compound T-4 (0.08 g, yield 55.8%, purity 96.32%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.09 (s, 1H), 9.01 (s, 1H), 8.52 (s, 1H), 8.27 (d, J = 7.2Hz, 1H), 7.85 (s, 2H), 7.38-7.29 (m, 2H), 6.85(t,J=11.4Hz,2H),5.87-5.78(m,1H),5.01(s,2H),4.61(s,2H),3.01-2.90(m,1H),2.66(d,J=16.9Hz,2H),2.15(s,1H).

[0100] Example 5: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-8-fluoro-2H-chromene-3-carboxamide (Compound T-5)

[0101] Synthesis of 8-fluoro-2H-chromene-3-carboxylic acid: 3-fluorosalicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 59.2%. HRMS (ESI - ):(MH) - The measured value is 193.0311.

[0102] Synthesis of compound T-5: The raw material 8-fluoro-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-5 (0.09 g, yield 62.8%, purity 99.83%). 1H NMR(300MHz,DMSO-d6)δ(ppm)11.08(s,1H),9.02(s,1H),8.50 (s,1H),8.26(d,J=6.3Hz,1H),7.84(d,J=9.5Hz,2H),7.30(s,1H),7.16-7.06(m,2H),6.91-6.85(m,1H),5. 83-5.76(m,1H),4.97(s,2H),4.61(d,J=5.2Hz,2H),2.99-2.87(m,1H),2.64(d,J=16.1Hz,2H),2.14(s,1H).

[0103] Example 6: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-8-methoxy-2H-chromene-3-carboxamide (Compound T-6)

[0104] Synthesis of 8-methoxy-2H-chromene-3-carboxylic acid: 2-hydroxy-3-methoxybenzaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 56.5%. HRMS (ESI - ):(MH) - The measured value is 205.0500.

[0105] Synthesis of compound T-6: The raw material 8-methoxy-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-6 (0.06 g, yield 40.8%, purity 97.63%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.04 (s, 1H), 9.01 (t, J = 5.9Hz, 1H), 8.50 (s, 1H), 8. 26(d,J=8.0Hz,1H),7.84(d,J=8.7Hz,2H),7.36(s,1H),7.00(d,J=8.0Hz,1H),6.91 (t,J=8.0Hz,1H),6.84(d,J=6.3Hz,1H),5.84-5.78(m,1H),4.92(s,2H),4.60(d,J =5.6Hz,2H),3.76(s,3H),2.99-2.87(m,1H),2.65-2.55(m,2H),2.14-2.09(m,1H).

[0106] Example 7: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-5-methoxy-2H-chromene-3-carboxamide (Compound T-7)

[0107] Synthesis of 5-methoxy-2H-chromene-3-carboxylic acid: 6-methoxysalicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 62.5%. HRMS (ESI - ):(MH) - The measured value is 205.0515.

[0108] Synthesis of compound T-7: The raw material 5-methoxy-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-7 (0.06 g, yield 40.8%, purity 97.85%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.06 (s, 1H), 9.04 (s, 1H), 8.50 (s, 1H), 8.24 (d, J= 7.9Hz,1H),7.83(d,J=8.2Hz,2H),7.53(s,1H),7.21(t,J=8.2Hz,1H),6.65(d,J=8 .3Hz,1H),6.51(d,J=8.1Hz,1H),5.82-5.73(m,1H),4.88(s,2H),4.58(d,J=5.6H z, 2H), 3.87 (d, J = 10.5Hz, 3H), 2.98-2.85 (m, 1H), 2.66-2.56 (m, 2H), 2.12 (s, 1H).

[0109] Example 8: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-methoxy-2H-chromene-3-carboxamide (Compound T-8)

[0110] Synthesis of 6-methoxy-2H-chromene-3-carboxylic acid: 5-methoxysalicylaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 58.6%. HRMS (ESI - ):(MH) - The measured value is 205.0511.

[0111] Synthesis of compound T-8: The raw material 6-methoxy-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-8 (0.06 g, yield 40.8%, purity 96.13%). 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.05 (s, 1H), 9.03 (t, J = 5.8Hz, 1H), 8.56 (s, 1H), 8. 26(d,J=8.Hz,1H),7.82(d,J=8.7Hz,2H),7.36(s,1H),7.00(d,J=8.0Hz,1H),6.92 (t,J=8.1Hz,1H),6.74(d,J=6.3Hz,1H),5.91-5.79(m,1H),4.90(s,2H),4.60(d,J =5.6Hz,2H),3.79(s,3H),2.98-2.87(m,1H),2.64-2.55(m,2H),2.14-2.09(m,1H).

[0112] Example 9: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-8-(trifluoromethoxy)-2H-chromene-3-carboxamide (Compound T-9)

[0113] Synthesis of 8-trifluoromethoxy-2H-chromene-3-carboxylic acid: 2-hydroxy-3-trifluoromethoxybenzaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 48.2%. HRMS (ESI - ):(MH) - The measured value is 259.0220.

[0114] Synthesis of compound T-9: The raw material 8-trifluoromethoxy-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-9 (0.09 g, yield 54.9%, purity 98.93%). 1 H NMR(300MHz,DMSO-d6)δ(ppm)11.04(s,1H),9.05(t,J=6.1Hz,1H),8.49(s,1H),8.26(d,J=8.1Hz,1H),7.85(d,J=9.5Hz,2H),7.40(s,1H),7.31(t,J =8.2Hz,2H),7.04(t,J=7.9Hz,1H),5.85-5.79(m,1H),5.06(s,2H),4.62( d,J=5.3Hz,2H),3.00-2.87(m,1H),2.65-2.54(m,2H),2.15-2.11(m,1H).

[0115] Example 10: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-(trifluoromethoxy)-2H-chromene-3-carboxamide (Compound T-10)

[0116] Synthesis of 6-trifluoromethoxy-2H-chromene-3-carboxylic acid: 5-trifluoromethoxy salicylaldehyde was used as the starting material according to the synthesis method of intermediate-3. The total yield of the two steps was 62.3%. HRMS (ESI - ):(MH) - The measured value is 259.0228.

[0117] Synthesis of compound T-10: The raw material 6-trifluoromethoxy-2H-chromene-3-carboxylic acid was used to prepare the product by the synthesis method of compound T-1 to obtain a white solid A-10 (0.12 g, yield 73.3%, purity 99.89%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.05 (s, 1H), 9.05 (t, J = 5.9Hz, 1H), 8.49 (s, 1 H),8.26(d,J=8.0Hz,1H),7.84(d,J=8.9Hz,2H),7.36(s,1H),7.30(s,1H),7. 25(d,J=8.7Hz,1H),6.97(d,J=8.7Hz,1H),5.84-5.79(m,1H),5.01(s,2H),4. 61(d,J=5.5Hz,2H),2.99-2.87(m,1H),2.64-2.54(m,2H),2.16-2.10(m,1H).

[0118] Example 11: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-8-methyl-2H-chromene-3-carboxamide (Compound T-11)

[0119] Synthesis of 8-methyl-2H-chromene-3-carboxylic acid: 2-hydroxy-3-methylbenzaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 60.2%. HRMS (ESI - ):(MH) - The measured value is 189.0545.

[0120] Synthesis of compound T-11: The raw material 8-methyl-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method of compound T-1 to obtain white solid T-11 (0.07 g, yield 49.2%, purity 98.35%). 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.05 (s, 1H), 9.03 (t, J = 6.2Hz, 1H), 8.38 (s, 1H), 8. 19(d,J=8.2Hz,1H),7.82(d,J=6.8Hz,2H),7.34(s,1H),7.01(d,J=8.0Hz,1H),6.82 (t,J=9.4Hz,1H),6.83(d,J=10.2Hz,1H),5.86-5.78(m,1H),4.94(s,2H),4.33(d,J =3.4Hz,2H),2.99-2.89(m,1H),2.71-2.63(m,2H),2,18(s,3H),2.14-2.09(m,1H).

[0121] Example 12: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-methyl-2H-chromene-3-carboxamide (Compound T-12)

[0122] Synthesis of 6-methyl-2H-chromene-3-carboxylic acid: 5-methyl salicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 57.6%. HRMS (ESI - ):(MH) - Measured value: 189.0548.

[0123] Synthesis of compound T-12: The raw material 6-methyl-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-12 (0.07 g, yield 49.2%, purity 98.96%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.00 (s, 1H), 8.97 (s, 1H), 8.55 (s, 1H), 8.13 (d, J= 9.7Hz,1H),7.81(d,J=6.5Hz,2H),7.33(s,1H),7.02(d,J=10.0Hz,1H),6.79(t,J =8.2Hz,1H),6.83(d,J=10.2Hz,1H),5.87-5.78(m,1H),4.92(s,2H),4.31(d,J=3 .5Hz,2H),2.98-2.87(m,1H),2.72-2.64(m,2H),2,17(s,3H),2.12-2.07(m,1H).

[0124] Example 13: 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-2H-chromene-3-carboxamide (Compound T-13)

[0125] Synthesis of 6-chloro-2H-chromene-3-carboxylic acid: 5-chlorosalicylaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 68.3%. HRMS (ESI - ):(MH) - The measured value is 209.0019.

[0126] Synthesis of compound T-13: The raw material 6-chloro-2H-chromene-3-carboxylic acid was used to prepare the compound according to the synthesis method of compound T-1 to obtain white solid A-6 (0.06 g, yield 40.4%, purity 96.87%). 1 H NMR(300MHz,DMSO-d6)δ(ppm)11.05(s,1H),9.02(s,1H),8.47(s,1H),8.26 (d,J=9.0Hz,1H),7.83(d,J=10.7Hz,2H),7.41(s,1H),7.29(s,1H),7.21(d ,J=7.4Hz,1H),6.91(d,J=7.3Hz,1H),5.86-5.72(m,1H),5.03(s,2H),4.59 (d,J=6.9Hz,2H),2.97-2.86(m,1H),2.64-2.54(m,2H),2.19-2.11(m,1H).

[0127] Example 14: 6-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-2H-chromene-3-carboxamide (Compound T-14)

[0128] Synthesis of 6-bromo-2H-chromene-3-carboxylic acid: 5-bromosalicylaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 62.5%. HRMS (ESI - ):(MH) - The measured value is 252.9513.

[0129] Synthesis of compound T-14: The raw material 6-bromo-2H-chromene-3-carboxylic acid was used to prepare the compound according to the synthesis method of compound T-1 to obtain white solid A-6 (0.07 g, yield 43.1%, purity 97.03%). 1H NMR(300MHz,DMSO-d6)δ(ppm)11.05(s,1H),9.03(s,1H),8.47(s,1H),8.2 7(d,J=9.5Hz,1H),7.82(d,J=9.7Hz,2H),7.38(s,1H),7.27(s,1H),7.19(d ,J=7.4Hz,1H),6.90(d,J=7.4Hz,1H),5.86-5.72(m,1H),5.04(s,2H),4.58 (d,J=6.9Hz,2H),2.97-2.87(m,1H),2.63-2.54(m,2H),2.19-2.11(m,1H).

[0130] Example 15: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-5-(trifluoromethyl)-2H-chromene-3-carboxamide (Compound T-15)

[0131] Synthesis of 5-(trifluoromethyl)-2H-chromene-3-carboxylic acid: 6-trifluoromethyl salicylaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 58.3%. HRMS (ESI - ):(MH) - The measured value is 243.0279.

[0132] Synthesis of compound T-15: The raw material 5-(trifluoromethyl)-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-15 (0.06 g, yield 37.8%, purity 98.83%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.05 (s, 1H), 9.20 (t, J = 3.1Hz, 1H), 8.46 (s, 1 H),8.25(d,J=8.1Hz,1H),7.84(d,J=8.3Hz,2H),7.44(t,J=8.8Hz,2H),7.36 (d,J=7.5Hz,1H),7.21(d,J=8.0Hz,1H),5.80-5.74(m,1H),5.01(s,2H),4.6 1(d,J=5.6Hz,2H),2.96-2.84(m,1H),2.68-2.57(m,2H),2.16-2.12(m,1H).

[0133] Example 16: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-vinyl-2H-chromene-3-carboxamide (Compound T-16)

[0134] Synthesis of 6-vinyl-2H-chromene-3-carboxylic acid: 5-vinyl salicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 56.8%. HRMS (ESI - ):(MH) - The measured value is 201.0568.

[0135] Synthesis of compound T-16: The raw material 6-vinyl-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method of compound T-1 to obtain white solid T-16 (0.08 g, yield 54.9%, purity 96.29%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.06 (s, 1H), 8.99 (s, 1H), 8.54 (s, 1H), 8.19 (d, J = 3.6Hz, 1H), 7.9 9(d,J=5.0Hz,1H),7.74(s,1H),7.43-7.37(m,1H),7.21(t,J=9.3Hz,1H),6.83(d,J=4.0Hz,1H), 6.64(t,J=9.7Hz,1H),6.21(s,1H),5.85-5.79(m,1H),5.76(d,J=6.9Hz,1H),5.19(d,J=6.6Hz,1 H), 5.06 (s, 2H), 4.62 (d, J = 5.3Hz, 2H), 2.96-2.84 (m, 1H), 2.62-2.51 (m, 2H), 2.21-2.15 (m, 1H).

[0136] Example 17: 6-(tert-Butyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-2H-chromene-3-carboxamide (Compound T-17)

[0137] Synthesis of 6-(tert-butyl)-2H-chromene-3-carboxylic acid: 5-tert-butyl salicylaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 47.6%. HRMS (ESI - ):(MH) - The measured value is 231.1023.

[0138] Synthesis of compound T-17: The raw material 6-(tert-butyl)-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-17 (0.07 g, yield 45.1%, purity 98.93%). 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.05 (s, 1H), 9.03 (s, 1H), 8.64 (s, 1H), 8.19 (d, J = 6. 9Hz,1H),8.01(d,J=7.5Hz,1H),7.83(s,1H),7.46(d,J=9.0Hz,1H),7.13(d,J=7.1H z,1H),7.01(s,1H),6.64(t,J=8.3Hz,1H),5.85-5.79(m,1H),5.06(s,2H),4.72(d, J=5.2Hz,2H),2.93-2.81(m,1H),2.61-2.51(m,2H),2.20-2.15(m,1H),1.25(s,9H).

[0139] Example 18: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-phenyl-2H-chromene-3-carboxamide (Compound T-18)

[0140] Synthesis of 6-phenyl-2H-chromene-3-carboxylic acid: 5-phenyl salicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 53.2%. HRMS (ESI - ):(MH) - The measured value is 251.0718.

[0141] Synthesis of compound T-18: The raw material 6-phenyl-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-18 (0.05 g, yield 31.0%, purity 96.54%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.03 (s, 1H), 8.90 (t, J = 6.2Hz, 1H), 8.55 (s, 1H), 8.13 (d, J = 7.3Hz, 1H), 7.98 (s, 1H), 7.76-7.63 (m, 4H), 7.52-7.4 1(m,5H),7.01(d,J=8.3Hz,1H),5.80-5.74(m,1H),5.01(s,2H),4.67(d ,J=5.6Hz,2H),2.91-2.83(m,1H),2.62-2.54(m,2H),2.19-2.11(m,1H).

[0142] Example 19: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6,8-difluoro-2H-chromene-3-carboxamide (Compound T-19)

[0143] Synthesis of 6,8-difluoro-2H-chromene-3-carboxylic acid: 3,5-difluorosalicylaldehyde was used as the starting material and prepared according to the synthesis method of intermediate-3. The total yield of the two steps was 52.4%. HRMS (ESI - ):(MH) - The measured value is 211.0220.

[0144] Synthesis of compound T-19: The raw material 6,8-difluoro-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-19 (0.06 g, yield 40.3%, purity 96.93%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.01 (s, 1H), 8.95 (s, 1H), 8.20 (s, 1H), 7.94 (d, J = 8.5Hz, 1H), 7.77 (t, J = 14.3Hz, 2H), 7.38 (t, J = 9.6Hz, 1H ),7.15(d,J=8.9Hz,1H),5.86-5.80(m,1H),5.11(s,2H),4.59(d,J=6.4Hz,2H),2.87-2.74(m,1H),2.75-2.65(m,2H),2.18-2.10(m,1H).

[0145] Example 20: 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-7-methyl-2H-chromene-3-carboxamide (Compound T-20)

[0146] Synthesis of 6-chloro-7-methyl-2H-chromene-3-carboxylic acid: 5-chloro-4-methyl salicylaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the two steps was 54.6%. HRMS (ESI - ):(MH) - The measured value is 223.0158.

[0147] Synthesis of compound T-20: The raw material 6-chloro-7-methyl-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-20 (0.08 g, yield 52.4%, purity 98.43%). 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.01 (s, 1H), 8.95 (t, J = 7.2Hz, 1H), 8.10 (s, 1H), 7.78 (s, 1H), 7.48 (d, J = 6.8Hz, 2H), 7.14 (d, J = 9.6Hz, 1H), 7.02(s,1H),6.62(s,1H),5.85-5.80(m,1H),5.08(s,2H),4.59(d,J=3.4Hz,2H),2.87-2.74(m,4H),2.62-2.57(m,2H),2.21-2.13(m,1H).

[0148] Example 21: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)chroman-3-carboxamide (Compound T-21)

[0149] Synthesis of chroman-3-carboxylic acid: Salicylaldehyde was used as the raw material and prepared according to the synthesis method of Intermediate-3. The total yield of the three steps was 49.3%. HRMS (ESI - ):(MH) - The measured value is 177.0559.

[0150] Synthesis of compound T-21: The raw material chroman-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-21 (0.08 g, yield 57.8%, purity 98.13%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.03 (s, 1H), 9.02 (s, 1H), 8.78 (s, 1H), 8.49 (d, J = 6.3Hz, 1H), 8.19 (t, J = 9.8Hz, 1H), 7.84 (d, J = 9.8Hz, 1H), 7.43 (d ,J=8.2Hz,1H),7.02-6.91(m,3H),5.84-5.78(m,1H),5.06(s,2H),4.62( d,J=5.3Hz,2H),2.88-2.73(m,4H),2.69-2.54(m,2H),2.22-2.14(m,1H).

[0151] Example 22: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-fluorochroman-3-carboxamide (Compound T-22)

[0152] Synthesis of 6-fluorochroman-3-carboxylic acid: 5-fluorosalicylaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the three steps was 51.2%. HRMS (ESI - ):(MH) - The measured value is 195.0468.

[0153] Synthesis of compound T-22: The raw material 6-fluorochroman-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-22 (0.06 g, yield 41.7%, purity 98.03%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.03 (s, 1H), 9.03 (s, 1H), 8.76 (s, 1H), 8.49 (d, J = 7.2Hz, 1H), 8.20 (t, J = 9.8Hz, 1H), 7.79 (d, J = 9.7Hz, 1H), 7.40 (d ,J=8.2Hz,1H),7.01-6.91(m,2H),5.85-5.79(m,1H),5.08(s,2H),4.65( d,J=5.6Hz,2H),2.88-2.74(m,4H),2.66-2.57(m,2H),2.23-2.15(m,1H).

[0154] Example 23: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-(trifluoromethoxy)chroman-3-carboxamide (Compound T-23)

[0155] Synthesis of 6-trifluoromethoxychroman-3-carboxylic acid: 5-trifluoromethoxysalicylaldehyde was used as the starting material and prepared according to the synthesis method of Intermediate-3. The total yield of the three steps was 50.8%. HRMS (ESI - ):(MH) - The measured value is 261.0386.

[0156] Synthesis of compound T-23: The raw material 6-trifluoromethoxychroman-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain white solid T-23 (0.07 g, yield 42.6%, purity 99.10%). 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.04 (s, 1H), 9.13 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 8.2Hz, 1H), 7.99 (t, J = 9.8Hz, 1H), 7.52 (d, J = 9.7Hz, 1 H),6.95-6.82(m,3H),5.81-5.75(m,1H),5.04(s,2H),4.61(d,J=5.3Hz,2H),2.69-2.62(m,4H),2.58-2.53(m,2H),2.19-2.11(m,1H).

[0157] Example 24: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (Compound T-24)

[0158] The raw material 1,2,3,4-tetrahydroquinoline-3-carboxylic acid was used to prepare the compound T-1 according to the synthetic method to obtain white solid T-24 (0.09 g, yield 65.2%, purity 98.63%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.06 (s, 1H), 8.97 (s, 1H), 8.62 (s, 1H), 8.13 (d, J = 8.4Hz 1H),7.78(d,J=7.6Hz,1H),7.31(t,J=10.2Hz,1H),7.12(t,J=9.6Hz,1H),6.91(d,J=12.8Hz,1H),6.72(t,J=9.65Hz,1H), 6.48-6.40(m,2H),5.87-5.81(m,1H),5.08(s,2H),4.65(s,2H),2.93-2.79(m,4H),2.69-2.55(m,2H),2.21-2.14(m,1H).

[0159] Example 25: N-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-2H-chromene-3-carboxamide (Compound T-25)

[0160] The raw material intermediate-2 was used to prepare the compound T-1 according to the synthetic method to obtain white solid T-25 (0.07 g, yield 50.8%, purity 99.03%). 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.06 (s, 1H), 9.12 (s, 1H), 8.43 (s, 1H), 8.19 (d, J = 9.8Hz, 1H), 8.02 (s, 1H), 7.92 (s, 2H), 7.39 (s, 1H) ,7.16(t,J=7.4Hz,1H)7.12-7.06(m,2H),5.86-5.79(m,1H),5.09(s,2H),2.99-2.85(m,1H),2.64-2.55(m,2H),2.16-2.12(m,1H).

[0161] Example 26: N-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-6-fluoro-2H-chromene-3-carboxamide (Compound T-26)

[0162] The raw material intermediate-2 was prepared by referring to the synthetic method of compound T-1 to obtain white solid T-26 (0.09 g, yield 62.7%, purity 98.27%). 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.02 (s, 1H), 9.11 (s, 1H), 8.43 (s, 1H), 8.21 (d, J = 9.9Hz, 1H), 7.94 (d, J = 9.5Hz, 1H), 7.58-7.49 (m, 2H ),7.23(t,J=10.2Hz,1H)7.06-6.97(m,2H),5.82-5.76(m,1H),5.05(s,2H),2.96-2.83(m,1H),2.60-2.50(m,2H),2.12-2.08(m,1H).

[0163] Example 27: N-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-6-(trifluoromethoxy)-2H-chromene-3-carboxamide (Compound T-27)

[0164] The raw material intermediate-2 was prepared by referring to the synthetic method of compound T-1 to obtain white solid T-27 (0.08 g, yield 48.60%, purity 97.93%). 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.01 (s, 1H), 9.19 (s, 1H), 8.32 (d, J = 8.9Hz, 1H), 8.26 (d, J = 6.7Hz, 1H), 8.03 (s, 1H), 7.95-7.86 (m, 2 H),7.21-7.14(m,1H),7.03-6.92(m,2H),5.85-5.79(m,1H),5.08(s,2H),2.99-2.87(m,1H),2.64-2.54(m,2H),2.16-2.10(m,1H).

[0165] Example 28: N-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-8-(trifluoromethoxy)-2H-chromene-3-carboxamide (Compound T-28)

[0166] The raw material intermediate-2 was used to prepare the compound T-1 by referring to the synthetic method to obtain white solid T-28 (0.09 g, yield 54.7%, purity 99.32%). 1 H NMR(300MHz,DMSO-d6)δ(ppm)11.06(s,1H),8.94(s,1H),8.47(s,1H),8.27( d,J=7.3Hz,1H),7.95(d,J=9.8Hz,1H),7.76-7.72(m,2H),7.21(t,J=11.6Hz 1H),7.04(t,J=9.3Hz,1H),6.92-6.87(m,1H),5.80-5.74(m,1H),5.02(s,2H),2.92-2.85(m,1H),2.65-2.54(m,2H),2.14-2.11(s,1H).

[0167] Biological Test Example 1: Study on GSPT1 Degradation in KG-1 Cells

[0168] KG-1 cells were grown in IMDM (containing 20% ​​FBS) and the cell concentration was adjusted to 10 6Cells / well were plated in 6-well plates with 1350 μl per well. 150 μl of DMSO and the test compound of the present invention were added at a concentration of 200 nM and cultured in a 5% CO2, 37°C incubator for 4 hours. The cells were centrifuged to discard the culture medium, and PBS was added for washing and discarded. Whole-cell lysates were prepared using a mixture containing protease inhibitors (100×, Ford Biotechnology), a protein phosphatase inhibitor mixture (100×, Ford Biotechnology), a super nuclease (Biyuntian) and a high-intensity RIPA lysis buffer (Thermo Fisher Scientific) and placed on ice for 30 minutes. The cell debris pellet was discarded by centrifugation, and the supernatant whole-cell lysate was collected and transferred to a new centrifuge tube. After performing the BCA protein assay, the sample was prepared using 5X loading buffer (Thermo Fisher Scientific). Proteins were separated by electrophoresis on a 4-20% precast SDS-PAGE gel and transferred to a PVDF membrane. The membrane was blocked with 5% NFDM / TBST at room temperature for 1 hour. The membrane was then incubated with the primary antibody overnight at 4°C and the secondary antibody for 2 hours at room temperature the following day. Signals were detected using a MINICHEM™ imaging system.

[0169] Primary Antibody:

[0170] Anti-GSPT1: Abcam ab234433

[0171] Anti-beta Actin: Fude Bio FD0060

[0172] Secondary Antibody:

[0173] Anti-rabbit peroxidase-linked secondary antibody: FDG007

[0174] The degradation effects of the compounds on GSPT1 protein are shown in Table 1, wherein A indicates that the degradation percentage of GSPT1 protein is not less than 70%, B indicates that the degradation percentage is less than 70% but not less than 30%, and C indicates that the degradation percentage is less than 30%.

[0175] Table 1 Degradation of GSPT1 protein by compounds

[0176] As can be seen from Table 1, some of the phthalazinone compounds of the present invention have a very significant effect on the degradation of GSPT1 protein.

[0177] Biological test example 2: Anti-KG-1 cell proliferation activity

[0178] KG-1 cells in the logarithmic growth phase were diluted with culture medium (RPMI + 10% FBS) and plated in 96-well plates at 5000 cells / well. The cells were cultured in a 5% CO2, 37°C incubator for 24 hours. The test compound of the present invention was prepared into a 10mM stock solution with DMSO and diluted with culture medium to set up 9 concentration gradients, with 3 replicates for each concentration. After drug addition, the cells were cultured in a 5% CO2, 37°C incubator for 72 hours. Cell proliferation was detected using the CCK8 method. The IC value of the compound on cell growth inhibition was determined using the enzyme-labeled assay. 50 IC values ​​were calculated using GraphPad Prism 7 software. 50 value.

[0179] The anti-proliferation activity of the compounds against KG-1 cells is shown in Table 2, where A represents IC 50 ≤30nM, B means 30 <IC 50 ≤300nM, C represents IC 50 >300nM.

[0180] Table 2 Anti-proliferation activity of compounds in KG-1 cells

[0181] As can be seen from Table 2, some of the phthalazinone compounds of the present invention have significant anti-proliferation inhibitory activity on KG-1 cells.

[0182] As described above, although the present invention has been shown and described with reference to certain preferred embodiments, it should not be construed as limiting the present invention itself. Various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A compound represented by the general formula I or a pharmaceutically acceptable salt, tautomer, mesomer, racemate, enantiomer, diastereomer thereof: in: represents a single bond or a double bond; X is selected from -CH2-, -NH-, -O-, -S- or -Se-; Each R1 is independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or a 3-10 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is unsubstituted or optionally substituted with 1-3 R a replace; Each R2 is independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or a 3-10 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is unsubstituted or optionally substituted with 1-3 R a replace; Each R3 is independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or a 3-10 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is unsubstituted or optionally substituted with 1-3 R a replace; R4 is selected from hydrogen, deuterium, C1-C 12 alkyl, R5 is selected from hydrogen, deuterium, C1-C 12 alkyl; R6, R7, R8, R9, R 10 , R 11 are independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or a 3-10 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is unsubstituted or optionally substituted with 1-3 R a replace; R a , R b are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, cyano, nitro, benzyl, -C(O)NR c R d 、-C(O)R c 、-C(O)OR c 、-OR c 、-OC(O)R c 、-OC(O)OR c 、-OC(O)NR c R d 、-NR c R d 、-SR c 、-S(O)R c , -S(O)2R c or a 3-10 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl group is unsubstituted or optionally substituted with 1-3 R c replace; R c , R d Each is independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl or halogenated C3-C6 cycloalkyl; m, p, q, t, and n are each independently selected from 0, 1, 2, or 3.

2. The compound according to claim 1, characterized in that: X is selected from -NH- or -O-.

3. The compound according to claim 1, characterized in that: Each R1 is independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, hydroxyl, nitro, C1-C 10 Aryl or -NR a R b ; R a , R b are independently selected from hydrogen, C1-C6 alkyl or -C(O)R c ; R c Selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or C3-C6 cycloalkyl.

4. The compound according to claim 3, characterized in that: Each R1 is independently selected from hydrogen, methyl, fluorine, chlorine, bromine, methoxy, trifluoromethyl, trifluoromethoxy, vinyl, tert-butyl or phenyl.

5. The compound according to claim 1, characterized in that: R2 and R3 are each independently selected from hydrogen.

6. The compound according to claim 1, characterized in that: R4 and R5 are each independently selected from hydrogen.

7. The compound according to claim 1, characterized in that: p, q, and n are each independently selected from 1.

8. The compound according to claim 1, characterized in that: m is selected from 0, 1 or 2.

9. The compound according to claim 1, characterized in that: t is selected from 0 or 1.

10. The compound according to claim 1, characterized in that Selected from:

11. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, tautomer, mesomorph, racemate, enantiomer, diastereomer thereof and a pharmaceutically acceptable carrier or excipient.

12. Use of the compound according to any one of claims 1 to 10 in the preparation of a medicament for treating or preventing diseases associated with GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC or C-MYC protein mutations, expression imbalances, conformational changes and functional abnormalities.

13. The use according to claim 12, characterized in that The related diseases are cancer, viral infection, aging, immune diseases or neurological diseases.

14. The use according to claim 13, characterized in that The cancer is selected from acute myeloid leukemia, liver cancer, acute lymphocytic leukemia, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, chronic lymphocytic leukemia CLL, chronic myeloid leukemia CML, colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, Hodgkin's lymphoma, laryngeal cancer, lung cancer, melanoma, mesothelioma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, skin cancer, testicular cancer, throat cancer, thyroid cancer or uterine cancer.

15. The use according to claim 13, characterized in that The lung cancer is non-small cell lung cancer.

16. Use of the compound according to any one of claims 1 to 10 in the preparation of a GSPT1 degrading agent.

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