Phthalazinone GSPT1 protein degradation agent and application thereof

Abstract

The invention discloses a compound shown as a general formula I or pharmaceutically acceptable salt, tautomer, meracemate, raceme, enantiomer and diastereoisomer of the compound. The degradation effect of the compound on GSPT1 protein and the anti-proliferation inhibition activity of AML and solid tumor cells are remarkably improved. Therefore, the compound provided by the invention can be used for preparing medicines for treating or preventing diseases related to GSPT1, IKZF1, IKZF2, IKZF3, CK1 alpha, N-MYC or C-MYC protein mutation, expression imbalance, allosteric and dysfunction; the method can be used for preparing the GSPT1 degradation agent. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a phthalazinone GSPT1 protein degrading agent and application 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 to regulate protein homeostasis. The rise of this technology has to some 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 can provide 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 target protein degradation. Molecular glues can promote dimerization or colocalization of two proteins by forming a ternary complex, 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 the body. Downregulation of GSPT1 can lead to abnormal expression of key proteins and inhibit proliferation or induce apoptosis in various tumor cells. Since GSPT1 was found to be a new substrate of E3 ubiquitin ligase CRBN, it can be targeted for degradation by molecular glue degraders. Currently, a variety of molecular glue degraders are in clinical and preclinical studies. These molecules are very effective in treating blood tumors and certain solid tumors. GSPT1 is multifunctional. In addition to being a second-class peptide chain release factor and participating in protein translation termination, it is also related to apoptosis, cell cycle regulation, tumor occurrence and development, and other processes. For example, during apoptosis, GSPT1 is processed by proteolysis to form another isoform, which contains a conserved N-terminal apoptosis inhibitor protein binder. GSPT1 interacts with inhibitor 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) protein, coupling translation termination and mRNA degradation.

[0005] Acute myeloid leukemia (AML) is a genetically and biologically heterogeneous myeloid malignancy characterized by abnormal proliferation of immature myeloid progenitor cells, which damages the body's normal hematopoietic function, causing severe infection, anemia, and bleeding. It is characterized by low survival rate and high relapse rate. Therefore, as a relatively rare malignancy, it has been regarded as an orphan disease by the US Food and Drug Administration. GSPT1, as a new substrate of CRL4-CRBN-E3 ubiquitin ligase, plays an important 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 mainly used to treat AML by intravenous injection, while BTX-1188 is an oral drug used to treat AML and NHL. Further studies have found that the degradation of GSPT1 is associated with the upregulation of ATF3 and ATF4 gene expression, and ATF3 and ATF4 genes are very important 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 apoptosis of cells.

[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 the gene expression in the total RNA extracted from the breast cancer samples they collected and identified five genes, including GSPT1, that can be used as potential therapeutic targets for triple-negative breast cancer. Recently, the study by Malta-Vacas et al. also showed that the longer GSPT1 allele 12-GGC is present in 5.1% of breast cancer patients. In addition, mRNA quantitative experiments also showed that GSPT1 is overexpressed in tumor tissues of patients with the 12-GGC allele relative to normal adjacent tissues. In addition, Miri et al. conducted a test on the GSPT1 gene and breast cancer susceptibility in breast cancer patients. The study found that the expression of GSPT1 was significantly increased in breast cancer tissues, and the presence of the longer allele 12-GGC in the GSPT1 exon can increase the risk of breast cancer by 3 times. Therefore, some scholars believe that the 12-GGC allele and cancer development are achieved by GSPT1 through the loss of protein function by regulating 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 the expression level of GSPT1 in intestinal gastric tumors was significantly higher than that in diffuse gastric tumors. In addition, they also evaluated the relationship between GSPT1 and the potential genetic susceptibility to gastric cancer and found that regardless of the genotype, patients with the 12-GGC allele had a 20-fold increased risk of gastric cancer compared with the average person. Tian et al. explored the potential impact of GSPT1 on the occurrence of gastric cancer and found that the expression level of GSPT1 was significantly increased in gastric cancer tissues. Some scholars believe that the overexpression of GSPT1 promotes tumor development by increasing the translation efficiency of specific oncogene mRNA, while others believe that it is through other effects of GSPT1 such as regulating the cell cycle and apoptosis. Since GSPT1 is also involved in cytoskeleton formation and controlling chromosome separation, the effect of GSPT1 on chromosome separation and cytoplasmic division may also be a potential mechanism for the gene to affect gastric cancer.

[0008] Liver cancer is a common tumor disease. According to clinical data, the expression of GSPT1 in liver cancer tissues is generally higher than that in normal cells. Since one of the main functions of GSPT1 is to regulate the transition of cells from the G1 phase to the S phase, some researchers have speculated that interfering with the mRNA expression of GSPT1 can change the cell cycle, thereby increasing the percentage of cells in the G1 phase, leading to a decrease in the vitality and proliferation of tumor cells. Although GSPT1 has a carcinogenic effect in the occurrence and development of liver cancer, some researchers have found that GSPT1 may inhibit the carcinogenic process in the development of liver cancer by constructing HepG2 cells that overexpress and knock down the GSTP1 gene.

[0009] Colorectal cancer is one of the most important malignant tumors of the digestive system. Xiao et al.'s study showed that GSPT18 was overexpressed in human colorectal cancer HCT116 cells compared with colorectal cells in the normal control group. Further experiments also showed that knocking down GSPT1 in colorectal cancer cells with high GSPT1 expression could inhibit the proliferation and migration of colorectal cancer cells. Research results showed that GSPT1 inhibited the cell cycle progression of HCT116 cells through the mTOR pathway. When the mTOR pathway was activated, it would lead to increased translation of mRNA subgroups. Therefore, GSPT1 may play the role of a proto-oncogene in the occurrence and development of colorectal cancer.

[0010] In summary, GSPT1 plays an important role in the occurrence and development of related solid tumors. However, due to its diverse functions and complex regulatory mechanisms, it plays different roles in different tumors. However, it is generally recognized that GSPT1 is a proto-oncogene in most tumors, and in certain specific types of tumors, it plays the role of a tumor suppressor gene. At present, there is still a lack of in-depth research on the relevant mechanism of action of GSPT1 in tumors, but there is no doubt that GSPT1 has become a powerful potential target in tumor treatment. Summary of the invention

[0011] Objective of the invention: One of the objectives of the present invention is to provide a phthalazinone compound of general formula I or a pharmaceutically acceptable salt, tautomer, mesomer, racemate, enantiomer, diastereomer thereof:

[0012]

[0013] in:

[0014] represents a single or 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 、-NRa 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;

[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 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;

[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 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;

[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 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;

[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 、-SRc 、-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,

[0026] X is selected from -NH- or -O-.

[0027] In certain preferred embodiments,

[0028] 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 ;

[0029] R a , R b are independently selected from hydrogen, C1-C6 alkyl or -C(O)R c ;

[0030] R c Selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or C3-C6 cycloalkyl.

[0031] In certain more preferred embodiments,

[0032] Each R1 is independently selected from hydrogen, methyl, fluorine, chlorine, bromine, methoxy, trifluoromethyl, trifluoromethoxy, vinyl, tert-butyl, and phenyl.

[0033] In certain preferred embodiments,

[0034] R2 and R3 are each independently selected from hydrogen.

[0035] In certain preferred embodiments,

[0036] R4 and R5 are each independently selected from hydrogen.

[0037] In certain preferred embodiments,

[0038] p, q, and n are each independently selected from 1.

[0039] In certain preferred embodiments,

[0040] m is selected from 0, 1 or 2.

[0041] In certain preferred embodiments,

[0042] t is selected from 0 or 1.

[0043] The above-mentioned compounds of general formula I of the present invention may also exist in the form of their salts, which are converted in vivo into compounds of general formula I. For example, within the scope of the present invention, the compounds of the present invention are converted into pharmaceutically acceptable salt forms according to processes known in the art, and they are used in the form of salts.

[0044] 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.

[0045] 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.

[0046] The compounds of the general formula I of the present invention are preferably the following compounds:

[0047]

[0048]

[0049]

[0050] Another object of the present invention is to provide a pharmaceutical composition, which comprises 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.

[0051] The pharmaceutical composition 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 composition 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, adhesives, colorants, fillers, emulsifiers, etc.

[0052] 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.

[0053] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can 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 dosage level selected depends on a variety of factors, including the activity of the specific compound of the present invention or its salt used, the route of administration, the time of administration, the excretion rate of the specific composition used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific composition used, the age, sex, weight, general health and previous medical history of the patient being treated, and similar factors well known in the medical field.

[0054] Another object of the present invention is to provide a compound of formula I or a pharmaceutically acceptable salt, tautomer, mesomer, racemate, enantiomer, diastereomer thereof for use 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.

[0055] The related diseases are cancer, viral infection, aging, immune diseases or neurological diseases; 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.

[0056] The present invention also provides the use of the compound of general formula I or its pharmaceutically acceptable salt, tautomer, mesomer, racemate, enantiomer, diastereomer in the preparation of GSPT1 degradation agent.

[0057] Beneficial effects:

[0058] The phthalazinone compounds of the present invention have significant degradation effects on GSPT1 protein and anti-proliferation inhibitory activity on AML cells. Therefore, the phthalazinone compounds of the present invention can be used to prepare drugs for treating or preventing diseases related to GSPT1, IKZF1, IKZF2, IKZF3, CK1α, N-MYC or C-MYC protein mutations, expression imbalances, allostery and functional abnormalities; and can be used to prepare GSPT1 degraders.

[0059] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0060] 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 enantiomers, diastereomers, and geometric (or conformational) isomer mixtures.

[0061] 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, which form non-toxic salts, such as hydrochlorides / chlorides. Suitable base salts are formed from bases, which form non-toxic salts, such as calcium and sodium salts. Hemi-salts of acids and bases, such as hemisulphate and hemicalcium salts, can also be formed.

[0062] The term "therapeutically effective amount" refers to an amount of a compound of the present application 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.

[0063] 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.

[0064] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, and the present invention preferably contains alkyl groups of 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, etc.

[0065] 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" refers to straight or branched unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0066] 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 The term "alkynyl" includes straight or branched hydrocarbon chain alkynyl groups as defined above having 2 to 6 carbon atoms.

[0067] 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.

[0068] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, and the cycloalkyl of the present invention preferably contains 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, condensed and bridged cycloalkyls.

[0069] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring 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 rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl.

[0070] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with 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, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.

[0071] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. It is preferably 6-14 members, and more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.

[0072] 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 are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring part 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; most preferably, it contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. The non-limiting examples of monocyclic heterocyclic radicals include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclic radicals include spiro heterocyclic radicals, condensed heterocyclic radicals and bridged heterocyclic radicals.

[0073] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 monocyclic 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 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between rings, the spiro heterocyclic group is divided into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably, it is a 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan single spiro heterocyclic group.

[0074] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, 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 a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group.

[0075] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings 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 bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

[0076] 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, and non-limiting examples thereof include:

[0077]

[0078] 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 π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0079] 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. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl.

[0080] 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, and non-limiting examples thereof include:

[0081]

[0082] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0083] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0084] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. DETAILED DESCRIPTION

[0085] The technical solution of the present invention is described in detail below through specific embodiments, but the protection scope of the present invention is not limited to the embodiments.

[0086] Synthesis of key intermediate-1:

[0087]

[0088] 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.

[0089] 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, dry the filter cake to obtain white solid compound 3 (12.16 g, yield 76.3%). HRMS (ESI - ):(M+H) + The measured value is 174.0188.

[0090] 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 brown solid compound 4 (10.01 g, yield 84.3%). HRMS (ESI + ):(M+H) + The measured value is 172.0510.

[0091] 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 sulfide (2.80 g, 117.07 mmol) under ice bath, stir at room temperature for 1 h, 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 using 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.

[0092] 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 turn, 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 turn, 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.

[0093] 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 by suction 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.

[0094] Synthesis of key intermediate-2:

[0095]

[0096] 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 purify the residue using a silica gel column to obtain a white solid compound 8 (8.71 g, yield 62.0%). HRMS (ESI + ):(M+H) + The measured value is 273.9711.

[0097] 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 in sequence. The mixture was stirred at room temperature for 4 hours. The mixture was filtered and the filtrate was concentrated. 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.

[0098] 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.

[0099] 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, 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.

[0100] Step 5: Dissolve 6-nitrophthalazine-1(2H)-one (3.37 g, 17.63 mmol) in 150 mL of N,N-dimethylformamide, add sodium hydrogen sulfide (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 to obtain a white solid compound 12 (2.14 g, yield 40.2%). HRMS (ESI + ):(M+H) + The measured value is 303.0711.

[0101] 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.

[0102] Synthesis of key intermediate-3:

[0103]

[0104] 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.

[0105] Step 2: Dissolve 2H-chromene-3-carbonitrile (2.30 g, 14.73 mmol) in 40 mL of 10% sodium hydroxide aqueous 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.

[0106] 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, which is Intermediate-3: chroman-3-carboxylic acid (0.76 g, yield 50.2%). HRMS (ESI - ):(MH) - The measured value is 177.0545.

[0107] Example 1: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-2H-chromene-3-carboxamide (Compound T-1)

[0108]

[0109] 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 in sequence, and stirred at room temperature for 1 hour. DIPEA (0.12 g, 0.94 mmol) was added and stirred at room temperature overnight. The reaction solution was poured into ice water, filtered, and the filter cake was purified using a silica gel column to obtain a white solid, namely compound T-1 (0.10 g, yield 72.6%, purity 98.93%). 1H 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).

[0110] 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)

[0111]

[0112] Synthesis of 5-fluoro-2H-chromene-3-carboxylic acid: The raw material 6-fluorosalicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 52.4%. HRMS (ESI - ):(MH) - The measured value is 193.0318.

[0113] Synthesis of compound T-2: The raw material 5-fluoro-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain a white solid, namely compound T-2 (0.08 g, yield 55.8%, purity 96.93%). 1 H 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).

[0114] 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)

[0115]

[0116] Synthesis of 6-fluoro-2H-chromene-3-carboxylic acid: The raw material 5-fluorosalicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 62.1%. HRMS (ESI - ):(MH) - The measured value is 193.0310.

[0117] Synthesis of compound T-3: The raw material 6-fluoro-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method 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).

[0118] 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)

[0119]

[0120] Synthesis of 7-fluoro-2H-chromene-3-carboxylic acid: The raw material 4-fluorosalicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 56.8%. HRMS (ESI - ):(MH) - The measured value is 193.0321.

[0121] Synthesis of compound T-4: The raw material 7-fluoro-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain a white solid, namely compound T-4 (0.08 g, yield 55.8%, purity 96.32%). 1H 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).

[0122] 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)

[0123]

[0124] Synthesis of 8-fluoro-2H-chromene-3-carboxylic acid: 3-fluorosalicylaldehyde was used as the raw 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.

[0125] 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%). 1 H 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), 7.16-7.0 6(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).

[0126] 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)

[0127]

[0128] Synthesis of 8-methoxy-2H-chromene-3-carboxylic acid: The raw material 2-hydroxy-3-methoxybenzaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 56.5%. HRMS (ESI - ):(MH) - Actual measured value: 205.0500.

[0129] 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).

[0130] 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)

[0131]

[0132] Synthesis of 5-methoxy-2H-chromene-3-carboxylic acid: The raw material 6-methoxy salicylaldehyde was prepared according to the synthesis method of intermediate-3, and the total yield of the two steps was 62.5%. HRMS (ESI - ):(MH) - The measured value is 205.0515.

[0133] 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%). 1H 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).

[0134] 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)

[0135]

[0136] Synthesis of 6-methoxy-2H-chromene-3-carboxylic acid: The raw material 5-methoxy salicylaldehyde was prepared according to the synthesis method of intermediate-3, and the total yield of the two steps was 58.6%. HRMS (ESI - ):(MH) - The measured value is 205.0511.

[0137] 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%). 1 H 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).

[0138] 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)

[0139]

[0140] Synthesis of 8-trifluoromethoxy-2H-chromene-3-carboxylic acid: The raw material 2-hydroxy-3-trifluoromethoxybenzaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 48.2%. HRMS (ESI - ):(MH) - The measured value is 259.0220.

[0141] 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).

[0142] 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)

[0143]

[0144] Synthesis of 6-trifluoromethoxy-2H-chromene-3-carboxylic acid: The raw material 5-trifluoromethoxy salicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 62.3%. HRMS (ESI - ):(MH) - The measured value is 259.0228.

[0145] Synthesis of compound T-10: The raw material 6-trifluoromethoxy-2H-chromene-3-carboxylic acid was used to prepare it by the synthesis method of compound T-1 to obtain 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).

[0146] 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)

[0147]

[0148] Synthesis of 8-methyl-2H-chromene-3-carboxylic acid: 2-hydroxy-3-methylbenzaldehyde was used as the raw 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.

[0149] Synthesis of compound T-11: The raw material 8-methyl-2H-chromene-3-carboxylic acid was used as a reference 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).

[0150] 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)

[0151]

[0152] Synthesis of 6-methyl-2H-chromene-3-carboxylic acid: The raw material 5-methyl salicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 57.6%. HRMS (ESI - ):(MH) - Measured value: 189.0548.

[0153] 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 of compound T-1 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).

[0154] 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)

[0155]

[0156] Synthesis of 6-chloro-2H-chromene-3-carboxylic acid: The raw material 5-chlorosalicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 68.3%. HRMS (ESI - ):(MH) - Actual measured value: 209.0019.

[0157] Synthesis of compound T-13: The raw material 6-chloro-2H-chromene-3-carboxylic acid was used to prepare the compound T-1 according to the synthesis method to obtain a 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).

[0158] 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)

[0159]

[0160] Synthesis of 6-bromo-2H-chromene-3-carboxylic acid: The raw material 5-bromosalicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 62.5%. HRMS (ESI - ):(MH) - The measured value is 252.9513.

[0161] 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%).1 H 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).

[0162] 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)

[0163]

[0164] Synthesis of 5-(trifluoromethyl)-2H-chromene-3-carboxylic acid: The raw material 6-trifluoromethyl salicylaldehyde was prepared according to the synthesis method of intermediate-3, and the total yield of the two steps was 58.3%. HRMS (ESI - ):(MH) - The measured value is 243.0279.

[0165] 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).

[0166] 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)

[0167]

[0168] Synthesis of 6-vinyl-2H-chromene-3-carboxylic acid: The raw material 5-vinyl salicylaldehyde was prepared according to the synthesis method of intermediate-3, and the total yield of the two steps was 56.8%. HRMS (ESI - ):(MH) - Actual measured value: 201.0568.

[0169] 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).

[0170] 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)

[0171]

[0172] Synthesis of 6-(tert-butyl)-2H-chromene-3-carboxylic acid: Prepared by using 5-tert-butyl salicylaldehyde as the raw material according to the synthesis method of intermediate-3, the total yield of the two steps is 47.6%. HRMS (ESI - ):(MH) - The measured value is 231.1023.

[0173] 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 of compound T-1 to obtain white solid T-17 (0.07 g, yield 45.1%, purity 98.93%). 1 H 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).

[0174] 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)

[0175]

[0176] Synthesis of 6-phenyl-2H-chromene-3-carboxylic acid: The raw material 5-phenyl salicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 53.2%. HRMS (ESI - ):(MH) - The measured value is 251.0718.

[0177] 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 of compound T-1 to obtain white solid T-18 (0.05 g, yield 31.0%, purity 96.54%). 1H 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).

[0178] 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)

[0179]

[0180] Synthesis of 6,8-difluoro-2H-chromene-3-carboxylic acid: The raw material 3,5-difluorosalicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 52.4%. HRMS (ESI - ):(MH) - Actual measured value: 211.0220.

[0181] 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).

[0182] 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)

[0183]

[0184] Synthesis of 6-chloro-7-methyl-2H-chromene-3-carboxylic acid: The raw material 5-chloro-4-methyl salicylaldehyde was used to prepare the intermediate-3, and the total yield of the two steps was 54.6%. HRMS (ESI - ):(MH) - The measured value is 223.0158.

[0185] 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%). 1 H 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).

[0186] Example 21: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)chroman-3-carboxamide (Compound T-21)

[0187]

[0188] Synthesis of chroman-3-carboxylic acid: The raw material salicylaldehyde was prepared according to the synthesis method of intermediate-3, and the total yield of the three steps was 49.3%. HRMS (ESI - ):(MH) - The measured value is 177.0559.

[0189] 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%). 1H 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).

[0190] Example 22: N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)methyl)-6-fluorochroman-3-carboxamide (Compound T-22)

[0191]

[0192] Synthesis of 6-fluorochroman-3-carboxylic acid: The raw material 5-fluorosalicylaldehyde was used to prepare the intermediate-3, and the total yield of the three steps was 51.2%. HRMS (ESI - ):(MH) - The measured value is 195.0468.

[0193] 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).

[0194] 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)

[0195]

[0196] Synthesis of 6-trifluoromethoxychroman-3-carboxylic acid: The raw material 5-trifluoromethoxysalicylaldehyde was prepared according to the synthesis method of intermediate-3, and the total yield of the three steps was 50.8%. HRMS (ESI - ):(MH) - The measured value is 261.0386.

[0197] 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%). 1 H 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).

[0198] 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)

[0199]

[0200] 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%). 1H 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).

[0201] Example 25: N-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-2H-chromene-3-carboxamide (Compound T-25)

[0202]

[0203] 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%). 1 H 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).

[0204] 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)

[0205]

[0206] The raw material intermediate-2 was used to prepare the compound T-1 according to the synthetic method to obtain white solid T-26 (0.09 g, yield 62.7%, purity 98.27%). 1H 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).

[0207] 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)

[0208]

[0209] The raw material intermediate-2 was used to prepare the compound T-1 according to the synthetic method to obtain white solid T-27 (0.08 g, yield 48.60%, purity 97.93%). 1 H 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).

[0210] 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)

[0211]

[0212] The raw material intermediate-2 was used to prepare the compound T-1 according to the synthetic method to obtain white solid T-28 (0.09 g, yield 54.7%, purity 99.32%). 1H 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 =11.6Hz1H),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).

[0213] Biological test example 1: Study on the degradation of GSPT1 in KG-1 cells

[0214] KG-1 cells were grown in IMDM (containing 20% ​​FBS) and the cell concentration was adjusted to 10 6 Cells / well were plated in 6-well plates, 1350 μl per well. 150 μl of DMSO and the test compound of the present invention were added, the compound concentration was 200 nM, and the cells were 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 of protease inhibitors (100×, Ford Biotechnology), a mixture of protein phosphatase inhibitors (100×, Ford Biotechnology), super nuclease (Biyuntian) and high-strength RIPA lysis buffer (Thermo Fisher), and placed on ice for 30 minutes. Centrifuge to discard the cell debris precipitate, collect the supernatant whole-cell lysate and transfer it to a new centrifuge tube. After the BCA protein assay, 5X loading buffer (Thermo Fisher) was used to prepare the sample. The samples were electrophoresed in 4-20% precast gel (SDS-PAGE gel) to separate proteins, then transferred to PVDF membrane and blocked with 5% NFDM / TBST at room temperature for 1 hour, incubated with primary antibody at 4°C overnight, and incubated with secondary antibody at room temperature for 2 hours the next day. The signal was detected using MINICHEM™ imaging system.

[0215] Primary Antibody:

[0216] Anti-GSPT1: Abcam ab234433

[0217] Anti-beta Actin: Fude Bio FD0060

[0218] Secondary Antibody:

[0219] Anti-rabbit peroxidase-linked secondary antibody: FDG007

[0220] 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%.

[0221] Table 1 Degradation of GSPT1 protein by compounds

[0222] Compound GSPT1 degradation Compound GSPT1 degradation T-1 B T-15 A T-2 A T-16 C T-3 B T-17 A T-4 B T-18 A T-5 B T-19 B T-6 B T-20 B T-7 A T-21 B T-8 B T-22 B T-9 B T-23 A T-10 A T-24 A T-11 B T-25 C T-12 B T-26 C T-13 B T-27 C T-14 B T-28 B

[0223] As can be seen from Table 1, some of the phthalazinone compounds of the present invention have a significant degradation effect on GSPT1 protein.

[0224] Biological test example 2: Anti-KG-1 cell proliferation activity

[0225] KG-1 cells in the logarithmic growth phase were diluted with culture medium (RPMI + 10% FBS), plated in 96-well plates at 5000 cells / well, and 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, diluted with culture medium to set 9 concentration gradients, with 3 replicates for each concentration, and cultured in a 5% CO2, 37°C incubator for 72 hours after drug addition. Cell proliferation was detected using the CCK8 method. The IC value of the compound's inhibition of cell growth was determined using the enzyme labeling method. 50 IC values ​​were calculated using GraphPad Prism 7 software. 50 value.

[0226] The anti-KG-1 cell proliferation activities of the compounds are shown in Table 2, where A represents IC 50 ≤30nM, B means 30 <IC 50 ≤300nM, C represents IC 50 >300nM.

[0227] Table 2 Anti-KG-1 cell proliferation activity of compounds

[0228] Compound <![CDATA[IC 50 ]]> Compound <![CDATA[IC 50 ]]> T-1 B T-15 A T-2 A T-16 C T-3 B T-17 A T-4 B T-18 A T-5 A T-19 B T-6 B T-20 B T-7 A T-21 B T-8 B T-22 A T-9 A T-23 A T-10 A T-24 B T-11 B T-25 B T-12 B T-26 B T-13 B T-27 B T-14 B T-28 B

[0229] As can be seen from Table 2, some of the phthalazinone compounds of the present invention have significant antiproliferation inhibitory activity on KG-1 cells.

[0230] 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 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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