Nitrogen-containing heterocyclic compound as well as preparation method and application thereof

Abstract

The invention relates to a nitrogen-containing heterocyclic ring compound as well as a preparation method and application thereof. The invention discloses a compound as shown in a formula (I) for treating cancer, and an isotope label, an enantiomer, a diastereoisomer, an atropisomer, a solvate, a prodrug or a pharmaceutically acceptable salt thereof. The compound provided by the invention has better inhibitory activity on WRN and has a good application prospect. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application No. 202310677169X filed on 06 / 08 / 2023, Chinese patent application No. 2023112254722 filed on 09 / 21 / 2023, and Chinese patent application No. 2023117691561 filed on 12 / 21 / 2023. This application cites the full text of the above Chinese patent application. Technical Field

[0002] The present invention relates to a WRN inhibitor and a preparation method and application thereof, and in particular to a class of nitrogen-containing heterocyclic compounds, a composition thereof and applications thereof in treating and preventing cancer. Background Art

[0003] Tumors are important diseases that affect human health. With the deepening of research in recent years, many breakthroughs have been made in the development of anti-tumor drugs, bringing new hope to patients. However, chemotherapy is still the main treatment for some tumors that tend to spread throughout the body and metastatic tumors in the middle and late stages. Most chemotherapy drugs are cytotoxic drugs that cannot recognize normal cells and cancer cells, so they are toxic to normal cells in the body. Therefore, it is particularly urgent to develop treatment strategies that are more selective for tumor cells.

[0004] In 1946, Theodosius Dobzhansky discovered and named the "synthetic lethality" effect in Drosophila, that is, when two specific genes mutate and become inactivated at the same time, the fruit fly will die; while the inactivation of any of these two genes alone will not cause fatal harm to the fruit fly (Dobzhansky, T. Genetics of natural populations; recombination and variability in populations of Drosophila seudoobscura. Genetics, 1946, 31: 269-290). Today, the concept of "synthetic lethality" has been applied to the field of tumor treatment, that is, for tumor cells with inactivated (deleted or mutated) genes, drugs can be used to inhibit another specific gene, thereby causing cancer cells rather than normal cells to die (Huang A, Garraway LA, Ashworth A, Weber B. Synthetic lethality as an engine for cancer drug target discovery. Nat Rev Drug Discov. 2020 Jan; 19(1): 23-38).PARP inhibitors (Olaparib, Rucaparib and Niraparib) designed based on the synthetic lethal interaction mechanism have been successfully used in the clinical treatment of Brca-mutated ovarian cancer, confirming the positive significance of synthetic lethality in clinical treatment (Kim G, et al. FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. Clin Cancer Res. 2015, 21: 4257–4261; Shapira-Frommer R, et al. A phase 2 open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. Ann Oncol. 2015, 33(suppl): 2476; Mirza, MR et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer cancer.N.Engl.J.Med.2016,375:2154–2164).

[0005] Microsatellites are short tandem repeat sequences that are commonly found in the human genome. Compared with normal cells, microsatellites in tumor cells will change in length due to the insertion or deletion of repeat units, which is called microsatellite instability (MSI). MSI is common in colorectal cancer (15%), gastric cancer (22%) and other solid tumors (Lorenzi M, Amonkar M, Zhang J, et al. Epidemiology of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in solid tumors: a structured literature review [J]. Journal of Oncology, 2020, 2020: 1-17). According to the degree of MSI, it can be divided into three categories: microsatellite high instability (MSI-high, MSI-H), microsatellite low instability (MSI-low, MSI-L) and microsatellite stable (MSS). MSI cancer patients have better overall prognosis and lower risk of metastasis (Kang S et al. The significance of microsatelliteinstability in colorectal cancer after controlling for clinicopathological factors. Medicine (Baltimore). 2018, 97(9): e0019).This is partly related to the high mutation load in MSI tumors, which leads to the production of neoantigens, thereby increasing immunogenicity and sensitivity to immune checkpoint inhibitors (Wang QX et al. The degree of microsatellite instability predicts response to PD-1 blockade immunotherapy in mismatch repair-deficient / microsatelliteinstability-high colorectal cancers. Exp Hematol Oncol. 2021, 10(1): 2; Lizardo DY et al. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside. Biochim Biophys Acta Rev Cancer. 2020, 1874(2): 1884-47; Corcoran RB, Grothey A. Efficacy of Immunotherapy in Microsatellite-Stable or Mismatch Repair Proficient Colorectal Cancer-Fact or Fiction? JAMA Oncol. 2020, 6(6): 823-824).However, a considerable proportion of MSI tumors do not respond to or develop resistance to immunotherapy and chemotherapy (Le DT et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High / Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J Clin Oncol. 2020, 38(1): 11-19; Overman MJ et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017, 18(9): 1182-1191; Fucà G et al. Ascites and resistance to immune checkpoint inhibition ind MMR / MSI-H metastatic colorectal and gastric cancers. J Immunother Cancer. 2022, 10(2): e004001.), so there is an urgent need for more effective targeted or combined treatments.

[0006] As the only member of the human RecQ helicase family that has both helicase and exonuclease activities, WRN plays an important role in DNA repair, replication, transcription, and telomere maintenance. WRN is composed of 1432 amino acids and has a molecular mass of 160kD. In intact human cells, WRN is mainly localized in the nucleolus; but after DNA damage occurs, it will quickly move to other nuclear regions. WRN contains an N-terminal 3'-5' exonuclease domain, an ATPase domain, an RQC domain (RecQ C-terminal), a HRDC domain (Helicase-and-ribonuclease DC-terminal), and a C-terminal nuclear localization signal sequence in its protein structure (Kitano K. Structural mechanisms of human RecQ helicases WRN and BLM. Front Genet. 2014, 5: 366). WRN can recognize specific DNA secondary structures such as DNA bubbles, replication forks, Holliday junctions, G4-quadruaplexes, and triple helices, and promote their unwinding, thereby participating in processes such as DNA replication and repair (Constantinou A, Tarsounas M, Karow JK, et al. Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest [J]. EMBO reports, 2000, 1 (1): 80-84.). WRN is a synthetic lethal target in MSI-H tumors (Chan EM, Shibue T, McFarland JM, et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers [J]. Nature, 2019, 568 (7753): 551-556).In previous studies, WRN gene knockdown or knockout, WRN helicase loss-of-function mutations, and small molecule WRN helicase inhibitors can significantly inhibit the cell growth of MSI-H tumors and the formation of subcutaneous transplanted tumors in mice (Ding Z, Zhang J, Pedamallu CS, et al. Identification and validation of WRN as a novel synthetic lethality target in context of microsatellite instability [J]. Cancer Research, 2020, 80 (16_Supplement): 1377-1377; Picco G et al. Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy. Cancer Discov. 2021, 11 (8): 1923-1937; Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells.Elife.2019, 8:e43333; Aggarwal MSommers JA, Shoemaker RH, et al. Inhibition of helicaseactivity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress [J]. Proceedings of the National Academy of Sciences, 2011, 108(4): 1525-1530).

[0007] It has been shown that WRN helicase activity is essential for the survival of MSI cell lines and cell lines with mismatch repair deficiency (dMMR), and helicase-deficient WRN is insufficient to rescue the impaired cell viability caused by WRN knockout or knockdown. Loss of WRN protein or inhibition of its helicase activity prevents normal DNA damage and repair processes, leading to increased DNA double-strand breaks (DSBs) and subsequent growth arrest and cell death. Therefore, the development of WRN inhibitors with higher activity and selectivity may meet the urgent need for the treatment of MSI-H cancers or mismatch repair deficiency (dMMR) cancers.

[0008] Covalent inhibitors are a class of small molecule inhibitors that exert their biological functions by irreversibly binding to target protein residues through covalent bonds. In general, covalent inhibition is a two-step process; first, the inhibitor reversibly binds to the target enzyme, thereby bringing the electron-rich chemical warhead in the small molecule close to the active residues in the enzyme. In the second step, the two reactive entities of the inhibitor react with the enzyme to form a covalent bond. Common covalent target heads include acrylamide, epoxy, chloroacetyl, oxygen sulfonyl fluoride and sulfonyl fluoride, etc., and common amino acid active residues include cysteine, serine, tyrosine, lysine, arginine and glutamate, etc. The first covalent inhibitors discovered were acetylsalicylic acid and penicillin. To date, more and more covalent inhibitors are being studied. Covalent inhibitors have the characteristics of high biochemical efficiency, strong and long-lasting effects, reduced dosage and frequency of administration, separation of pharmacodynamics and pharmacokinetics, rapid clearance of drugs and maintenance of efficacy, prevention of drug resistance, and targeting rare, non-conserved residues of specific proteins to achieve high selectivity. Therefore, covalent inhibitors will have good application prospects in anti-tumor applications. Summary of the invention

[0009] In order to overcome the defects in the prior art, the present invention provides a class of compounds and a preparation method and application thereof. The compounds of the present invention have good inhibitory activity on WRN.

[0010] The present invention provides a compound as shown in formula (I), its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in,

[0013] X 1 C=O or CR 0 ;X 2 N or NR 5 ;X 3 NH or N; X 5 CR6 R 7 or NR 6 ;X 6 N or CR 8 ;

[0014] When X 1 When C=O, X 2 NR 5 and is a single bond;

[0015] When X 1 CR 0 When X 2 is N and is a double bond;

[0016] R 0 is hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy, cyano, amino, -CONH2, or carboxyl;

[0017] Or when X 3 When N, X 1 CR 0 , R 0 For-(CR b R c ) m - and with X 3 connected, m is 1, 2 or 3, that is, X 1 With X 3 and the C atoms between them together form a 5-7 membered heterocyclic group; each R b and R c Each is independently selected from hydrogen, deuterium, unsubstituted or substituted C1-C6 alkyl, halogen, hydroxyl, carboxyl, amino, cyano, -CONH2; the substituted C1-C6 alkyl refers to being substituted by one or more selected from halogen, hydroxyl, carboxyl, amino, cyano;

[0018] R 1 , R 2 , R 3 , R 4 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, -CONH2, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl refers to being substituted by one or more selected from halogen, hydroxyl, carboxyl, amino, cyano;

[0019] R 5 is hydrogen or C1-C6 alkyl;

[0020] R 8is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR 8x R 8y , cyano, hydroxyl, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, -CONH2; R 8x and R 8y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0021] X 4 for

[0022] R 10 is hydrogen or C1-C6 alkyl or C1-C6 alkoxy; R 11 is hydrogen or C1-C6 alkyl;

[0023] p is 0, 1, or 2;

[0024] R 9 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR 9x R 9y , cyano, hydroxyl, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, -CONH2; R 9x and R 9y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0025] R a is C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, or 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

[0026] or R a With R 9 and the carbon atoms connected to them constitute C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

[0027] When X 4 for X 5 CR6 R 7 , and X 1 When C=O, R a With R 9 can only form with the carbon atoms to which they are attached C6-C10 aryl groups which are unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl groups which are unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl groups which are unsubstituted or substituted by one or more substituents selected from Group A, and 5-10 membered heteroaryl groups which are unsubstituted or substituted by one or more substituents selected from Group A;

[0028] Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ;

[0029] i is 0, 1, or 2;

[0030] R 12 and R 13 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0031] R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0032] R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B2;

[0033] The substituents of group B2 include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, -NR x R y , C6-C10 aryl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0034] The heteroatoms in the 3-6 membered heterocyclic group, 3-10 membered heterocyclic group and 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0035] In a preferred technical solution, the compound represented by formula (I) has a structure represented by formula (II):

[0036]

[0037] in,

[0038] R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R a , X 4 , X 5 and p are defined as above;

[0039] When X 4 for And X 5 CR 6 R 7 When R a With R 9 They can only form with the carbon atoms connected to them C6-C10 aryl groups which are unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl groups which are unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl groups which are unsubstituted or substituted by one or more substituents selected from Group A, and 5-10 membered heteroaryl groups which are unsubstituted or substituted by one or more substituents selected from Group A.

[0040] In a preferred technical solution, the compound represented by formula (I) has a structure represented by formula (V):

[0041]

[0042] in,

[0043] n is 1, 2, 3 or 4;

[0044] R d is deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ;

[0045] R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , X 4 , X 5 The definitions of , i and p are the same as described above.

[0046] In a preferred technical solution, the compound represented by formula (II) has a structure represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), and formula (II-8):

[0047]

[0048] in,

[0049] R 1 , R 2 , R 3 , R 4 , R 6 , R 7Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, unsubstituted or substituted C1-C6 alkyl, -CONH2; the substituted C1-C6 alkyl refers to being substituted by one or more selected from halogen, hydroxyl, carboxyl, amino, cyano;

[0050] R 5 is hydrogen or C1-C6 alkyl;

[0051] R 8 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR 8x R 8y , cyano, hydroxyl, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, -CONH2; R 8x and R 8y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0052] R 9 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR 9x R 9y , cyano, hydroxyl, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, -CONH2; R 9x and R 9y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0053] R a is C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, or 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

[0054] or R a With R 9 and the carbon atoms connected to them constitute C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A;

[0055] When the compound represented by formula (II) is formula (II-7) or formula (II-8), R a With R9 can only form with the carbon atoms to which they are attached C6-C10 aryl groups which are unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl groups which are unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl groups which are unsubstituted or substituted by one or more substituents selected from Group A, and 5-10 membered heteroaryl groups which are unsubstituted or substituted by one or more substituents selected from Group A;

[0056] Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ;

[0057] i is 0, 1, or 2;

[0058] R 12 and R 13 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0059] R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0060] R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B2;

[0061] The substituents of group B2 include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, -NRx R y , C6-C10 aryl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0062] The heteroatoms in the 3-6 membered heterocyclic group, 3-10 membered heterocyclic group and 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0063] In a preferred technical solution, the compound of formula (I) is selected from the following structures:

[0064]

[0065] R 1 , R 2 , R 3 , R 4 , R 9 , R a , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and p are defined as above.

[0066] The present invention also provides a compound as shown in formula (V-1), its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or a pharmaceutically acceptable salt thereof:

[0067]

[0068] in,

[0069] R 1 , R 2 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, cyano, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl refers to being substituted by one or more selected from halogen, amino, and cyano;

[0070] R 5 is hydrogen or C1-C6 alkyl;

[0071] R 8 is hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, -NR 8x R 8y , cyano, hydroxyl, carboxyl, -CONH2; R8x and R 8y Each is independently H or C1-C3 alkyl;

[0072] Y 1 N or CR d1 , Y 2 N or CR d2 , Y 3 N or CR d3 , Y 4 N or CR d4 ;

[0073] R d1 , R d2 , R d3 , R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, -COOH, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ;

[0074] i is 0, 1, or 2;

[0075] R 12 and R 13 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C6 cycloalkoxy;

[0076] R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0077] R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0078] Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B1, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B1; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0079] The substituents of group B1 include: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR B1x R B1y , cyano, hydroxyl, carboxyl, -CONH2; R B1x and R B1y Each is independently H or C1-C6 alkyl;

[0080] The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0081] As a preferred technical solution, the compound represented by formula (V-1), its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof:

[0082]

[0083] in,

[0084] R 1 , R 2 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, or C1-C3 alkyl;

[0085] R 5 is hydrogen or C1-C3 alkyl;

[0086] R8 is hydrogen, deuterium, halogen, C1-C3 alkyl, -NR 8x R 8y , hydroxyl; R 8x and R 8y Each is independently H or C1-C3 alkyl;

[0087] Y 1 N or CR d1 , Y 2 N or CR d2 , Y 3 N or CR d3 , Y 4 N or CR d4 ;

[0088] R d1 , R d2 , R d3 , R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, -COOH, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ;

[0089] i is 0, 1, or 2;

[0090] R 12 and R 13 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C6 cycloalkoxy;

[0091] R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0092] R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0093] Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B1, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B1; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0094] The substituents of group B1 include: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR B1x R B1y , cyano, hydroxyl, carboxyl, -CONH2; R B1x and R B1y Each is independently H or C1-C6 alkyl;

[0095] The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0096] As a preferred technical solution, the compound represented by formula (V-1) has a structure represented by formula (V-2):

[0097]

[0098] Among them, R 1 , R 2 , R 6 , R 7 , R 8 , R d1 , R d2 , R d3 and R d4 The definition of is the same as above.

[0099] As a preferred technical solution, R 1 , R 2 , R 6 , R 7 are each independently hydrogen, deuterium, C1-C6 alkyl, halogen or halogenated C1-C6 alkyl; R 8 , R d1 , R d2 , R d3 and R d4 The definition of is the same as above.

[0100] As a preferred technical solution,

[0101] R d1 , R d2 , R d3 and R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, -COOH, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ;

[0102] i is 0, 1, or 2;

[0103] R 12 and R 13 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C6 cycloalkoxy;

[0104] R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0105] R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0106] Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B1, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B1; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0107] The substituents of group B1 include: deuterium, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0108] The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0109] As a preferred technical solution,

[0110] R d1 , R d2 , R d3 and R d4 Each independently is -(CH2) i R 16 ;

[0111] i is 0, 1, or 2;

[0112] R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0113] Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by C1-C6 alkyl, C3-C8 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, 3-10 membered heterocyclyl which is unsubstituted or substituted by C1-C6 alkyl, 5-10 membered heteroaryl which is unsubstituted or substituted by C1-C6 alkyl; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0114] The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0115] As a preferred technical solution, the compound represented by formula (V-1) has a structure represented by formula (V-3):

[0116]

[0117] Among them, R d1 , R d2 , R d3 and R d4 The definition of is the same as above.

[0118] As a preferred technical solution,

[0119] R d1 , R d2 , R d3 and R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, -COOH, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) iR 15 、-(CH2) i R 16 ;

[0120] i is 0, 1, or 2;

[0121] R 12 and R 13 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C6 cycloalkoxy;

[0122] R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0123] R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0124] Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B1, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B1; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0125] The substituents of group B1 include: deuterium, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0126] The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0127] As a preferred technical solution,

[0128] R d1 , R d2 , R d3 and R d4 Each independently is -(CH2) i R 16 ;

[0129] i is 0, 1, or 2;

[0130] R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B;

[0131] Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by C1-C6 alkyl, C3-C8 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, 3-10 membered heterocyclyl which is unsubstituted or substituted by C1-C6 alkyl, 5-10 membered heteroaryl which is unsubstituted or substituted by C1-C6 alkyl; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0132] The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0133] As a preferred technical solution, R d1 , R d2 , R d3 and R d4 Each independently is C1-C6 alkyl, -NR x R y, C3-C6 cycloalkyl, halogen, C1-C6 alkyl substituted by one or more substituents selected from halogen, C3-C6 cycloalkyl, C2-C6 alkynyl; R x and R y Each is independently H or C1-C6 alkyl.

[0134] As a preferred technical solution, R d1 , R d2 , R d3 and R d4 Each independently is C1-C6 alkyl, -NR x R y , C3-C6 cycloalkyl, or halogenated C1-C6 alkyl.

[0135] As a preferred technical solution, R d1 , R d2 , R d3 and R d4 Each is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, halogen, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -N(CH3)2,

[0136] As a preferred technical solution, R d1 , R d2 , R d3 and R d4 Each is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -N(CH3)2.

[0137] As a preferred technical solution, R d1 , R d2 and R d4 is hydrogen; R d3 Methyl, ethyl, n-propyl, isopropyl, tert-butyl, halogen, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -N(CH3)2,

[0138] As a preferred technical solution, the compound of formula (V-1) is selected from the following structures:

[0139]

[0140] Among them, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , Y1 , Y 2 , Y 3 and Y 4 The definition is the same as above. As a preferred technical solution, the compound of formula (V-3) is selected from the following structures:

[0141]

[0142] R d1 , R d2 , R d3 and R d4 The definition of is the same as above.

[0143] In a specific embodiment, the compound as shown in formula (I) can be selected from the following compounds:

[0144]

[0145]

[0146] The present invention also provides a method for preparing the compound represented by formula (I), its pharmaceutically acceptable salt, its isotope-labeled substance, its solvate, its pharmaceutically acceptable salt solvate or its prodrug. Specifically, the following preparation methods are provided:

[0147] Method 1:

[0148]

[0149] Among them, R 0 , R 1 , R 2 , R 3 , R 4 , R 9 , R a , X 4 , X 5 , X 6 and p are defined as above;

[0150] X 7 is hydroxyl, halogen, C1-C6 alkoxy or

[0151] Compound A-1 and compound A-2 react in the presence of a condensing agent and a base to obtain compound III. The condensing agent used in the reaction can be thionyl chloride, pentafluorophenyl trifluoroacetate, oxalyl chloride, ethyl chloroformate, N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt), O-(7-azabenzotriazol-1-yl)-di(dimethylamino)carbonium hexafluorophosphate (HATU), 1H-benzotriazole-1-oxytris(1-pyrrolidinyl)phosphine hexafluorophosphate (PyBOP), n-propylphosphonic anhydride (T3P), diethyl cyanophosphate (DECP). The base used in the reaction can be an inorganic base such as sodium carbonate, or an organic base such as pyridine, triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA).

[0152] Method 2:

[0153]

[0154] Wherein, Y is selected from Cl, Br or OTf; X B Selected from -B(OH)2, -BF3K, or -B(pin); R b’ is selected from hydrogen, deuterium, unsubstituted or substituted C1-C6 alkyl, halogen, hydroxyl, carboxyl, amino, and cyano; the substituted C1-C6 alkyl refers to being substituted by one or more selected from halogen, hydroxyl, carboxyl, and amino; R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R a , R b , R c The definition of is the same as above.

[0155] Compound C-1 undergoes Suzuki reaction with compound C-2 to obtain compound C-3; compound C-3 undergoes addition reaction with compound C-4, followed by intramolecular cyclization to obtain compound C-5.

[0156] Method 3:

[0157]

[0158] X is selected from Cl or Br; R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R a , R b , R cThe definition of is the same as above.

[0159] Compound D-1 undergoes a substitution reaction with compound C-4, followed by intramolecular cyclization to obtain compound D-3.

[0160] The present invention also provides a method for preparing a compound represented by formula (V-1), a pharmaceutically acceptable salt thereof, an isotope-labeled substance thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof:

[0161]

[0162] Among them, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 and Y 4 The definition of is the same as above;

[0163] X 7 is hydroxyl, halogen, C1-C6 alkoxy or

[0164] Compound V-S1 and compound C-4 react in the presence of a condensing agent and a base to obtain compound V-1. The condensing agent used in the reaction can be one or more of thionyl chloride, pentafluorophenyl trifluoroacetate, oxalyl chloride, ethyl chloroformate, N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt), O-(7-azabenzotriazol-1-yl)-di(dimethylamino)carbonium hexafluorophosphate (HATU), 1H-benzotriazole-1-oxytris(1-pyrrolidinyl)phosphine hexafluorophosphate (PyBOP), n-propylphosphonic anhydride (T3P), and diethyl cyanophosphate (DECP). The base used in the reaction can be an inorganic base such as sodium carbonate, or an organic base such as pyridine, triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA).

[0165] The present invention also provides a pharmaceutical composition, which includes the above-mentioned compound as shown in formula (I) or formula (V-1), its pharmaceutically acceptable salt, its isotope-labeled substance, its solvate, its pharmaceutically acceptable salt solvate or its prodrug and pharmaceutical excipients.

[0166] In the composition, the amount of the compound represented by formula (I) or formula (V-1), its pharmaceutically acceptable salt, its isotope-labeled substance, its solvate, its solvate of a pharmaceutically acceptable salt or its prodrug can be an effective therapeutic amount.

[0167] The present invention also provides a use of the above-mentioned compound as shown in formula (I) or formula (V-1), its pharmaceutically acceptable salt, its isotope-labeled product, its solvate, its pharmaceutically acceptable salt solvate or its prodrug in the preparation of WRN inhibitors or drugs; the drug is a drug for treating and / or preventing diseases by inhibiting WRN.

[0168] The present invention also provides a use of the above-mentioned compound as shown in formula (I) or formula (V-1), its pharmaceutically acceptable salt, its isotope-labeled product, its solvate, its solvate of pharmaceutically acceptable salt or its prodrug in the preparation of drugs for treating and / or preventing cancer.

[0169] The present invention also provides a method for treating and / or preventing cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned compound as shown in formula (I) or formula (V-1), a pharmaceutically acceptable salt thereof, an isotope-labeled substance thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0170] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0171] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0172] The term "solvate" refers to a substance formed by the combination of a compound and a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0173] The term "pharmaceutically acceptable solvate" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.), wherein the amount of the solvent may be stoichiometric or non-stoichiometric.

[0174] A "-" at the end of a group means that the group is attached to the rest of the molecule through that site. For example, CH3-C(=O)- refers to an acetyl group.

[0175] When the group valence bond has a wavy line When, for example, The wavy line indicates the point of attachment of the group to the rest of the molecule.

[0176] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0177] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, replacing a methylene group with a carbonyl group.

[0178] The term "alkyl" refers to a linear or branched, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0179] The term "alkoxy" refers to a group R X -O-, R X The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0180] The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 Double bond. Alkenyl groups include but are not limited to: vinyl, wait.

[0181] The term "alkynyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon triple bonds. Alkenyl includes, but is not limited to, ethynyl, The term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C6), which is a single ring. Cycloalkyl includes, but is not limited to: wait.

[0182] The term "cycloalkoxy" refers to a group R Y -O-, R YThe same definition as the term "cycloalkyl". Cycloalkoxy includes, but is not limited to, cyclopropyloxy and the like.

[0183] The term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6-C 10 ) is a cyclic, unsaturated, monovalent hydrocarbon group, which is a single ring or multiple rings (for example, 2 or 3). When it is a multiple ring, the single rings share two atoms and a bond, and each ring has aromaticity. Aryl includes, but is not limited to, phenyl, naphthyl, etc.

[0184] In the present invention, the term "heterocyclic group" refers to a non-aromatic cyclic group containing at least one carbon atom and at least one (e.g., 1-3) ring heteroatom selected from N, O, and S, wherein the sulfur atom may be optionally oxidized or aminated. Examples of "heterocyclic groups" include cycloalkyl groups as defined in the present invention in which one or more ring carbon atoms are selected from -O-, -N=, -NR-, -S-, -S(=O)- and -S(=O)2-, The group formed by partial replacement of 1-4 Alkyl, C 3-6 Cycloalkyl or nitrogen protecting group (for example, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). "Heterocyclic group" includes monocyclic and fused rings, bridged rings, spirocyclic and other bicyclic structures and may be partially or completely saturated, such as 4-10-membered saturated or unsaturated heterocyclic groups, 4-6-membered saturated or unsaturated heterocyclic groups, 3-8-membered heterocyclic groups, 3-6-membered heterocyclic groups, etc.; such as tetrahydrofuranyl, pyrrolidinyl, oxetanyl, oxetanyl, azetidinyl, oxiranyl, aziridine, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, azepanyl, oxetanyl, etc. For example, the heterocyclic group described in the present invention may be preferably selected from the following groups:

[0185]

[0186] In the present invention, the term "heteroaryl" refers to a monocyclic or bicyclic or condensed polycyclic aromatic hydrocarbon group having a specified number of ring atoms (e.g., 5-10 members), which contains at least one (e.g., 1-3) ring heteroatom independently selected from N, O and S (e.g., N) in the ring, and the remaining ring atoms are carbon atoms; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, pyrimidinyl, 1,2,4-triazolyl, benzoxazolyl, imidazopyridinyl, triazolopyridinyl, benzofuranyl, pyrazolopyrimidinyl, benzodioxolyl, indolyl, quinolyl, isoquinolyl, etc.

[0187] The term "heteroaromatic ring" satisfies at least one of the following conditions, and the rest of the definition is the same as the term "heteroaryl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0188] The term "isotopically labeled" refers to an isotopically labeled compound in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature, compared to the nitrogen-containing compound as shown in Formula (I). Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the invention, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or prodrugs thereof containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 H or D) substitution may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the present invention may be specifically limited to substitution with deuterium or tritium. In addition, the presence of hydrogen in a substituent without the term deuterium or tritium being separately listed does not exclude deuterium or tritium, but may also contain deuterium or tritium.

[0189] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0190] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives. For details, please refer to the "Pharmacopoeia of the People's Republic of China (2020 Edition)" and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0191] The term "treating" refers to removing the cause or alleviating the symptoms.

[0192] The term "prevention" refers to reducing the risk of developing a disease.

[0193] The term "patient" refers to any animal, usually a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0194] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0195] The reagents and raw materials used in the present invention are commercially available.

[0196] The positive improvement effect of the present invention is that the compounds of the present invention have better inhibitory activity on WRN. DETAILED DESCRIPTION

[0197] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0198] In each embodiment, 1 HNMR was recorded by BRUKER AVANCE NEO 400 MHz, JNM-ECZ400s NMR, and chemical shifts were expressed in δ (ppm); LCMS was recorded by Shimadzu LC-20AD, Agilent 1260 mass spectrometers; preparative HPLC separation was performed using WATERS2545, Shimadzu LP-20AP liquid chromatographs.

[0199] In the following experimental descriptions, the following abbreviations may be used:

[0200]

[0201]

[0202] Example 1 N-((3R)-1-imino-1-oxo-2,3-dihydro-1H-1λ 6 -thiophen-3-yl)-2-oxo-6-(4-methylphenyl)-1,2-dihydropyridine-3-carboxamide

[0203]

[0204] Step 1: Add potassium carbonate (6.02 g, 43.6 mmol) to a solution of (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (5.00 g, 21.8 mmol) in methanol (50 mL) at room temperature. Add dimethyl (1-diazo-2-oxopropyl)phosphonate (8.37 g, 43.6 mmol) to the reaction mixture at 0°C and stir at room temperature for 16 hours. TLC detection (PE:EA=4:1) showed that the raw material was completely consumed and the desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE with 0-20% EA) to obtain a transparent oily (R)-4-ethynyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (4.20 g, yield 87.5%). LCMS calculated value C 12 H 20 NO3[M+H] + :m / z=226.1, detected value [M- t- Bu+H] + :170.1.

[0205] Step 2: Stir (R)-4-ethynyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (4.40 g, 19.6 mmol) in hydrochloric acid methanol (50 mL, 4N) at room temperature for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The mixed solution was concentrated under reduced pressure to obtain a pale yellow solid crude product (R)-2-aminobut-3-yn-1-ol (2.80 g, crude product). LCMS calculated value C4H8NO[M+H] + :m / z=86.1, detected value: 86.1.

[0206] Step 3: (R)-2-aminobutan-3-yn-1-ol (2.80 g, 32.9 mmol), potassium carbonate (9.08 g, 65.8 mmol) and benzyl chloroformate (8.39 g, 49.4 mmol) were stirred at room temperature for 12 hours in a mixed solution of tetrahydrofuran and water (1 / 1) (30 mL). LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The reaction mixture was extracted with water (100 mL) and ethyl acetate (300 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE with 0-30% EA) to obtain a white solid (R)-(1-hydroxybutan-3-yn-2-yl)benzyl carbamate (1.95 g, yield 27.8%). LCMS calculated value C 12 H 14 NO3[M+H] + :m / z=220.1, detected value: 220.1.

[0207] The fourth step: (R)-(1-hydroxy but-3-alkynes-2-yl) benzyl carbamate (1.40g, 6.36mmol), thiobenzoic acid (1.32g, 9.54mmol), triphenylphosphine (2.51g, 9.54mmol), tetrahydrofuran (20mL) mixed solution of diisopropyl azodicarboxylate (1.93g, 9.54mmol) was stirred at room temperature for 2 hours under N2 protection. LCMS detection shows that the raw material is completely consumed, and the desired compound is detected. The reaction mixture is diluted with water (100mL) and extracted with ethyl acetate (300mL). The organic phase is washed with salt water (40mL), and anhydrous sodium sulfate drying is filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EA in PE) to give (R)-S-(2-(((benzyloxy)carbonyl)amino)but-3-yn-1-yl)thiobenzoate (1.20 g, yield 57.2%). LCMS calculated value C 19 H 18 NO3S[M+H] + :m / z=340.1, detected value: 340.1.

[0208] Step 5: Sodium methoxide (572 mg, 10.6 mmol) was added to a solution of (R)-S-(2-(((benzyloxy)carbonyl)amino)but-3-yn-1-yl)thiobenzoate (1.20 g, 3.53 mmol) in methanol (30 mL). The reaction mixture was stirred at room temperature for 2 hours. LCMS detection showed that the starting material was completely consumed and the desired compound was detected. The reaction mixture was extracted with water (100 mL) and ethyl acetate (300 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE with 0-30% EA) to give a white solid (R)-(2,3-dihydrothiophene-3-yl)benzylcarbamate (700 mg, yield 84.4%). LCMS calculated value C 12 H 14 NO2S[M+H] + :m / z=236.1, detected value: 236.1.

[0209] Step 6: A mixture of (R)-(2,3-dihydrothiophene-3-yl)benzylcarbamate (300 mg, 1.27 mmol), ammonium acetate (293 mg, 3.81 mmol), and iodobenzene acetate (1.02 g, 3.18 mmol) in methanol (5 mL) was stirred at room temperature for 0.5 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The reaction mixture was quenched with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (60 mL). The organic phase was washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to obtain the product as a transparent oil ((3R)-1-imino-1-oxo-2,3-dihydro-1H-1λ 6 -thiophen-3-yl)carbamic acid benzyl ester (180 mg, yield 53.1%). LCMS calculated value C 12 H 15 N2O3S[M+H] + :m / z=267.1, detected value: 267.1.

[0210] Step 7: ((3R)-1-imino-1-oxido-2,3-dihydro-1H-1λ 6 33% hydrobromic acid acetic acid solution (2 mL) was added to a solution of benzyl (1-thiophene-3-yl)carbamate (180 mg, 0.674 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 0.5 hours. LCMS detection showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure and used directly in the next step.

[0211] Step 8: (3R)-3-amino-1-imino-2,3-dihydro-1H-1λ 6 A mixture of -thiophene-1-oxide (120 mg, 0.909 mmol, crude), N,N-diisopropylethylamine (586 mg, 4.55 mmol), 2-oxo-6-(4-methylphenyl)-1,2-dihydropyridine-3-carboxylic acid pentafluorophenyl ester (287 mg, 0.727 mmol) in DMF (3 mL) was stirred at room temperature for 0.5 hours. LCMS detection showed that the starting material was completely consumed and the desired compound was detected. The mixture was purified by Prep-HPLC (column: Xbridge-C18 150×19 mm, 5 μm; mobile phase: [ACN-H2O (0.05% NH3)]; B%: 10%-90%, 16 minutes) to obtain the product as a white solid N-((3R)-1-imino-1-oxo-2,3-dihydro-1H-1λ 6 -thiophen-3-yl)-2-oxo-6-(4-methylphenyl)-1,2-dihydropyridine-3-carboxamide (18.0 mg, yield 5.77%). LCMS calculated value C 17 H 18 N3O3S[M+H] + :m / z=344.1, detected value: 344.1. 1 H NMR (400MHz, CDCl3) δ11.18(s,1H),9.97(m,1H),8.58(m,1H),7.58(dd,J=8.1,4.8Hz,2H),7.36(d, J=7.1Hz,2H),6.72(m,2H),6.54(m,1H),5.57-5.44(m,1H),3.81(m,1H),3.27(m,1H),2.46(s,3H).

[0212] Step 9: 18.0 mg of compound N-((3R)-1-imino-1-oxo-2,3-dihydro-1H-1λ 6 6-(4-methylphenyl)-1,2-dihydropyridine-3-carboxamide was purified by Chiral-HPLC (column: Chiralpak-OJ; mobile phase: [carbon dioxide-ethanol (neutral)] to give the product white solid isomer 1 (4.54 mg) and isomer 2 (3.61 mg).

[0213] N-((3R)-1-Imino-1-oxido-2,3-dihydro-1H-1λ 6 -thiophen-3-yl)-2-oxo-6-(p-tolyl)-1,2-dihydropyridine-3-carboxamide (isomer 1), LCMS calculated value C 17 H18 N3O3S[M+H] + :m / z=344.1, detected value: 344.1. 1 H NMR (400MHz, CDCl3) δ10.96(s,1H),10.00(d,J=7.7Hz,1H),8.58(m,1H),7.56(d,J=8.2Hz,2H),7.36(d,J=8.0Hz,2H),6. 77-6.67(m,2H),6.56(m,1H),5.58-5.47(m,1H),3.79(dd,J=13.5,7.9Hz,1H),3.32(dd,J=13.6,4.9Hz,1H),2.46(s,3H).

[0214] N-((3R)-1-Imino-1-oxido-2,3-dihydro-1H-1λ 6 -thiophen-3-yl)-2-oxo-6-(p-tolyl)-1,2-dihydropyridine-3-carboxamide (isomer 2), LCMS calculated value C 17 H 18 N3O3S[M+H] + :m / z=344.1, detected value: 344.1. 1 H NMR (400MHz, CDCl3) δ10.78(s,1H),9.97(d,J=7.7Hz,1H),8.58(m,1H),7.57(d,J=8.2Hz,2H),7.36(d,J=7.9Hz,2H),6.8 5-6.64(m,2H),6.56(m,1H),5.61-5.45(m,1H),3.84(dd,J=13.4,7.9Hz,1H),3.24(dd,J=13.4,5.2Hz,1H),2.46(s,3H).

[0215] Synthesis of Intermediate 1-11 2-Oxo-6-(p-methylphenyl)-1,2-dihydropyridine-3-carboxylic acid pentafluorophenyl ester

[0216]

[0217] Step 1: Add sodium methoxide (3.95 g, 73.2 mmol) to a solution of 2,6-dichloronicotinate (15.0 g, 73.2 mmol) in dichloromethane (150 mL) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE with 0-10% EA) to obtain a white solid 6-chloro-2-methoxynicotinate (12.0 g, yield 81.6%). LCMS calculated value C8H9ClNO3[M+H] + :m / z=202.1, detected value: 202.1.

[0218] Step 2: Dissolve 6-chloro-2-methoxynicotinic acid methyl ester (12.0 mg, 59.4 mmol) in dioxane / water (130 mL, 4:1), add potassium carbonate (16.4 g, 119 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (4.34 g, 5.94 mmol), and p-methylphenylboronic acid (9.62 g, 71.3 mmol) at room temperature. The reaction mixture was stirred at 100 ° C for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE with 0-20% EA) to obtain a white solid 2-methoxy-6-(p-methylphenyl)nicotinic acid methyl ester (10.5 g, yield 67.1%). LCMS calculated value C 15 H 16 NO3[M+H] + :m / z=258.1, detected value: 258.1.

[0219] Step 3: Add 2-methoxy-6-(p-methylphenyl)nicotinic acid methyl ester (6.40 g, 24.8 mmol) to concentrated hydrochloric acid (50 mL). The reaction was stirred in a sealed tube at 100°C for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The reaction solution was filtered and the filter cake was dehydrated to obtain a gray solid 2-oxo-6-(p-methylphenyl)-1,2-dihydropyridine-3-carboxylic acid (5.10 g, yield 83.6%). LCMS calculated value C 13 H 12 NO3[M+H] + :m / z=230.1, detected value: 230.1.

[0220] Step 4: Add pentafluorophenyl trifluoroacetate (4.89 g, 17.5 mmol) to a solution of 2-oxo-6-(p-methylphenyl)-1,2-dihydropyridine-3-carboxylic acid (2.00 g, 8.73 mmol) in pyridine (20 mL), and stir at 50°C for 1 hour. Dilute the reaction mixture with water (150 mL) and stir, filter, and remove water from the filter cake to obtain a crude brown solid 2-oxo-6-(p-methylphenyl)-1,2-dihydropyridine-3-carboxylic acid pentafluorophenyl ester (2.00 g, crude product). This intermediate can be used directly in the next step without purification.

[0221] Example 2 N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-7-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0222]

[0223] Step 1: Add 2,2.2-trifluoroacetic acid pentafluorophenyl ester (276 mg, 0.986 mmol) to a pyridine (3 mL) solution of 7-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.493 mmol) at room temperature. The reaction mixture was stirred at 50°C for 1 hour. After adding water (10 mL) to the reaction mixture and stirring, it was filtered and the filter cake was dehydrated to obtain a brown solid 7-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (80.0 mg, crude product) which was directly used in the next step.

[0224] Step 2: A mixed solution of 7-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (80.0 mg, 0.217 mmol), N,N-diisopropylethylamine (83.9 mg, 0.650 mmol) and 3-amino-2,3-dihydrothiophene-1,1-dioxide hydrochloride (44.0 mg, 0.260 mmol) in DMF (3 mL) was stirred at room temperature for 1 hour. LCMS detection showed that the starting material was completely consumed and the desired compound was detected. The mixture was purified by Prep-HPLC (column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: [ACN-H2O (0.1% formic acid)]; B%: 30%-60%, 16 minutes) to give the product as a white solid N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-7-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (23.2 mg, yield 33.7%). LCMS calculated value C 15 H 15 N2O4S[M+H] + :m / z=319.1, detected value: 319.1. 1H NMR (400MHz, DMSO-d6) δ12.46(s,1H),10.19(d,J=7.9Hz,1H),8.82(s,1H),7.85(d,J=8.1Hz,1H),7.28(d,J=6.6Hz,1H),7.22(s,1H), 7.15(d,J=8.1,1H),7.00(d,J=6.6Hz,1H),5.49-5.33(m,1H),3.75(dd,J=13.8,7.9Hz,1H),3.29(dd,J=8.8,4.9Hz,1H),2.43(s,3H).

[0225] Example 3 (R)-N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide and Example 4 (S)-N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0226]

[0227] Step 1: At room temperature, 2-amino-4-bromobenzaldehyde (5.00 g, 25.0 mmol) was dissolved in methanol (75 mL), and dimethyl malonate (9.25 g, 70.0 mmol), piperidine (6.38 g, 75.0 mmol) and acetic acid (150 mg, 2.50 mmol) were added to the mixture. The reaction solution was heated to 60 ° C and stirred for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. After the reaction was cooled to room temperature, the precipitate was filtered, and the solid was washed with methanol and dried to obtain a light brown solid 7-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (2.60 g, yield 36.8%). LCMS calculated value C 11 H9BrNO3[M+H] + :m / z=282.0 / 284.0, detected value: 282.1 / 284.1.

[0228] Step 2: Dissolve 7-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (500 mg, 1.77 mmol) in 1,4-dioxane (10 mL) and water (2 mL), add 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborinane (253 mg, 1.51 mmol), potassium carbonate (245 mg, 1.77 mmol) and tetrakis(triphenylphosphine)palladium (205 mg, 0.18 mmol). The system was stirred at 90 ° C for 16 hours under a nitrogen atmosphere. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The mixture was cooled, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE:EA=3:1) to obtain solid 2-oxo-7-(propen-2-yl)-1,2-dihydroquinoline-3-carboxylic acid methyl ester (210 mg, yield 48.6%). LCMS calculated value C 14 H 14 NO3[M+H] + :m / z=244.1, detected value: 244.1.

[0229] Step 3: Dissolve 2-oxo-7-(propylene-2-yl)-1,2-dihydroquinoline-3-carboxylic acid methyl ester (210 mg, 0.82 mmol) in methanol (5 mL) solution at room temperature, and add palladium carbon (100 mg, 10% content) to the mixture. The system was stirred at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The reaction mixture was filtered and concentrated to give solid 7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (170 mg, yield 80.3%). LCMS calculated value C 14 H 16 NO3[M+H] + :m / z=246.1, detected value: 246.1.

[0230] Step 4: Dissolve 7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (150 mg, 0.61 mmol) in methanol (6 mL), add an aqueous solution (1.5 mL) of sodium hydroxide (122 mg, 3.06 mmol), and stir the system at 40 ° C for 3 hours. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Adjust the pH to 2 with 0.5N HCl, filter and dry the resulting precipitate to obtain solid 7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (115 mg, yield 81.3%). LCMS calculated value C 13 H 14 NO3[M+H] + :m / z=232.1, detected value: 232.1.

[0231] Step 5: Dissolve 7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.43 mmol) in pyridine (2 mL), add pentafluorophenyl trifluoroacetate (242 mg, 0.87 mmol), and stir the system at 60 ° C for 2.5 hours. Cool, add water (5 mL), and filter to collect the formed solid to obtain a white solid 7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid perfluorophenyl ester (105 mg, yield 61.1%). LCMS calculated value C 19 H 13 F5NO3[M+H] + :m / z=398.1, detected value: 398.1.

[0232] Step 6: 3-amino-2,3-dihydrothiophene 1,1-dioxide hydrochloride (15.1 mg, 0.26 mmol) and N,N-diisopropylethylamine (107 mg, 0.33 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (100 mg, 0.25 mmol) was added. The system was stirred at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Dichloromethane (10 mL) and water (10 mL) were added, the separated organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by Prep-HPLC (column: GeminiPrep C18 150×21.2 mm, 5 μm; mobile phase: [water (0.1% formic acid in water)-ACN]; B%: 20%-50%, 30 minutes) to obtain the product white solid N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (10.1 mg, yield 11.6%). LCMS calculated value C 17 H 19 N2O4S[M+H] + :m / z=347.1, detected value: 347.1. 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),7.85(d,J=8.2Hz,1H),7.27(s,1H),7.25-7.21(m,2H),6.97(dd,J=6.6,3.0Hz ,1H),5.37(m,1H),3.73(dd,J=13.8,7.9Hz,1H),3.23(dd,J=13.8,4.0Hz,1H),2.98(m,1H),1.22(d,J=6.9Hz,6H).

[0233] Step 7: N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (80.0 mg) was subjected to chiral separation (instrument: SFC Thar prep 80, chromatographic column: CHIRALPAK WHELK-01: 250 mm × 21.1 mm, 5 μm; mobile phase: 40% ethanol (0.2% ammonia water)) to obtain Example 3 and Example 4.

[0234] (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (26.2 mg, yield 32.7%). LCMS calculated value C 17 H 19 N2O4S[M+H] + :m / z=347.1, detected value: 347.1. 1 HNMR (400MHz, DMSO-d6) δ12.4(s,1H),10.2(d,J=7.8Hz,1H),8.82(s,1H),7.88(d,J=8.2Hz,1H),7.34-7.21(m,3H),7.00(d d,J=6.6,3.0Hz,1H),5.40(m,1H),3.75(dd,J=13.8,7.9Hz,1H),3.28(d,J=4.1Hz,1H),2.99(m,1H),1.24(d,J=6.9Hz,6H).

[0235] (S)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (26.5 mg, yield 32.7%). LCMS calculated value C 17 H 19 N2O4S[M+H] + :m / z=347.1, detected value: 347.1. 1 HNMR (400MHz, DMSO-d6) δ12.4(s,1H),10.2(d,J=7.8Hz,1H),8.82(s,1H),7.88(d,J=8.2Hz,1H),7.30-7.21(m,3H),7.00(d d,J=6.6,3.0Hz,1H),5.40(m,1H),3.75(dd,J=13.8,7.9Hz,1H),3.28(d,J=4.0Hz,1H),2.99(m,1H),1.24(d,J=6.9Hz,6H).

[0236] Example 5 N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-propyl-1,2-dihydroquinoline-3-carboxamide

[0237]

[0238] Step 1: Dissolve 7-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (500 mg, 1.77 mmol) in 1,4-dioxane (10 mL) and water (2 mL), add 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (143 mg, 1.51 mmol), potassium carbonate (245 mg, 1.77 mmol) and tetrakis(triphenylphosphine)palladium (205 mg, 0.18 mmol). The system was stirred at 90 ° C for 16 hours under a nitrogen atmosphere. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool and filter, concentrate the filtrate, and the residue was chromatographed on a silica gel column (PE:EA=3:1) to obtain solid 7-allyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (210 mg, yield 48.6%). LCMS calculated value C 14 H 14 NO3[M+H] + :m / z=244.1, detected value: 244.1.

[0239] Step 2: Dissolve 7-allyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (210 mg, 0.82 mmol) in methanol (2 mL) at room temperature and add palladium carbon (100 mg, 10% content). Replace the air with hydrogen three times and stir the system at room temperature for 1 hour. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Filtration and concentration give solid 2-oxo-7-propyl-1,2-dihydroquinoline-3-carboxylic acid methyl ester (160 mg, crude product). LCMS calculated value C 14 H 16 NO3[M+H] + :m / z=246.1, detected value: 246.1.

[0240] Step 3: Dissolve methyl 2-oxo-7-propyl-1,2-dihydroquinoline-3-carboxylate (160 mg, 0.65 mmol) in methanol (2 mL), add an aqueous solution (2 mL) of sodium hydroxide (131 mg, 3.27 mmol), and stir the system at 40 ° C for 3 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Adjust the pH to 2 with 0.5N HCl, filter, and dry the solid to obtain 2-oxo-7-propyl-1,2-dihydroquinoline-3-carboxylic acid (100 mg, yield 66.3%). LCMS calculated value C 13 H14 NO3[M+H] + :m / z=232.1, detected value: 232.1.

[0241] Step 4: Dissolve 2-oxo-7-propyl-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.43 mmol) in pyridine (2 mL) and add pentafluorophenyl trifluoroacetate (242 mg, 0.87 mmol). The system was stirred at 60 ° C for 2.5 hours. The resulting mixture was cooled to room temperature, water (5 mL) was added, filtered, and the solid was dried to obtain a white solid 2-oxo-7-propyl-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (100 mg, yield 58.2%). LCMS calculated value C 19 H 13 F5NO3[M+H] + :m / z=398.1, detected value: 398.1.

[0242] Step 5: 3-amino-2,3-dihydrothiophene 1,1-dioxide (15.1 mg, 0.26 mmol) and N,N-diisopropylethylamine (107 mg, 0.33 mmol) were dissolved in DMF (2 mL), and 2-oxo-7-propyl-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (100 mg, 0.25 mmol) was added. The system was stirred at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Dichloromethane (10 mL) and water (10 mL) were added, the separated organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by Prep-HPLC (column: Gemini Prep C18 150×21.2 mm, 5 μm; mobile phase: [water (0.1% formic acid in water)-ACN]; B%: 20%-50%, 30 minutes) to give the product white solid N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-7-propyl-1,2-dihydroquinoline-3-carboxamide (9.85 mg, yield 11.3%). LCMS calculated value C 17 H 19 N2O4S[M+H] + :m / z=347.1, detected value: 347.1. 1H NMR (400MHz, DMSO-d6) δ12.5 (s, 1H), 10.2 (d, J = 7.6Hz, 1H), 8.82 (s, 1H), 7.87 (d ,J=8.2Hz,1H),7.28(dd,J=6.6,2.0Hz,1H),7.23(s,1H),7.17(dd,J=8.1,1.4Hz ,1H),7.00(dd,J=6.7,3.0Hz,1H),5.44-5.36(m,1H),3.75(dd,J=15.0,7.4Hz,1 H), 3.31-3.26 (m, 1H), 2.66 (t, J = 7.6Hz, 2H), 1.63 (m, 2H), 0.91 (t, J = 7.3Hz, 3H).

[0243] Example 6 7-Dimethylamino-N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0244]

[0245] Step 1: Stir a solution of 7-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (1.00 g, 3.55 mmol), dimethylamine (8.85 mL, 17.7 mmol, 2M methanol solution), and N,N-diisopropylethylamine (1.37 g, 10.6 mmol) in DMF (10 mL) at 120°C for 16 hours. Cool, dilute with water (20 mL), extract with ethyl acetate (80 mL), wash the organic phase with brine (50 mL), dry with anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (0-10% MeOH in DCM) to obtain a yellow solid 7-dimethylamino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (190 mg, yield 22.1%). LCMS calculated value C 13 H 15 N2O3[M+H] + :m / z=247.1, detected value: 247.0.

[0246] Step 2: Dissolve methyl 7-dimethylamino-2-oxo-1,2-dihydroquinoline-3-carboxylate (180 mg, 0.73 mmol) in methanol (5 mL), and add an aqueous solution (2 mL) of lithium hydroxide (52.5 mg, 2.19 mmol). The system was stirred at room temperature for 4 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Concentrate under reduced pressure, dilute with water (5 mL), adjust the pH to 3 with 1N hydrochloric acid aqueous solution, and filter to obtain a yellow solid 7-dimethylamino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, yield 58.9%). LCMS calculated value C12 H 13 N2O3[M+H] + :m / z=233.1, detected value: 233.0.

[0247] Step 3: Dissolve 7-dimethylamino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.43 mmol) in pyridine (5 mL), add 2,2,2-trifluoroacetic acid pentafluorophenyl ester (241 mg, 0.86 mmol), and stir the system at 60 ° C for 3 hours under nitrogen protection. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Cool, dilute with water (4 mL), filter, and dry the solid to obtain a yellow compound 7-dimethylamino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (75.0 mg, yield 62.1%). LCMS calculated value C 18 H 12 F5N2O3[M+H] + :m / z=399.1, detected value: 399.0.

[0248] Step 4: Add N,N-diisopropylethylamine (72.9 mg, 0.56 mmol) and 3-amino-2,3-dihydrothiophene 1,1-dioxide hydrochloride (38.1 mg, 0.23 mmol) to a DMF (3 mL) solution of 7-dimethylamino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (75.0 mg, 0.19 mmol), and stir the system at room temperature for 1 hour. LCMS detection showed that the starting material was completely consumed and the desired compound was detected. The system was diluted with water (20 mL), extracted with ethyl acetate (80 mL), the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by Prep-HPLC (column: GeminiC18 150×21.2 mm, 5 μm; mobile phase: [water (0.1% formic acid in water)-ACN]; B%: 25%-95%, 16 minutes) to obtain the product white solid 7-dimethylamino-N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (10.0 mg, yield 15.3%). LCMS calculated value C 16 H 18 N3O4S[M+H] + :m / z=348.4, detected value: 348.4. 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),10.17(d,J=8.0Hz,1H),8.61(s,1H),7.69(d,J=8.8Hz,1H),7.26(dd,J=6.0Hz,2.0Hz,1H),6.98(dd, J=6.8Hz, 3.2Hz, 1H), 6.81 (dd, J=8.8Hz, 2.4Hz, 1H), 6.48 (d, J=2.4Hz, 1H), 5.37 (m, 1H), 3.76-3.70 (m, 1H), 3.26-3.22 (m, 1H), 3.04 (s, 6H).

[0249] Example 7 7-(tert-butyl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0250]

[0251] Step 1: Dissolve 2-amino-4-(tert-butyl)benzoic acid (500 mg, 2.59 mmol) in tetrahydrofuran (5 mL), slowly add borane (5.17 mL, 5.17 mmol, 1 M tetrahydrofuran solution). The system was stirred at 60 ° C for 2 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool to room temperature, add methanol (20 mL) to quench the reaction, remove the solvent under reduced pressure, and purify the resulting residue by silica gel column chromatography (0-10% MeOH in DCM) to obtain a colorless oily product (2-amino-4-(tert-butyl)phenyl)methanol (350 mg, yield 75.4%). LCMS calculated value C 11 H 18 NO[M+H] + :m / z=180.1, detected value: 180.2.

[0252] Step 2: Dissolve (2-amino-4-(tert-butyl)phenyl)methanol (350 mg, 1.96 mmol) in dichloromethane (3.5 mL) and add manganese dioxide (1.53 g, 17.6 mmol). The system was stirred at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Filtration and concentration, the residue was purified by silica gel column chromatography (PE with 0-20% EA) to obtain a white solid product 2-amino-4-(tert-butyl)benzaldehyde (200 mg, yield 57.8%). LCMS calculated value C 11 H 16 NO[M+H] + :m / z=178.1, detected value: 178.2.

[0253] Step 3: Dissolve 2-amino-4-(tert-butyl)benzaldehyde (200 mg, 1.13 mmol) in methanol (2 mL), add dimethyl malonate (417 mg, 3.16 mmol), piperidine (288 mg, 3.39 mmol) and acetic acid (6.78 mg, 0.11 mmol). Stir the system at 60 ° C for 16 hours. Cool and filter, wash and dry the solid to obtain 7-(tert-butyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (150 mg, yield 51.2%). LCMS calculated value C 15 H 18 NO3[M+H] + :m / z=260.1, detected value: 260.2.

[0254] Step 4: Dissolve methyl 7-(tert-butyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate (150 mg, 0.58 mmol) in methanol (3 mL), add a solution of sodium hydroxide (116 mg, 2.89 mmol) in water (0.5 mL). Stir the system at room temperature for 1 hour. Concentrate the reaction solution, adjust the pH to 4 with 1N hydrochloric acid, and collect the solid by filtration to obtain 7-(tert-butyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, crude product). LCMS calculated value C 14 H 16 NO3[M+H] + :m / z=246.1, detected value: 246.1.

[0255] Step 5: Dissolve 7-(tert-butyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.41 mmol) in pyridine (2 mL) and add pentafluorophenyl trifluoroacetate (228 mg, 0.82 mmol). Stir the system at 60 ° C for 3 hours. Cool to room temperature, add water (8 mL), and filter to collect the formed solid to obtain 7-(tert-butyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (100 mg, crude product). LCMS calculated value C 20 H 15 F5NO3[M+H] + :m / z=412.1, detected value: 412.1.

[0256] Step 6: 3-amino-2,3-dihydrothiophene 1,1-dioxide hydrochloride (61.9 mg, 0.36 mmol) and N,N-diisopropylethylamine (40.8 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (2 mL), 7-(tert-butyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (100 mg, 0.24 mmol) was added, and the system was stirred at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Dichloromethane (5 mL) and water (5 mL) were added, the organic phase was washed with brine (5 mL) and dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by Prep-HPLC (column: Gemini PrepC18 150×21.2 mm, 5 μm; mobile phase: [water (0.1% formic acid in water)-ACN]; B%: 20%-50%, 30 minutes) to obtain a white solid 7-(tert-butyl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (44.0 mg, yield 50.2%). LCMS calculated value C 18 H 21 N2O4S[M+H] + :m / z=361.1, detected value: 361.2. 1 HNMR (400MHz, DMSO-d6) δ12.42(s,1H),10.23(d,J=7.9Hz,1H),8.83(s,1H),7.89(d,J=8.4Hz,1H),7.44(s,1H),7.41(dd,J=8.4,1.6Hz,1H),7.2 9(dd,J=6.6,1.9Hz,1H),7.01(dd,J=6.6,3.0Hz,1H),5.44-5.39(m,1H),3.76(dd,J=13.8,7.9Hz,1H),3.31(dd,J=13.8,4.0Hz,1H),1.32(s,9H).

[0257] Example 8 (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0258]

[0259] Step 1: Stir a mixed solution of 4-bromo-5-fluoro-2-nitrobenzaldehyde (2.00 g, 8.10 mmol), iron powder (3.60 g, 64.8 mmol), and ammonium chloride (4.33 g, 81.0 mmol) in ethanol / water (20 mL, 4:1) at 80 ° C for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE with 0-10% EA) to obtain a white solid 2-amino-4-bromo-5-fluorobenzaldehyde (500 mg, yield 28.8%). LCMS calculated value C7H6BrFNO[M+H] + :m / z=218.0 / 220.0, detected value: 217.9 / 220.0.

[0260] Step 2: Add 2-amino-4-bromo-5-fluorobenzaldehyde (500 mg, 2.30 mmol), dimethyl malonate (851 mg, 6.45 mmol), piperidine (586 mg, 6.90 mmol), acetic acid (13.8 mg, 0.230 mmol) and methanol (10 mL) to the reaction bottle, and stir the system at 60 ° C for 2 hours. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. The system is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain a white solid 7-bromo-6-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (500 mg, yield 72.7%). LCMS calculated value C 11 H8BrFNO3[M+H] + :m / z=300.0 / 302.0, detected value: 299.9 / 302.0.

[0261] Step 3: 7-bromo-6-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (350 mg, 1.17 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborinane (392 mg, 2.33 mmol), tetrakis(triphenylphosphine)palladium (135 mg, 0.12 mmol), potassium carbonate (484 mg, 3.50 mmol) in a mixture of 1,4-dioxane / water 10 mL, 10:1) was stirred overnight at 90°C under nitrogen protection. The mixture was cooled, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE with 0-30% EA) to obtain a white solid 6-fluoro-2-oxo-7-(prop-1-en-2-yl)-1,2-dihydroquinoline-3-carboxylic acid methyl ester (200 mg, yield 65.6%). LCMS calculated value C 14 H 13 FNO3[M+H] + :m / z=262.1, detected value: 262.0.

[0262] Step 4: A system of 6-fluoro-2-oxo-7-(prop-1-en-2-yl)-1,2-dihydroquinoline-3-carboxylic acid methyl ester (200 mg, 0.77 mmol) and palladium carbon (80 mg) in tetrahydrofuran (5 mL) was stirred at room temperature under hydrogen for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Filtration and concentration, the residue was purified by silica gel column chromatography (PE with 0-30% EA) to obtain a white solid 6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (120 mg, yield 59.5%). LCMS calculated value C 14 H 15 FNO3[M+H] + :m / z=264.1, detected value: 264.1.

[0263] Step 5: To a mixed solution of 6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (120 mg, 0.46 mmol) and methanol (2 mL), an aqueous solution of sodium hydroxide (2 mL, 2 N) was added, and the system was stirred at room temperature for 3 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Concentrate under reduced pressure, dilute with water (5 mL), adjust the pH to 3 with 1N hydrochloric acid aqueous solution, and filter to obtain a white solid 6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (45.0 mg, yield 39.6%). LCMS calculated value C 13 H 13 FNO3[M+H] + :m / z=250.1, detected value: 250.0.

[0264] Step 6: Add 2,2,2-trifluoroacetic acid pentafluorophenyl ester (102 mg, 0.36 mmol) dropwise to a pyridine (2 mL) solution of 6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (45.0 mg, 0.18 mmol), and stir the system at 60 ° C for 2 hours under nitrogen protection. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Add water (20 mL) and stir, filter, and vacuum dry the filter cake to obtain a yellow solid 6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid perfluorophenyl ester (80.0 mg, crude product). LCMS calculated value C 19 H 12 F6NO3[M+H] + :m / z=416.1, detected value: 415.9.

[0265] Step 7: Dissolve 6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid perfluorophenyl ester (80.0 mg, 0.19 mmol) in N,N-dimethylformamide (3 mL), add N,N-diisopropylethylamine (125 mg, 0.96 mmol), 3-amino-2,3-dihydrothiophene 1,1-dioxide hydrochloride (36.0 mg, 0.21 mmol). The system was stirred at room temperature for 2 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (0-10% MeOH in DCM) to obtain a crude product, which was then purified by Prep-HPLC (chromatographic column: Gemini Prep C18 150×21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% formic acid); gradient: 30%-60%) to obtain the product, N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (23.9 mg, yield 34.0%) as a white solid. LCMS calculated value C 17 H 18 FN2O4S[M+H] + :m / z=365.1, detected value: 365.1.

[0266] Step 8: N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (17.0 mg) was subjected to chiral separation (instrument: SFC Thar prep 80, chromatographic column: CHIRALPAK IC 250 mm×20 mm, 5 μm; mobile phase: 40% methanol (0.2% ammonia water)) to obtain (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-6-fluoro-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (7.00 mg, yield 41.2%). LCMS calculated value C 17 H 18 FN2O4S[M+H] + :m / z=365.1, detected value: 365.1. 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),10.21(d,J=8.0,1H),8.84(s,1H),7.83(d,J=10.8,1H),7.37(d,J=6.4,1H),7.30-7 .28(m,1H),7.01-6.99(m,1H),5.40(s,1H),3.78-3.72(m,1H),3.29-3.28(m,1H),3.27-3.19(m,1H),1.25(d,J=6.8,6H).

[0267] Example 9 (R)-7-cyclopropyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0268]

[0269] Step 1: Add 7-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (500 mg, 1.77 mmol), cyclopropylboronic acid (457 mg, 5.32 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (145 mg, 0.177 mmol), potassium carbonate (980 mg, 7.09 mmol), 1,4-dioxane (10 mL) and water (1 mL) in the reaction bottle, and stir the system at 90 ° C for 3 hours under nitrogen protection. Cool, filter and concentrate, and purify the residue by silica gel column chromatography (0-10% MeOH in DCM) to obtain yellow solid 7-cyclopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (280 mg, yield 51.9%). LCMS calculated value C 14 H 14 NO3[M+H] + :m / z=244.1, detected value: 244.0.

[0270] Step 2: Add an aqueous solution (1 mL) of lithium hydroxide (96.6 mg, 2.30 mmol) to a mixed solvent of tetrahydrofuran (2 mL) and methanol (1 mL) of methyl 7-cyclopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (280 mg, 1.15 mmol). The system was stirred at room temperature for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Concentrate under reduced pressure, dilute with water (5 mL), adjust the pH to 3 with 1N hydrochloric acid aqueous solution, and filter to obtain a yellow solid 7-cyclopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (200 mg, yield 60.6%). LCMS calculated value C 13 H 12 NO3[M+H] + :m / z=230.1, detected value: 230.0.

[0271] Step 3: Add 2,2,2-trifluoroacetic acid pentafluorophenyl ester (956 mg, 3.40 mmol) dropwise to a pyridine (5 mL) solution of 7-cyclopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (260 mg, 1.13 mmol), and stir the system at 60 ° C for 2 hours under nitrogen protection. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Cool, dilute with water (20 mL) and stir, filter, and dry the filter cake in vacuum to obtain a yellow solid 7-cyano-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (200 mg, crude product). LCMS calculated value C 19 H 11 F5NO3[M+H] + :m / z=396.1, detected value: 396.0.

[0272] Step 4: Dissolve 7-cyclopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pentafluorophenyl ester (200 mg, 0.51 mmol) in N,N-dimethylformamide (5 mL), add N,N-diisopropylethylamine (733 mg, 5.67 mmol), 3-amino-2,3-dihydrothiophene 1,1-dioxide hydrochloride (212 mg, 1.25 mmol), and stir the system at room temperature for 2 hours. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (0-10% MeOH in DCM) to obtain a crude product, which was then purified by preparative HPLC (column: Gemini Prep C18 150×21.2 mm, 5 μm; mobile phase: [water (0.1% FA in water)-ACN]; B%: 20%-50%, 30 minutes) to obtain the product as a white solid 7-cyclopropyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (40.0 mg, yield 9.71%). LCMS calculated value C 17 H 17 N2O4S[M+H] + :m / z=345.1, detected value: 345.0.

[0273] Step 5: 7-cyclopropyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (40.0 mg) was separated by chiral separation (instrument: SFC Thar prep 80. Chromatographic column: CHIRALPAK WHELK-01: 250 mm × 21.1 mm, 5 μm; mobile phase: 40% ethanol (0.2% ammonia water) to obtain the product white solid (R)-7-cyclopropyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (11.8 mg, yield 29.5%). LCMS calculated value C 17 H 17 N2O4S[M+H] + :m / z=345.1, detected value: 345.0. 1 H NMR (400MHz, DMSO-d6) δ12.36 (s, 1H), 10.19 (d, J = 7.8Hz, 1H), 8.80 (s, 1H), 7.83 (d, J = 8.3Hz, 1H), 7.28 (d, J = 6.1Hz, 1H), 7.13 (s, 1H), 7.00 (d, J = 7. 4Hz, 2H), 5.40 (s, 1H), 3.75 (dd, J=13.7, 7.9Hz, 1H), 3.30 (dd, J=14.0, 4. 0Hz, 1H), 2.09-2.00 (m, 1H), 1.09 (d, J = 6.5Hz, 2H), 0.78 (d, J = 4.1Hz, 2H).

[0274] Example 10 (R)-7-cyclobutyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0275]

[0276] Step 1: Dissolve methyl 7-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylate (2.00 g, 7.09 mmol) in N,N-dimethylacetamide (10 mL), add cyclobutyl bromide (1.44 g, 10.6 mmol), pyridine-2-carboxamidamide hydrochloride (223 mg, 1.42 mmol), trifluoroacetic acid (8.08 mg, 0.07 mmol), manganese powder (1.17 g, 21.3 mmol), sodium iodide (532 mg, 3.54 mmol) and nickel iodide (443 mg, 1.42 mmol). The system was stirred at 90 ° C for 3 hours under nitrogen protection. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The mixture was cooled and filtered, water (20 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain solid 7-cyclobutyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (200 mg, yield 10.8%). LCMS calculated value C 15 H 16 NO3[M+H] + :m / z=258.1, detected value: 258.1.

[0277] Step 2: Dissolve methyl 7-cyclobutyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (200 mg, 0.777 mmol) in methanol (3 mL), add an aqueous solution (1.5 mL) of sodium hydroxide (156 mg, 3.89 mmol). Stir the system at 40 ° C for 2 hours. Cool to room temperature, adjust the pH to 4 with 1N hydrochloric acid, and collect the solid by filtration to obtain 7-cyclobutyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (135 mg, crude product). LCMS calculated value C 14 H 14 NO3[M+H] + :m / z=244.1, detected value: 244.1.

[0278] Step 3: Dissolve 7-cyclobutyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (135 mg, 0.54 mmol) in pyridine (2 mL) and add pentafluorophenyl trifluoroacetate (299 mg, 1.07 mmol). Stir the system at 60 ° C for 3 hours. Cool to room temperature, add water (8 mL), and filter to collect the solid to obtain 7-cyclobutyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid perfluorophenyl ester (110 mg, yield 50.4%). LCMS calculated value C 20 H 13 F5NO3[M+H] + :m / z=410.1, detected value: 410.1.

[0279] Step 4: 3-amino-2,3-dihydrothiophene-1,1-dioxide hydrochloride (34.1 mg, 0.26 mmol) and diisopropylethylamine (40.9 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (2 mL), 7-cyclobutyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid perfluorophenyl ester (100 mg, 0.24 mmol) was added, and the system was stirred at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Dichloromethane (10 mL) and water (5 mL) were added, the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by Prep-HPLC (column: Gemini Prep C18 150×21.2 mm, 5 μm; mobile phase: [water (0.1% formic acid)-ACN]; B%: 20%-50%, 30 minutes) to obtain the product 7-cyclobutyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (27.6 mg, yield 27.6%) as a white solid. LCMS calculated value C 18 H 19 N2O4S[M+H] + :m / z=359.1, detected value: 359.1.

[0280] Step 5: 7-cyclobutyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (27.6 mg) was separated by chiral column (instrument: SFC Thar prep 80, chromatographic column: CHIRALPAK WHELK-01: 250 mm × 21.1 mm, 5 μm; mobile phase: 40% ethanol (0.2% ammonia water)) to obtain (R)-7-cyclobutyl-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (4.33 mg, yield 32.3%), LCMS calculated value C 18 H 19 N2O4S[M+H] + :m / z=359.1, detected value: 359.1. 1H NMR (400MHz, DMSO-d6) δ10.2(d,J=7.8Hz,1H),8.82(s,1H),7.89(d,J=8.2Hz,1H),7.32-7.22(m,2H),7.20(d,J=8.2Hz,1H),7.00(dd,J=6.6,3.0Hz ,1H),5.40(s,1H),3.75(dd,J=13.8,7.9Hz,1H),3.70-3.59(m,1H),3.31- 3.26(m,1H),2.38-2.31(m,2H),2.11-2.07(m,3H),1.85(t,J=8.9Hz,1H).

[0281] Example 11 (R)-7-(cyclopropyldifluoromethyl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0282]

[0283] The first step: 7-bromo-2-methoxyquinoline-3-carboxylic acid methyl ester (2.00 g, 6.75 mmol) was dissolved in N, N-dimethylformamide (10 mL), Pd (dppp) Cl2 (99.6 mg, 0.169 mmol), sodium carbonate (716 mg, 6.75 mmol) and triethylsilane (1.57 g, 13.5 mmol) were added in sequence, the air was replaced with carbon monoxide 3 times, and the system was stirred at 90 ° C for 18 hours under a carbon monoxide (2 bar) atmosphere. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool down, filter and concentrate, add water (20 mL), extract with ethyl acetate (60 mL), wash the organic phase with saturated brine (60 mL), dry over anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (DCM: MeOH = 30: 1) to obtain yellow solid 7-formyl-2-methoxyquinoline-3-carboxylic acid methyl ester (1.10 g, yield 66.2%). LCMS calculated value C 13 H 12 NO4[M+H] + :m / z=246.1, detected value: 245.8.

[0284] Step 2: Dissolve 7-formyl-2-methoxyquinoline-3-carboxylic acid methyl ester (1.00 g, 4.08 mmol) in tetrahydrofuran (10 mL), slowly add cyclopropylmagnesium bromide (4.48 mL, 4.48 mmol, 1 M tetrahydrofuran solution) at -40 ° C, stir the system at -40 ° C for 10 minutes, then warm to 0 ° C and continue stirring for 1 hour. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Add saturated aqueous ammonium chloride solution (10 mL) to quench the reaction, extract with ethyl acetate (60 mL), wash with saturated brine (20 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (PE: EA = 2: 1) to obtain yellow oily 7-(cyclopropyl (hydroxy) methyl)-2-methoxyquinoline-3-carboxylic acid methyl ester (476 mg, yield 40.7%). LCMS calculated value C 16 H 18 NO4[M+H] + :m / z=288.1, detected value: 288.1.

[0285] Step 3: Dissolve 7-(cyclopropyl(hydroxy)methyl)-2-methoxyquinoline-3-carboxylic acid methyl ester (476 mg, 1.66 mmol) in dichloromethane (10 mL), add Dess-Martin periodinane (1.05 mg, 2.49 mmol), and stir the reaction at room temperature for 2 hours. LCMS detection shows that the raw material is completely consumed, and the desired compound is detected. Filtration and concentration, the residue is purified by silica gel column chromatography (PE:EA=3:1) to obtain a white solid 7-(cyclopropanecarbonyl)-2-methoxyquinoline-3-carboxylic acid methyl ester (260 mg, yield 54.6%). LCMS calculated value C 16 H 16 NO4[M+H] + :m / z=286.1, detected value: 286.1.

[0286] Step 4: At room temperature, 7-(cyclopropanecarbonyl)-2-methoxyquinoline-3-carboxylic acid methyl ester (260 mg, 0.91 mmol) was dissolved in bis(2-methoxyethyl)aminosulfur trifluoride (2.20 g, 13.7 mmol), and ethanol (1 drop) was added to the mixture. The system was stirred at 75°C for 5 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool, filter and concentrate, and the residue was purified by silica gel column chromatography (PE:EA=3:1) to obtain a yellow solid 7-(cyclopropyldifluoromethyl)-2-methoxyquinoline-3-carboxylic acid methyl ester (30.0 mg, yield 10.7%). LCMS calculated value C 16 H 16 F2NO3[M+H] + :m / z=308.1, detected value: 308.1.

[0287] Step 5: Dissolve methyl 7-(cyclopropyldifluoromethyl)-2-methoxyquinoline-3-carboxylate (35.0 mg, 0.098 mmol) in methanol (1 mL), add 1N sodium hydroxide (0.60 mL, 0.60 mmol) aqueous solution, and stir the system at 40°C for 2 hours. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Adjust the pH to 4 with 1N hydrochloric acid aqueous solution, filter, and vacuum dry the solid to obtain crude 7-(cyclopropyldifluoromethyl)-2-methoxyquinoline-3-carboxylic acid (30 mg). LCMS calculated value C 15 H 14 F2NO3[M+H] + :m / z=294.1, detected value: 293.8.

[0288] Step 6: Dissolve 7-(cyclopropyldifluoromethyl)-2-methoxyquinoline-3-carboxylic acid (30.0 mg, 0.10 mmol) in pyridine (1 mL), add pentafluorophenyl trifluoroacetate (40.8 mg, 0.20 mmol), and stir the system at 60 ° C for 3 hours. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Cool to room temperature, add water (10 mL), extract with ethyl acetate (30 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain 7-(cyclopropyldifluoromethyl)-2-methoxyquinoline-3-carboxylic acid perfluorophenyl ester crude product (50 mg).

[0289] Step 7: Dissolve (R)-3-amino-2,3-dihydrothiophene 1,1-dioxide hydrobromide (18.5 mg, 0.14 mmol) and N,N-diisopropylethylamine (42.0 mg, 0.33 mmol) in N,N-dimethylformamide (2 mL), add 7-(cyclopropyldifluoromethyl)-2-methoxyquinoline-3-carboxylic acid perfluorophenyl ester (50 mg, 0.11 mmol), and stir the system at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Add water (5 mL), filter, and dry the solid in vacuum to obtain (R)-7-(cyclopropyldifluoromethyl)-N-(1,1-dioxido-2,3-dihydrothiophene-3-yl)-2-methoxyquinoline-3-carboxamide (25.0 mg, yield 56.1%). LCMS calculated value C 19 H 19 F2N2O4S[M+H] + :m / z=409.1, detected value: 409.1.

[0290] Step 8: Dissolve (R)-7-(cyclopropyldifluoromethyl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-methoxyquinoline-3-carboxamide (25 mg, 0.061 mmol) in dichloromethane (1 mL), add hydrobromic acid acetic acid solution (1 mL, 33% content). The system was stirred at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Dichloromethane (5 mL) and water (5 mL) were added, the organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: Xbridge-C18 150×19 mm, 5 μm; mobile phase: [water (0.05% ammonia)-ACN]; B%: 30%-90%, 30 minutes) to obtain the product as a white solid (R)-7-(cyclopropyldifluoromethyl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (10 mg, yield 41.5%). LCMS calculated value C 18 H 17 F2N2O4S[M+H] + :m / z=395.1, detected value: 395.0. 1 H NMR (400MHz, DMSO-d6) δ10.24(d,J=7.7Hz,1H),8.90(s,1H),8.09(d,J=8.3Hz,1H),7.60(s,1H),7.46(d,J=8.3Hz,1H),7.29(dd,J=6.6,1. 9Hz,1H),7.01(dd,J=6.6,3.0Hz,1H),5.41(s,1H),3.76(dd,J=13.8,7.9Hz,1H),3.31-3.29(m,1H),1.80-1.68(m,1H),0.74-0.69(m,4H).

[0291] Example 12 (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-6-fluoro-7-(2-methylbut-3-yn-2-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0292]

[0293] Step 1: Slowly add acetic acid (10 mL) and water (5 mL) to a system of 4-bromo-5-fluoro-2-nitrobenzaldehyde (2.00 g, 8.10 mmol) and iron powder (3.60 g, 64.3 mmol) in ethanol (30 mL). The system was stirred at room temperature for two hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Filtered on diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE with 0-10% EA) to obtain a white solid 2-amino-4-bromo-5-fluorobenzaldehyde (500 mg, yield 28.8%). LCMS calculated value C7H6BrFNO[M+H] + :m / z=218.0 / 220.0, detected value: 217.9 / 220.0.

[0294] Step 2: Stir a mixed solution of 2-amino-4-bromo-5-fluorobenzaldehyde (500 mg, 2.30 mmol), dimethyl malonate (851 mg, 6.45 mmol), piperidine (586 mg, 6.90 mmol), and acetic acid (10.6 mg, 0.23 mmol) in methanol (10 mL) at 60 ° C for 2 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool to room temperature, filter on diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain a white solid 7-bromo-6-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (500 mg, yield 72.7%). LCMS calculated value C 11 H8BrFNO3[M+H] + :m / z=300.0 / 302.0, detected value: 299.9 / 302.0.

[0295] Step 3: A system of 7-bromo-6-fluoro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (1.30 g, 4.35 mmol), silver carbonate (796 mg, 6.53 mmol), and iodomethane (975 mg, 6.53 mmol) in tetrahydrofuran (10 mL) was stirred overnight at 60 ° C under nitrogen protection. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool to room temperature, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (PE with 0-30% EA) to obtain a white solid 7-bromo-6-fluoro-2-methoxyquinoline-3-carboxylic acid methyl ester (800 mg, yield 58.8%). LCMS calculated value C 12 H 10 BrFNO3[M+H] + :m / z=314.0 / 316.0, detected value: 314.1 / 316.1.

[0296] Step 4: A system of 7-bromo-6-fluoro-2-methoxyquinoline-3-carboxylic acid methyl ester (800 mg, 2.56 mmol), trimethyl ((2-methylprop-1-en-1-yl)oxy) silane (737 mg, 5.11 mmol), zinc fluoride (526 mg, 5.11 mmol) and di(tri-tert-butylphosphine) palladium (262 mg, 0.511 mmol) in N,N-dimethylformamide (5 mL) was stirred at 100°C under nitrogen for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool to room temperature, filter on diatomaceous earth, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (PE with 0-30% EA) to obtain a white solid 6-fluoro-2-methoxy-7-(2-methyl-1-oxoprop-2-yl)quinoline-3-carboxylic acid methyl ester (140 mg, yield 18.0%). LCMS calculated value C 16 H 17 FNO4[M+H] + :m / z=306.1, detected value: 306.0.

[0297] Step 5: Add potassium carbonate (162 mg, 1.17 mmol) to a methanol (2 mL) system of 6-fluoro-2-methoxy-7-(2-methyl-1-oxopropyl-2-yl)quinoline-3-carboxylic acid methyl ester (120 mg, 0.39 mmol) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (151 mg, 0.79 mmol). The system was stirred at room temperature for 3 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Filtration and concentration, the residue was purified by silica gel column chromatography (PE with 0-30% EA) to obtain a white solid 6-fluoro-2-methoxy-7-(2-methylbut-3-yn-2-yl)quinoline-3-carboxylic acid methyl ester (70.0 mg, yield 50.7%). LCMS calculated value C 17 H 17 FNO3[M+H] + :m / z=302.1, detected value: 302.0.

[0298] Step 6: A system of 6-fluoro-2-methoxy-7-(2-methylbut-3-yn-2-yl)quinoline-3-carboxylic acid methyl ester (70.0 mg, 0.23 mmol) and sodium hydroxide (46.0 mg, 1.16 mmol) in methanol / water (1 mL, 1:1) was stirred at room temperature for 2 hours under nitrogen protection. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The system was adjusted to pH = 5 with 1N dilute hydrochloric acid, filtered, and the filter cake was vacuum dried to obtain a yellow solid 6-fluoro-2-methoxy-7-(2-methylbut-3-yn-2-yl)quinoline-3-carboxylic acid (63.0 mg, crude product). LCMS calculated value C 16 H 15FNO3[M+H] + :m / z=288.1, detected value: 288.0.

[0299] Step 7: Dissolve 6-fluoro-2-methoxy-7-(2-methylbut-3-yn-2-yl)quinoline-3-carboxylic acid (63.0 mg, 0.22 mmol) in pyridine (2 mL), add 2,2,2-trifluoroacetic acid pentafluorophenyl ester (123 mg, 0.44 mmol), and stir the system at 60 ° C for 2 hours under nitrogen protection. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Add water (20 mL), solid precipitates, filter, and vacuum dry the filter cake to obtain a yellow solid 6-fluoro-2-methoxy-7-(2-methylbut-3-yn-2-yl)quinoline-3-carboxylic acid perfluorophenyl ester (58.0 mg, crude product). LCMS calculated value C 22 H 14 F6NO3[M+H] + :m / z=454.1, detected value: 454.0.

[0300] Step 8: 6-fluoro-2-methoxy-7-(2-methylbut-3-yn-2-yl)quinoline-3-carboxylic acid perfluorophenyl ester (58.0 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (82.6 mg, 0.64 mmol) and (R)-3-amino-2,3-dihydrothiophene-1,1-dioxide hydrobromide (41.0 mg, 0.19 mmol) were added, and the system was stirred at room temperature for 2 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (0-10% MeOH in DCM) to give the crude product (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-6-fluoro-2-methoxy-7-(2-methylbut-3-yn-2-yl)quinoline-3-carboxamide (43.0 mg, yield 83.5%). LCMS calculated value C 20 H 20 FN2O4S[M+H] + :m / z=403.1, detected value: 403.1.

[0301] Step 9: Dissolve (R)-N-(1,1-dioxido-2,3-dihydrothiophene-3-yl)-6-fluoro-2-methoxy-7-(2-methylbut-3-yn-2-yl)quinoline-3-carboxamide (43.0 mg, 0.11 mmol) in dichloromethane (2 mL), add hydrobromic acid acetic acid solution (2 mL, 33% content). The system was stirred at room temperature for 2 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. The product was concentrated under reduced pressure and the residue was purified by Prep-HPLC (chromatographic column: Gemini Prep C18 150×21.2mm, 5μm; mobile phase: ACN-H2O (0.1% formic acid); gradient: 30%-60%) to obtain the product white solid (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-6-fluoro-7-(2-methylbut-3-yn-2-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (20 mg, yield 48.2%). LCMS calculated value C 19 H 18 FN2O4S[M+H] + :m / z=389.1, detected value: 389.1. 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),10.17(d,J=7.9Hz,1H),8.80(s,1H),7.83(d,J=12.3Hz,1H),7.77(d,J=7.0Hz,1H),7.25(dd, J=6.6,1.9Hz,1H),6.96(dd,J=6.6,3.1Hz,1H),5.36-5.35(m,1H),3.73-3.68(m,1H),3.40(s,1H),3.31-3.24(m,1H),1.61(s,6H).

[0302] Example 13 (R)-7-(1,1-difluoro-prop-2-ynyl)-N-[1,1-dioxido-2,3-dihydrothiophen-3-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0303]

[0304] Step 1: Stir 7-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (48.0 g, 0.17 mol), silver carbonate (70.4 g, 0.26 mol) and iodomethane (36.2 g, 0.26 mol) in tetrahydrofuran / dichloromethane (800 mL, 10:1) at 60 ° C for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool, filter and concentrate, and purify the residue by silica gel column chromatography (PE with 10-15% EA) to obtain a white solid 7-bromo-2-methoxyquinoline-3-carboxylic acid methyl ester (20.0 g, yield 40.0%). LCMS calculated value C 12 H 11 BrNO3[M+H] + :m / z=296.0 / 298.0, detected value: 296.1 / 298.1.

[0305] Step 2: Dissolve 7-bromo-2-methoxyquinoline-3-carboxylic acid methyl ester (2.00 g, 6.75 mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (961 mg, 6.75 mmol) in 1,4-dioxane (20 mL), add sodium iodide (2.02 g, 13.5 mmol) and cuprous iodide (64.3 mg, 338 μmol) at room temperature, and stir the system at 120 ° C for 16 hours under a nitrogen atmosphere. LCMS shows that the reaction is complete and cooled to room temperature. Add ethyl acetate (50 mL), filter, and concentrate the filtrate to obtain a crude product, which is purified by column chromatography (PE: EA = 8: 1) to obtain compound 7-iodo-2-methoxyquinoline-3-carboxylic acid methyl ester (1.53 g, yield 66.0%). LCMS calculated value C 12 H 11 INO3[M+H] + :m / z=344.0, detected value: 344.1.

[0306] Step 3: Dissolve 7-iodo-2-methoxyquinoline-3-carboxylic acid methyl ester (1.00 g, 2.91 mmol) and ethyl 2-bromo-2,2-difluoroacetate (651 mg, 3.21 mmol) in dimethyl sulfoxide (10 mL), add copper powder (741 mg, 11.7 mmol) at room temperature, and stir the system at 55 ° C under nitrogen atmosphere for 16 hours. LCMS shows that the reaction is complete, cool to room temperature, add water (50 mL), extract with ethyl acetate (100 mL), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by column chromatography (PE: EA = 8: 1) to obtain compound 7-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-methoxyquinoline-3-carboxylic acid methyl ester (720 mg, yield 72.8%). LCMS calculated value C 16 H 16 F2NO5[M+H]+ :m / z=340.1, detected value: 340.3.

[0307] Step 4: Dissolve 7-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-methoxyquinoline-3-carboxylic acid methyl ester (800 mg, 2.36 mmol) in tetrahydrofuran (30 mL), methanol (30 mL) and water (30 mL), add lithium hydroxide (339 mg, 14.2 mmol) at room temperature, and stir the system at 40 ° C for 0.5 hours. LCMS shows that the reaction is complete. Cool to room temperature, adjust the pH value to 5-6 with 1N dilute hydrochloric acid, add ethyl acetate (50 mL) and extract twice, combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product as a white solid 7-[carboxyl (difluoro) methyl]-2-methoxyquinoline-3-carboxylic acid (700 mg, crude product). LCMS calculated value C 13 H 10 F2NO5[M+H] + :m / z=298.0, detected value: 298.2.

[0308] Step 5: Dissolve 7-[carboxyl(difluoro)methyl]-2-methoxyquinoline-3-carboxylic acid (700 mg, 2.36 mmol) and 1-[(triisopropylsilyl)ethynyl]-1,2-benzimidoyl-3(1H)-one (1.01 g, 2.36 mmol) in acetonitrile (5 mL) and water (5 mL), add potassium persulfate (1.27 g, 4.71 mmol) at room temperature, replace the air with nitrogen three times, and stir the system at 90 ° C for 1 hour. LCMS shows that the reaction is complete. Cool to room temperature, extract with ethyl acetate (40 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain the crude product 7-(1,1-difluoro-3-triisopropylsilyl-prop-2-ynyl)-2-methoxyquinoline-3-carboxylic acid (600 mg, crude product). LCMS calculated value C 23 H 30 F2NO3Si[M+H] + :m / z=434.2, detected value: 434.3.

[0309] Step 6: Dissolve 7-(1,1-difluoro-3-triisopropylsilyl-prop-2-ynyl)-2-methoxyquinoline-3-carboxylic acid (500 mg, 1.15 mmol) in pyridine (5 mL), add pentafluorophenyl trifluoroacetate (646 mg, 2.31 mmol) at room temperature, and stir the system at 60 ° C for 0.5 hours. LCMS shows that the reaction is complete. Cool to room temperature, add water (10 mL), extract with ethyl acetate (40 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain the crude product 7-(1,1-difluoro-3-triisopropylsilyl-prop-2-ynyl)-2-methoxyquinoline-3-carboxylic acid perfluorophenyl ester (400 mg, crude product). LCMS calculated value C 29 H 29 F7NO3Si[M+H] + :m / z=600.2, detected value: 600.1.

[0310] Step 7: Dissolve 7-(1,1-difluoro-3-triisopropylsilyl-prop-2-ynyl)-2-methoxyquinoline-3-carboxylic acid perfluorophenyl ester (400 mg, 0.67 mmol) and (R)-3-amino-2,3-dihydrothiophene-1,1-dioxide hydrobromide (68 mg, 0.51 mmol) in N,N-dimethylformamide (5 mL), add N,N-diisopropylethylamine (172 mg, 1.33 mmol) at room temperature, and stir the system at room temperature for 0.5 hour. LCMS showed that the reaction was complete, water (10 mL) was added, extracted with ethyl acetate (40 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (PE:EA=4:1) to obtain compound 7-(1,1-difluoro-3-triisopropylsilyl-prop-2-ynyl)-N-[(3R)-1,1-dioxo-2,3-dihydrothiophen-3-yl]-2-methoxyquinoline-3-carboxamide (153 mg, yield 41.8%). LCMS calculated value C 27 H 35 F2N2O4SSi[M+H] + :m / z=549.2, detected value: 549.4.

[0311] Step 8: 7-(1,1-difluoro-3-triisopropylsilyl-prop-2-ynyl)-N-[(3R)-1,1-dioxo-2,3-dihydrothiophen-3-yl]-2-methoxyquinoline-3-carboxamide (160 mg, 292 μmol) was dissolved in N,N-dimethylformamide (2 mL), lithium chloride (502 mg, 2.92 mmol) and p-toluenesulfonic acid (124 mg, 2.92 mmol) were added at room temperature, and the system was stirred at 100° C. for 1 hour. LCMS showed that the reaction was complete. Cool to room temperature, add water (10 mL), extract with ethyl acetate (40 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain the crude product 7-(1,1-difluoro-3-triisopropylsilyl-prop-2-ynyl)-N-[(3R)-1,1-dioxo-2,3-dihydrothiophen-3-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide (110 mg, crude product). LCMS calculated value C 26 H 33 F2N2O4SSi[M+H] + :m / z=535.2, detected value: 535.1.

[0312] Step 9: 7-(1,1-difluoro-3-triisopropylsilyl-prop-2-ynyl)-N-[(3R)-1,1-dioxo-2,3-dihydrothiophen-3-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide (100 mg, 187 μmol) was dissolved in methanol (1 mL), potassium fluoride (109 mg, 1.87 mmol) was added at room temperature, and the system was stirred at 40° C. for 1 hour. LCMS showed that the reaction was complete. Cool to room temperature, add water (5 mL), extract with ethyl acetate (20 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify the crude product with reverse phase high performance liquid chromatography column: ChromCore C18 250×21.2 mm, 10 μm; mobile phase: [water (1% formic acid)-ACN]; B%: 30%-45%, 15 minutes) to obtain a white solid (R)-7-(1,1-difluoro-prop-2-ynyl)-N-[1,1-dioxo-2,3-dihydrothiophen-3-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide (43.9 mg, yield 60.2%). LCMS calculated value C 17 H 13 F2N2O4S[M+H] + :m / z=379.1, detected value: 379.2. 1H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.15(d,J=8.3Hz,1H),7.76(s,1H),7.55(d,J=9.7Hz,1H),7.27(dd,J=6.7,1.8Hz,1H), 6.99 (dd, J = 6.6, 3.0 Hz, 1H), 5.39 (s, 1H), 4.83 (t, J = 4.8 Hz, 1H), 3.75 (dd, J = 13.8, 8.0 Hz, 1H), 3.32 (dd, J = 13.8, 4.1 Hz, 1H).

[0313] Example 14 (R)-8-amino-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

[0314]

[0315] Step 1: At room temperature, dissolve 3-amino-4-bromo-2-nitrobenzoic acid methyl ester (5.00 g, 18.2 mmol) in N, N-dimethylformamide (50 mL), add 4-dimethylaminopyridine (222 mg, 1.82 mmol), N, N-diisopropylethylamine (4.69 g, 36.4 mmol), cool the reaction solution to 0 ° C, slowly drop acetyl chloride (1.57 g, 20.0 mmol), then heat the system to 65 ° C and stir for 16 hours. LCMS detected the desired compound. Add water (20 mL) to the reaction solution, and extract with ethyl acetate (100 mL), dry the organic phase with sodium sulfate, filter and concentrate under reduced pressure, and purify the residue by silica gel column chromatography (PE with 0-30% EA) to obtain yellow solid 3-acetylamino-4-bromo-2-nitrobenzoic acid methyl ester (2.20 g, yield 38.3%). LCMS calculated value C 10 H 10 BrN2O5[M+H] + :m / z=317.0 / 319.0, detected value: 316.9 / 319.0.

[0316] Step 2: At room temperature, 3-acetylamino-4-bromo-2-nitrobenzoic acid methyl ester (2.00 g, 6.31 mmol), isopropenylboronic acid pinacol ester (1.27 g, 7.57 mmol), tetrakis(triphenylphosphine)palladium (729 mg, 0.631 mmol), potassium carbonate (1.31 g, 9.46 mmol) were dissolved in a mixed solvent of water (2 mL) and dioxane (20 mL). The system was stirred at 90 ° C for 16 hours under nitrogen protection. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cooling, filtration and concentration were performed, and the residue was chromatographed on a silica gel column (PE with 0-20% EA) to obtain a light yellow solid 3-acetylamino-2-nitro-4-(prop-1-ene-2-yl)benzoic acid methyl ester (1.20 g, yield 68.4%). LCMS calculated value C 13 H 15 N2O5[M+H] + :m / z=279.1, detected value: 279.0.

[0317] Step 3: At room temperature, the compound 3-acetylamino-2-nitro-4-(prop-1-en-2-yl)benzoic acid methyl ester (1.20 g, 4.31 mmol) was dissolved in methanol (5 mL), palladium carbon (480 mg, 10% content) was added, and the system was stirred at room temperature for 6 hours under a hydrogen atmosphere. LCMS detection showed that the raw material was completely consumed, and the desired compound was detected. Filtration and concentration were performed to obtain a yellow solid 3-acetylamino-2-amino-4-isopropylbenzoic acid methyl ester (650 mg, yield 60.3%). LCMS calculated value C 13 H 19 N2O3[M+H] + :m / z=251.1, detected value: 251.0.

[0318] Step 4: Dissolve the compound 3-acetylamino-2-amino-4-isopropylbenzoic acid methyl ester (650 mg, 2.60 mmol) in tetrahydrofuran (20 mL), cool to 0 ° C, add lithium aluminum tetrahydride (197 mg, 5.20 mmol) in batches, and stir the system at room temperature for 4 hours. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. The reaction mixture is quenched with aqueous sodium hydroxide solution (15%), filtered and concentrated, and the residue is purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain the product white solid N-(2-amino-3-(hydroxymethyl)-6-isopropylphenyl) acetamide (370 mg, yield 55.0%). LCMS calculated value C 12 H 19 N2O2[M+H] + :m / z=223.1, detected value: 223.2.

[0319] Step 5: Dissolve the compound N-(2-amino-3-(hydroxymethyl)-6-isopropylphenyl)acetamide (350 mg, 1.57 mmol) in tetrahydrofuran (30 mL), add manganese dioxide (685 mg, 7.87 mmol), and stir the system at room temperature for 4 hours. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Filtration and concentration, the residue is purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain the product white solid N-(2-amino-3-formyl-6-isopropylphenyl)acetamide (240 mg, yield 55.0%). LCMS calculated value C 12 H 17 N2O2[M+H] + :m / z=221.1, detected value: 221.2.

[0320] Step 6: At room temperature, the compound N-(2-amino-3-formyl-6-isopropylphenyl)acetamide (240 mg, 1.09 mmol) was dissolved in methanol (75 mL), and dimethyl malonate (403 mg, 3.05 mmol), piperidine (278 mg, 3.27 mmol) and acetic acid (6.54 mg, 0.11 mmol) were added. The system was stirred at 60 ° C for 16 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain a white solid 8-acetylamino-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (180 mg, yield 54.7%). LCMS calculated value C 16 H 19 N2O4[M+H] + :m / z=303.1, detected value: 303.2.

[0321] Step 7: Dissolve the compound 8-acetylamino-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (180 mg, 0.595 mmol) in methanol (6 mL), and add an aqueous solution (2 mL) of lithium hydroxide (42.8 mg, 1.79 mmol). The system was stirred at room temperature for 4 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Concentrate under reduced pressure, dilute the residue with water (5 mL), adjust the pH to 3 with 1N hydrochloric acid aqueous solution, and filter to obtain a yellow solid 8-acetylamino-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, yield 58.4%). LCMS calculated value C 15 H 17 N2O4[M+H] + :m / z=289.1, detected value: 289.2.

[0322] Step 8: Dissolve the compound 8-acetylamino-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.35 mmol) in pyridine (5 mL), add 2,2,2-trifluoroacetic acid perfluorophenyl ester (216 mg, 0.77 mmol) dropwise, and stir the system at 60 ° C for 3 hours under nitrogen protection. LCMS detection shows that the raw material is completely consumed and the desired compound is detected. Cool to room temperature, add water (4 mL) to dilute, precipitate solid, filter and dry to obtain yellow solid 8-acetylamino-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid perfluorophenyl ester (75.0 mg, yield 47.6%). LCMS calculated value C 21 H 16 F5N2O4[M+H] + :m / z=455.1, detected value: 455.0.

[0323] Step 9: 8-acetylamino-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid perfluorophenyl ester (50.0 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (42.6 mg, 0.33 mmol) and 3-amino-2,3-dihydrothiophene-1,1-dioxide hydrobromide (35.3 mg, 0.16 mmol) were added, and the system was stirred at room temperature for 1 hour. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Dilute with water (20 mL), extract with ethyl acetate (80 mL), wash the organic phase with brine (50 mL), dry with anhydrous sodium sulfate, filter and concentrate, and purify the residue by Prep-HPLC (column: Gemini Prep C18 150×21.2 mm, 5 μm; mobile phase: [water (0.1% formic acid in water)-ACN]; B%: 25%-95%, 16 minutes) to obtain the product as a white solid (R)-8-acetylamino-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (22.0 mg, yield 49.6%). LCMS calculated value C 19 H 22 N3O5S[M+H] + :m / z=404.1, detected value: 404.1.

[0324] Step 10: At room temperature, compound (R)-8-acetylamino-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (25.0 mg, 0.06 mmol) was dissolved in methanol (5 mL), concentrated sulfuric acid (2 drops) was added, and the system was stirred at 30° C. for 48 hours under nitrogen protection. The desired compound was detected by LCMS. The residue was filtered and concentrated, and purified by Prep-HPLC (column: Gemini Prep C18 150×21.2 mm, 5 μm; mobile phase: [water (0.05% ammonia)-ACN]; B%: 10%-80%, 15 minutes) to obtain a white solid (R)-8-amino-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (5.16 mg, yield 23.1%). LCMS calculated value C 17 H 20 N3O4S[M+H] + :m / z=362.1, detected value: 362.0. 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),10.22(d,J=7.8Hz,1H),8.71(s,1H),7.28(dd,J=6.6,1.9Hz,1H),7.20(d,J=8.3Hz,1H),7.11(d,J=8.3Hz,1H), 7.01(dd,J=6.6,3.0Hz,1H),5.52(s,2H),5.40(s,1H),3.75(dd,J=13.8,7 .9Hz, 1H), 3.30 (d, J = 4.2Hz, 1H), 3.22-3.15 (m, 1H), 1.18 (d, J = 5.8Hz, 6H).

[0325] Example 15 (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7,7-dimethyl-2-oxo-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxamide

[0326]

[0327] Step 1: At room temperature, 3-methylbut-2-enoyl chloride (2.38 g, 20.1 mmol) was added dropwise to a solution of methyl 3-amino-2-bromobenzoate (4.20 g, 18.3 mmol) and pyridine (2.89 g, 36.5 mmol) in dichloromethane (50 mL). The system was stirred at room temperature for 2 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Dichloromethane (100 mL) was added, and the mixture was washed with water (100 mL) and brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE with 0-25% EA) to obtain methyl 2-bromo-3-(3-methylbut-2-enoylamino)benzoate (5.70 g, yield 100%) as a white solid. LCMS calculated value C 13 H 15 BrNO3[M+H] + :m / z=312.0 / 314.0, detected value: 312.2 / 314.2.

[0328] Step 2: At room temperature, anhydrous aluminum chloride (16.8 g, 126 mmol) was added in batches to a solution of 2-bromo-3-(3-methylbut-2-enoylamino)benzoic acid methyl ester (13.1 g, 42.0 mmol) in 1,2-dichloroethane (250 mL). The system was stirred at 40°C for 16 hours. LCMS detection showed that the raw material was consumed and the desired compound was detected. The product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE with 0-20% EA) to obtain a yellow solid 8-bromo-4,4-dimethyl-2-carbonyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid methyl ester (4.50 g, yield 34.4%). LCMS calculated value C 13 H 15 BrNO3[M+H] + :m / z=312.0 / 314.0, detected value: 312.0 / 314.0.

[0329] Step 3: At 0°C, slowly add borane-dimethyl sulfide complex (28.2mL, 28.2mmol, 1M tetrahydrofuran solution) to a solution of 8-bromo-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid methyl ester (4.40g, 14.1mmol) in tetrahydrofuran (60mL). The system was stirred at 60°C for 7 hours under nitrogen protection. Cooled to room temperature, methanol (100mL) was slowly poured in. The system was stirred at reflux for 30 minutes, and the solvent was removed under reduced pressure to obtain (8-bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-7-yl) methanol (3.80g, crude product), which was directly used in the next step reaction. LCMS calculated value C 12 H 17 BrNO[M+H] +:m / z=270.0 / 272.0, detected value: 270.1 / 272.1.

[0330] Step 4: (8-bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)methanol (3.80 g, 14.1 mmol), imidazole (1.92 g, 28.1 mmol) and 4-dimethylaminopyridine (170 mg, 1.41 mmol) were dissolved in N,N-dimethylformamide (15 mL), tert-butyldimethylsilyl chloride (3.18 g, 21.1 mmol) was added, and the system was stirred at room temperature for 3 hours. The reaction mixture was diluted with ice water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE with 0-5% EA) to give 8-bromo-7-(((tert-butyldimethylsilyloxy)methyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (4.95 g, yield 91.6%) as a white solid. LCMS calculated value C 18 H 31 BrNOSi[M+H] + :m / z=384.1 / 386.1, detected value: 384.3 / 386.3.

[0331] Step 5: Under nitrogen protection at -78°C, add n-butyl lithium (0.20 mL, 0.32 mmol, 1.6 M n-hexane solution) to a solution of (8-bromo-4,4-dimethyl-2,3-dihydro-1H-quinolin-7-yl)methoxydimethyl tert-butylsilane (100 mg, 0.26 mmol) in tetrahydrofuran (5 mL). The system is stirred at -78°C for 1 hour, and then a solution of benzyl bromide (53.4 mg, 0.31 mmol) in tetrahydrofuran (5 mL) is added dropwise. The system is slowly warmed to room temperature and stirred for 30 minutes. The reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE with 0-5% EA) to give 1-benzyl-8-bromo-7-(((tert-butyldimethylsilyloxy)methyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (102 mg, yield 82.6%) as a white solid. LCMS calculated value C 25 H 37 BrNOSi[M+H] + :m / z=474.2 / 476.2; Detected value: 474.4 / 476.4.

[0332] Step 6: Under nitrogen protection, a toluene (2 mL) system of (1-benzyl-8-bromo-4,4-dimethyl-2,3-dihydroquinolin-7-yl)methoxy-dimethyl-tert-butylsilane (100 mg, 0.21 mmol), 4-methoxybenzylamine (86.7 mg, 0.63 mmol), BrettPhos Pd G3 (19.0 mg, 0.02 mmol), Brettphos (22.6 mg, 0.04 mmol) and sodium tert-butoxide (60.7 mg, 0.63 mmol) was stirred at 110 °C for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE with 0-20% EA) to give 1-benzyl-7-(((tert-butyldimethylsilyloxy)methyl)-N-(4-methoxybenzyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-8-amine (73.0 mg, 65.3%) as a white solid. LCMS calculated value: C 33 H 47 N2O2Si[M+H] + :m / z=531.3, detected value: 531.3.

[0333] Step 7: To a solution of 1-benzyl-7-[(dimethyl-tert-butylsilyl)oxymethyl]-N-[(4-methoxyphenyl)methyl]-4,4-dimethyl-2,3-dihydroquinolin-8-amine (45.0 mg, 0.08 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammonium fluoride (0.03 mL, 0.03 mmol, 1 M tetrahydrofuran solution) at room temperature, and the system was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL), the organic phase was washed with water (50 mL) and brine (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE with 0-10% EA) to obtain a white solid (1-benzyl-8-((4-methoxybenzyl)amino)-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)methanol (27.0 mg, yield 76.4%). LCMS calculated value C 27 H 33 N2O2[M+H] + :m / z=417.3, detected value: 417.4.

[0334] Step 8: A solution of (8-amino-4,4-dimethyl-2,3-dihydro-1H-quinolin-7-yl)methanol (970 mg, 2.33 mmol) and 2-iodobenzoic acid (1.96 g, 6.99 mmol) in dimethyl sulfoxide (10 mL) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE with 0-10% EA) to obtain a white solid 1-benzyl-8-((4-methoxybenzyl)amino)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (920 mg, yield 95.3%). LCMS calculated value C 27 H 31 N2O2[M+H] + :m / z=415.2, detected value: 415.4.

[0335] Step 9: Add trifluoroacetic acid (1 mL) to a solution of 1-benzyl-8-[(4-methoxyphenyl)methylamino]-4,4-dimethyl-2,3-dihydroquinoline-7-carbaldehyde (850 mg, 2.05 mmol) in dichloromethane (30 mL). The system was stirred at room temperature for 10 minutes. The system was poured into an aqueous sodium bicarbonate solution (50 mL, 1 M), extracted with dichloromethane (150 mL), the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE with 0-10% EA) to obtain a white solid 8-amino-1-benzyl-4,4-dimethyl-2,3-dihydroquinoline-7-carbaldehyde (565 mg, yield 93.6%). LCMS calculated value C 19 H 23 N2O[M+H] + :m / z=295.2, detected value: 295.2.

[0336] Step 10: At room temperature, 8-amino-1-benzyl-4,4-dimethyl-2,3-dihydroquinoline-7-carbaldehyde (565 mg, 1.92 mmol) was dissolved in ethanol (30 mL), diethyl malonate (922 mg, 5.76 mmol), piperidine (490 mg, 5.76 mmol) and acetic acid (11.5 mg, 0.19 mmol) were added, and the system was stirred at 100 ° C for 8 hours. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. Cool and filter, wash the solid with a small amount of ethanol and dry to obtain a white solid 10-benzyl-7,7-dimethyl-2-carbonyl-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxylic acid ethyl ester (653 mg, yield 87.1%). LCMS calculated value C 24 H 27N2O3[M+H] + :m / z=391.2, detected value: 391.3.

[0337] Step 11: Under a hydrogen atmosphere, a mixture of 10-benzyl-7,7-dimethyl-2-carbonyl-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxylic acid ethyl ester (165 mg, 0.42 mmol) and palladium carbon (166 mg, 10% content) in ethanol (9 mL) and acetic acid (3 mL) was stirred at room temperature for 30 minutes. Filter and concentrate to obtain a white solid 7,7-dimethyl-2-carbonyl-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxylic acid ethyl ester (170 mg, crude product), which was directly used in the next step. LCMS calculated value C 17 H 21 N2O3[M+H] + :m / z=301.2, detected value: 301.2.

[0338] Step 12: At room temperature, ethyl 7,7-dimethyl-2-carbonyl-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxylate (170 mg, crude product) was dissolved in tetrahydrofuran (6 mL) and methanol (4 mL), and an aqueous solution (1.5 mL) of lithium hydroxide (65.8 mg, 2.75 mmol) was added. The system was stirred at room temperature for 30 minutes. LCMS detection showed that the raw material was completely consumed and the desired compound was detected. 1N dilute hydrochloric acid was added to the reaction mixture to adjust the pH to 4, and the solid was collected by filtration to obtain 7,7-dimethyl-2-carbonyl-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxylic acid (166 mg, crude product), which was directly used in the next step reaction. LCMS calculated value C 15 H 17 N2O3[M+H] + :m / z=273.1, detected value: 273.2.

[0339] Step 13: Dissolve 7,7-dimethyl-2-carbonyl-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxylic acid (166 mg, crude product) in pyridine (1 mL), add pentafluorophenyl trifluoroacetate (236 mg, 0.84 mmol) dropwise, and stir the system at room temperature for 1 hour. Dilute with water (8 mL), filter, and slurry the solid with ether to obtain yellow solid 7,7-dimethyl-2-carbonyl-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxylic acid pentafluorophenyl ester (50.0 mg, yield 27.0%). LCMS calculated value C 21 H 16 F5N2O3[M+H] +:m / z=439.1, detected value: 439.2.

[0340] Step 14: To a solution of 7,7-dimethyl-2-carbonyl-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxylic acid pentafluorophenyl ester (50.0 mg, 0.11 mmol) in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine (0.06 mL, 0.34 mmol) and (R)-1,1-dioxo-2,3-dihydrothiophene-3-amine hydrobromide (72.8 mg, 0.34 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate (50 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by slurrying with diethyl ether to obtain a yellow solid (R)-N-(1,1-dioxo-2,3-dihydrothiophen-3-yl)-7,7-dimethyl-2-oxo-1,2,7,8,9,10-hexahydro-1,10-phenanthroline-3-carboxamide (33.0 mg, yield 74.7%). LCMS calculated value C 19 H 22 N3O4S[M+H] + :m / z=388.1, detected value: 388.2. 1 H NMR (400MHz, DMSO-d6) δ11.36 (s, 1H), 10.22 (d, J = 7.7Hz, 1H), 8.69 (s, 1H), 7.2 7(dd,J=6.6,2.0Hz,1H),7.21(d,J=8.3Hz,1H),7.12(d,J=8.4Hz,1H),7.01(dd, J=6.6,3.0Hz,1H),6.17(s,1H),5.44-5.35(m,1H),3.75(dd,J=13.8,7.9Hz,1H ), 3.33 (d, J = 3.4Hz, 2H), 3.29 (d, J = 4.1Hz, 1H), 1.73-1.66 (m, 2H), 1.28 (s, 6H).

[0341] Biological evaluation

[0342] 1. Biochemical activity test: DNA unwinding fluorescence assay of WRN helicase

[0343] The fluorescence (FI)-based WRN helicase assay was used to detect the helicase inhibition of compounds on WRN. The recombinant His-tagged WRN (517-1238) used in the experiment was expressed in insect cells and purified to 90% purity by Ni-NTA column; the fluorescently labeled ssDNA was synthesized by GenScript, with the specific sequence of 5'-BHQ / GCACTG GCC GTC GTT TTA CGG TCGTGA CT-3'; 5'-TTT TTT ACT TAA CGA CGG CCA GTG C / TAMRA / -3'; after annealing, the dsDNA substrate was formed for experimental determination.

[0344] Add 40 μL of compound to a 384-well plate for dilution, and dilute each compound into 10 concentrations at a dilution ratio of 1:3. Use Echo to transfer 0.15 μL of diluted compound row by row to a 384-well reaction plate, with 2 replicates per column. Add 5 μL of WRN enzyme working solution to each well and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 20 minutes. Add 5 μL of dsDNA substrate working solution and centrifuge at 1000 rpm for 1 minute. Add 5 μL of ATP working solution to start the unwinding reaction. Incubate at 25°C for 20 minutes. Use BMG to read the emission fluorescence value at 685 nm after excitation at 620 nm. Use Graphpad 9.0 to fit the logarithm of activity % and compound concentration to a nonlinear regression (dose response-variable slope) to calculate the IC 50 .

[0345] Table 1. DNA unwinding fluorescence test results of WRN helicase

[0346] Example <![CDATA[IC 50 (μM)]]> 3 D 4 C 7 D 10 D 11 D 12 D 13 D 14 D 15 D Ref.1 C

[0347] Note 1: Ref.1 is selected from patent WO2023062575A1, the structure is

[0348] Note 2: A refers to IC 50 >1.0μM, B refers to 0.2μM <IC 50 ≤1.0μM, C refers to 0.05μM <IC 50 ≤0.2μM, D refers to IC 50 ≤0.05μM.

[0349] The specific values ​​of the test results in Table 1 are shown in Table 1-1 below:

[0350] Table 1-1. DNA unwinding fluorescence test results of WRN helicase

[0351]

[0352]

[0353] The above data show that the example compounds of the present invention have good inhibitory activity on WRN helicase function and are significantly better than the reference compounds.

[0354] 2. Cell activity test: SW48 cell proliferation inhibition activity test

[0355] The antiproliferative effect of the compounds on human colon cancer cell lines was evaluated by ATP quantification, and the activity correlated well with the number of viable cells. The cell line SW48 (ATCC, CCL-231) was cultured in DMEM (Gibco, 11965118) medium supplemented with 10% (v / v) fetal bovine serum (Gibco, 10099141C). The cell lines were cultured according to the standard instructions of the American Type Culture Collection. The cell lines were identified by short tandem repeat profiles.

[0356] In the proliferation assay, 4000 SW48 cells were seeded in a 96-well clear flat-bottom black TC-treated plate (Corning, 3603) in 200 μL of culture medium per well and cultured overnight in culture medium to recover. Compounds were added in increasing concentration gradients, and DMSO treatment was used as a positive control. After 5 days of treatment, the microplate was equilibrated to room temperature for 30 minutes, and the number of viable cells was measured by adding CellTiter-Glo reagent (Promega, G7573). Chemiluminescence readings were measured on Spark (Tecan). The relative survival of each group was expressed as a percentage change relative to the positive control group, and then fitted to a four-parameter nonlinear curve using the program GraphPad 10 software to calculate the IC 50 .

[0357] Table 2. Results of the proliferation inhibition activity test of SW48 cells

[0358] Example <![CDATA[IC 50 (μM)]]> 3 C 4 B 7 B 8 B 9 C 10 C 11 B 12 C 13 C 14 C 15 C Ref.1 B

[0359] Note 1: Ref.1 is selected from patent WO2023062575A1, the structure is

[0360] Note 2: A refers to IC 50 >5μM, B refers to 0.5μM <IC 50 ≤5μM, C refers to IC 50 ≤0.5μM.

[0361] The specific values ​​of the test results in Table 2 are shown in Table 2-1 below:

[0362] Table 2-1. Results of the proliferation inhibition activity test of SW48 cells

[0363] Example <![CDATA[IC 50 (μM)]]> 3 0.29 4 3.5 7 0.65 8 0.62 9 0.47 10 0.19 11 0.64 12 0.027 13 0.19 14 0.49 15 0.37 Ref.1 0.74

[0364] The above data show that the example compounds of the present invention have good inhibitory activity on SW48 cell proliferation and are significantly better than the reference compounds.

[0365] 3. In vitro metabolic stability test: human liver microsome stability test

[0366] 1. Buffer Preparation

[0367] Buffer A: 1.0 L of 0.1 M potassium dihydrogen phosphate buffer (containing 1.0 mM EDTA dipotassium salt);

[0368] Buffer B: 1.0 L of 0.1 M potassium dihydrogen phosphate buffer (containing 1.0 mM EDTA dipotassium salt);

[0369] Buffer C: Add buffer A to 700 mL of buffer B and adjust the pH to 7.4.

[0370] 2. Preparation of reference compound (ketanserin) and test compound solutions

[0371] (1) 500 μM solution: Prepare a 10 mM stock solution of the test compound and add 10 μL of the 10 mM stock solution to 190 μL ACN;

[0372] (2) 1.5 μM dosing solution (dissolved in human liver microsome solution (final concentration 0.75 mg / mL)): Add 1.5 μL of the 500 μM solution prepared in step (1) and 18.75 μL of 20 mg / mL liver microsomes to 479.75 μL of buffer C (operate on ice) and vortex gently to mix.

[0373] 3. Experimental Procedure

[0374] Dissolve NADPH in buffer C to prepare NADPH stock solution (6mM), and add 30μL of 1.5μM dosing solution (containing 0.75mg / mL liver microsomes) to the wells set at different time points (0 minutes, 5 minutes, 15 minutes, 30 minutes, and 45 minutes) on a 96-well plate (operate on ice). Prepare the 0-minute sample: first add 135μL ACN (containing internal standard) to the well at 0 minutes, and then add 15μL of 6mM NADPH solution. Preheat the 96-well plate containing 1.5μM dosing solution and NADPH solution at 37°C for 5 minutes. Add the preheated 15μL of 6mM NADPH solution to the wells set at 5 minutes, 15 minutes, 30 minutes, and 45 minutes to start the reaction and start timing. When the timer shows 5 minutes, 15 minutes, 30 minutes, and 45 minutes, add 135μL ACN (containing internal standard) to terminate the reaction. After quenching, the 96-well plate was shaken on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm / min), and then the sample was centrifuged at 5594xg for 15 minutes in a centrifuge (Thermo Multifuge×3R). 30 μL of supernatant from each well was added to a 96-well sample plate containing 150 μL of purified water, vortexed and sent for LC / MS / MS analysis.

[0375] Table 3. Results of human liver microsome stability test

[0376] Example <![CDATA[T 1 / 2 (min)]]> 12 181 Ref.1 39

[0377] Note 1: Ref.1 is selected from patent WO2023062575A1, the structure is

[0378] The above data show that the compounds of the examples of the present invention have higher stability in human liver microsomes and are significantly better than the reference compounds.

Claims

1. A compound represented by formula (I), its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or a pharmaceutically acceptable salt thereof: in, X 1 C=O or CR 0 ;X 2 N or NR 5 ;X 3 NH or N; X 5 CR 6 R 7 or NR 6 ;X 6 N or CR 8 ; When X 1 When C=O, X 2 NR 5 and is a single bond; When X 1 CR 0 When X 2 is N and is a double bond; R 0 is hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy, cyano, amino, -CONH2, or carboxyl; Or when X 3 When N, X 1 CR 0 , R 0 For-(CR b R c ) m - and with X 3 Connected, m is 1, 2 or 3, that is, X 1 With X 3 and the C atoms between them together form a 5-7 membered heterocyclic group; each R b and R c Each is independently selected from hydrogen, deuterium, unsubstituted or substituted C1-C6 alkyl, halogen, hydroxyl, carboxyl, amino, cyano, -CONH2; the substituted C1-C6 alkyl refers to being substituted by one or more selected from halogen, hydroxyl, carboxyl, amino, cyano; R 1 , R 2 , R 3 , R 4 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, -CONH2, unsubstituted or substituted C1-C6 alkyl; the substituted C1-C6 alkyl refers to being substituted by one or more selected from halogen, hydroxyl, carboxyl, amino, cyano; R 5 is hydrogen or C1-C6 alkyl; R 8 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR 8x R 8y , cyano, hydroxyl, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, -CONH2; R 8x and R 8y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; X 4 for R 10 is hydrogen or C1-C6 alkyl or C1-C6 alkoxy; R 11 is hydrogen or C1-C6 alkyl; p is 0, 1, or 2; R 9 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR 9x R 9y , cyano, hydroxyl, carboxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, -CONH2; R 9x and R 9y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R a is C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, or 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A; or R a With R 9 and the carbon atoms connected to them constitute C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group A, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group A; When X 4 for X 5 CR 6 R 7 , and X 1 When C=O, R a With R 9 can only form with the carbon atoms to which they are attached C6-C10 aryl groups which are unsubstituted or substituted by one or more substituents selected from Group A, C3-C8 cycloalkyl groups which are unsubstituted or substituted by one or more substituents selected from Group A, 3-10 membered heterocyclyl groups which are unsubstituted or substituted by one or more substituents selected from Group A, and 5-10 membered heteroaryl groups which are unsubstituted or substituted by one or more substituents selected from Group A; Group A substituents include: oxo, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ; i is 0, 1, or 2; R 12 and R 13 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B2; The substituents of group B2 include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, -NR x R y , C6-C10 aryl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; R x and R y Each is independently H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-6 membered heterocyclic group, 3-10 membered heterocyclic group and 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

2. The compound of formula (I) as claimed in claim 1, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) has a structure represented by formula (V): in, n is 1, 2, 3 or 4; R d is deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, carboxyl, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ; R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , X 4 , X 5 , i and p are as defined in claim 1.

3. A compound represented by formula (V-1), its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or a pharmaceutically acceptable salt thereof: in, R 1 , R 2 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, or C1-C3 alkyl; R 5 is hydrogen or C1-C3 alkyl; R 8 is hydrogen, deuterium, halogen, C1-C3 alkyl, -NR 8x R 8y , hydroxyl; R 8x and R 8y Each is independently H or C1-C3 alkyl; Y 1 N or CR d1 , Y 2 N or CR d2 , Y 3 N or CR d3 , Y 4 N or CR d4 ; R d1 , R d2 , R d3 , R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, -COOH, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ; i is 0, 1, or 2; R 12 and R 13 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C6 cycloalkoxy; R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B1, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B1; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group B1 include: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR B1x R B1y , cyano, hydroxyl, carboxyl, -CONH2; R B1x and R B1y Each is independently H or C1-C6 alkyl; The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

4. The compound represented by formula (V-1) according to claim 3, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof: in, R 1 , R 2 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, or C1-C3 alkyl; R 5 is hydrogen or C1-C3 alkyl; R 8 is hydrogen, deuterium, halogen, C1-C3 alkyl, -NR 8x R 8y , hydroxyl; R 8x and R 8y Each is independently H or C1-C3 alkyl; Y 1 N or CR d1 , Y 2 N or CR d2 , Y 3 N or CR d3 , Y 4 N or CR d4 ; R d1 , R d2 , R d3 , R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, -COOH, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ; i is 0, 1, or 2; R 12 and R 13 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C6 cycloalkoxy; R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B1, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B1; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group B1 include: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -NR B1x R B1y , cyano, hydroxyl, carboxyl, -CONH2; R B1x and R B1y Each is independently H or C1-C6 alkyl; The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

5. The compound of formula (V-1) according to claim 3, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (V-1) has a structure represented by formula (V-2): Among them, R 1 , R 2 , R 6 , R 7 , R 8 , R d1 , R d2 , R d3 and R d4 The definition is the same as that described in claim 3.

6. The compound of formula (V-1) according to claim 5, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 , R d3 and R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, -COOH, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ; i is 0, 1 or 2; R 12 and R 13 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C6 cycloalkoxy; R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B1, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B1; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group B1 include: deuterium, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy; The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

7. The compound of formula (V-1) according to claim 5, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 , R d3 and R d4 Each independently is -(CH2) i R 16 ; i is 0, 1, or 2; R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by C1-C6 alkyl, C3-C8 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, 3-10 membered heterocyclyl which is unsubstituted or substituted by C1-C6 alkyl, 5-10 membered heteroaryl which is unsubstituted or substituted by C1-C6 alkyl; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

8. The compound of formula (V-1) according to claim 3, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (V-1) has a structure represented by formula (V-3): Among them, R d1 , R d2 , R d3 and R d4 The definition is the same as that described in claim 3.

9. The compound of formula (V-1) according to claim 8, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 , R d3 and R d4 Each is independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C2-C6 alkenyl, C2-C6 alkynyl, -COOH, -CONH2, -(CH2) i S02R 12 、-(CH2) i P(O)R 12 R 13 、-CONR 17 R 14 、-NR 17 CO-R 14 、-NR 17 R 14 、-O(CH2) i R 15 、-(CH2) i R 16 ; i is 0, 1, or 2; R 12 and R 13 are independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C6 cycloalkoxy; R 17 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R 14 , R 15 and R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 14 , R 15 and R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by one or more substituents selected from Group B1, C3-C8 cycloalkyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 3-10 membered heterocyclyl which is unsubstituted or substituted by one or more substituents selected from Group B1, 5-10 membered heteroaryl which is unsubstituted or substituted by one or more substituents selected from Group B1; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The substituents of group B1 include: deuterium, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy; The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

10. The compound of formula (V-1) according to claim 8, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 , R d3 and R d4 Each independently is -(CH2) i R 16 ; i is 0, 1, or 2; R 16 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted 3-10 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted C6-C10 aryl; R 16 The substitution mentioned herein refers to substitution by one or more substituents selected from Group B; Substituents in Group B include: oxo, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkynyl, C4-C6 cycloalkoxy, -SCH3, -SO2CH3, -NR x R y 、-NR x COR y 、-CONR x R y , C6-C10 aryl which is unsubstituted or substituted by C1-C6 alkyl, C3-C8 cycloalkyl which is unsubstituted or substituted by C1-C6 alkyl, 3-10 membered heterocyclyl which is unsubstituted or substituted by C1-C6 alkyl, 5-10 membered heteroaryl which is unsubstituted or substituted by C1-C6 alkyl; R x and R y Each is independently H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; The heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

11. The compound of formula (V-1) according to claim 8, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 , R d3 and R d4 Each independently is C1-C6 alkyl, -NR x R y , C3-C6 cycloalkyl, halogen, C1-C6 alkyl substituted by one or more substituents selected from halogen, C3-C6 cycloalkyl, C2-C6 alkynyl; R x and R y Each is independently H or C1-C6 alkyl.

12. The compound of formula (V-1) according to claim 8, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 , R d3 and R d4 Each independently is C1-C6 alkyl, -NR x R y , C3-C6 cycloalkyl, or halogenated C1-C6 alkyl.

13. The compound of formula (V-1) according to claim 8, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 , R d3 and R d4 Each is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, halogen, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -N(CH3)2, 14. The compound of formula (V-1) according to claim 8, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 , R d3 and R d4 Each is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -N(CH3)2.

15. The compound of formula (V-1) according to claim 8, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R d1 , R d2 and R d4 is hydrogen; R d3 Methyl, ethyl, n-propyl, isopropyl, tert-butyl, halogen, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -N(CH3)2, 16. The compound of formula (V-1) according to claim 3, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (V-1) is selected from the following structures: Among them, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 and Y 4 The definition is the same as that described in claim 3.

17. The compound of formula (V-3) according to claim 8, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (V-3) is selected from the following structures: R d1 , R d2 , R d3 and R d4 The definition is the same as that described in claim 8.

18. The compound of formula (V-1) according to claim 3, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (V-1) is selected from the following compounds:

19. A pharmaceutical composition comprising a compound of formula (V-1) as described in any one of claims 1 to 18, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

20. A use of a compound as shown in formula (V-1) as described in any one of claims 1 to 18, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or a pharmaceutically acceptable salt thereof in the preparation of a WRN inhibitor or a drug; the drug is a drug for treating and / or preventing a disease by inhibiting WRN.

21. Use of a compound of formula (V-1) as described in any one of claims 1 to 18, its isotope-labeled substance, enantiomer, diastereomer, atropisomer, solvate, prodrug or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing cancer.

22. A method for treating and / or preventing cancer, characterized in that: The method comprises administering to the patient a therapeutically effective amount of a compound of formula (V-1) as described in any one of claims 1 to 18, its isotope label, enantiomer, diastereomer, atropisomer, solvate, prodrug or a pharmaceutically acceptable salt thereof.

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