Aryl heterocyclic SLC7A11 inhibitor as well as preparation method and application thereof

Abstract

The invention relates to an aryl heterocyclic SLC7A11 inhibitor and a preparation method and application thereof, and the novel SLC7A11 inhibitor can be used for preventing and / or treating diseases related to SLC7A11, such as pancreatic cancer, liver cancer, osteosarcoma, glioma and other tumors and chronic diseases such as fatty liver, liver cirrhosis, hepatic fibrosis, pulmonary fibrosis, diabetic skin injury and the like. Or amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to a SLC7A11 inhibitor and a preparation method and use thereof. The inhibitor and a pharmaceutical composition containing the same can be used to prevent and / or treat diseases or conditions related to SLC7A11. Background Art

[0002] System xC - It is a sodium-independent antiporter that releases intracellular glutamate and takes up extracellular cystine in a 1:1 ratio (Bannai S (1986) Exchange of cystine and glutamate across plasmamembrane of human fibroblasts. J Biol Chem 261: 2256-2263), performs glutathione biosynthesis and antioxidant defense, and is overexpressed in a variety of human cancers and associated with poor prognosis, such as pancreatic cancer, liver cancer, glioma, renal cancer, lung cancer, mesothelioma and uveal melanoma (Badgley MA, et al. Science. 2020. PMID: 32241947). It consists of two subunits connected by disulfide bonds, including the heavy chain subunit solute carrier family 3 member 2 (SLC3A2; also known as CD98 or 4F2hc) and the light chain subunit solute carrier family 7 member 11 (SLC7A11). Studies have shown that tumor cells promote tumor growth by inhibiting ferroptosis of tumor cells by overexpressing SLC7A11. Ferroptosis is a new form of regulated cell death that is iron-dependent and induced by excessive lipid peroxidation.

[0003] In 2020, the number of new cases of pancreatic ductal adenocarcinoma (PDAC) reached 420,000, and the number of deaths reached 410,000. It is estimated that by 2030, pancreatic cancer may become the second leading cause of death among malignant tumors. PDAC is a fatal cancer that is resistant to traditional therapies, with a 5-year survival rate of <9%. More than 90% of PDAC cases carry KRAS mutations, which both promote proliferation and alter cell metabolism. Mutant KRAS signaling leads to increased production of reactive oxygen species (ROS), which damage cellular components. To compensate, PDAC cells upregulate metabolic programs that use cysteine-derived metabolites (such as glutathione) to detoxify ROS (DeNicola GM et al., Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106-109 (2011). [PubMed: 21734707]). Most cellular cysteine ​​is obtained via the system xC-antiporter, which exchanges extracellular oxidized cysteine ​​(cystine) for intracellular glutamate. However, germline deletion of the system xC-gene SLC7A11 is well tolerated in unstressed mice (Sato Het al., Redox imbalance in cystine / glutamate transporter-deficient mice. J. Biol. Chem 280, 37423-37429 (2005). [PubMed: 16144837]), indicating that the basal cystine import requirement of normal cells is low.Studies have shown that SLC7A11 deletion via CRISPR-Cas9 has been shown to induce ferroptosis in cultured PDAC cells and slow the engraftment and growth of xenografts (Daher B et al., Genetic Ablation of the Cystine Transporter xCT in PDAC Cells Inhibits mTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses. Cancer Res. 79, 3877-3890 (2019). [PubMed: 31175120]), and systemic xC-inhibition has been shown to limit the growth of lymphoma xenografts, inducing lipid oxidation signatures and other indicators of ferroptosis (Zhang Y et al., Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model. Cell Chem. Biol 26,623-633e629(2019).[PubMed:30799221]).

[0004] Most pancreatic cancer patients are diagnosed at an advanced stage, and there is currently a lack of effective therapeutic drugs for pancreatic cancer patients. Most pancreatic cancer treatments, including standard treatment gemcitabine and novel molecular targeted therapies, have shown impressive activity against PDAC cells in culture and in some preclinical animal models, but have little clinical efficacy. The main reason for this poor prognosis is the drug-refractory nature of PDAC, which is caused by inherent chemoresistance and physical barriers to drug delivery. The dense fibrotic microenvironment drives these mechanisms. Fibrosis alters tumor vasculature, physically hinders drug access, and creates a harsh hypoxic and nutrient-deprived microenvironment, which promotes a more metastatic and chemoresistant mesenchymal phenotype. Pancreatic cancer has a defective vasculature that severely affects drug delivery. The architects of the pancreatic cancer microenvironment are cancer-associated fibroblasts (CAFs). On the one hand, CAFs are activated by hypoxia signals released by PDAC cells, leading to a self-perpetuating cycle of excessive extracellular matrix (ECM) protein deposition, thereby producing fibrosis; on the other hand, CAFs transmit pro-survival signals to PDAC cells, thereby promoting PDAC cell survival and epithelial-to-mesenchymal transition (DOI: 10.3389 / fphys.2014.00141; DOI: 10.1002 / ags3.12225; DOI: 10.1016 / j.trecan.2019.09.010).

[0005] Based on the above pathological characteristics of pancreatic cancer, it is necessary to target both pancreatic cancer cells and pancreatic cancer-associated fibroblasts to achieve good drug efficacy. Studies have confirmed that the high expression of SLC7A11 in the tumor stroma of clinical patients with PDAC has a poor independent prognosis and poor overall survival, rather than tumor cells. Knockdown of SLC7A11 in CAFs can inhibit its proliferation. Knockdown of SLC7A11 in CAFs significantly inhibits the viability of co-cultured cells of pancreatic cancer tumor cells and CAFs. Knockdown of SLC7A11 in pancreatic cancer cells has no significant effect on tumor growth. Knockdown of SLC7A11 in both PDAC cells and CAFs in clinical patients significantly inhibits tumor growth, metastasis and fibrosis. Studies have confirmed that cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine the response to SLC7A11 inhibition (Doi: 10.1158 / 0008-5472.CAN-20-2496). New drugs are urgently needed to improve patients' survival and quality of life. In addition, SLC7A11 is also associated with many types of diseases, such as tumors such as liver cancer, osteosarcoma, and glioma, chronic diseases such as fatty liver, cirrhosis, liver fibrosis, pulmonary fibrosis, diabetic skin damage, and neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Therefore, the development of highly active small molecule SLC7A11 inhibitors has significant social and market value. Summary of the invention

[0006] The inventors are committed to developing a novel SLC7A11 inhibitor, an aromatic heterocyclic compound, which can be used to prevent and / or treat diseases related to SLC7A11, such as pancreatic cancer, liver cancer, osteosarcoma, glioma and other tumors, as well as chronic diseases such as fatty liver, cirrhosis, liver fibrosis, pulmonary fibrosis, diabetic skin lesions, or neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.

[0007] The aromatic heterocyclic compound is a compound having a structure represented by formula (I) or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in,

[0010] X is selected from: N, CR 3 ;

[0011] Optionally, X is: CR 3 ;

[0012] Z 1 Independently selected from: C, N;

[0013] Z 2 Independently selected from: O, NR 6 , CR6 ;

[0014] Dashed lines indicate no chemical bonds or single bonds;

[0015] R 1 is selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl, alicyclic group optionally substituted by alkyl;

[0016] R 2 With R 3 Each is independently selected from: H, halogen, alkyl, cyano, haloalkyl, alkenyl, alkynyl, cycloalkyl, alicyclic group optionally substituted by alkyl, -N(R 6 )R 7 、-OR 8 、-C(O)N(R 9 )R 10 、-P(O)(R 9 )R 10 , -SO 2 R';

[0017] R 6 , R 7 Each is independently selected from: H, alkyl, haloalkyl, cycloalkyl, alicyclic optionally substituted by alkyl, alkanoyl, haloalkanoyl, cycloalkyl-aminoacyl, -SO 2 R', or 6 , R 7 They are connected to each other and to the N to which they are connected together to form an alicyclic group which is optionally substituted by an alkyl group;

[0018] R 8 Each is independently selected from: H, alkyl, haloalkyl, cycloalkyl, alicyclic group optionally substituted by alkyl, alkanoyl, haloalkanoyl, heteroaryl;

[0019] R 9 , R 10 Each is independently selected from: H, alkyl, haloalkyl, cycloalkyl, heterocyclic group optionally substituted by alkyl, or, when R 9 and R 10 When connected to the same N or -P(O), R 9 and R 10 It can also form an alicyclic group optionally substituted by an alkyl group together with the N or -P(O) to which it is commonly connected;

[0020] Each R' is independently selected from: alkyl, haloalkyl, cycloalkyl, alicyclic, amino, alkylamino, cycloalkyl-amino;

[0021] R 4Selected from: optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alicyclic group, wherein the substituent in the optionally substituted alkyl is selected from: halogen, cyano, hydroxyl, alkoxy;

[0022] R 5 Selected from -CF 3 , acetyl;

[0023] Optionally, R 5 Selected from or R 2 and R 5 Together with the benzene ring to which it is attached, it forms the following structure:

[0024] Each Ra is independently selected from alkyl, haloalkyl;

[0025] Optionally, R 5 Selected from

[0026] The substituents in the "alicyclic group optionally substituted by an alkyl group", "haloalkanoyl group", "haloalkyl group" and "optionally substituted alkyl group" are 1 or more, preferably 1, 2 or 3;

[0027] Optionally, the compound represented by formula (I) is in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture of these isomers.

[0028] Optionally, the halogen atoms in the "halogen", "haloalkyl" and "haloalkanoyl" are independently selected from F, Cl, Br and I;

[0029] Optionally, the alkyl groups in the “alkyl”, “haloalkyl”, “alkoxy”, “alkanoyl”, “haloalkanoyl” and “heterocyclic group optionally substituted by alkyl” are each independently C 1 -C 10 Straight or branched chain alkyl; optionally, C 1 -C 7 Straight or branched chain alkyl; optionally, C 1 -C 5a linear or branched alkyl group; optionally, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl or 2,2,3-trimethylbutyl;

[0030] Optionally, the "alkenyl" is a C 2 -C 15 Straight or branched alkenyl, optionally C 2 -C 10 Straight or branched alkenyl, optionally C 2 -C 8 Straight or branched alkenyl, optionally C 2 -C 6 Straight or branched alkenyl, optionally C 2 -C 4 Straight or branched alkenyl, optionally selected from ethenyl, propenyl, butenyl, pentenyl;

[0031] Optionally, the "alkynyl" group contains one or more triple bonds. 2 -C 15 A straight chain or branched alkynyl group, optionally, is C 2 -C 10 A straight chain or branched alkynyl group, optionally, is C 2 -C 8 A straight chain or branched alkynyl group, optionally, is C 2 -C 6 A straight chain or branched alkynyl group, optionally, is C 2 -C 4 Straight or branched alkynyl; optionally, selected from ethynyl, propynyl, hexynyl;

[0032] Optionally, the cycloalkyl group in the "cycloalkyl group", "cycloalkyl-aminoacyl group" and "cycloalkyl-amino group" is C 3 -C 10 Monocyclic or bicyclic cycloalkyl, optionally, C 3 -C 7 Monocyclic cycloalkyl, optionally, is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

[0033] Optionally, the alicyclic group in the "alicyclic group", "alicyclic group optionally substituted by an alkyl group" and "alicyclic group-amino" is a 3-10-membered non-aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; optionally, the alicyclic group is a 3-10-membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and O on the ring; optionally, the alicyclic group is a 3-6-membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and O on the ring; optionally, the alicyclic group is a 3-10-membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and S on the ring; optionally, the alicyclic group is a 3-10-membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and S on the ring; The heterocycle is a 3-6 membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and S on the ring; optionally, the heterocyclic group in the "heterocyclic group", "heterocyclic group optionally substituted by alkyl" and "heterocyclic group-amino" is selected from methyl-substituted azetidinyl, methyl-substituted azetidinyl, methyl-substituted azetidinyl, methyl-substituted azetidinyl, azetidinyl, azetidinyl, oxolanyl, oxolanyl, azetidinyl, piperidinyl, piperazinyl, alkenylpiperidine; optionally, the heterocyclic group in the "heterocyclic group", "heterocyclic group optionally substituted by alkyl" and "heterocyclic group-amino" is selected from methyl-substituted azetidinyl, ...

[0034] Optionally, the heteroaromatic ring of the "heteroaryl" is a 5-10 membered heteroaromatic ring containing 1-2 heteroatoms selected from N and O on the ring; optionally, the heteroaryl is selected from pyridyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolyl, quinazolinyl; optionally, the heteroaryl is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl.

[0035] Optionally, the compound represented by the above formula (I) or its deuterated product, or a pharmaceutically acceptable salt thereof, is selected from the following compounds:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044] On the other hand, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, characterized in that the method comprises the following reaction scheme:

[0045] Compound I-1 was prepared using the following method I:

[0046]

[0047] In various types, R 1 , R 2 , R 3 , R 4 , R 5 The groups are as defined in formula (I).

[0048] The synthesis reaction of Ib can be carried out in the presence of a reaction reagent, an activator, and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the activator can be selected from, but not limited to, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, etc.; the base can be selected from, but not limited to, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, etc.

[0049] The synthesis reaction of Id can be carried out in the presence of a reaction reagent, a catalyst, and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the catalyst can be selected from, but not limited to, sodium iodide, potassium iodide, etc.; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0050] The synthesis reaction of I-1 can be carried out in the presence of a reaction reagent and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, or any mixture thereof; the base can be selected from, but not limited to, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, or the like.

[0051] Alternatively, the following method II is used to synthesize compound I-1:

[0052]

[0053] In various types, R1 , R 2 , R 3 , R 4 , R 5 The groups are as defined in formula (I).

[0054] The synthesis reaction of Ib can be carried out in the presence of a reaction reagent, an activator, and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the activator can be selected from, but not limited to, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, etc.; the base can be selected from, but not limited to, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, etc.

[0055] The synthesis reaction of II-a can be carried out in a solvent in the presence of a reaction reagent, a catalyst, and a base. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the catalyst can be selected from, but not limited to, sodium iodide, potassium iodide, etc.; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0056] The synthesis reaction of II-b can be carried out in the presence of a reaction reagent, an acid or a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc. or any mixture thereof; the acid can be selected from, but not limited to, hydrochloric acid, trifluoroacetic acid, acetic acid, boric acid, sulfuric acid, etc.; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0057] The synthesis reaction of I-1 can be carried out in the presence of a reaction reagent and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, or any mixture thereof; the base can be selected from, but not limited to, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, or the like.

[0058] Or use the following method III to synthesize compound III-1:

[0059]

[0060] In various types, R 1 , R 2 , R 3 , R 4 , R 5 The groups are as defined in formula (I).

[0061] The synthesis reaction of III-c can be carried out in the presence of a reaction reagent, a condensation reagent, an activation reagent and a base in a solvent. The solvent can be selected from but not limited to tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc. or any mixture thereof; the condensation reagent can be selected from but not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, carbonyldiimidazole, etc.; the activation reagent can be selected from but not limited to 1-hydroxy-7-azabenzotriazole, etc.; the base can be selected from but not limited to N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, etc.

[0062] The synthesis reaction of III-d can be carried out in the presence of a reaction reagent, a catalyst, and a base in a solvent for coupling reaction. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, ethanol, DME, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the catalyst can be selected from, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, methanesulfonic acid (2-dicyclohexylphosphine) The base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, etc.

[0063] The synthesis reaction of III-e can be carried out in the presence of a reaction reagent, a catalyst, and an activator in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, ethanol, DME, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the catalyst can be selected from, but not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonic acid(2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine gold chloride, etc.; the activator can be selected from but not limited to silver hexafluoroantimonate, silver tetrafluoroborate, etc.

[0064] The synthesis reaction of III-f can be carried out in the presence of a reaction reagent and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, or any mixture thereof; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, or the like.

[0065] The synthesis reaction of III-g can be carried out in a solvent in the presence of a reaction reagent, a catalyst, and a base. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the catalyst can be selected from, but not limited to, sodium iodide, potassium iodide, etc.; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0066] The synthesis reaction of III-h and III-h-1 can be carried out in a solvent in the presence of a reaction reagent, an acid or a base. The solvent can be selected from but not limited to tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc. or any mixture thereof; the acid can be selected from but not limited to hydrochloric acid, trifluoroacetic acid, acetic acid, boric acid, sulfuric acid, etc.; the base can be selected from but not limited to potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0067] The synthesis reaction of III-1 and III-1-bp can be carried out in a solvent in the presence of a reaction reagent and a base. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the base can be selected from, but not limited to, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, etc.

[0068] Alternatively, the following method IV is used to synthesize compound III-1:

[0069]

[0070] In various types, R 1 , R 2 , R 3 , R 4 , R 5 The groups are as defined in formula (I).

[0071] The synthesis reaction of IV-b can be carried out in the presence of a reaction reagent and an acid in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, or any mixture thereof; the acid can be selected from, but not limited to, hydrochloric acid, trifluoroacetic acid, acetic acid, boric acid, sulfuric acid, aluminum chloride, ferric chloride, or the like.

[0072] The synthesis reaction of IV-c can be carried out in the presence of a reaction reagent and an oxidant in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, or any mixture thereof; the oxidant can be selected from, but not limited to, tin dioxide, manganese dioxide, sodium hypochlorite, or the like.

[0073] The synthesis reaction of IV-d can be carried out in the presence of a reaction reagent and a reducing agent in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, methanol, water, etc., or any mixture thereof; the reducing agent can be selected from, but not limited to, sodium borohydride, lithium borohydride, platinum dioxide, etc.

[0074] The synthesis reaction of IV-e can be carried out in the presence of a reaction reagent and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, or any mixture thereof; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, or the like.

[0075] The synthesis reaction of IV-f can be carried out in the presence of a reaction reagent, a catalyst, and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the catalyst can be selected from, but not limited to, sodium iodide, potassium iodide, etc.; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0076] The synthesis reaction of IV-g can be carried out in the presence of a reaction reagent, an acid or a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc. or any mixture thereof; the acid can be selected from, but not limited to, hydrochloric acid, trifluoroacetic acid, acetic acid, boric acid, sulfuric acid, etc.; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0077] The synthesis reaction of III-1 can be carried out in the presence of a reaction reagent and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the base can be selected from, but not limited to, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, etc.

[0078] Compound IV-1 was prepared using the following method V:

[0079]

[0080] In various types, R 1 , R 2 , R 3 , R 4 , R 5 The groups are as defined in formula (I).

[0081] The synthesis reaction of Vb can be carried out in the presence of a reaction reagent, an activator, and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the activator can be selected from, but not limited to, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, etc.; the base can be selected from, but not limited to, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, etc.

[0082] The synthesis reaction of Vc can be carried out in the presence of a reaction reagent, a catalyst, and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc., or any mixture thereof; the catalyst can be selected from, but not limited to, sodium iodide, potassium iodide, etc.; the base can be selected from, but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0083] The synthesis reaction of Vd can be carried out in the presence of a reaction reagent, an acid or a base in a solvent. The solvent can be selected from but not limited to tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, etc. or any mixture thereof; the acid can be selected from but not limited to hydrochloric acid, trifluoroacetic acid, acetic acid, boric acid, sulfuric acid, etc.; the base can be selected from but not limited to potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, etc.

[0084] The synthesis reaction of IV-1 can be carried out in the presence of a reaction reagent and a base in a solvent. The solvent can be selected from, but not limited to, tetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, water, or any mixture thereof; the base can be selected from, but not limited to, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, pyridine, or the like.

[0085] Optionally, the compound of formula (I) or its deuterated product, or a pharmaceutically acceptable salt thereof, includes anionic salts and cationic salts of the compound of formula (I) or its deuterated product;

[0086] Optionally, the pharmaceutically acceptable salt includes an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound represented by formula (I) or its deuterated product; optionally, the alkali metal includes sodium, potassium, lithium, and cesium, and the alkaline earth metal includes magnesium, calcium, and strontium;

[0087] Optionally, the pharmaceutically acceptable salt includes a salt formed by the compound represented by formula (I) or its deuterated product and an organic base;

[0088] Optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5, 1,8-diazabicyclo[5.4.0]undecene-7, 1,4-diazabicyclo[2.2.2]octane; Optionally, the trialkylamine includes trimethylamine, triethylamine, N-ethyldiisopropylamine; Optionally, the N-alkylmorpholine includes N-methylmorpholine;

[0089] Optionally, the pharmaceutically acceptable salt includes a salt formed by the compound represented by formula (I) or its deuterated product and an acid;

[0090] Optionally, the acid includes an inorganic acid and an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, and pamoic acid.

[0091] Another aspect of the present invention provides a pharmaceutical composition, which comprises the compound represented by the above formula (I) or its deuterated product, or their pharmaceutically acceptable salts, and pharmaceutical excipients.

[0092] The pharmaceutical excipients are conventionally selected in the pharmaceutical field, and the present invention has no particular limitation thereto.

[0093] In another aspect, the present invention provides the use of the compound represented by the above formula (I) or its deuterated product, or their pharmaceutically acceptable salts, or the above pharmaceutical composition in the preparation of SLC7A11 inhibitors.

[0094] Another aspect of the present invention provides the use of the compound represented by the above formula (I), its pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of drugs for treating tumor diseases such as pancreatic cancer, liver cancer, osteosarcoma, glioma, etc.

[0095] In another aspect, the present invention provides the use of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a drug for treating chronic diseases such as fatty liver, cirrhosis, liver fibrosis, pulmonary fibrosis, diabetic skin lesions, or neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.

[0096] Beneficial effects of the present invention:

[0097] The compounds obtained by the present invention can effectively inhibit the activity of SLC7A11 and can be used to prevent and / or treat diseases related to SLC7A11. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1 The compounds (including compound 186, compound 199 / 200, compound 184 / 185) promote the efferocytosis of BMDC cells. DETAILED DESCRIPTION

[0099] The present invention is further described by the following examples. It should be understood that the examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0100] Example 1

[0101]

[0102] Synthesis of 1-fluoro-5-isopropoxy-4-nitro-2-(trifluoromethyl)benzene:

[0103]

[0104] Sodium metal (66 mg, 2.89 mmol) was added to isopropanol (10 mL), and the mixture was heated at 80 ° C for 2 hours. The mixture was added dropwise to a solution of 1,5-difluoro-2-nitro-4-(trifluoromethyl)benzene (600 mg, 2.63 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, the residue was diluted with ethyl acetate (30 mL), and washed with saturated brine (30 mL). Drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure gave a yellow oily crude product 1-3 (650 mg, 88%)

[0105] LC-MS: [M+H] + :No MS.

[0106] 1 H NMR: (400MHz, CDCl 3 )δ8.16(d,J=7.6Hz,1H),6.87(d,J=12.0Hz,1H),4.72-4.66(m,1H),1.44(d,J=6.0Hz,6H).

[0107] Synthesis of 4-fluoro-2-isopropoxy-5-(trifluoromethyl)aniline:

[0108]

[0109] 20% palladium hydroxide / carbon (68 mg, 0.48 mmol) was added to a solution of 1-fluoro-5-isopropoxy-4-nitro-2-(trifluoromethyl)benzene 1-3 (650 mg, 2.42 mmol) in methanol (20 mL), and the mixture was hydrogenated with a hydrogen balloon for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a black oily crude product 1-4 (550 mg, 93%).

[0110] LC-MS: [M+H] + :238.1.

[0111] Synthesis of 2-(chloromethyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one:

[0112]

[0113] To a solution of 2-(2-chloroacetamide)benzoic acid 1-5 (90 mg, 0.42 mmol, doi.org / 10.1016 / j.bmcl.2011.05.031) in acetonitrile (10 mL) were added N,N-diisopropylethylamine (54 mg, 0.42 mmol) and phosphorus trichloride (116 mg, 0.84 mmol), and the mixture was stirred at room temperature for 10 minutes. Then a solution of 4-fluoro-2-isopropoxy-5-(trifluoromethyl)aniline 1-4 (100 mg, 0.42 mmol) in acetonitrile (0.5 mL) was added, and the mixture was stirred at 70 ° C for 5 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (60 mL) and washed with saturated brine (30 mL×2). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 2) to give a white solid product 1-6 (160 mg, 87%)

[0114] LC-MS: [M+H] + :415.1.

[0115] Synthesis of (S)-4-((3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester:

[0116]

[0117] A mixture of 2-(chloromethyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazoline-4(3H)-one 1-6 (100 mg, 0.24 mmol), (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 1-7 (48 mg, 0.24 mmol), potassium carbonate (50 mg, 0.36 mmol) and potassium iodide (40 mg, 0.24 mmol) in acetonitrile (20 mL) was heated at 80 ° C for 16 hours. The mixture was concentrated in vacuo, the residue was diluted with ethyl acetate (30 mL), and washed with saturated brine (20 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 3) to give a yellow solid product 1-8 (100 mg, 68%).

[0118] LC-MS: [M+H] + :579.3.

[0119] Synthesis of (S)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-2-((2-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one:

[0120]

[0121] To a solution of (S)-tert-butyl 4-((3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-3-methylpiperazine-1-carboxylate 1-8 (100 mg, 0.17 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give a yellow oily crude product 1-9 (80 mg, 92%).

[0122] LC-MS: [M+H] + :479.2.

[0123] Synthesis of (S)-2-((4-(2-(4-chlorophenoxy)acetyl)-2-methylpiperazin-1-yl)methyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one:

[0124]

[0125] To a solution of (S)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-2-((2-methylpiperazine-1-yl)methyl)quinazoline-4(3H)-one 1-9 (80 mg, 0.17 mmol) and N,N-diisopropylethylamine (64.7 mg, 0.50 mmol) in dichloromethane (10 mL) was added 2-(4-chlorophenoxy)acetyl chloride (41 mg, 0.20 mmol) at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (50 mL) and washed with saturated brine (30 mL×2). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative high performance chromatography (acetonitrile-water 0.1% formic acid, gradient 40%-80%) to give compound 136 (60 mg, 82%) of Example 1 as a white solid product.

[0126] LC-MS: [M+H] + :647.3.

[0127] 1 H NMR: (400MHz, CD 3 OD)δ8.13(d,J=7.2Hz,1H),7.82 -7.73(m,2H),7.65(d,J=8.0Hz,1H),7.50(t,J=7.6Hz,1H),7.22 -7.13(m,3H),6.84-6.81(m,2H),4.70-4.59(m,3H),3.76-3.64(m,2H),3.47 -3.29(m,2H),3.10-3.05(m,1H),2.94-2.79(m,1H),2.62-2.53(m,1H),2.30- 2.10(m,2H),1.15(d,J=6.0Hz,3H),1.10(d,J=6.0Hz,3H),0.68-0.60(m,3H).

[0128] Example 2 / 3

[0129]

[0130] Compound 136 (50 mg) of Example 1 was chiral separated by SFC (chromatographic column: CHIRALPAK WHELK-O 1250 mm×21.1 mm, 5 μm, mobile phase: carbon dioxide-ethanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (21.1mg, 23mg)

[0131] Single configuration compound (short retention time)

[0132] It was analyzed by chiral analysis chromatography conditions, RT = 8.88min

[0133] LC-MS: [M+H] + :647.2.

[0134] HPLC: 96.63% [214nm].

[0135] 1 H NMR: (400MHz, CD 3 OD)δ8.13(d,J=7.2Hz,1H),7.82 -7.73(m,2H),7.65(d,J=8.0Hz,1H),7.50(t,J=7.6Hz,1H),7.22 -7.13(m,3H),6.84-6.81(m,2H),4.70-4.59(m,3H),3.76-3.64(m,2H),3.47 -3.29(m,2H),3.10-3.05(m,1H),2.94-2.79(m,1H),2.62-2.53(m,1H),2.30- 2.10(m,2H),1.15(d,J=6.0Hz,3H),1.10(d,J=6.0Hz,3H),0.68-0.60(m,3H).

[0136] Single configuration compound (longer retention time)

[0137] It was analyzed by chiral analysis chromatography conditions, RT = 10.33min

[0138] LC-MS: [M+H] + :647.1.

[0139] HPLC: 98.34% [214nm].

[0140] 1 H NMR: (400MHz, CD 3OD)δ8.13(d,J=7.2Hz,1H),7.82 -7.73(m,2H),7.65(d,J=8.0Hz,1H),7.50(t,J=7.6Hz,1H),7.22 -7.13(m,3H),6.84-6.81(m,2H),4.70-4.59(m,3H),3.76-3.64(m,2H),3.47 -3.29(m,2H),3.10-3.05(m,1H),2.94-2.79(m,1H),2.62-2.53(m,1H),2.30- 2.10(m,2H),1.15(d,J=6.0Hz,3H),1.10(d,J=6.0Hz,3H),0.68-0.60(m,3H).

[0141] Example 4

[0142]

[0143] Synthesis of 1-cyclopropyloxy-2-nitro-4-(trifluoromethyl)benzene:

[0144]

[0145] Potassium carbonate (187.0 mg, 0.57 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene 4-1 (100.0 mg, 0.48 mmol) in N,N-dimethylformamide (10 mL), stirred for 15 minutes, and then cyclopropanol 4-2 (27.8 mg, 0.48 mmol) was added, and the mixture was stirred at 70 ° C for 16 hours. After dilution with water (30 mL), it was extracted with ethyl acetate (30 mL x 3), and the combined organic layer was washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 1) to give the product 4-3 (70 mg, 57%) as a white solid.

[0146] 1 H NMR: (400MHz, DMSO-d 6 )δ8.31(d,J=2.0Hz,1H),8.09(dd,J=8.9,2.1Hz,1H),7.83(d,J=8.8Hz,1H),4.22(dt,J=9.0,3.0Hz,1H),0.92 -0.88(m,2H),0.80 -0.76(m,2H).

[0147] Synthesis of 2-cyclopropyloxy-5-(trifluoromethyl)aniline:

[0148]

[0149] Saturated aqueous ammonium chloride solution (1 mL) and iron powder (45 mg, 0.80 mmol) were added to a solution of 1-cyclopropyloxy-2-nitro-4-(trifluoromethyl)benzene 4-3 (50 mg, 0.20 mmol) in ethanol (20 mL), and the mixture was reacted at 80 ° C for 16 hours. Then the mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with saturated brine (20 mL) and extracted with ethyl acetate (30 mL x 3), the combined organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the filtrate was dried under vacuum to obtain a white solid product 4-4 (45 mg crude).

[0150] LC-MS: [M+H] + :218.1.

[0151] According to steps 3, 4, 5 and 6 in Example 1, replacing raw material 1-4 with 4-4 can obtain Example 4 (S)-2-((4-(2-(4-chlorophenoxy)acetyl)-2-methylpiperazin-1-yl)methyl)-3-(2-cyclopropyloxy-5-(trifluoromethyl)phenyl)quinazoline-4(3H)-one (39.5 mg).

[0152] LC-MS: [M+H]+: 627.0.

[0153] HPLC: 99.37%.

[0154] 1 H NMR: (400MHz, CD3OD) δ8.24 (d, J=8.0Hz, 1H), 7.93-7.84 (m, 3H), 7.77-7.74 (m, 2H),7.61(t,J=7.6Hz,1H),7.30-7.25(m,2H),6.95-6.92(m,2H),4.80-4.71(m ,2H),4.03-3.91(m,2H),3.62-3.51(m,2H),3.25-3.20(m,1H),3.05-2.97(m,1 H),2.81-2.69(m,2H),2.28-2.20(m,2H),0.87-0.81(m,2H),0.69-0.56(m,5H).

[0155] Example 5 / 6

[0156]

[0157] Compound 3 (37.5 mg) of Example 4 was chiral separated by SFC (chromatographic column: CHIRALPAK OJ-H 250 mm20 mm, 5 μm mobile phase: carbon dioxide-methanol (NH 4OH 0.2%) gradient: 0~40%) to obtain the title compound (13.1mg, 14.1mg)

[0158] Single configuration compound (short retention time)

[0159] It was analyzed by chiral analysis chromatography conditions, RT = 2.19min

[0160] LC-MS: [M+H]+: 627.0.

[0161] HPLC: 100%.

[0162] 1 H NMR: (400MHz, CD3OD) δ8.24 (d, J=8.0Hz, 1H), 7.93-7.84 (m, 3H), 7.77-7.74 (m, 2H),7.61(t,J=7.6Hz,1H),7.30-7.25(m,2H),6.95-6.92(m,2H),4.80-4.71(m ,2H),4.03-3.91(m,2H),3.62-3.51(m,2H),3.25-3.20(m,1H),3.05-2.97(m,1 H),2.81-2.69(m,2H),2.28-2.20(m,2H),0.87-0.81(m,2H),0.69-0.56(m,5H).

[0163] Single configuration compound (longer retention time)

[0164] It was analyzed by chiral analysis chromatography conditions, RT = 2.54min

[0165] LC-MS: [M+H]+: 627.0.

[0166] HPLC: 100%.

[0167] 1 H NMR: (400MHz, CD3OD) δ8.24 (d, J=8.0Hz, 1H), 7.93-7.84 (m, 3H), 7.77-7.74 (m, 2H),7.61(t,J=7.6Hz,1H),7.30-7.25(m,2H),6.95-6.92(m,2H),4.80-4.71(m ,2H),4.03-3.91(m,2H),3.62-3.51(m,2H),3.25-3.20(m,1H),3.05-2.97(m,1 H),2.81-2.69(m,2H),2.28-2.20(m,2H),0.87-0.81(m,2H),0.69-0.56(m,5H).

[0168] Example 7

[0169]

[0170] Referring to Example 1, by replacing 1-7 with 7-1, (S)-2-((4-(2-(4-chlorophenoxy)acetyl)-2-ethylpiperazin-1-yl)methyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one compound 139 (55.8 mg, 34.9%) can be obtained.

[0171] LC-MS: [M+H]+: 661.2.

[0172] HPLC: 99.2%

[0173] 1 HNMR(400MHz,CD3OD)δ8.20(d,J=8.0Hz,1H),7.90-7.79(m,2H),7.74-7.72(m,1H),7 .55(t,J=7.6Hz,1H),7.31-7.19(m,3H),6.93-6.86(m,2H),4.82-4.63(m,3H),3.80-3 .31(m,4H),3.24-2.91(m,2H),2.76-2.56(m,1H),2.43-1.90(m,2H),1.43-1.25(m,1H ),1.23(d,J=6.0Hz,3H),1.17(d,J=6.0Hz,3H),1.05-0.81(m,1H),0.78-0.68(m,3H).

[0174] Example 8

[0175]

[0176] Referring to Example 1, by replacing 1-7 with 8-1, (S)-2-((4-(2-(4-chlorophenoxy)acetyl)-2-isopropylpiperazin-1-yl)methyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one compound 141 (52.8 mg, 30.5%) can be obtained.

[0177] LC-MS: [M+H] + :675.3.

[0178] HPLC: 99.8%

[0179] 1 HNMR (400MHz, CD 3OD)δ8.19(d,J=8.0Hz,1H),7.70 -7.52(m,4H),7.33 -7.18(m,3H),6.94 -6.88(m,2H),4.82 -4.62(m,3H),4.18-4.00(m,1H),3.88

[0180] -3.60(m,2H),3.45-3.31(m,2H),3.19 -2.18(m,5H),2.02 -1.74(m,1H),1.25(d,J=6.0Hz,3H),1.16(d,J=6.0Hz,3H),0.87 -0.82(m,2H),0.74(d,J=6.8Hz,1H),0.65-0.60(m,1H),0.45(t,J=6.8Hz,2H).

[0181] Example 9

[0182]

[0183] Referring to Example 1, by replacing 1-7 with 9-1, 2-((4-(2-(4-chlorophenoxy)acetyl)-2-cyclopropylpiperazin-1-yl)methyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one, compound 142 (35.1 mg, 29.0%) can be obtained.

[0184] LC-MS: [M+H]+: 673.3.

[0185] HPLC: 98.5%

[0186] 1 H NMR(400MHz,CD3OD)δ8.03(d,J=7.8Hz,1H),7.73-7.64(m,2H),7.58-7.50(m,1H),7.43-7.36(m ,1H),7.12-7.02(m,3H),6.71(dd,J=8.8Hz,2.0Hz,2H),4.61-4.47(m,3H),4.34-4.31(m,1H),4. 14-3.78(m,2H),3.53-3.46(m,1H),3.05-2.62(m,3H),2.06-1.96(m,1H),1.57-1.21(m,1H),1.0 9-1.04(m,3H),1.04-0.95(m,3H),0.78(t,J=7.4Hz,1H),0.39-0.11(m,2H),0.05--0.21(m,2H).

[0187] Example 10

[0188]

[0189] Synthesis of 3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one:

[0190]

[0191] A mixture of 2-(chloromethyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one 1-6 (90 mg, 0.22 mmol) and piperazine 10-1 (81 mg, 0.43 mmol) in tetrahydrofuran (20 mL) was heated at 70° C. for 16 hours. The mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate (30 mL) and washed with saturated brine (20 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid product 10-2 (100 mg).

[0192] LC-MS: [M+H] + :465.2.

[0193] Synthesis of (2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one:

[0194]

[0195] 2-(4-chlorophenoxy)acetyl chloride 1-10 (41 mg, 0.20 mmol) was added to a solution of 3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-2-(piperazine-1-ylmethyl)quinazoline-4(3H)-one 10-2 (100 mg, 0.22 mmol) and N,N-diisopropylethylamine (111.1 mg, 0.86 mmol) in dichloromethane (10 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (50 mL) and washed with saturated brine (30 mL×2). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative high performance chromatography (acetonitrile-water 0.1% formic acid, gradient 40%-80%) to give a white solid product compound 14 (115 mg, 84.56%).

[0196] LC-MS: [M+H] + :633.1.

[0197] HPLC: 98.63% [214nm].

[0198] 1 H NMR: (400MHz, CD3OD) δ8.26(dd,J=8.0,1.2Hz,1H),7.96-7.88(m,2H),7.81(d,J=8.0Hz,1H),7.63(t,J=7.2Hz,1H),7.23-7.12( m,3H),6.98-6.91(m,2H),4.84-4.75(m,3H),3.36-3.20(m,6H),2.53-2.30(m,4H),1.27(d,J=6.0Hz,3H),1.21(d,J=6.0Hz,3H).

[0199] Example 11 / 12

[0200]

[0201] Compound 14 (81 mg) was chiral separated by SFC (chromatographic column: CHIRALPAK AD-H250mm 20mm, 5μm mobile phase: carbon dioxide-isopropanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (36mg, 40mg)

[0202] Single configuration compound (short retention time)

[0203] It was analyzed by chiral analysis chromatography conditions, RT = 2.04min

[0204] LC-MS: [M+H] + :633.2.

[0205] HPLC: 98.71% [214nm].

[0206] 1 H NMR: (400MHz, CD3OD) δ8.26(dd,J=8.0,1.2Hz,1H),7.96-7.88(m,2H),7.81(d,J=8.0Hz,1H),7.63(t,J=7.2Hz,1H),7.23-7.12( m,3H),6.98-6.91(m,2H),4.84-4.75(m,3H),3.36-3.20(m,6H),2.53-2.30(m,4H),1.27(d,J=6.0Hz,3H),1.21(d,J=6.0Hz,3H).

[0207] Single configuration compound (longer retention time)

[0208] It was analyzed by chiral analysis chromatography conditions, RT = 2.93min

[0209] LC-MS: [M+H] + :633.1.

[0210] HPLC: 99.44% [214nm].

[0211] 1 H NMR: (400MHz, CD3OD) δ8.26(dd,J=8.0,1.2Hz,1H),7.96-7.88(m,2H),7.81(d,J=8.0Hz,1H),7.63(t,J=7.2Hz,1H),7.23-7.12( m,3H),6.98-6.91(m,2H),4.84-4.75(m,3H),3.36-3.20(m,6H),2.53-2.30(m,4H),1.27(d,J=6.0Hz,3H),1.21(d,J=6.0Hz,3H).

[0212] Embodiment 13

[0213]

[0214] Synthesis of 2-bromo-6-isopropoxy-3-(trifluoromethyl)aniline:

[0215]

[0216] To a solution of 2-isopropoxy-5-(trifluoromethyl)aniline 13-1 (500 mg, 2.28 mmol) in carbon tetrachloride (20 mL) at -10 ° C, N-bromosuccinimide (406 mg, 2.28 mmol) was slowly added, and the mixture was stirred at 0 ° C for 2 hours. The mixture was quenched with aqueous sodium sulfite solution (20 mL) and then extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 5) to give a yellow oily product 13-2 (550 mg, 73%).

[0217] LC-MS: [M+H] + :298.0,300.0.

[0218] 1 H NMR: (400MHz, CDCl 3 )δ7.04(d,J=8.8Hz,1H),6.71(d,J=8.8Hz,1H),4.65-4.58(m,1H),1.38(d,J=6.0Hz,6H).

[0219] Synthesis of 6-isopropoxy-2-methyl-3-(trifluoromethyl)aniline:

[0220]

[0221] 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (55 mg, 0.067 mmol) was added to a solution of 2-bromo-6-isopropoxy-3-(trifluoromethyl)aniline 13-2 (200 mg, 0.67 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trimethoxytriborane 13-3 (168 mg, 1.34 mmol) and potassium carbonate (185 mg, 1.34 mmol) in N,N-dimethylformamide (20 mL), and the mixture was heated at 110 ° C for 16 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 6) to give a white solid product 13-4 (110 mg, 67%).

[0222] LC-MS: [M+H] + :234.2.

[0223] 1 H NMR: (400MHz, CDCl 3 )δ7.17(d,J=8.8Hz,1H),6.72(d,J=8.8Hz,1H),4.67-4.61(m,1H),2.38(s,3H),1.39(d,J=6.0Hz,6H).

[0224] Referring to step 3 in Example 1 and step 1 and step 2 in Example 10, replacing 1-4 with 13-4 can give 2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(6-isopropoxy-2-methyl-3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one, compound 75 (90 mg, 57%).

[0225] LC-MS: [M+H] + :629.2.

[0226] HPLC: 95.37% [214nm].

[0227] 1 H NMR: (400MHz, DMSO-d 6)δ8.16(dd,J=8.0,1.2Hz,1H),7.93-7.88(m,1H),7.79(dd,J=12.4,8.4H z,2H),7.64-7.58(m,1H),7.33-7.25(m,3H),6.92-6.87(m,2H),4.82-4.7 2(m,3H),3.29-3.18(m,4H),3.15(d,J=6.4Hz,2H),2.46-2.32(m,2H),2.2 0(s,3H),1.92-1.81(s,2H),1.16(d,J=6.0Hz,3H),1.06(d,J=6.0Hz,3H).

[0228] Example 14 / 15

[0229]

[0230] Compound 75 (80 mg) was chiral separated by SFC (chromatographic column: AD-H 250 mm×20 mm, 5 μm, mobile phase: carbon dioxide-ethanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (23.5mg, 24.1mg)

[0231] Single configuration compound (short retention time)

[0232] It was analyzed by chiral analysis chromatography conditions, RT = 2.52min

[0233] LC-MS: [M+H] + :629.3.

[0234] HPLC: 96.41% [214nm].

[0235] 1 H NMR: (400MHz, DMSO-d 6 )δ8.16(d,J=7.6Hz,1H),7.91(t,J=7.6Hz,2H),7.79(dd,J=12.4,8.4Hz,2 H),7.60(t,J=7.6Hz,1H),7.31-7.25(m,3H),6.90(d,J=8.8Hz,2H),4.81-4 .73(m,3H),3.27-3.15(m,4H),3.15(d,J=6.0Hz,2H),2.42-2.34(m,2H),2. 20(s,3H),1.91-1.80(m,2H),1.16(d,J=6.0Hz,3H),1.07(d,J=6.0Hz,3H).

[0236] Single configuration compound (longer retention time)

[0237] It was analyzed by chiral analysis chromatography conditions, RT = 3.00min

[0238] LC-MS: [M+H] + :629.3.

[0239] HPLC: 99.03% [214nm].

[0240] 1 H NMR: (400MHz, DMSO-d 6 )δ8.16(d,J=7.6Hz,1H),7.91(t,J=7.6Hz,1H),7.79(dd,J=12.4,8.8Hz,2 H),7.60(t,J=7.6Hz,1H),7.31-7.26(m,3H),6.90(d,J=8.8Hz,2H),4.84-4 .71(m,3H),3.28-3.16(m,4H),3.15(d,J=6.0Hz,2H),2.44-2.33(m,2H),2. 20(s,3H),1.92-1.80(m,2H),1.16(d,J=6.0Hz,3H),1.07(d,J=6.0Hz,3H).

[0241] Example 16

[0242]

[0243] Synthesis of 6-isopropoxy-2-(prop-1-en-2-yl)-3-(trifluoromethyl)aniline:

[0244]

[0245] 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (37 mg, 0.05 mmol) was added to a solution of 2-bromo-6-isopropoxy-3-(trifluoromethyl)aniline 13-2 (150 mg, 0.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane 14-1 (101 mg, 0.6 mmol) and sodium carbonate (107 mg, 1 mmol) in dioxane (15 mL) and water (3 mL), and the mixture was heated at 80 ° C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 8) to give a yellow oily product 14-2 (100 mg, 72.8%).

[0246] LC-MS: [M+H] + :260.1.

[0247] Synthesis of 6-isopropoxy-2-isopropyl-3-(trifluoromethyl)aniline:

[0248]

[0249] A mixture of 6-isopropoxy-2-(prop-1-en-2-yl)-3-(trifluoromethyl)aniline 14-2 (100 mg, 0.39 mmol) and palladium hydroxide on carbon (54 mg) in methanol (20 mL) was hydrogenated with a hydrogen balloon for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a yellow oily crude product 14-3 (100 mg, 75%).

[0250] LC-MS: [M+H] + :262.1.

[0251] Referring to step 3 in Example 1 and step 1 and step 2 in Example 10, replacing 1-4 with 14-3 can give 2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(6-isopropoxy-2-isopropyl-3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one, compound 78 (13 mg, 19%).

[0252] LC-MS: [M+H] + :657.3.

[0253] HPLC: 98.85% [214nm].

[0254] 1H NMR: (400MHz, CD3OD) δ8.20(d,J=8.0Hz,1H),7.92-7.85(m,2H),7.78(d,J=8.0Hz,1H),7.58(t,J=7.6Hz,1H),7.22-7.20(m,3H),6.91 (d,J=8.8Hz,2H),4.77-4.69(m,3H),3.62-3.52(m,4H),3.42-3.32(m,1H),3.28-3.24(m,2H),2.65-2.41(m,4H),1.21-1.09(m,12H).

[0255] Embodiment 17

[0256]

[0257] Synthesis of 4-bromo-2-isopropoxy-5-(trifluoromethyl)aniline:

[0258]

[0259] N-bromosuccinimide (448 mg, 2.5 mmol) was added to a solution of 2-isopropoxy-5-(trifluoromethyl)aniline 13-1 (554 mg, 2.5 mmol) in anhydrous acetonitrile (10 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure in a vacuum and diluted with ethyl acetate (100 mL), and washed with water (100 mL x 2) and saturated brine (100 mL) in turn. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to give a black oily product 17-1 (520 mg, 69%).

[0260] LC-MS: [M+H] + :298.1.

[0261] 1 HNMR (400MHz, CDCl 3 )δ7.11(s,1H),7.03(s,1H),4.59(dt,J=12.0,6.0Hz,1H),1.38(d,J=6.0Hz,6H).

[0262] Synthesis of 2-isopropoxy-4-methyl-5-(trifluoromethyl)aniline:

[0263]

[0264] 2,4,6-trimethyl-1,3,5,2,4,6-trioxytriborane 13-3 (0.4 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (24.5 mg, 0.033 mmol) and sodium carbonate (71 mg, 0.67 mmol) were added to a solution of 4-bromo-2-isopropoxy-5-(trifluoromethyl)aniline 17-1 (100 mg, 0.33 mmol) in dioxane / water (10 / 5 mL) at room temperature. The mixture was heated to 80°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (50 mL), and washed with water (100 mL) and saturated brine (100 mL) in sequence. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give a yellow oily product 17-2 (60 mg, 76.5%).

[0265] LC-MS: [M+H] + :234.2.

[0266] Referring to step 3 in Example 1 and step 1 and step 2 in Example 10, replacing 1-4 with 17-2 can give 2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(2-isopropoxy-4-methyl-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one, compound 17 (16.5 mg, 20%).

[0267] LC-MS: [M+H] + :628.9.

[0268] HPLC: 98.2%

[0269] 1 H NMR (400MHz, CD 3 OD)δ8.24(d,J=8.0Hz,1H),7.84-7.82(m,2H),7.72(s,1H),7.62(t,J=7.2Hz,1H),7.28-7.22(m,3H),6.93-6.90(m,2H),4.82- 4.75(m,3H),3.98-3.94(m,1H)3.86-3.44(m,5H),3.25-2.88(m,4H),2.57(s,3H),1.25(d,J=6.0Hz,3H),1.15(d,J=6.0Hz,3H).

[0270] Embodiment 18

[0271]

[0272] Referring to step 3 in Example 1 and step 1 and step 2 in Example 10, replacing 1-4 with 13-1 can give 2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one, compound 1 (46.1 mg, 18%).

[0273] LC-MS: [M+H] + :615.2.

[0274] HPLC: 100%

[0275] 1 HNMR (400MHz, CD 3 OD)δ8.25(d,J=7.9Hz,1H),7.96-7.85(m,3H),7.81(s,1H),7.63(t,J=7.5Hz,1H),7.46(d,J=8.9Hz,1H),7.27-7.22(m,2H),6.97-6. 91(m,2H),4.86-4.79(m,4H),4.32-4.27(m,1H),3.95-3.91(m,4H),3.56-3.34(m,4H),1.26(d,J=6.0Hz,3H),1.16(d,J=6.0Hz,3H).

[0276] Embodiment 19

[0277]

[0278] Synthesis of N-(5-acetyl-2-isopropoxyphenyl)-2-iodobenzamide:

[0279]

[0280] 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (290 mg, 1.51 mmol) was added to a solution of 2-iodobenzoic acid 19-1 (250 mg, 1 mmol), 1-(3-amino-4-isopropoxyphenyl)ethanone 19-2 (195 mg, 1 mol), N,N-diisopropylethylamine (391 mg, 3.02 mmol) and 1-hydroxy-7-azabenzotriazole (163 mg, 1.21 mmol) in dichloromethane (20 mL). The mixture was diluted with dichloromethane (30 mL) and washed with saturated brine (30 mL×3). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 1) to give a yellow solid product 19-3 (350 mg, 74%).

[0281] LC-MS: [M+H] + :424.0.

[0282] Synthesis of N-(5-acetyl-2-isopropoxyphenyl)-2-(3-hydroxypropyl-1-yl)benzamide:

[0283]

[0284] A mixture of N-(5-acetyl-2-isopropoxyphenyl)-2-iodobenzamide 19-3 (350 mg, 0.83 mmol), prop-2-yn-1-ol 19-4 (93 mg, 1.65 mmol), CuI (32 mg, 0.16 mmol) and bis(triphenylphosphine)palladium(II) chloride (58 mg, 0.083 mmol) in triethylamine (20 mL) was heated at 35 ° C for 17 hours. After cooling to room temperature, the mixture was concentrated in vacuo, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 1) to give the product 19-5 (350 mg, 96% yield) as a slightly yellow solid.

[0285] LC-MS: [M+H] + :352.2.

[0286] 1 HNMR:(400MHz,CDCl 3 )δ9.25(d,J=2.0Hz,1H),9.18(s,1H),7.96-7.93(m,1H),7.77(dd,J=8.8,2.4Hz,1H),7.57-7.54(m,1H),7. 49-7.46(m,2H),7.01(d,J=8.8Hz,1H),4.72-4.67(m,1H),4.47(s,2H),2.62(s,3H),1.40(d,J=6.0Hz,6H).

[0287] Synthesis of (Z)-1-(3-((3-(hydroxymethyl)-1H-isochrome-1-ylidene)amino)-4-isopropoxyphenyl)ethan-1-one:

[0288]

[0289] To a solution of silver hexafluoroantimonate (17 mg, 0.050 mmol) and (triphenylphosphine) gold chloride (25 mg, 0.050 mmol) in dichloromethane (10 mL) and dioxane (10 mL) was added N-(5-acetyl-2-isopropoxyphenyl)-2-(3-hydroxypropyl-1-yl)benzamide 19-5 (350 mg, 0.99 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, the residue was diluted with dichloromethane (60 mL), and washed with saturated brine (40 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 1) to give 19-6 (200 mg, 45.7%) as a yellow solid.

[0290] LC-MS: [M+H] + :352.1.

[0291] 1 HNMR:(400MHz,CDCl 3 )δ9.16(s,1H),7.99(s,1H),7.87(d,J=8.4Hz,1H),7.78-7.72(m,1H),7.64-7.58(m,1H),7.45(d,J=6.8Hz, 1H),7.02(d,J=8.8Hz,1H),6.67(s,1H),4.67-4.60(m,1H),4.38(s,2H),2.54(s,3H),1.26(d,J=6.0Hz,6H).

[0292] Synthesis of (Z)-1-(3-((3-(chloromethyl)-1H-isochrome-1-ylidene)amino)-4-isopropoxyphenyl)ethan-1-one:

[0293]

[0294] To a solution of (Z)-1-(3-((3-(hydroxymethyl)-1H-isochrome-1-ylidene)amino)-4-isopropoxyphenyl)ethane-1-one 19-6 (200 mg, 0.57 mmol) and N,N-diisopropylethylamine (147 mg, 1.13 mmol) in dichloromethane (20 mL) at 0°C, methylsulfonyl chloride (78 mg, 0.68 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane (30 mL) and washed with saturated brine (30 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 3) to give a yellow solid product 19-7 (150 mg, 58.29%).

[0295] LC-MS: [M+H] + :370.1.

[0296] 1 HNMR:(400MHz,CDCl 3 )δ8.63(s,1H),7.82-7.74(m,2H),7.62(t,J=7.6Hz,1H),7.53(t,J=7.6Hz,1H),7.33(d,J=7.6Hz,1H),6.97( d,J=8.4Hz,1H),6.42(s,1H),4.67-4.60(m,1H),4.15(s,2H),2.58-2.52(m,3H),1.29(dd,J=6.0,0.4Hz,6H).

[0297] Synthesis of tert-butyl (Z)-4-((1-((5-acetyl-2-isopropoxyphenyl)imino)-1H-isochrome-3-yl)methyl)piperazine-1-carboxylate:

[0298]

[0299] To a solution of (Z)-1-(3-((3-(chloromethyl)-1H-isochrom-1-ylidene)amino)-4-isopropoxyphenyl)ethane-1-one 19-7 (150 mg, 0.41 mmol), tert-butyl piperazine-1-carboxylate 19-8 (75 mg, 0.41 mmol) and potassium carbonate (112 mg, 0.81 mmol) in acetonitrile (20 mL) was added potassium iodide (67 mg, 0.41 mmol), and the mixture was stirred at 80 ° C for 16 hours. The mixture was concentrated in vacuo, the residue was diluted with ethyl acetate (50 mL), and washed with saturated brine (30 mL×2). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol=20 / 1) to give a yellow solid product 19-9 (100 mg, 45%).

[0300] LC-MS: [M+H] + :520.2.

[0301] 1 HNMR:(400MHz,CDCl 3)δ8.47(d,J=7.6Hz,1H),7.71(d,J=8.0Hz,1H),7.68-7.64(m,2H),7.57(t,J =7.6Hz,1H),7.38(d,J=7.6Hz,1H),6.99(d,J=8.0Hz,1H),6.68(s,1H),4.59 -4.49(m,1H),4.14-3.98(m,2H),3.81(s,2H),3.61-3.41(m,2H),3.21-3.10 (m,2H),2.84-2.70(m,2H),2.56(s,3H),1.46(s,9H),1.22(d,J=6.0Hz,6H).

[0302] Synthesis of 2-(5-acetyl-2-isopropoxyphenyl)-3-(piperazin-1-ylmethyl)isoquinolin-1(2H)-one:

[0303]

[0304] To a solution of (Z)-tert-butyl 4-((1-((5-acetyl-2-isopropoxyphenyl)imino)-1H-isochrome-3-yl)methyl)piperazine-1-carboxylate 19-9 (90 mg, 0.077 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to give a mixture of yellow solid crude products 19-10 and 19-11 (70 mg, crude product).

[0305] LC-MS: [M+H] + :420.2.

[0306] Synthesis of 2-(5-acetyl-2-isopropoxyphenyl)-3-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)isoquinolin-1(2H)-one:

[0307]

[0308] 2-(4-chlorophenoxy)acetyl chloride 1-10 (29.3 mg, 0.14 mmol) was added to a solution of 19-10 and 19-11 (60 mg, 0.14 mmol) and N, N-diisopropylethylamine (55.4 mg, 0.43 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed with saturated brine (30 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by sequentially passing through preparative plate chromatography (dichloromethane / methanol=20 / 1) and efficient preparative liquid phase (acetonitrile-water (0.05% ammonia), gradient 30%-90%) to obtain a white solid product 19-bp (9.9 mg, 11.7%) and a white solid product, compound 150 (11.2 mg, 13.2%).

[0309] Example 19-bp

[0310] LC-MS: [M+H] + :588.3.

[0311] HPLC: 99.54% [214nm]

[0312] 1 H NMR: (400MHz, CD 3 OD)δ8.33(d,J=8.0Hz,1H),7.79(dd,J=8.4,2.0Hz,1H),7.69-7.63(m,2H),7.55-7.4 9(m,1H),7.42(d,J=7.6Hz,1H),7.27(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,1H),6.95(d, J=8.8Hz,2H),6.43(s,1H),4.78(s,2H),4.75-4.68(m,1H),3.52-3.46(m,4H),3.31-3 .30(m,2H),2.58(s,3H),2.48-2.44(m,2H),2.43-2.37(m,2H),1.28(d,J=6.0Hz,6H).

[0313] Example 19 (Compound 150):

[0314] LC-MS: [M+H] + :588.0.

[0315] HPLC: 98.09% [214nm].

[0316] 1 H NMR: (400MHz, CD 3OD)δ8.31(d,J=8.0Hz,1H),8.17(dd,J=8.8,2.0Hz,1H),8.04(d,J=2.0Hz,1 H),7.79(t,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.57(t,J=7.6Hz,1H),7.31 -7.25(m,3H),6.93(d,J=8.8Hz,2H),6.82(s,1H),4.83 -4.76(m,3H),3.48-3.38(m,4H),3.19-3.10(m,2H),2.62(s,3H),2.42-2.30(m,2H),2.16-2.05(m,2H),1.26-1.20(m,6H).

[0317] Embodiment 20

[0318]

[0319] Synthesis of 3-methyl-1H-isochrome-1-one:

[0320]

[0321] A mixture of 2-iodobenzoic acid 20-1 (2 g, 8.1 mmol), pentane-2,4-dione 20-2 (807 mg, 8.1 mmol), cuprous iodide (150 mg, 0.81 mmol) and potassium phosphate (3.44 g, 16.1 mmol) in N, N-dimethylformamide (20 mL) was heated at 100 ° C for 16 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL × 3). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 3) to give a brown solid product 20-3 (1 g, 73%).

[0322] LC-MS: [M+H] + :161.2.

[0323] 1 H NMR: (400MHz, DMSO-d 6 )δ8.10(d,J=8.4Hz,1H),7.87-7.75(m,1H),7.55-7.52(m,2H),2.25(s,3H).

[0324] Synthesis of 2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-3-methylisoquinolin-1(2H)-one:

[0325]

[0326] Trimethylaluminum (1.25 mL, 2.5 mmol, 2 mol in hexane) was added to a mixture of 4-fluoro-2-isopropoxy-5-(trifluoromethyl)aniline 1-4 (296 mg, 1.25 mmol) in toluene (10 mL), and stirred at room temperature for 10 minutes. Then 3-methylisochrome-1-one 20-3 (200 mg, 1.25 mol) was added, and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated in vacuo, the residue was diluted with ethyl acetate (50 mL), and washed with sodium bicarbonate aqueous solution (20 mL) and saturated brine (30 mL) in turn. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 4) to give a yellow oily product 20-4 (100 mg, 20%).

[0327] LC-MS: [M+H] + :380.1.

[0328] 1 HNMR:(400MHz,CDCl 3 )δ8.33(d,J=8.0Hz,1H),7.67-7.59(m,1H),7.51-7.40(m,3H),6.85(d,J=12.0Hz,1H),6.41(s ,1H),4.54(dt,J=12.2,6.0Hz,1H),1.98(s,3H),1.26(d,J=6.0Hz,3H),1.22(d,J=6.0Hz,3H).

[0329] Synthesis of 2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde:

[0330]

[0331] To a solution of 2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-3-methylisoquinolin-1(2H)-one 20-4 (100 mg, 0.26 mmol) in dioxane (20 mL) was added selenium dioxide (29 mg, 0.26 mmol), and the mixture was heated at 70°C for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 20-5 (100 mg, 77%) as a yellow solid.

[0332] LC-MS: [M+H] + :394.0.

[0333] Synthesis of 2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-3-(hydroxymethyl)isoquinolin-1(2H)-one:

[0334]

[0335] To a solution of 2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde 20-5 (100 mg, 0.25 mmol) in methanol (10 mL) was added sodium borohydride (10 mg, 0.25 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, the residue was diluted with water (20 mL), and extracted with ethyl acetate (30 mL x2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 20-6 (100 mg, 94%) as a yellow solid.

[0336] LC-MS: [M+H] + :396.1.

[0337] Synthesis of 3-(chloromethyl)-2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one:

[0338]

[0339] To a solution of 2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-3-(hydroxymethyl)isoquinolin-1(2H)-one 20-6 (100 mg, 0.25 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) in dichloromethane (10 mL) was added methylsulfonyl chloride (19 mg, 0.25 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed with saturated brine (30 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 20-7 (100 mg, 91%) as a yellow solid.

[0340] LC-MS: [M+H] + :414.0.

[0341] Synthesis of (S)-tert-butyl 4-((2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)-3-methylpiperazine-1-carboxylate:

[0342]

[0343] To a solution of 3-(chloromethyl)-2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one 20-7 (100 mg, 0.24 mmol), (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester 1-7 (48.7 mg, 0.24 mmol) and potassium carbonate (33 mg, 0.24 mmol) in acetonitrile (30 mL) was added potassium iodide (40 mg, 0.24 mmol), and the mixture was heated at 70° C. for 16 hours. The mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate (50 mL) and washed with saturated brine (30 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to silica gel chromatography (ethyl acetate / petroleum ether=1 / 2) to give the crude product 20-8 (100 mg, 64%) as a yellow solid

[0344] LC-MS: [M+H] + :578.3.

[0345] Synthesis of (S)-2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-3-((2-methylpiperazin-1-yl)methyl)isoquinolin-1(2H)-one:

[0346]

[0347] To a solution of (S)-tert-butyl 4-((2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)-3-methylpiperazine-1-carboxylate 20-8 (100 mg, 0.17 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to give a yellow oily crude product 20-9 (80 mg, 98%).

[0348] LC-MS: [M+H] + :478.2.

[0349] Synthesis of (S)-3-((4-(2-(4-chlorophenoxy)acetyl)-2-methylpiperazin-1-yl)methyl)-2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one:

[0350]

[0351] To a solution of (S)-2-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)-3-((2-methylpiperazin-1-yl)methyl)isoquinolin-1(2H)-one 20-9 (80 mg, 0.17 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) in dichloromethane (10 mL) was added 2-(4-chlorophenoxy)acetyl chloride (34 mg, 0.17 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed with saturated brine (30 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 1) to give a white solid product, compound 153 (47 mg, 41%).

[0352] LC-MS: [M+H] + :646.3.

[0353] HPLC: 95.73% [214nm].

[0354] 1 H NMR: (400MHz, DMSO) δ8.17(d,J=8.0Hz,1H),7.82-7.71(m,2H),7.68(d,J=8.8Hz,1H),7.5 3-7.47(m,1H),7.48-7.40(m,1H),7.31(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,2H),6.74-6.72 (m,1H),4.85-4.69(m,3H),3.64-3.35(m,2H),3.26-3.02(m,1H),2.86-2.75(m,2H),2.62 -2.56(m,1H),2.44-2.34(m,1H),2.15-1.81(m,2H),1.19-1.10(m,6H),0.63-0.42(m,3H).

[0355] Example 21 / 22

[0356]

[0357] Compound 153 (47 mg) was chirally separated by SFC (chromatographic column: WHELK-O1 250 mm × 21.1 mm, 5 μm, mobile phase: carbon dioxide-ethanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (13.9mg, 19.4mg)

[0358] Single configuration compound (short retention time)

[0359] It was analyzed by chiral analysis chromatography conditions, RT = 10.35min

[0360] LC-MS: [M+H] + :646.3.

[0361] HPLC: 95.73% [214nm].

[0362] 1 H NMR: (400MHz, DMSO) δ8.17(d,J=8.0Hz,1H),7.82-7.71(m,2H),7.68(d,J=8.8Hz,1H),7.5 3-7.47(m,1H),7.48-7.40(m,1H),7.31(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,2H),6.74-6.72 (m,1H),4.85-4.69(m,3H),3.64-3.35(m,2H),3.26-3.02(m,1H),2.86-2.75(m,2H),2.62 -2.56(m,1H),2.44-2.34(m,1H),2.15-1.81(m,2H),1.19-1.10(m,6H),0.63-0.42(m,3H).

[0363] Single configuration compound (longer retention time)

[0364] It was analyzed by chiral analysis chromatography conditions, RT = 12.72min

[0365] LC-MS: [M+H] + :646.3.

[0366] HPLC: 95.73% [214nm].

[0367] 1H NMR: (400MHz, DMSO) δ8.17(d,J=8.0Hz,1H),7.82-7.71(m,2H),7.68(d,J=8.8Hz,1H),7.5 3-7.47(m,1H),7.48-7.40(m,1H),7.31(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,2H),6.74-6.72 (m,1H),4.85-4.69(m,3H),3.64-3.35(m,2H),3.26-3.02(m,1H),2.86-2.75(m,2H),2.62 -2.56(m,1H),2.44-2.34(m,1H),2.15-1.81(m,2H),1.19-1.10(m,6H),0.63-0.42(m,3H).

[0368] Example 23 / 24

[0369]

[0370] Compound 78 (13 mg) was chiral separated by SFC (chromatographic column: WHELK-O1 250 mm × 21.1 mm, 5 μm, mobile phase: carbon dioxide-ethanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (2.6mg, 3.3mg)

[0371] Single configuration compound (short retention time)

[0372] It was analyzed by chiral analysis chromatography conditions, RT = 1.98min

[0373] LC-MS: [M+H] + :657.3.

[0374] HPLC: 98.85% [214nm].

[0375] 1 H NMR: (400MHz, CD3OD) δ8.20(d,J=8.0Hz,1H),7.92-7.85(m,2H),7.78(d,J=8.0Hz,1H),7.58(t,J=7.6Hz,1H),7.22-7.20(m,3H),6.91 (d,J=8.8Hz,2H),4.77-4.69(m,3H),3.62-3.52(m,4H),3.42-3.32(m,1H),3.28-3.24(m,2H),2.65-2.41(m,4H),1.21-1.09(m,12H).

[0376] Single configuration compound (longer retention time)

[0377] It was analyzed by chiral analysis chromatography conditions, RT = 8.68min

[0378] LC-MS: [M+H] + :657.3.

[0379] HPLC: 98.85% [214nm].

[0380] 1 H NMR: (400MHz, CD3OD) δ8.20(d,J=8.0Hz,1H),7.92-7.85(m,2H),7.78(d,J=8.0Hz,1H),7.58(t,J=7.6Hz,1H),7.22-7.20(m,3H),6.91 (d,J=8.8Hz,2H),4.77-4.69(m,3H),3.62-3.52(m,4H),3.42-3.32(m,1H),3.28-3.24(m,2H),2.65-2.41(m,4H),1.21-1.09(m,12H).

[0381] Embodiment 25

[0382]

[0383] According to Example 1, 25-1 was replaced with 1-4 to obtain the current product (S)-5-(2-((4-(2-(4-chlorophenoxy)acetyl)-2-methylpiperazin-1-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-4-isopropoxy-2-methylbenzoic acid methyl ester (25.3 mg, 64.6% yield)

[0384] LC-MS: [M+H]+: 633.0.

[0385] HPLC: 100%.

[0386] 1H NMR: (400MHz, CD3OD) δ8.24(d,J=8.0Hz,1H),8.02-7.99(m,1H),7.93-7.88(m,1H),7.77(d,J=8.3H z,1H),7.60(t,J=7.6Hz,1H),7.28(d,J=8.6Hz,2H),7.15(s,1H),6.97-6.92(m,2H),4.83-4.72(m, 3H),3.86(d,J=4.6Hz,3H),3.82-3.61(m,2H),3.52-3.46(m,1H),3.27-2.98(m,2H),2.89-2.61(m, 5H),2.45-2.18(m,2H),1.27(dd,J=6.0,3.1Hz,3H),1.19(dd,J=6.0,1.8Hz,3H),0.81-0.58(m,3H).

[0387] Embodiment 26

[0388]

[0389] According to Example 1, 26-2 was replaced with 1-4 to obtain the current product (S)-3-(2-((4-(2-(4-chlorophenoxy)acetyl)-2-methylpiperazin-1-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-4-isopropoxy-2-methylbenzoic acid methyl ester (21.0 mg, 41.7% yield)

[0390] LC-MS: [M+H]+: 633.0.

[0391] HPLC:94.76%.

[0392] 1H NMR: (400MHz, CD3OD) δ8.26(d,J=8.0Hz,1H),8.11(d,J=7.6Hz,1H),7.92(t,J=7.6Hz,1H),7.81 -7.79(m,1H),7.62(t,J=7.6Hz,1H),7.27(d,J=8.8Hz,2H),7.17(t,J=8.0Hz,1H),6.95-6.93(m ,2H),4.80-4.71(m,3H),3.91(s,3H),3.73-3.41(m,3H),3.26-3.15(m,1H),3.07-2.92(m,1H), 2.81-2.04(m,7H),1.29-1.24(m,3H),1.16-1.12(m,3H),0.83-0.78(m,2H),0.49-0.44(m,1H).

[0393] Embodiment 27

[0394]

[0395] Referring to the steps of Example 1, 27-1 was used instead of 1-7 to obtain the target compound (R)-2-((4-(2-(4-chlorophenoxy)acetyl)-2-methylpiperazin-1-yl)methyl)-3-(4-fluoro-2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (60.7 mg, yield: 31.0%, purity: 97.01%)

[0396] LC-MS: [M+H] + :647.3.

[0397] HPLC: 97.01%

[0398] 1 H NMR (400MHz, CD 3 OD)δ8.20(d,J=7.2Hz,1H),7.91-7.80(m,2H),7.71(dd,J=10.2,5.8Hz,1H), 7.60-7.54(m,1H),7.34-7.19(m,3H),6.95-6.82(m,2H),4.80-4.61(m,3H), 3.93-3.69(m,1H),3.65-3.36(m,2H),3.25-3.07(m,2H),3.02-2.53(m,2H), 2.39-2.06(m,2H),1.29-1.19(m,3H),1.18-1.16(m,3H),0.63-0.59(m,3H).

[0399] Example 28 / 29

[0400]

[0401] Compound 140 (60.7 mg) was chiral separated by SFC (chromatographic column: AD-H 250 mm×20 mm, 5 μm, mobile phase: carbon dioxide-ethanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (18.9mg, 17.6mg)

[0402] Single configuration compound (short retention time)

[0403] It was analyzed by chiral analysis chromatography conditions, RT = 2.04min

[0404] LC-MS: [M+H]+: 647.3.

[0405] HPLC: 97.01%

[0406] 1 H NMR (400MHz, CD 3 OD)δ8.20(d,J=7.2Hz,1H),7.91-7.80(m,2H),7.71(dd,J=10.2,5.8Hz,1H), 7.60-7.54(m,1H),7.34-7.19(m,3H),6.95-6.82(m,2H),4.80-4.61(m,3H), 3.93-3.69(m,1H),3.65-3.36(m,2H),3.25-3.07(m,2H),3.02-2.53(m,2H), 2.39-2.06(m,2H),1.29-1.19(m,3H),1.18-1.16(m,3H),0.63-0.59(m,3H).

[0407] Single configuration compound (longer retention time)

[0408] It was analyzed by chiral analysis chromatography conditions, RT = 3.13min

[0409] LC-MS: [M+H]+: 647.3.

[0410] HPLC: 97.60%

[0411] 1 H NMR (400MHz, CD 3 OD)δ8.20(d,J=7.2Hz,1H),7.91-7.80(m,2H),7.71(dd,J=10.2,5.8Hz,1H), 7.60-7.54(m,1H),7.34-7.19(m,3H),6.95-6.82(m,2H),4.80-4.61(m,3H), 3.93-3.69(m,1H),3.65-3.36(m,2H),3.25-3.07(m,2H),3.02-2.53(m,2H), 2.39-2.06(m,2H),1.29-1.19(m,3H),1.18-1.16(m,3H),0.63-0.59(m,3H).

[0412] Embodiment 30

[0413]

[0414] Synthesis of 4-(methylthio)-2-nitrophenol:

[0415]

[0416] To a solution of 4-(methylthio)phenol (500mg, 3.57mmol) in acetonitrile (20mL) was added tert-butyl nitrite (331mg, 3.21mmol), and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30mL) and washed with saturated brine (30mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 4) to obtain the product 30-2 (200mg, yield: 29%) as a yellow solid.

[0417] LC-MS: [M+H] + :No MS.

[0418] 1 H NMR: (400MHz, CDCl 3 )δ10.50(s,1H),7.96(d,J=2.4Hz,1H),7.52(dd,J=8.8,2.4Hz,1H),7.11(d,J=8.8Hz,1H),2.51(s,3H).

[0419] Synthesis of 1-isopropoxy-4-(methylthio)-2-nitrobenzene:

[0420]

[0421] 2-Iodopropane (137.7 mg, 0.81 mmol) was added to a solution of 4-(methylthio)-2-nitrophenol (100 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08 mmol) in N, N-dimethylformamide (10 mL), and the mixture was heated at 60 ° C for 16 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 3) to give a yellow oily product 30-3 (100 mg, yield: 77.4%).

[0422] LC-MS: [M+H] + :No MS.

[0423] 1HNMR: (400MHz, CDCl3) δ7.66 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.61 (dt, J = 12.4, 6.0 Hz, 1H), 1.37 (d, J = 6.0 Hz, 6H).

[0424] Synthesis of 2-isopropoxy-5-(methylthio)aniline:

[0425]

[0426] A mixture of 1-isopropoxy-4-(methylthio)-2-nitrobenzene (90 mg, 0.40 mmol) and palladium carbon (11 mg, 20% wet) in ethanol (10 mL) was hydrogenated under hydrogen atmosphere for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a yellow oily product 30-4 (75 mg, yield: 86%).

[0427] LC-MS: [M+H] + :198.1.

[0428] Synthesis of 2-(chloromethyl)-3-(2-isopropoxy-5-(methylthio)phenyl)quinazolin-4(3H)-one:

[0429]

[0430] N, N-diisopropylethylamine (48 mg, 0.37 mmol) and phosphorus trichloride (77 mg, 0.56 mmol) were added to a solution of 2-(2-chloroacetylamino)benzoic acid (80 mg, 0.37 mmol) in acetonitrile (20 mL), and the mixture was stirred at room temperature for 10 minutes. A solution of 2-isopropoxy-5-(methylthio)aniline (74 mg, 0.37 mmol) in acetonitrile (1 mL) was added, and the mixture was stirred at 60 ° C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with sodium bicarbonate aqueous solution (10 mL) and extracted with ethyl acetate (20 mL x3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 3) to give the product 30-5 (70 mg, yield: 90%) as a yellow solid.

[0431] LC-MS: [M+H] + :375.1.

[0432] Synthesis of tert-butyl 4-((3-(2-isopropoxy-5-(methylthio)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate:

[0433]

[0434] To a solution of 2-(chloromethyl)-3-(2-isopropoxy-5-(methylthio)phenyl)quinazoline-4(3H)-one (70 mg, 0.19 mmol), tert-butyl piperazine-1-carboxylate (35 mg, 0.19 mmol) and potassium carbonate (52 mg, 0.37 mmol) in acetonitrile (20 mL) was added potassium iodide (31 mg, 0.19 mmol), and the mixture was stirred at 80 ° C for 16 hours. The mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate (30 mL) and washed with saturated brine (20 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol=20 / 1) to give a yellow solid product 30-6 (50 mg, yield: 87%).

[0435] LC-MS: [M+H] + :525.2.

[0436] Synthesis of tert-butyl 4-((3-(2-isopropoxy-5-(S-methylsulfonylamino)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate:

[0437]

[0438] To a solution of tert-butyl 4-((3-(2-isopropoxy-5-(methylthio)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (80mg, 0.15mmol) in methanol (20mL) was added ammonium carbamate (47.6mg, 0.61mmol) and iodophenyl diacetate (147mg, 0.45mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, the residue was diluted with water (20mL) and extracted with ethyl acetate (20mL x 3). The combined organic layers were washed with saturated brine (40mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol=15 / 1) to give the product 30-7 (40mg, yield: 42.5%) as a yellow solid.

[0439] LC-MS: [M+H] + :556.2.

[0440] Synthesis of 3-(2-isopropoxy-5-(S-methylsulfonylanilide)phenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one:

[0441]

[0442] To a solution of tert-butyl 4-((3-(2-isopropoxy-5-(S-methylsulfonylamino)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (40 mg, 0.072 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the crude product 30-8 (30 mg, yield: 82%) as a yellow solid.

[0443] LC-MS: [M+H] + :456.2.

[0444] Synthesis of 2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(2-isopropoxy-5-(S-methylsulfonylimino)phenyl)quinazolin-4(3H)one:

[0445]

[0446] 2-(4-chlorophenoxy)acetyl chloride (13.5 mg, 0.066 mmol) was added to a solution of 3-(2-isopropoxy-5-(S-methylsulfonylanilide)phenyl)-2-(piperazine-1-ylmethyl)quinazoline-4(3H)-one (30 mg, 0.066 mmol) and N,N-diisopropylethylamine (26 mg, 0.20 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed with saturated brine (20 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative plate (dichloromethane / methanol=15 / 1) to give the product compound 189 (34 mg, yield: 80%) as a white solid.

[0447] LC-MS: [M+H] + :624.3.

[0448] HPLC: 97.13%.

[0449] 1 H NMR: (400MHz, DMSO-d 6)δ8.15(d,J=8.0Hz,1H),8.05-7.97(m,2H),7.88(t,J=7.6Hz,1H),7.74(d, J=8.0Hz,1H),7.58(t,J=7.6Hz,1H),7.42(d,J=8.8Hz,1H),7.31(d,J=8.8H z,2H),6.90(d,J=8.8Hz,2H),4.85-4.76(m,3H),4.27(s,1H),3.46-3.38(m ,1H),3.29-3.14(m,5H),3.12(s,3H),2.25-2.02(m,4H),1.17-1.11(m,6H).

[0450] Embodiment 31

[0451]

[0452] Synthesis of 3-(2-isopropoxy-5-(methylthio)phenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one:

[0453]

[0454] A mixture of 2-(chloromethyl)-3-(2-isopropoxy-5-(methylthio)phenyl)quinazoline-4(3H)-one (50 mg, 0.14 mmol) and piperazine (34.5 mg, 0.40 mmol) was dissolved in THF (20 mL) and heated under reflux for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 31-1 (60 mg) which was directly used in the next step.

[0455] LC-MS: [M+H] + :425.1.

[0456] Synthesis of 2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(2-isopropoxy-5-(methylthio)phenyl)quinazolin-4(3H)one:

[0457]

[0458] N,N-diisopropylethylamine (27.4 mg, 0.21 mmol) and 2-(4-chlorophenoxy)acetyl chloride (29.0 mg, 0.14 mmol) were added to a solution of 3-(2-isopropoxy-5-(methylthio)phenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (60 mg, 0.14 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 6 hours. The residue was extracted with aqueous sodium bicarbonate solution (20 mL) and dichloromethane (30 mL x 3), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-efficiency preparative liquid phase to give compound 180 (61.6 mg, yield: 71%) as a white solid.

[0459] LC-MS: [M+H] + :593.0.

[0460] HPLC: 95.67%.

[0461] 1 H NMR: (400MHz, DMSO-d 6 )δ8.14(dd,J=8.0,1.2Hz,1H),7.89-7.85(m,1H),7.72(d,J=8.0Hz,1H),7.59-7.55(m, 1H),7.44(d,J=2.4Hz,1H),7.38(dd,J=8.8,2.4Hz,1H),7.33-7.28(m,2H),7.20(d,J=8. 8Hz,1H),6.93-6.88(m,2H),4.78(s,2H),4.63-4.56(m,1H),3.30-3.15(m,6H),2.47(s, 3H),2.38-2.24(m,2H),2.11-2.01(m,2H),1.13(d,J=6.0Hz,3H),1.05(d,J=6.0Hz,3H).

[0462] Embodiment 32

[0463]

[0464] Synthesis of 1-isopropoxy-4-(methylsulfonyl)-2-nitrobenzene:

[0465]

[0466] Potassium carbonate (152.8 mg, 1.11 mmol) was added to a solution of 4-(methylsulfonyl)-2-nitrophenol (200.0 mg, 0.92 mmol) in DMF (10 mL). After stirring for 15 minutes, 2-iodopropane (313.1 mg, 1.85 mmol) was added and the mixture was stirred at 70 ° C for 16 hours. Dilute with water (30 mL), extract with ethyl acetate (30 mL x 3), wash the combined organic layer with saturated sodium chloride solution (60 mL x 3) 3 times, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the product 32-2 (170 mg, yield: 68%) as a white solid.

[0467] LC-MS: [M+Na] + :282.0.

[0468] 1 H NMR: (400MHz, DMSO-d 6 )δ8.38(d,J=2.3Hz,1H),8.12(dd,J=8.9,2.4Hz,1H),7.65(d,J=9.0Hz,1H),5.02-4.96(m,1H),3.28(s,3H),1.33(d,J=6.0Hz,6H).

[0469] Synthesis of 2-isopropoxy-5-(methylsulfonyl)aniline:

[0470]

[0471] Palladium hydroxide on carbon (467.0 mg, 20% water content, 0.38 mmol) was added to a solution of 1-isopropoxy-4-(methylsulfonyl)-2-nitrobenzene (150 mg, 0.58 mmol) in methanol (20 mL), and the mixture was reacted in hydrogen (0.4 MPa) for 3 hours. The filtrate was then collected by filtration and dried in vacuo to obtain a white solid product 32-2 (110.0 mg, yield: 75%).

[0472] LC-MS: [M+H] + :230.1.

[0473] Synthesis of 2-(chloromethyl)-3-(2-isopropoxy-5-(methylsulfonyl)phenyl)quinazolin-4(3H)-one:

[0474]

[0475] N, N-diisopropylethylamine (68.3 mg, 0.53 mmol) was added to a solution of 2-(2-chloroacetylamino)benzoic acid (94.0 mg, 0.44 mmol) in acetonitrile (20 mL), stirred for 2 minutes, and phosphorus trichloride (151.1 mg, 1.10 mmol) was added. After stirring for 10 minutes, a solution of 2-isopropoxy-5-(methylsulfonyl)aniline (100.9 mg, 0.44 mmol) in acetonitrile (2 mL) was added, and the mixture was heated to reflux for 6 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 15 / 1) to give the product 32-3 (140 mg, yield: 72%) as a white solid.

[0476] LC-MS: [M+H] + :407.0.

[0477] Synthesis of 3-(2-isopropoxy-5-(methylsulfonyl)phenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one:

[0478]

[0479] 2-(Chloromethyl)-3-(2-isopropoxy-5-(methylsulfonyl)phenyl)quinazolin-4(3H)-one (140 mg, 0.34 mmol) and piperazine (88.9 mg, 1.03 mmol) were dissolved in THF (20 mL) and the mixture was heated to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 32-8 (130 mg crude) which was directly used in the next step.

[0480] LC-MS: [M+H] + :457.2.

[0481] Synthesis of 2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(2-isopropoxy-5-(methylsulfonyl)phenyl)quinazolin-4(3H)one:

[0482]

[0483] 3-(2-isopropoxy-5-(methylsulfonyl)phenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one

[0484] (140 mg, 0.30 mmol) was added to a solution of dichloromethane (20 mL) with N, N-diisopropylethylamine (59.4 mg, 0.46 mmol) and 2-(4-chlorophenoxy)acetyl chloride (62.9 mg, 0.30 mmol), and the mixture was stirred at room temperature for 6 hours. The residue was extracted with aqueous sodium bicarbonate solution (20 mL) and dichloromethane (30 mL x 3), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-efficiency preparative liquid phase to obtain compound 183 (125.2 mg, yield: 66%) as a white solid.

[0485] LC-MS: [M+H]+: 625.2.

[0486] HPLC: 100%.

[0487] 1 H NMR: (400MHz, DMSO-d 6 )δ8.15(d,J=8.0Hz,1H),8.10(d,J=2.4Hz,1H),8.00(dd,J=8.8,2.4Hz,1H),7.89-7.86(m 1H),7.74(d,J=8.0Hz,1H),7.59(t,J=7.6Hz,1H),7.47(d,J=9.0Hz,1H),7.32-7.29(m,2H),6.92-6.88(m,2H),4.84-4.80(m,1H),4. 77(s,2H),3.41-3.30(m,5H),3.24-3.13(m,4H),2.29-2.23(m,1H),2.17-2.05(m,3H),1.17(d,J=6.0Hz,3H),1.12(d,J=6.0Hz,3H).

[0488] Example 33 / 34

[0489]

[0490] Compound 183 (125 mg) was chirally separated by SFC (chromatographic column: WHELK-O1 250 mm × 21.1 mm, 5 μm, mobile phase: carbon dioxide-ethanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (47mg, 48.8mg)

[0491] Single configuration compound (short retention time)

[0492] It was analyzed by chiral analysis chromatography conditions, RT = 3.29min

[0493] LC-MS: [M+H]+: 625.2.

[0494] HPLC: 99.72%.

[0495] 1 H NMR: (400MHz, DMSO-d 6 )δ8.15(d,J=8.0Hz,1H),8.10(d,J=2.4Hz,1H),8.00(dd,J=8.8,2.4Hz,1H),7.89-7.86(m 1H),7.74(d,J=8.0Hz,1H),7.59(t,J=7.6Hz,1H),7.47(d,J=9.0Hz,1H),7.32-7.29(m,2H),6.92-6.88(m,2H),4.84-4.80(m,1H),4. 77(s,2H),3.41-3.30(m,5H),3.24-3.13(m,4H),2.29-2.23(m,1H),2.17-2.05(m,3H),1.17(d,J=6.0Hz,3H),1.12(d,J=6.0Hz,3H).

[0496] Single configuration compound (longer retention time)

[0497] It was analyzed by chiral analysis chromatography conditions, RT = 4.29min

[0498] LC-MS: [M+H]+: 625.2.

[0499] HPLC: 100%.

[0500] 1 H NMR: (400MHz, DMSO-d 6 )δ8.15(d,J=8.0Hz,1H),8.10(d,J=2.4Hz,1H),8.00(dd,J=8.8,2.4Hz,1H),7.89-7.86(m 1H),7.74(d,J=8.0Hz,1H),7.59(t,J=7.6Hz,1H),7.47(d,J=9.0Hz,1H),7.32-7.29(m,2H),6.92-6.88(m,2H),4.84-4.80(m,1H),4. 77(s,2H),3.41-3.30(m,5H),3.24-3.13(m,4H),2.29-2.23(m,1H),2.17-2.05(m,3H),1.17(d,J=6.0Hz,3H),1.12(d,J=6.0Hz,3H).

[0501] Embodiment 35

[0502]

[0503] Referring to Example 1, 35-3 was substituted for 1-4 to obtain the target compound 186 (13.48 mg)

[0504] LC-MS: [M+H]+: 626.0.

[0505] HPLC:99.66%.

[0506] 1 HNMR (400MHz, CD 3 OD)δ8.28(d,J=8.0Hz,1H),8.10(dd,J=8.8,2.2Hz,1H),8.00(d,J=2.2Hz,1H),7.96 (t,J=7.6Hz,1H),7.87(d,J=8.0Hz,1H),7.66(t,J=7.6Hz,1H),7.45(d,J=8.8Hz,1H) ,7.28(d,J=8.8Hz,2H),6.96(d,J=9.0Hz,2H),4.87-4.80(m,3H),4.00-3.96(m,1H) ,3.88-3.67(m,5H),3.20-2.90(m,4H),1.29(d,J=6.0Hz,3H),1.20(d,J=6.0Hz,3H).

[0507] Embodiment 36

[0508]

[0509] Synthesis of 4-bromo-1-isopropoxy-2-nitrobenzene:

[0510]

[0511] 2-Iodoisopropane (3.91 g, 23 mmol) and potassium carbonate (3.18 g, 23 mmol) were added to a solution of 4-bromo-2-nitrophenol (2.5 g, 11.5 mmol) in N,N-dimethylformamide (50 mL) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated brine (250 mL x 2). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow oily product 36-2. (2.7 g, yield: 91.0%).

[0512] 1H NMR (400 MHz, DMSO-d 6 )δ8.08(d,J=2.5Hz,1H),7.79(dd,J=9.0,2.5Hz,1H),7.38(d,J=9.1Hz,1H),4.82(dt,J=12.1,6.0Hz,1H),1.28(d,J=6.0Hz,6H).

[0513] Synthesis of 5-bromo-2-isopropoxyaniline:

[0514]

[0515] Reduced iron powder (215 mg, 3.84 mmol) was added to a solution of 4-bromo-1-isopropoxy-2-nitrobenzene (500 mg, 1.92 mmol) in ethanol / saturated ammonium chloride (20 / 10 mL) at room temperature, and the mixture was stirred at 70°C for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure in a vacuum. The concentrate was diluted with water (50 mL), and a saturated sodium bicarbonate solution was added to adjust the pH to 9-10. The mixed solution was extracted with dichloromethane (100 mL x2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily crude product 36-3 (450 mg) which was directly used in the next step.

[0516] LC-MS: [M+H] + :230.1.

[0517] Synthesis of 3-(5-bromo-2-isopropoxyphenyl)-2-chloromethylquinazol-4(3H)one:

[0518]

[0519] At 0°C, N,N-diisopropylethylamine (101 mg, 0.79 mmol) and phosphorus trichloride (135 mg, 0.98 mmol) were added to a solution of 2-(2-chloroacetylamino)benzoic acid (140 mg, 0.66 mmol) in dioxane (10 mL). After the mixture was stirred at room temperature for 20 minutes, 5-bromo-2-isopropoxyaniline (151 mg, 0.66 mmol) was added. The mixture was heated to 70°C and stirred for 6 hours. The reaction solution was concentrated under reduced pressure and diluted with dichloromethane (50 mL). The organic phase was washed with water (50 mL x 2) and saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 20:1) to obtain a yellow solid product 36-4 (260 mg, yield: 97%).

[0520] LC-MS: [M+H]+: 407.5.

[0521] Synthesis of tert-butyl 4-(3-(5-bromo-2-isopropoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate:

[0522]

[0523] To a solution of 3-(5-bromo-2-isopropoxyphenyl)-2-chloromethylquinazol-4(3H)one (270 mg, 0.66 mmol) in acetonitrile (10 mL) was added tert-butyl piperazine-1-carboxylate (124 mg, 0.66 mmol), potassium iodide (132 mg, 0.8 mmol) and potassium carbonate (119 mg, 0.86 mmol) at room temperature, and the mixture was stirred at 80 ° C for 16 hours. The reaction solution was concentrated under reduced pressure and diluted with dichloromethane (100 mL). The mixture was washed with water (50 mL x 3) and saturated brine (50 mL x 2). The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give a dark yellow oil 36-5 (300 mg, yield: 81%).

[0524] LC-MS: [M+H] + :557.1.

[0525] Synthesis of tert-butyl 4-((3-(5-(diphenylmethylene)amino)-2-isopropoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate:

[0526]

[0527] To a solution of tert-butyl 4-(3-(5-bromo-2-isopropoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-carboxylic acid 1-carboxylate (500 mg, 0.90 mmol) in dioxane (20 mL) at room temperature, diphenyl ketone imine (243 mg, 1.34 mmol), tris(dibenzylacetone)dipalladium (82 mg, 0.09 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (52 mg, 0.09 mmol) and cesium carbonate (583 mg, 1.79 mmol) were added. The mixture was stirred at 90°C for 20 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (100 mL), and washed with water (100 mL x 3) and saturated brine (200 mL) in sequence. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to give a yellow solid product 36-7 (350 mg, yield: 59.0%).

[0528] LC-MS: [M+H] + :658.3.

[0529] Synthesis of tert-butyl 4-(3-(5-amino-2-isopropoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate:

[0530]

[0531] 0.5N aqueous hydrochloric acid solution (2 mL) was added to a solution of tert-butyl 4-((3-(5-(diphenylmethylene)amino)-2-isopropoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (460 mg, 0.70 mmol) in tetrahydrofuran (10 mL), and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure in a vacuum to obtain a yellow oil 36-8 (450 mg crude product) which was directly used in the next step reaction.

[0532] LC-MS: [M+H] + :494.1.

[0533] Synthesis of tert-butyl 4-(3-(2-isopropoxy-5-(2,2,2-trifluoroacetylamino)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate:

[0534]

[0535] N,N-diisopropylethylamine (52 mg, 0.4 mmol) and trifluoroacetic anhydride (55 mg, 0.3 mmol) were added to a solution of tert-butyl 4-(3-(5-amino-2-isopropoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (100 mg, 0.2 mmol) in dichloromethane (10 mL) at 0°C. The mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with dichloromethane (50 mL), washed with water (100 mL x 2) and saturated brine (100 mL) in turn. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow oil 36-9 (115 mg, yield: 96%).

[0536] LC-MS: [M+H] + :590.4.

[0537] Synthesis of 2,2,2-trifluoro-N-(4-isopropoxy-3-(4-oxo-2-(piperazin-1-ylmethyl)quinazoline-3(4H)-phenyl)acetamide:

[0538]

[0539] Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 4-(3-(2-isopropoxy-5-(2,2,2-trifluoroacetylamino)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperazine-1-carboxylate (110 mg, 1.86 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure in vacuo to obtain a yellow oil 36-10 (172 mg crude product) which was directly used in the next reaction.

[0540] LC-MS: [M+H] + :490.2.

[0541] Synthesis of N-(3-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-4-oxoquinazoline-3(4H)-yl)-4-isopropoxyphenyl)-2,2,2-trifluoroethylamine:

[0542]

[0543] To a dichloromethane solution (10 mL) of 2,2,2-trifluoro-N-(4-isopropoxy-3-(4-oxo-2-(piperazin-1-ylmethyl)quinazoline-3(4H)-phenyl)acetamide (95 mg, 0.19 mmol) were added N,N-diisopropylethylamine (50 mg, 0.39 mmol) and 2-(4-chlorophenoxy)acetyl chloride (52 mg, 0.25 mmol) at 0°C, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with dichloromethane (50 mL) and washed with water (100 mL x 2) and saturated brine (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (acetonitrile-water (0.1% formic acid) gradient: 45-50) to obtain a white solid product, compound 192 (18 mg, yield: 14%).

[0544] LC-MS: [M+H] + :658.2.

[0545] HPLC: 98.2%

[0546] 1 HNMR (400MHz, CD 3OD)δ8.25(dd,J=8.0,1.2Hz,1H),7.95-7.89(m,1H),7.86-7.81(m,2H),7.70(d d,J=9.0,2.6Hz,1H),7.65-7.60(m,1H),7.32(d,J=9.0Hz,1H),7.26-7.21(m,2 H),6.95-6.90(m,2H),4.81(s,2H),4.72-4.65(m,1H),4.26-3.69(m,5H),3.47 -3.29(m,3H),3.26-2.98(m,2H),1.23(d,J=6.0Hz,3H),1.11(d,J=6.0Hz,3H).

[0547] Embodiment 37

[0548]

[0549] Referring to Example 36, methanesulfonyl chloride was substituted for trifluoroacetic anhydride to obtain the target product Compound 195 (26.3 mg)

[0550] LC-MS: [M+H] + :640.3.

[0551] HPLC: 99.5%

[0552] 1 HNMR (400MHz, CD 3 OD)δ8.25(d,J=7.6Hz,1H),7.92-7.85(m,2H),7.63(t,J=7.6Hz,1H),7.4 4-7.35(m,2H),7.29-7.23(m,3H),7.00-6.89(m,2H),4.83(s,2H),4.65-4 .62(m,1H),4.35-4.20(m,1H),4.00-3.79(m,4H),3.52-3.21(m,4H),3.2 2-3.19(m,1H),3.00(s,3H),1.22(d,J=6.0Hz,3H),1.09(d,J=6.0Hz,3H).

[0553] Embodiment 38

[0554]

[0555] Synthesis of 6-hydroxy-7-nitro-3,4-dihydroisoquinolin-1(2H)-one:

[0556]

[0557] At -10 ° C, sodium nitrate (170.4 mg, 2.00 mmol) was added to a solution of 6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (327.0 mg, 2.00 mmol) in concentrated sulfuric acid (5 mL), and stirred at -10 ° C for 2 hours. The reactant was quenched by adding ice cubes, diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic layer was washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether=1 / 1) to give the product 38-2 (150 mg, yield: 35%) as a white solid.

[0558] LC-MS: [M+H] + :209.0.

[0559] 1 H NMR: (400MHz, DMSO-d 6 )δ11.58(s,1H),8.29(s,1H),8.03(s,1H),7.01(s,1H),3.42-3.37(m,2H),2.91(d,J=6.4Hz,2H).

[0560] Synthesis of 6-isopropoxy-7-nitro-3,4-dihydroisoquinolin-1(2H)-one:

[0561]

[0562] Potassium carbonate (199.2 mg, 1.44 mmol) was added to a solution of 6-hydroxy-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (150.0 mg, 0.72 mmol) in N,N-dimethylformamide (10 mL). After stirring for 15 minutes, 2-iodopropane (183.8 mg, 1.08 mmol) was added and the mixture was stirred at 70 ° C for 16 hours. Dilute with water (30 mL), extract with ethyl acetate (30 mL x 3), wash the combined organic layer with saturated sodium chloride solution (60 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the product 38-3 (170 mg, yield: 94%) as a white solid.

[0563] LC-MS: [M+H] + :251.1.

[0564] Synthesis of 2-cyclopropyl-6-isopropoxy-7-nitro-3,4-dihydroisoquinolin-1(2H)-one:

[0565]

[0566] Cyclopropylboronic acid (68.7 mg, 0.80 mmol), copper acetate (72.6 mg, 0.40 mmol), 4-dimethylaminopyridine (195.3 mg, 1.6 mmol) and pyridine (79.1 mg, 1.00 mmol) were added to a solution of 6-isopropoxy-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.40 mmol) in 1,4-dioxane (10 mL), and then reacted at 100 ° C for 16 hours under an oxygen atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with aqueous sodium chloride solution (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the product 38-3 (70 mg, yield: 57%) as a white solid.

[0567] LC-MS: [M+H] + :291.1.

[0568] Synthesis of 7-amino-2-cyclopropyl-6-isopropoxy-3,4-dihydroisoquinolin-1(2H)-one:

[0569]

[0570] Palladium hydroxide on carbon (60.4 mg, 25% water content) was added to a solution of 2-cyclopropyl-6-isopropoxy-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (30 mg, 0.10 mmol) in methanol (20 mL), and the mixture was hydrogenated with a hydrogen balloon for 3 hours. The filtrate was then collected by filtration and concentrated under reduced pressure to give a white solid product 38-4 (25 mg, yield: 96%).

[0571] LC-MS: [M+H] + :261.2.

[0572] Synthesis of 2-(chloromethyl)-3-(2-cyclopropyl-6-isopropoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)quinazolin-4(3H)-one:

[0573]

[0574] To a solution of 2-(2-chloroacetylamino)benzoic acid (40.0 mg, 0.19 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (29.1 mg, 0.22 mmol), stirred for 2 minutes, phosphorus trichloride (64.3 mg, 0.47 mmol) was added, stirred for 10 minutes, and a solution of 7-amino-2-cyclopropyl-6-isopropoxy-3,4-dihydroisoquinolin-1(2H)-one (48.8 mg, 0.19 mmol) dissolved in acetonitrile (2 mL) was added, and the mixture was heated under reflux for 6 hours, cooled to room temperature, and then concentrated in vacuo. The residue was diluted with aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol=15 / 1) to give the product 38-5 (40 mg, yield: 50%) as a white solid.

[0575] LC-MS: [M+H] + :438.1.

[0576] Synthesis of 3-(2-cyclopropyl-6-isopropoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one:

[0577]

[0578] 2-(Chloromethyl)-3-(2-cyclopropyl-6-isopropoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)quinazolin-4(3H)-one (40 mg, 0.09 mmol) and piperazine (23.6 mg, 0.27 mmol) were dissolved in tetrahydrofuran (20 mL) and the mixture was heated under reflux for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid 38-6 (35 mg crude product) which was directly used in the next step.

[0579] LC-MS: [M+H] + :488.3.

[0580] Synthesis of 2-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)methyl)-3-(2-cyclopropyl-6-isopropoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)quinazolin-4(3H)-one:

[0581]

[0582] To a solution of 3-(2-cyclopropyl-6-isopropoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one (35 mg, 0.07 mmol) in dichloromethane (20 mL) were added N,N-diisopropylethylamine (13.9 mg, 0.10 mmol) and 2-(4-chlorophenoxy)acetyl chloride (14.7 mg, 0.17 mmol), and the mixture was stirred at room temperature for 6 hours. After adding aqueous sodium bicarbonate solution (20 mL), the mixture was extracted with dichloromethane (30 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a crude product, and then purified by preparative plate (petroleum ether / ethyl acetate = 1 / 1) to give compound 198 (19.6 mg, yield: 41%) as a white solid.

[0583] LC-MS: [M+H] + :656.2.

[0584] HPLC:98.08%.

[0585] 1 H NMR: (400MHz, CD 3 OD)δ8.25(dd,J=8.0,1.2Hz,1H),8.02(s,1H),7.94-7.89(m,1H),7.80(d,J=8.0Hz,1H),7.64 -7.59(m,1H),7.29-7.25(m,2H),7.13(s,1H),6.96-6.93(m,2H),4.80-4.75(m,3H),3.72-3.6 4(m,2H),3.60-3.35(m,6H),3.10-3.08(m,2H),2.88-2.83(m,1H),2.64-2.40(m,2H),2.34-2. 07(m,2H),1.25(d,J=6.0Hz,3H),1.19(d,J=6.0Hz,3H),0.95-0.90(m,2H),0.81-0.77(m,2H).

[0586] Example 39 / 40

[0587]

[0588] Compound 198 (17.6 mg) was chiral separated by SFC (chromatographic column: OJ-H 250 mm × 20 mm, 5 μm, mobile phase: carbon dioxide-methanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (5.2mg, 5.5mg)

[0589] Single configuration compound (short retention time)

[0590] It was analyzed by chiral analysis chromatography conditions, RT = 2.11min

[0591] LC-MS: [M+H] + :656.2.

[0592] HPLC: 100%.

[0593] 1 H NMR: (400MHz, CD 3 OD)δ8.25(dd,J=8.0,1.2Hz,1H),8.02(s,1H),7.94-7.89(m,1H),7.80(d,J=8.0Hz,1H),7.64 -7.59(m,1H),7.29-7.25(m,2H),7.13(s,1H),6.96-6.93(m,2H),4.80-4.75(m,3H),3.72-3.6 4(m,2H),3.60-3.35(m,6H),3.10-3.08(m,2H),2.88-2.83(m,1H),2.64-2.40(m,2H),2.34-2. 07(m,2H),1.25(d,J=6.0Hz,3H),1.19(d,J=6.0Hz,3H),0.95-0.90(m,2H),0.81-0.77(m,2H).

[0594] Single configuration compound (longer retention time)

[0595] It was analyzed by chiral analysis chromatography conditions, RT = 4.27min

[0596] LC-MS: [M+H] + :656.2.

[0597] HPLC: 97.07%.

[0598] 1 H NMR: (400MHz, CD 3OD)δ8.25(dd,J=8.0,1.2Hz,1H),8.02(s,1H),7.94-7.89(m,1H),7.80(d,J=8.0Hz,1H),7.64 -7.59(m,1H),7.29-7.25(m,2H),7.13(s,1H),6.96-6.93(m,2H),4.80-4.75(m,3H),3.72-3.6 4(m,2H),3.60-3.35(m,6H),3.10-3.08(m,2H),2.88-2.83(m,1H),2.64-2.40(m,2H),2.34-2. 07(m,2H),1.25(d,J=6.0Hz,3H),1.19(d,J=6.0Hz,3H),0.95-0.90(m,2H),0.81-0.77(m,2H).

[0599] Embodiment 41

[0600]

[0601] Referring to Example 20, 41-1 was substituted for 1-4 to obtain the target compound 204 (7 mg)

[0602] LC-MS: [M+H]+: 669.0.

[0603] HPLC:99.79%.

[0604] 1H NMR: (400MHz, CD 3 OD)δ8.30(d,J=8.2Hz,1H),7.94-7.89(m,1H),7.80-7.76(m,1H),7.70(d,J=8.0Hz,1H),7.58-7. 54(m,1H),7.28-7.26(m,2H),7.09(s,1H),6.97-6.91(m,2H),6.84-6.83(m,1H),4.81-4.71(m,3 H),3.75-3.62(m,3H),3.60-3.41(m,4H),3.11-3.02(m,3H),2.96-2.81(m,3H),2.78-2.70(m,1H ),1.27-1.16(m,6H),0.94-0.90(m,2H),0.79-0.77(m,3H),0.63-0.62(m,1H),0.56-0.55(m,1H).

[0605] Embodiment 42

[0606]

[0607] Referring to Example 1, cyclopropanol was substituted for isopropanol 1-2 to obtain the target compound 6 (30 mg)

[0608] LC-MS: [M+H] + :645.0.

[0609] HPLC: 98.9%.

[0610] 1 H NMR(400MHz,MeOD)δ8.23(d,J=7.0Hz,1H),7.90-7.88(m,2H),7.76(d,J=8.0H z,1H),7.63-7.56(m,2H),7.28-7.26(m,2H),6.96-6.94(m,2H),4.81-4.71(m, 2H),4.05-4.03(m,1H),3.82-3.70(m,1H),3.64-3.62(m,2H),3.30-3.04(m,2H ),2.79-2.74(m,2H),2.33-2.28(m,2H),0.86-0.84(m,2H),0.77-0.60(m,5H).

[0611] Example 43 / 44

[0612]

[0613] Compound 6 (30 mg) was chiral separated by SFC (chromatographic column: OJ-H 250 mm × 20 mm, 5 μm, mobile phase: carbon dioxide-methanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (13.1mg, 12.9mg)

[0614] Single configuration compound (short retention time)

[0615] It was analyzed by chiral analysis chromatography conditions, RT = 2.05min

[0616] LC-MS: [M+H] + :645.0.

[0617] HPLC: 98.9%.

[0618] 1H NMR(400MHz,MeOD)δ8.23(d,J=7.0Hz,1H),7.90-7.88(m,2H),7.76(d,J=8.0H z,1H),7.63-7.56(m,2H),7.28-7.26(m,2H),6.96-6.94(m,2H),4.81-4.71(m, 2H),4.05-4.03(m,1H),3.82-3.70(m,1H),3.64-3.62(m,2H),3.30-3.04(m,2H ),2.79-2.74(m,2H),2.33-2.28(m,2H),0.86-0.84(m,2H),0.77-0.60(m,5H).

[0619] Single configuration compound (longer retention time)

[0620] It was analyzed by chiral analysis chromatography conditions, RT = 2.81min

[0621] LC-MS: [M+H] + :645.0.

[0622] HPLC: 95.9%.

[0623] 1 H NMR(400MHz,MeOD)δ8.23(d,J=7.0Hz,1H),7.90-7.88(m,2H),7.76(d,J=8.0H z,1H),7.63-7.56(m,2H),7.28-7.26(m,2H),6.96-6.94(m,2H),4.81-4.71(m, 2H),4.05-4.03(m,1H),3.82-3.70(m,1H),3.64-3.62(m,2H),3.30-3.04(m,2H ),2.79-2.74(m,2H),2.33-2.28(m,2H),0.86-0.84(m,2H),0.77-0.60(m,5H).

[0624] Example 45 / 46

[0625]

[0626] Compound 1 (40 mg) was chirally separated by SFC (chromatographic column: WHELK-O1 250 mm × 21.1 mm, 5 μm, mobile phase: carbon dioxide-methanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (6.9mg, 8.1mg)

[0627] Single configuration compound (short retention time)

[0628] It was analyzed by chiral analysis chromatography conditions, RT = 8.7min

[0629] LC-MS: [M+H] + :615.2.

[0630] HPLC: 99.74%

[0631] 1 HNMR (400MHz, CD 3 OD)δ8.25(d,J=7.9Hz,1H),7.96-7.85(m,3H),7.81(s,1H),7.63(t,J=7.5Hz,1H),7.46(d,J=8.9Hz,1H),7.27-7.22(m,2H),6.97-6. 91(m,2H),4.86-4.79(m,4H),4.32-4.27(m,1H),3.95-3.91(m,4H),3.56-3.34(m,4H),1.26(d,J=6.0Hz,3H),1.16(d,J=6.0Hz,3H).

[0632] Single configuration compound (longer retention time)

[0633] It was analyzed by chiral analysis chromatography conditions, RT = 11.45min

[0634] LC-MS: [M+H] + :615.2.

[0635] HPLC: 99.66%

[0636] 1 HNMR (400MHz, CD 3 OD)δ8.25(d,J=7.9Hz,1H),7.96-7.85(m,3H),7.81(s,1H),7.63(t,J=7.5Hz,1H),7.46(d,J=8.9Hz,1H),7.27-7.22(m,2H),6.97-6. 91(m,2H),4.86-4.79(m,4H),4.32-4.27(m,1H),3.95-3.91(m,4H),3.56-3.34(m,4H),1.26(d,J=6.0Hz,3H),1.16(d,J=6.0Hz,3H).

[0637] Embodiment 47

[0638]

[0639] Synthesis of 3-isopropoxy-6-(trifluoromethyl)pyridin-2-amine:

[0640]

[0641] To a solution of 2-bromo-3-isopropoxy-6-(trifluoromethyl)pyridine (500 mg, 1.75 mmol) in ethylene glycol (5 mL) and ammonia (5 mL), cuprous oxide (25 mg, 0.175 mmol), DMEDA (15.46 mg, 0.175 mmol) and potassium carbonate (242.4 mg, 1.75 mmol) were added, and the mixture was stirred at 80 ° C in a sealed pot for 15 hours. Water (20 mL) was added to quench the reaction. It was extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a colorless liquid propoxy-6-(trifluoromethyl)pyridine-2-amine (120 mg, yield: 27.8%).

[0642] LC-MS: [M+H] + :221.0.

[0643] Synthesis of 2-(chloromethyl)-3-(3-isopropoxy-6-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one:

[0644]

[0645] To a solution of 2-(2-chloroacetylamino)benzoic acid (100 mg, 0.468 mmol) in acetonitrile (10 mL), DIEA (72.6 mg, 0.561 mmol) was added. The mixture was stirred at 25 ° C for 5 minutes, and then phosphorus trichloride (160.7 mg, 1.17 mmol) was added. The mixture was stirred at 25 ° C for 10 minutes. 3-isopropoxy-6-(trifluoromethyl)pyridine-2-amine (103.5 mg, 0.468 mmol) was added later, and the mixture was stirred at 80 ° C for 15 hours. Water (20 mL) was added to quench the reaction. Extract with ethyl acetate (20 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product. The crude product was purified by thin layer chromatography (petroleum ether: ethyl acetate = 3: 1) to give a white solid 47-3 (90 mg, yield: 43.9%).

[0646] LC-MS: [M+H] + :398.0.

[0647] Synthesis of (S)-4-((3-(3-isopropoxy-6-(trifluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester:

[0648]

[0649] To 2-(chloromethyl)-3-(3-isopropoxy-6-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one (100 mg, 0.25 mmol) in acetonitrile (20 mL), tert-butyl-(S)-3-methylpiperazine-1-carboxylate (50.4 mg, 0.25 mmol), potassium carbonate (51.9 mg, 0.376 mmol), potassium iodide (41.6 mg, 0.25 mmol) were added. The mixture was stirred at 80 °C for 5 hours. Water (20 mL) was added for dilution. It was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product. The crude product was purified by thin layer chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid 47-4 (110 mg, yield: 62.2%).

[0650] LC-MS: [M+H] + :562.0.

[0651] Synthesis of (S)-3-(3-isopropoxy-6-(trifluoromethyl)pyridin-2-yl)-2-((2-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one:

[0652]

[0653] Trifluoroacetic acid (1 mL) was added to a dichloromethane solution (5 mL) of 47-4 (110 mg, 0.195 mmol), and the mixture was stirred at 25° C. for 15 hours. The mixture was concentrated in vacuo to give a crude product 47-5 (90 mg, yield: 69.7%), which was directly used in the next step.

[0654] LC-MS: [M+H] + :462.1.

[0655] Synthesis of (S)-2-((4-(2-(4-chlorophenoxy)acetyl)-2-methylpiperazin-1-yl)methyl)-3-(3-isopropoxy-6-(trifluoromethyl)pyridin-2-yl)quinazolin-4(3H)-one:

[0656]

[0657] To a dichloromethane solution (5 mL) of 47-5 (80 mg, 0.173 mmol), 2-(4-chlorophenoxy)acetyl chloride (35.4 mg, 0.173 mmol) and DIEA (44.7 mg, 0.346 mmol) were added, and the mixture was stirred at 25°C for 15 hours. The organic phase was concentrated in vacuo to obtain a crude product. The crude product was purified by HPLC ((ACN-H2O-(0.1% TFA), 20-30%) to obtain the product compound 207 (31.8 mg, yield: 28.2%)

[0658] LC-MS: [M+H] + :630.0.

[0659] HPLC: 96.7%.

[0660] 1 H NMR (400MHz, CD 3 OD)δ8.24(d,J=8.0Hz,1H),8.04-7.95(m,1H),7.89-7.78(m,3H),7.62(t,J=7.6Hz,1H),7.28-7.16(m,2H),6.90-6.85(m,2H),4.8 7-4.84(m,1H),4.76-4.74(m,2H),4.25-3.80(m,2H),3.73-3.30(m,3H),3.22-2.36(m,4H),1.32-1.22(m,6H),1.17-0.82(m,3H).

[0661] Embodiment 48

[0662]

[0663] Synthesis of tert-butyl 3-formyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate:

[0664]

[0665] At -78 ° C, to a solution of tert-butyl 5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (200.0 mg, 0.89 mmol) in tetrahydrofuran (10 mL) was slowly added n-butyl lithium (0.54 mL, 1.33 mmol, 2.5 Min Hexane), kept stirring at -78 ° C for 1 hour, N, N-dimethylformamide (130.4 mg, 1.78 mmol) was added, and the mixture was warmed to room temperature and stirred for 16 hours. Saturated aqueous ammonium chloride solution (5 mL) was added to quench, extracted with ethyl acetate (30 mL x 3), the combined organic layer was washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the product 48-2 (170 mg, yield: 65%) as a white solid.

[0666] LC-MS: [M+H] + :252.1.

[0667] Synthesis of tert-butyl 3-(hydroxymethyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate:

[0668]

[0669] At 0°C, sodium borohydride (51.0 mg, 1.35 mmol) was added to a solution of 48-2 (170 mg, 0.67 mmol) in methanol (20 mL), and then the mixture was heated to room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was added with saturated sodium chloride aqueous solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol=15 / 1) to give the product 48-3 (70 mg, yield: 39%) as a white solid.

[0670] LC-MS: [M+H] + :254.1.

[0671] Synthesis of tert-butyl 3-((4-chlorophenoxy)methyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate:

[0672]

[0673] Under nitrogen protection at 0°C, p-chlorophenol (30.4 mg, 0.24 mmol), triphenylphosphine (92.9 mg, 0.35 mmol) and diisopropyl azodicarboxylate (71.6 mg, 0.35 mmol) were added to a solution of 48-3 (60.0 mg, 0.24 mmol) in tetrahydrofuran (20 mL), and then the mixture was warmed to room temperature for 16 hours. The mixture was quenched with saturated aqueous sodium chloride solution (20 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 15 / 1) to give a white solid product 48-4 (50 mg crude) which was directly used in the next step.

[0674] LC-MS: [M+H] + :364.0.

[0675] Synthesis of 3-((4-chlorophenoxy)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine:

[0676]

[0677] To a solution of 48-4 (50.0 mg, 0.12 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL), stirred at room temperature for 3 hours, and concentrated under reduced pressure to give a white solid 48-5 (60 mg crude) which was directly used in the next reaction.

[0678] LC-MS: [M+H] + :264.1.

[0679] Synthesis of 2-((3-((4-chlorophenoxy)methyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methyl]-3-(2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one:

[0680]

[0681] 2-(Chloromethyl)-3-(2-isopropoxy-5-(trifluoromethyl)phenyl)quinazoline-4(3H)-one 18-1 (45.3 mg, 0.11 mmol), potassium carbonate (62.9 mg, 0.45 mmol) and potassium iodide (18.9 mg, 0.11 mmol) were added to a solution of 48-5 (30 mg, 0.11 mmol) in acetonitrile (20 mL), and the mixture was heated under reflux for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, and then purified by high performance liquid preparative purification to obtain compound 208 (6.1 mg, 8%) as a white solid.

[0682] LC-MS: [M+H] + :623.9.

[0683] HPLC: 97.96%.

[0684] 1 H NMR: (400MHz, CD 3 OD)δ8.25(d,J=8.0Hz,1H),7.94-7.90(m,1H),7.83-7.77(m,3H),7.64-7.60(m,1H) ),7.33-7.29(m,2H),7.16(d,J=9.4Hz,1H),7.07-7.03(m,2H),6.68(s,1H),5.12(s ,2H),4.47-4.43(m,1H),4.06-4.00(m,1H),3.81-3.79(m,1H),3.70-3.60(m,2H), 3.57-3.50(m,2H),2.75-2.71(m,2H),1.13(d,J=6.0Hz,3H),1.03(d,J=6.0Hz,3H).

[0685] Example 49 / 50

[0686]

[0687] Compound 208 (4.1 mg) was chirally separated by SFC (chromatographic column: IC 250 mm × 20 mm, 5 μm, mobile phase: carbon dioxide-methanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (1.2mg, 0.9mg)

[0688] Single configuration compound (short retention time)

[0689] It was analyzed by chiral analysis chromatography conditions, RT = 4.03min

[0690] LC-MS: [M+H] + :623.9.

[0691] HPLC:88.23%.

[0692] 1 H NMR: (400MHz, CD 3 OD)δ8.25(d,J=8.0Hz,1H),7.94-7.90(m,1H),7.83-7.77(m,3H),7.64-7.60(m,1H) ),7.33-7.29(m,2H),7.16(d,J=9.4Hz,1H),7.07-7.03(m,2H),6.68(s,1H),5.12(s ,2H),4.47-4.43(m,1H),4.06-4.00(m,1H),3.81-3.79(m,1H),3.70-3.60(m,2H), 3.57-3.50(m,2H),2.75-2.71(m,2H),1.13(d,J=6.0Hz,3H),1.03(d,J=6.0Hz,3H).

[0693] Single configuration compound (longer retention time)

[0694] It was analyzed by chiral analysis chromatography conditions, RT = 4.44min

[0695] LC-MS: [M+H] + :623.9.

[0696] HPLC: 95.26%.

[0697] 1 H NMR: (400MHz, CD 3OD)δ8.25(d,J=8.0Hz,1H),7.94-7.90(m,1H),7.83-7.77(m,3H),7.64-7.60(m,1H) ),7.33-7.29(m,2H),7.16(d,J=9.4Hz,1H),7.07-7.03(m,2H),6.68(s,1H),5.12(s ,2H),4.47-4.43(m,1H),4.06-4.00(m,1H),3.81-3.79(m,1H),3.70-3.60(m,2H), 3.57-3.50(m,2H),2.75-2.71(m,2H),1.13(d,J=6.0Hz,3H),1.03(d,J=6.0Hz,3H).

[0698] Embodiment 51

[0699]

[0700] Synthesis of tert-butyl 3-hydroxymethyl-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate:

[0701]

[0702] To a solution of 6-tert-butyl 3-ethyl 2-methyl-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-3,6-dicarboxylate 51-1 (65 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (17.5 mg, 0.44 mmol) at 0°C. The mixture was stirred at room temperature for 4 hours. The reaction solution was quenched with saturated ammonium chloride solution. The reaction solution was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product 51-2 (65 mg) in the form of a transparent oil, which was directly used in the next step.

[0703] LC-MS: [M+H] + :268.1.

[0704] Synthesis of tert-butyl 3-chloromethyl-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate:

[0705]

[0706] To a solution of 51-2 (65 mg, 0.24 mmol) in dichloromethane (10 mL) was added thionyl chloride (43 mg, 0.36 mmol) at room temperature. The mixture was stirred at 40 ° C for 6 hours. The reaction solution was diluted with dichloromethane (50 mL) and washed with water (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oily crude product 51-3 (51 mg, yield: 51.4%), which was directly used for the next step reaction.

[0707] LC-MS: [M+H] + :286.2.

[0708] Synthesis of tert-butyl 3-((4-chlorophenoxy)methyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate:

[0709]

[0710] To a solution of 51-3 (50 mg, 0.17 mmol) in acetonitrile (5 mL) was added 4-chlorophenol (27 mg, 0.21 mmol) and potassium carbonate (36 mg, 0.26 mmol) at room temperature. The mixture was stirred at 80 ° C for 16 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (50 mL) and washed with water (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain product 51-4 (70 mg yield: 84.7%).

[0711] LC-MS: [M+H] + :378.1.

[0712] Synthesis of 3-((4-chlorophenoxy)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine:

[0713]

[0714] Trifluoroacetic acid (2 mL) was added to a solution of 51-4 (66 mg, 0.17 mmol) in dichloromethane (10 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The solution was concentrated under vacuum to give the product 51-5 (70 mg crude product) which was directly used in the next step.

[0715] LC-MS: [M+H] + :278.2.

[0716] Synthesis of 2-((3-((4-chlorophenoxy)methyl)-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[34-c]pyridin-6-yl)methyl)-3-(2-isopropoxy-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one:

[0717]

[0718] To a solution of 3-((4-chlorophenoxy)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (70 mg, 0.18 mmol) 51-5 in acetonitrile (10 mL) was added 18-1 (49 mg, 0.18 mmol), potassium iodide (38 mg, 0.23 mmol) and potassium carbonate (49 mg, 0.35 mmol) at room temperature. The mixture was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (50 mL). The organic phase was washed with water (300 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (acetonitrile-water (0.1% formic acid) gradient: 50-70) to obtain compound 214 (19.57 mg, yield: 17.6%).

[0719] LC-MS: [M+H] + :638.3.

[0720] HPLC: 99.8%

[0721] 1 HNMR (400MHz, CD 3 OD)δ8.26-8.24(m,1H),7.91-7.84(m,1H),7.79-7.68(m,3H),7.57(t,J=7.6 Hz,1H),7.26-7.19(m,2H),7.12(d,J=8.8Hz,1H),6.96-6.87(m,2H),5.00(s ,2H),4.45-4.41(m,1H),3.64-3.59(m,1H),3.59(s,3H),3.44-3.40(m,1H), 3.34(s,2H),2.53-2.19(m,4H),1.31(d,J=6.0Hz,3H),1.13(d,J=6.0Hz,3H).

[0722] Example 52 / 53

[0723]

[0724] Compound 214 (17 mg) was chiral separated by SFC (chromatographic column: AD-H 250 mm × 20 mm, 5 μm, mobile phase: carbon dioxide-ethanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (4.6mg, 4.8mg)

[0725] Single configuration compound (short retention time)

[0726] It was analyzed by chiral analysis chromatography conditions, RT = 2.43min

[0727] LC-MS: [M+H] + :638.3.

[0728] HPLC: 99.8%

[0729] 1 HNMR (400MHz, CD 3 OD)δ8.26-8.24(m,1H),7.91-7.84(m,1H),7.79-7.68(m,3H),7.57(t,J=7.6 Hz,1H),7.26-7.19(m,2H),7.12(d,J=8.8Hz,1H),6.96-6.87(m,2H),5.00(s ,2H),4.45-4.41(m,1H),3.64-3.59(m,1H),3.59(s,3H),3.44-3.40(m,1H), 3.34(s,2H),2.53-2.19(m,4H),1.31(d,J=6.0Hz,3H),1.13(d,J=6.0Hz,3H).

[0730] Single configuration compound (longer retention time)

[0731] It was analyzed by chiral analysis chromatography conditions, RT = 3.15min

[0732] LC-MS: [M+H] + :638.3.

[0733] HPLC: 99.8%

[0734] 1 HNMR (400MHz, CD 3OD)δ8.26-8.24(m,1H),7.91-7.84(m,1H),7.79-7.68(m,3H),7.57(t,J=7.6 Hz,1H),7.26-7.19(m,2H),7.12(d,J=8.8Hz,1H),6.96-6.87(m,2H),5.00(s ,2H),4.45-4.41(m,1H),3.64-3.59(m,1H),3.59(s,3H),3.44-3.40(m,1H), 3.34(s,2H),2.53-2.19(m,4H),1.31(d,J=6.0Hz,3H),1.13(d,J=6.0Hz,3H).

[0735] Example 54 / 55

[0736]

[0737] Compound 17 (14 mg) was chirally separated by SFC (chromatographic column: WHELK-O1 250 mm × 21.1 mm, 5 μm, mobile phase: carbon dioxide-methanol (NH 4 OH 0.2%) gradient: 0~40%) to obtain the title compound (2.9mg, 3.5mg)

[0738] Single configuration compound (short retention time)

[0739] It was analyzed by chiral analysis chromatography conditions, RT = 8.84min

[0740] LC-MS: [M+H] + :628.9.

[0741] HPLC: 99.7%

[0742] 1 H NMR (400MHz, CD 3 OD)δ8.24(d,J=8.0Hz,1H),7.84-7.82(m,2H),7.72(s,1H),7.62(t,J=7.2Hz,1H),7.28-7.22(m,3H),6.93-6.90(m,2H),4.82- 4.75(m,3H),3.98-3.94(m,1H)3.86-3.44(m,5H),3.25-2.88(m,4H),2.57(s,3H),1.25(d,J=6.0Hz,3H),1.15(d,J=6.0Hz,3H).

[0743] Single configuration compound (longer retention time)

[0744] It was analyzed by chiral analysis chromatography conditions, RT = 11.45min

[0745] LC-MS: [M+H] + :628.9.

[0746] HPLC: 99.1%

[0747] 1 H NMR (400MHz, CD 3 OD)δ8.24(d,J=8.0Hz,1H),7.84-7.82(m,2H),7.72(s,1H),7.62(t,J=7.2Hz,1H),7.28-7.22(m,3H),6.93-6.90(m,2H),4.82- 4.75(m,3H),3.98-3.94(m,1H)3.86-3.44(m,5H),3.25-2.88(m,4H),2.57(s,3H),1.25(d,J=6.0Hz,3H),1.15(d,J=6.0Hz,3H).

[0748] In the following embodiments, the IKE structure is as follows:

[0749]

[0750] Example 56 Activity test of the compound in inhibiting glutamate release

[0751] The following is an in vitro assay for the inhibitory activity of compounds in glutamate release. This assay can be used to evaluate or characterize the inhibitory activity of compounds of the invention as SLC7A11 inhibitors.

[0752] 1. Cell plating:

[0753] 1) T75 culture flask, discard the culture, add 1 ml PBS to wash once, and aspirate and discard the PBS;

[0754] 2) Add 1 ml of 0.25% trypsin and digest in a 37°C cell culture incubator for 1 min. Observe the rounding and shedding of cells under a microscope.

[0755] 3) Add 1 ml of complete medium to terminate digestion, add 2 ml of medium to a 15 ml centrifuge tube and centrifuge (1000 rpm, 3 min);

[0756] 4) After discarding the supernatant, add 1 ml of complete culture medium, gently pipette to mix, take 10 μl and add it to 190 μl of complete culture medium (diluted 20 times), gently pipette to mix and count;

[0757] 5) According to the counting results, dilute the cells to 6x10 5 / ml, vortex each tube before plating, then add to the separation tank, spread the plate with a dispenser, 100ul / well;

[0758] 2. Compound treatment and fluorescence detection

[0759] 1) 60,000 cells / well of a 96-well plate, cell density > 95% confluence, 24 hours after cell plating, discard the culture medium, wash out the culture medium containing glutamine with EBSS (Earle's Balanced Salt Solution), wash three times.

[0760] 2) Preparation of compounds: Add 10 ml EBSS to a 15 ml centrifuge tube, add 100 ul 8 mM cystein (100x), vortex to mix, take out 1 ml as the Total group, use this cystein-containing EBSS to prepare 500 ul 10 uM compound (vortex to mix after preparation), add 0.5‰ DMSO to the remaining cystein-containing EBSS, and then dilute 8 concentration gradients in 3 times (i.e. 10.000, 3.333, 1.111, 0.370, 0.123, 0.041, 0.014, 0.005, DMSO), add drugs, 100 ul / well, and incubate at 37°C for 4 h.

[0761] 3) Use a pipette to remove 90ul of culture medium from each well, and add 45ul of Tris buffer (100mM, pH 7.4) containing glutamate oxidase (0.02U / mL), horseradish peroxidase (0.125U / mL) and Amplex UltraRed (10μM). Detect fluorescence after 15min (Ex 530, Em 590, with shaking).

[0762] 4) Process the data according to the following formula:

[0763] Inhibition Rate (%) = 1-(Unknown-Blank)) / (Totals-Blanks))*100.

[0764] IC of compounds inhibiting glutamate release 50 The (nM) values ​​are shown in Table 1.

[0765] Table 1

[0766]

[0767]

[0768] Example 57 Compounds inhibit the activity of HT1080 cells

[0769] 1. Compound dissolution: Dissolve in DMSO to a 20 mM stock solution

[0770] 2. Cell plating:

[0771] 1) For T75 culture flask, discard the culture, add 2 ml PBS to wash once, and aspirate and discard the PBS;

[0772] 2) Add 1 ml of 0.25% trypsin and digest in a 37°C cell culture incubator for 1 min. Observe the rounding and shedding of cells under a microscope.

[0773] 3) Add 1 ml of complete medium to terminate digestion, add 2 ml of medium to a 1.5 ml centrifuge tube and centrifuge (1000 rpm, 3 min);

[0774] 4) After discarding the supernatant, add 1 ml of complete culture medium, gently pipette to mix, take 10 μl and add it to 190 μl of complete culture medium (diluted 20 times), gently pipette to mix and count;

[0775] 5) According to the counting results, dilute the cells to 1.5x10 5 (Take 5 plates of cells as an example, divide the required cells into 5 15ml centrifuge tubes, fill up to 10ml / tube with complete medium, vortex mix each tube before plating, then add to the separation tank, use a spray gun to spread the plate, 100ul / well, and ensure that the time used to spread each plate is consistent and does not exceed 30s);

[0776] 6) Label the 96-well plates as plate1, plate2, plate3, plate4, and plate5 according to the order of plating.

[0777] 3. Drug preparation:

[0778] 1) Taking a 96-well plate as an example, prepare two 15 ml centrifuge tubes, tube 1 contains 6 ml complete medium + 0.1% DMSO, tube 2 contains 6 ml complete medium + 0.1% Fer-1; tube 3 contains 1 ml complete medium with 0.6% DMSO.

[0779] 2) Prepare 600ul of stock solution (100uM) containing 0.5% compound;

[0780] 3) After the preparation is completed, add 0.5% DMSO to tube 1 and tube 2 in step 1;

[0781] 4) Prepare 2x 9 1.5ml tubes for each compound, add 400ul of the medium in tube 1 to 8 of the tubes, and add 400ul of the medium in tube 2 to the other 8 tubes. Take 200ul of the compound stock solution and add it to the 9 dilution tubes in turn [vortex each tube before adding to the next tube]

[0782] 5) Add the prepared compounds to the 96-well plate. (PBS in the edge wells also needs to be quantified to 100ul)

[0783] 6) Mark the laying time on each board

[0784] CCK8 detection

[0785] 1. Add 10ul of CCK8 to the 96-well plate in the order marked on the 96-well plate using a 10ul single-shot gun (mark the time for adding CCK8 and keep it consistent on each plate). The time between plates also needs to be recorded and kept consistent.

[0786] 2. After 2 hours, take out the wells from the 96-well plate in order to test OD450 (before testing, observe whether there are bubbles. If so, puncture the bubbles with a 1 ml syringe needle).

[0787] In vitro determination of IC of compounds inhibiting HT1080 cell activity 50 The (nM) values ​​are shown in Table 2.

[0788] Table 2:

[0789]

[0790] Example 58 Compounds inhibit the activity of pancreatic cancer Su86.86 cells

[0791] 1. Compound dissolution: Dissolve in DMSO to a 20 mM stock solution

[0792] 2. Cell plating:

[0793] 1) For T75 culture flask, discard the culture, add 2 ml PBS to wash once, and aspirate and discard the PBS;

[0794] 2) Add 1 ml of 0.25% trypsin and digest in a 37°C cell culture incubator for 1 min. Observe the rounding and shedding of cells under a microscope.

[0795] 3) Add 1 ml of complete medium to terminate digestion, add 2 ml of medium to a 1.5 ml centrifuge tube and centrifuge (1000 rpm, 3 min);

[0796] 4) After discarding the supernatant, add 1 ml of complete culture medium, gently pipette to mix, take 10 μl and add it to 190 μl of complete culture medium (diluted 20 times), gently pipette to mix and count;

[0797] 5) According to the counting results, dilute the cells to 1.5x10 5 (Take 5 plates of cells as an example, divide the required cells into 5 15ml centrifuge tubes, fill up to 10ml / tube with complete medium, vortex mix each tube before plating, then add to the separation tank, use a spray gun to spread the plate, 100ul / well, and ensure that the time used to spread each plate is consistent and does not exceed 30s);

[0798] 6) Label the 96-well plates as plate1, plate2, plate3, plate4, and plate5 according to the order of plating.

[0799] Drug preparation:

[0800] 7) Taking a 96-well plate as an example, prepare two 15 ml centrifuge tubes, tube 1 contains 6 ml complete medium + 0.1% DMSO, tube 2 contains 6 ml complete medium + 0.1% Fer-1; tube 3 contains 1 ml complete medium with 0.6% DMSO.

[0801] 8) Prepare 600ul of mother solution (100uM) containing 0.5% compound respectively;

[0802] 9) After the preparation is completed, add 0.5% DMSO to tube 1 and tube 2 in step 1;

[0803] 10) For each compound, prepare 2x 9 1.5ml tubes, add 400ul of the medium in tube 1 to 8 tubes, and add 400ul of the medium in tube 2 to the other 8 tubes. Take 200ul of the compound stock solution and add it to the 9 dilution tubes in turn [vortex each tube before adding to the next tube]

[0804] 11) Add the prepared compounds to the 96-well plate. (PBS in the edge wells also needs to be quantified to 100ul)

[0805] 12) Mark the time of laying each board

[0806] CCK8 detection

[0807] 1. Add 10ul of CCK8 to the 96-well plate in the order marked on the 96-well plate using a 10ul single-shot gun (mark the time for adding CCK8 and keep it consistent on each plate). The time between plates also needs to be recorded and kept consistent.

[0808] 2. After 2 hours, take out the wells from the 96-well plate in order to test OD450 (before testing, observe whether there are bubbles. If so, puncture the bubbles with a 1 ml syringe needle).

[0809] In vitro determination of the IC of the compound in inhibiting pancreatic cancer Su86.86 cells50 The (nM) values ​​are shown in Table 3.

[0810] Table 3

[0811]

[0812] Example 59 Detection of the Effect of Compounds on Promoting Cell Evoked Bone Marrow-derived Dendritic Cells (BMDC) Cell Evoked

[0813] The experimental process is as follows:

[0814] 1) After euthanizing db / db mice, the tibia was removed to isolate bone marrow cells;

[0815] 2) Culture in medium containing 12.5 ng / mL GM-CSF and induce differentiation for 10 days;

[0816] 3) For differentiated BMDC cells, use CellTrace TM The kit was Far red labeled and set aside.

[0817] 4) Resuspend 10 million / mL Jurkat T cells in 1 mL 0.1% BSA solution and use CellTrace TM The kit marked it with Violet;

[0818] 5) The labeled Jurkat T cells were incubated in a medium containing 1 μM staurosporine for 3 hours to induce early cell apoptosis, and the apoptosis rate was detected before use;

[0819] 6) Far red-labeled BMDC cells were mixed with apoptosis-induced Jurkat T cells at a ratio of 1:5, and different concentrations of compounds (including compound 186, compound 199 / 200, compound 184 / 185) were added for treatment and incubated at 37°C for 4 h;

[0820] 7) Transfer the cells to a V-bottom 96-well plate, wash the cells once with staining buffer, centrifuge at 350xg for 5 min, and stain with PI (1:100) for 15 min at room temperature.

[0821] 8) Wash twice with staining buffer, then resuspend the stained cells with 100 μL staining buffer. Use the cells for FACS LSRFortessa analysis.

[0822] The results are as follows Figure 1 As shown, compound 186, compound 199 / 200, and compound 184 / 185 have a significant effect of promoting BMDC efferocytosis and exhibit a good dose effect.

Claims

1. A compound represented by formula (I) or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof: in, X is selected from: N, CR3; Z1 is independently selected from: C, N; Z2 is independently selected from: O, NR6, CR6; Dashed lines indicate no chemical bonds or single bonds; R1 is selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl, alicyclic group optionally substituted by alkyl; R2 and R3 are each independently selected from: H, halogen, alkyl, cyano, haloalkyl, alkenyl, alkynyl, cycloalkyl, alicyclic optionally substituted by alkyl, -N(R6)R7, -OR8, -C(O)N(R9)R 10 、-P(O)(R9)R 10 , -SO2R'; R6 and R7 are each independently selected from: H, alkyl, haloalkyl, cycloalkyl, alicyclic optionally substituted by alkyl, alkanoyl, haloalkanoyl, cycloalkyl-aminoacyl, -SO2R', or, R6 and R7 are connected to each other and to the N to which they are connected to form alicyclic optionally substituted by alkyl; R8 is independently selected from the group consisting of: H, alkyl, haloalkyl, cycloalkyl, alicyclic optionally substituted by alkyl, alkanoyl, haloalkanoyl, heteroaryl; R9, R 10 Each is independently selected from: H, alkyl, haloalkyl, cycloalkyl, heterocyclic group optionally substituted by alkyl, or, when R9 and R 10 When connected to the same N or -P(O), R9 and R 10 It can also form an alicyclic group optionally substituted by an alkyl group together with the N or -P(O) to which it is commonly connected; Each R' is independently selected from: alkyl, haloalkyl, cycloalkyl, alicyclic, amino, alkylamino, cycloalkyl-amino; R4 is selected from: optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alicyclic group, wherein the substituent in the optionally substituted alkyl is selected from: halogen, cyano, hydroxyl, alkoxy; R5 is selected from -CF3, acetyl; The number of substituents in the "alicyclic group optionally substituted by an alkyl group", "haloalkanoyl group", "haloalkyl group" and "optionally substituted alkyl group" is 1 or more, preferably 1, 2 or 3; Optionally, the compound represented by formula (I) is in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture of these isomers.

2. The compound of formula (I) according to claim 1 or its deuterated form, or a pharmaceutically acceptable salt thereof: in, X is: CR3; Z1 is independently selected from: C, N; Z2 is independently selected from: O, NR6, CR6; Dashed lines indicate no chemical bonds or single bonds; R1 is selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl, alicyclic group optionally substituted by alkyl; R2 and R3 are each independently selected from: H, halogen, alkyl, cyano, haloalkyl, alkenyl, alkynyl, cycloalkyl, alicyclic optionally substituted by alkyl, -N(R6)R7, -OR8, -C(O)N(R9)R 10 、-P(O)(R9)R 10 , -SO2R'; R6 and R7 are each independently selected from: H, alkyl, haloalkyl, cycloalkyl, alicyclic optionally substituted by alkyl, alkanoyl, haloalkanoyl, cycloalkyl-aminoacyl, -SO2R', or, R6 and R7 are connected to each other and to the N to which they are connected to form alicyclic optionally substituted by alkyl; R8 is independently selected from the group consisting of: H, alkyl, haloalkyl, cycloalkyl, alicyclic optionally substituted by alkyl, alkanoyl, haloalkanoyl, heteroaryl; R9, R 10 Each is independently selected from: H, alkyl, haloalkyl, cycloalkyl, heterocyclic group optionally substituted by alkyl, or, when R9 and R 10 When connected to the same N or -P(O), R9 and R 10 It can also form an alicyclic group optionally substituted by an alkyl group together with the N or -P(O) to which it is commonly connected; Each R' is independently selected from: alkyl, haloalkyl, cycloalkyl, alicyclic, amino, alkylamino, cycloalkyl-amino; R4 is selected from: optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, alicyclic group, wherein the substituent in the optionally substituted alkyl is selected from: halogen, cyano, hydroxyl, alkoxy; R5 is selected from -CF3, acetyl; The number of substituents in the "alicyclic group optionally substituted by an alkyl group", "haloalkanoyl group", "haloalkyl group" and "optionally substituted alkyl group" is 1 or more, preferably 1, 2 or 3; Optionally, the compound represented by formula (I) is in the form of its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture of these isomers.

3. The compound of formula (I) according to claim 1 or 2, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R5 is selected from Or R2 and R5 together with the benzene ring to which they are connected form the following structure: Each Ra is independently selected from alkyl, haloalkyl; Optionally, R5 is selected from 4. The compound of formula (I) according to any one of claims 1 to 3, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The halogen atoms in the "halogen", "haloalkyl" and "haloalkanoyl" are independently selected from F, Cl, Br and I; Optionally, the alkyl groups in the “alkyl”, “haloalkyl”, “alkoxy”, “alkanoyl”, “haloalkanoyl” and “aliphatic heterocyclic group optionally substituted by alkyl” are each independently C1-C 10 linear or branched alkyl; optionally, C1-C7 linear or branched alkyl; optionally, C1-C5 linear or branched alkyl; optionally, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl ... hexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl or 2,2,3-trimethylbutyl; Optionally, the "alkenyl" is a C2-C 15 Straight or branched alkenyl, optionally C2-C 10 Straight or branched alkenyl, optionally, C2-C8 straight or branched alkenyl, optionally, C2-C6 straight or branched alkenyl, optionally, C2-C4 straight or branched alkenyl, optionally, selected from ethenyl, propenyl, butenyl, pentenyl; Optionally, the "alkynyl" group contains one or more triple bonds. 15 A straight chain or branched alkynyl group, optionally, is C2-C 10 Straight chain or branched chain alkynyl, optionally, C2-C8 straight chain or branched chain alkynyl, optionally, C2-C6 straight chain or branched chain alkynyl, optionally, C2-C4 straight chain or branched chain alkynyl; optionally, selected from ethynyl, propynyl, hexynyl; Optionally, the cycloalkyl in the "cycloalkyl", "cycloalkyl-aminoacyl" and "cycloalkyl-amino" is C3-C 10 Monocyclic or bicyclic cycloalkyl, optionally, is C3-C7 monocyclic cycloalkyl, optionally, is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; Optionally, the alicyclic group in the "alicyclic group", "alicyclic group optionally substituted by an alkyl group" and "alicyclic group-amino" is a 3-10-membered non-aromatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; optionally, the alicyclic group is a 3-10-membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and O on the ring; optionally, the alicyclic group is a 3-6-membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and O on the ring; optionally, the alicyclic group is a 3-10-membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and S on the ring; optionally, the alicyclic group is a 3-10-membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and S on the ring; The heterocycle is a 3-6 membered non-aromatic heterocycle containing 1 or 2 heteroatoms selected from N and S on the ring; optionally, the heterocyclic group in the "heterocyclic group", "heterocyclic group optionally substituted by alkyl" and "heterocyclic group-amino" is selected from methyl-substituted azetidinyl, methyl-substituted azetidinyl, methyl-substituted azetidinyl, methyl-substituted azetidinyl, azetidinyl, azetidinyl, oxolanyl, oxolanyl, azetidinyl, piperidinyl, piperazinyl and alkenylpiperidine; optionally, the heterocyclic group in the "heterocyclic group", "heterocyclic group optionally substituted by alkyl" and "heterocyclic group-amino" is selected from Optionally, the heteroaromatic ring of the "heteroaryl" is a 5-10 membered heteroaromatic ring containing 1-2 heteroatoms selected from N and O on the ring; optionally, the heteroaryl is selected from pyridyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolyl, quinazolinyl; optionally, the heteroaryl is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl.

5. The compound of formula (I) according to any one of claims 1 to 4, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

6. The compound of formula (I) according to any one of claims 1 to 5, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salts include anionic salts and cationic salts of the compound represented by formula (I) or its deuterated product; Optionally, the pharmaceutically acceptable salt includes an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound represented by formula (I) or its deuterated product; optionally, the alkali metal includes sodium, potassium, lithium, and cesium, and the alkaline earth metal includes magnesium, calcium, and strontium; Optionally, the pharmaceutically acceptable salt includes a salt formed by the compound represented by formula (I) or its deuterated product and an organic base; Optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5, 1,8-diazabicyclo[5.4.0]undecene-7, 1,4-diazabicyclo[2.2.2]octane; Optionally, the trialkylamine includes trimethylamine, triethylamine, N-ethyldiisopropylamine; Optionally, the N-alkylmorpholine includes N-methylmorpholine; Optionally, the pharmaceutically acceptable salt includes a salt formed by the compound represented by formula (I) or its deuterated product and an acid; Optionally, the acid includes an inorganic acid and an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, and pamoic acid.

7. A pharmaceutical composition comprising the compound of formula (I) or a deuterated product thereof according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

8. Use of the compound of formula (I) according to any one of claims 1 to 6 or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a SLC7A11 inhibitor.

9. Use of the compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating tumor diseases such as pancreatic cancer, liver cancer, osteosarcoma, glioma, etc.

10. Use of the compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating chronic diseases such as fatty liver, cirrhosis, liver fibrosis, pulmonary fibrosis, diabetic skin lesions, or neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.

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