PRMT5 inhibitor as well as pharmaceutical composition, pharmaceutical preparation and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a PRMT5 inhibitor as well as a pharmaceutical composition, a pharmaceutical preparation and application thereof. Specifically, the compound disclosed by the invention has a structure as shown in a formula I, has excellent in-vitro inhibitory activity on PRMT5, can be used as a PRMT5 small-molecule inhibitor, is used for preventing / treating diseases (such as cancers, cardiovascular diseases or myelofibrosis and the like) which are at least partially mediated by PRMT5, and is used for preparing medicines for preventing / treating the diseases, such as cancers, cardiovascular diseases or myelofibrosis and the like. Good application prospects are realized. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a small molecule inhibitor targeting PRMT5, a pharmaceutical composition and a pharmaceutical preparation containing the small molecule inhibitor, and medical uses thereof. Background Art

[0002] Arginine methylated modification is one of the common types of protein post-translational modification, which refers to the formation of methylation modification on the arginine guanidinium group of the substrate protein. The enzyme that catalyzes the formation of arginine methylation modification is called protein arginine methyltransferase (PRMT). There are 9 members in the arginine methyltransferase family (PRMT1 to PRMT9). They participate in the regulation of various physiological and pathological processes by catalyzing the methylation of various substrate proteins, affecting the stability, localization, activity of substrate proteins, or interacting with substrate proteins. Studies have found that PRMT plays a regulatory role in the occurrence, development, drug resistance or metastasis of tumors, showing its potential as a tumor biomarker or therapeutic target. Two articles in 2016 (Kryukov GV, et al., (2016), Science, doi: 10.1126 / science.aad5214; Mavrakis KJ, et al., (2016), Science, doi: 10.1126 / science.aad5944) first reported the "synthetic lethality" effect of inhibiting PRMT5 in tumors lacking methylthioadenosine phosphorylase (MTAP). Currently, more than 10 PRMT-specific inhibitors have been developed, and some have entered the clinical trial stage.

[0003] Protein arginase methyltransferase 5 (PRMT5) is an epigenetic target with clinical potential. It is a type II arginine methyltransferase that modifies histones and other proteins post-translationally through symmetric dimethylation. PRMT5 plays an important role in regulating key cellular processes, including DNA repair, cell cycle progression, transcriptional regulation, and RNA splicing. Upregulation of PRMT5 levels can lead to the proliferation and invasion of tumor cells in a variety of different cancers, including glioblastoma, melanoma, blood tumors (such as leukemia, lymphoma, multiple myeloma), bladder urothelial carcinoma, colorectal cancer, lung cancer, gastric cancer, ovarian cancer, prostate cancer, etc. At present, drugs that act as PRMT5 inhibitors are all in the clinical stage, among which AMG-193 from Amgen, MRTX1719 from Mirati Therapeutics, SKL27969 from SK Life Science, and TNG908 from Tango Therapeutics have made the fastest progress and have completed Phase I clinical trials.

[0004] In summary, the development of new PRMT5 inhibitors has very important clinical value and significance. Summary of the invention

[0005] Problem that the invention aims to solve

[0006] The present invention is intended to provide a novel small molecule PRMT5 inhibitor, in particular a new compound with good biological properties that can be safely applied to the human body. The present invention is also intended to provide a pharmaceutical composition and a pharmaceutical preparation comprising the inhibitor, and the use thereof in preventing and / or treating PRMT5-related diseases.

[0007] Solutions for solving problems

[0008] In a first aspect, the present invention provides a compound having a structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance (e.g., deuterated substance) or prodrug thereof:

[0009]

[0010] in:

[0011] represents a single bond or a double bond;

[0012] X1 for CR 6 or N;

[0013] X2 for CR 4 or N;

[0014] X3 for CR5 or N;

[0015] X4 for CR 3 or NR 3 ;

[0016] L is a single bond or oxygen;

[0017] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 3-6 membered heterocyclyl;

[0018] m is 0, 1, 2, 3, 4 or 5;

[0019] If present, each R 1 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C≡CR 1a , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0020] If present, each R 1a are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, 4 or 5 R # replace;

[0021] If present, each R # Each independently selected from halogen, cyano, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0022] R 2 is hydrogen or methyl;

[0023] R 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group and -(C 1-6 Alkylene)-NH2;

[0024] If present, R 4 is selected from the group consisting of hydrogen, amino, hydroxyl and carboxyl;

[0025] If present, R 5 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or, R 5 and R 3 Connected to each other 5-10 The ring B of the carbonyl group, the 5-10 membered heterocyclic group and the 5-10 membered heteroaryl group; 5-10 The carbocyclyl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-6 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0026] If present, R 6 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C1-6 Haloalkoxy and -(C 1-6 Alkylene)-NH2.

[0027] In a second aspect, the present invention provides the following compounds or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope-labeled substances (e.g., deuterated substances) or prodrugs thereof:

[0028] (1) 7-phenylquinolin-2-amine;

[0029] (2) 7-(pyridin-3-yl)quinolin-2-amine;

[0030] (3) 7-(pyridin-2-yl)quinolin-2-amine;

[0031] (4) 7-(1-methyl-1H-pyrazol-4-yl)quinolin-2-amine;

[0032] (5) 7-(thiazol-5-yl)quinolin-2-amine;

[0033] (6) 7-(isothiazol-4-yl)quinolin-2-amine;

[0034] (7) 7-(1,5-dimethyl-1H-pyrazol-4-yl)quinolin-2-amine;

[0035] (8) 7-(1-methyl-5-phenyl-1H-pyrazol-4-yl)quinolin-2-amine;

[0036] (9) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)benzonitrile;

[0037] (10) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-methoxybenzonitrile;

[0038] (11) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-chlorobenzonitrile;

[0039] (12) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-methylbenzonitrile;

[0040] (13) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile;

[0041] (14) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxybenzonitrile;

[0042] (15) 3-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-2-naphthocarbonitrile;

[0043] (16) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)benzo[b]thiophene-3-carbonitrile;

[0044] (17) 7-(1-methyl-5-(piperidin-1-yl)-1H-pyrazol-4-yl)quinolin-2-amine;

[0045] (18) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0046] (19) 2-(4-(2-aminoquinolin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0047] (20) 2-(4-(2-aminoquinolin-8-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0048] (21) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxybenzonitrile;

[0049] (22) 2-(4-(2-aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluorobenzonitrile;

[0050] (23) 2-(4-(2-amino-4-methylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0051] (24) 2-(4-(2-amino-4-methylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclobutoxy-3-fluorobenzonitrile;

[0052] (25) 2-(4-(2-amino-4-methylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(cyclopentyloxy)-3-fluorobenzonitrile;

[0053] (26) 2-(4-(2-amino-4-methylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(oxetan-3-yloxy)benzonitrile;

[0054] (27) 2-(4-(2-amino-3-fluoro-4-methylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0055] (28) 2-(4-(2-amino-3-bromo-4-methylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0056] (29) 2-(4-(4-amino-2,3-dihydro-1H-cyclopenta[c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0057] (30) 4-((2-aminoquinolin-7-yl)oxy)-6-cyclopropyloxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile;

[0058] (31) 2-(4-(2-aminoquinazolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0059] (32) 2-(4-(2-amino-3-cyclopropylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile; (33) 2-(4-(2-amino-3-methylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0060] (34) 2-(4-(4-amino-1,3-dihydrofuro[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0061] (35) 2-(4-(4-amino-2,3-dihydrofuro[3,2-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0062] (36) 2-(4-(4-aminoimidazo[1,2-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0063] (37) 2-(4-(2-amino-3,4-dimethylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile; (38) 2-(4-(2-amino-4-cyclopropylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile; (39) 2-(4-(2-amino-4-(difluoromethyl)quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile;

[0064] (40) 2-(4-(2-amino-4-methylquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluoro-4-(prop-1-yn-1-yl)benzonitrile; and

[0065] (41) 2-(4-(2-Aminoquinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthocarbonitrile.

[0066] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label (e.g., deuterated substance) or prodrug, and at least one pharmaceutically acceptable carrier.

[0067] Preferably, in the above-mentioned pharmaceutical composition, the pharmaceutically acceptable carrier includes but is not limited to diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, glidants, flavoring agents, olfactory agents, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, opacifiers (opacifiers), etc.

[0068] In a fourth aspect, the present invention provides a pharmaceutical preparation, which is made of the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label (e.g., deuterated substance) or prodrug, or made of the above-mentioned pharmaceutical composition. Alternatively, the present invention provides a pharmaceutical preparation, which contains the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label (e.g., deuterated substance) or prodrug, or the above-mentioned pharmaceutical composition as an active ingredient.

[0069] In the fifth aspect, the present invention provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label (such as deuterated substance) or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation for the preparation of a drug for preventing and / or treating a disease mediated at least in part by PRMT5. Alternatively, the present invention provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label (such as deuterated substance) or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation for preventing and / or treating a disease mediated at least in part by PRMT5. Alternatively, the present invention provides a method for preventing and / or treating a disease that is at least partially mediated by PRMT5, comprising administering the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance (e.g., deuterated substance) or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation to a subject in need.

[0070] The disease at least partially mediated by PRMT5 herein refers to a disease or its complications that can achieve clinically beneficial effects such as alleviation, improvement, cessation of progression, alleviation or no longer deterioration by inhibiting PRMT5 activity. Preferably, in the above-mentioned use, the disease at least partially mediated by PRMT5 is cancer, cardiovascular disease or myelofibrosis. More preferably, the cancer includes glioblastoma, melanoma, blood tumors (such as leukemia, lymphoma, multiple myeloma), bladder urothelial carcinoma, colorectal cancer, lung cancer, gastric cancer, ovarian cancer, breast cancer, cervical cancer, squamous cell carcinoma, brain tumor, prostate cancer and myelodysplastic syndrome. More preferably, the cardiovascular disease includes myocardial hypertrophy, heart failure and arrhythmia.

[0071] In a sixth aspect, the present invention provides a drug combination form (also referred to as a "drug combination product"), which comprises the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, and at least one additional therapeutic agent.

[0072] Effects of the Invention

[0073] The compounds of the present invention have excellent in vitro inhibitory activity against PRMT5, can be used as PRMT5 small molecule inhibitors, and have excellent pharmacodynamic properties and metabolic stability. The compounds of the present invention can be used to prevent / treat diseases at least partially mediated by PRMT5, and to prepare drugs for preventing / treating such diseases, and have good application prospects and important clinical significance. DETAILED DESCRIPTION

[0074] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein; it should also be understood that the terms used herein are only used to describe and not to limit specific embodiments. In the absence of a definition, the term should be interpreted according to the meaning commonly understood by those skilled in the art.

[0075] [Definition of terms]

[0076] Unless otherwise stated, the following terms have the following meanings.

[0077] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is substantially non-toxic to an organism. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting the compound of the present invention with a pharmaceutically acceptable inorganic acid or organic acid, which are also known as acid addition salts. Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid (which can form sulfates or acid sulfates), phosphoric acid (which can form phosphates or acid phosphates), etc. Common organic acids include, but are not limited to, trifluoroacetic acid, citric acid (which can form citric acid monosalt, disalt or trisalt), maleic acid (which can form maleic acid monosalt or disalt), fumaric acid (which can form fumaric acid monosalt or disalt), succinic acid (which can form succinic acid monosalt or disalt), tartaric acid (which can form tartaric acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), malonic acid (which can form malonic acid monosalt or disalt), malic acid (which can form malic acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), lactic acid, pyruvic acid, salicylic acid, formic acid, acetic acid, propionic acid, benzoic acid, glycolic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Pharmaceutically acceptable salts may also include salts formed by the compounds of the present invention and pharmaceutically acceptable organic or inorganic bases, which are also called base addition salts. Common base addition salts include, but are not limited to, alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts or N-containing organic bases formed by reacting with N-containing groups. + (C 1-6 Common inorganic or organic bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia water, triethylamine or tetrabutylammonium hydroxide. Pharmaceutically acceptable salts can be synthesized by general chemical methods.

[0078] The term "hydrate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and water through non-covalent intermolecular forces. Common hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, and the like. The term "solvate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one solvent molecule through non-covalent intermolecular forces. The term "solvate" includes "hydrates". Common solvates include, but are not limited to, hydrates, ethanolates, acetoneates, and the like. It should be understood that the present invention encompasses all solvate forms having PRMT5 inhibitory activity.

[0079] The term "isomers" refers to compounds that have the same number and types of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0080] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since there are asymmetric centers and other chemical structures that may cause stereoisomerism in the compounds of the present invention, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention and their salts include asymmetric carbon atoms, they can exist in the form of a single stereoisomer, a racemate, an enantiomer, and a mixture of diastereomers. Generally, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds can be prepared or separated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or single stereoisomer-enriched (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85% or ≥80%) mixtures. As described below, a single stereoisomer of a compound is prepared synthetically from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereoisomers followed by separation or recrystallization, chromatography, use of a chiral resolution agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with a specific stereochemistry are either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise stated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

[0081] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0082] The term "cis-trans isomer" refers to stereoisomers formed by the different positions of atoms (or groups) located on both sides of a double bond or ring system relative to a reference plane; in cis isomers, the atoms (or groups) are located on the same side of the double bond or ring system, and in trans isomers, the atoms (or groups) are located on opposite sides of the double bond or ring system. Unless otherwise indicated, all cis-trans isomeric forms of the compounds of the present invention are within the scope of the present invention.

[0083] The term "isotopically labeled" refers to a compound formed by replacing a specific atom in a structure with an isotope thereof. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 For example, deuterated species may be defined as a compound in which a hydrogen atom is replaced with deuterium (ie, D), and the amount of deuterium at that position greatly exceeds (eg, at least 1000 times exceeds) the abundance of deuterium that occurs naturally.

[0084] The term "prodrug" refers to a derivative compound that can directly or indirectly provide a compound of the present invention after administration to a patient. Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to a patient (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

[0085] The term "aryl" refers to a monocyclic or fused polycyclic group with aromatic properties (which may be substituted or fused to other fragments), whose ring atoms are all C atoms, for example, 6 to 20, 6 to 14 or 6 to 10 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl and 1,2,3,4-tetrahydronaphthalene. The term "C 6-10 "Aryl" refers to an aromatic group having 6 to 10 carbon atoms, C 6-10 Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalene, and the like.

[0086] The term "heteroaryl" refers to a monocyclic or fused polycyclic group with aromatic properties (which can be substituted or fused to other fragments), at least one (e.g., 1, 2, 3 or 4) ring atom is a heteroatom selected from N, O, S and P, and the remaining ring atoms are C, for example, a 5- to 12-membered ring, especially a 5- to 10-membered ring. Non-limiting examples of heteroaryl include, but are not limited to

[0087] The term "5-10 membered heteroaryl" refers to a heteroaryl group having 5 to 10 (e.g., 5, 6, 7, 8, 9 or 10) ring atoms, wherein 1 to 4 heteroatoms selected from N, O, S and P may be contained, and non-limiting examples of 5-10 membered heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl and quinolinyl, etc.

[0088] The term "alkyl" refers to a linear or branched monovalent hydrocarbon group containing no unsaturation. 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms, C 1-6 Non-limiting examples of alkyl groups include, but are not limited to, methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), sec-butyl (-CH(CH3)CH2CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), neopentyl (-CH2C(CH3)3), and the like.

[0089] The term "alkylene" refers to a divalent hydrocarbon group formed by further losing a hydrogen atom from an alkyl group and does not contain unsaturation. 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms. 1-6 "Alkylene" refers to an alkylene group having 1 to 6 carbon atoms, C 1-6 Non-limiting examples of alkylene include, but are not limited to, methylene (—CH 2 —), 1,2-ethylene (—CH 2 CH 2 —), 1,1-ethylene (—CH(CH 3 ) —), and the like.

[0090] The term "cycloalkyl" refers to a fully saturated monocyclic or polycyclic (e.g., spirocyclic, fused or bridged) cyclic hydrocarbon group (which may be substituted or fused to other fragments), for example, having 3 to 10, 3 to 8 or 3 to 6 carbon atoms. 3-10 "Cycloalkyl" refers to a cycloalkyl group having 3 to 10 carbon atoms; the term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms; the term "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms. 3-6 Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0091] The term "cycloalkenyl" refers to a monocyclic or polycyclic (e.g., spirocyclic, fused or bridged) cyclic hydrocarbon group containing one or two double bonds but no aromaticity (which may be substituted or fused to other fragments), for example, having 3 to 10, 3 to 8 or 3 to 6 carbon atoms. 3-10 "Cycloalkenyl" refers to a cycloalkenyl group having 3 to 10 carbon atoms; the term "C 3-8 "Cycloalkenyl" refers to a cycloalkenyl group having 3 to 8 carbon atoms; the term "C 3-6 "Cycloalkenyl" refers to a cycloalkenyl group having 3 to 6 carbon atoms. 3-6 Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, and the like.

[0092] The term "carbocyclic group" includes, but is not limited to, "cycloalkyl", "cycloalkenyl", etc. 5-10 "Carbocyclic group" includes but is not limited to "C 5-10 Cycloalkyl", "C 5-10 Cycloalkenyl" etc.

[0093] The term "heterocycloalkyl" refers to a fully saturated monocyclic cyclic hydrocarbon group (which may be substituted or fused to other fragments), at least one (e.g., 1, 2, 3, or 4) of which is a heteroatom selected from N, O, S, and P, and the remaining ring atoms are C, for example, a 3- to 10-membered ring, or a 5- to 10-membered ring, or a 3- to 6-membered ring. The term "3- to 6-membered heterocycloalkyl" refers to a heterocycloalkyl group having 3 to 6 ring atoms, which may contain 1 or 2 heteroatoms selected from N, O, S, and P. Non-limiting examples of "3- to 6-membered heterocycloalkyl" include, but are not limited to, oxirane, thioethane, cyclonitroethane, azetidinyl, oxadiazolyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, cyclopentylsulfoxide, cyclopentylsulfone, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, 1,4-diphosphinyl, 1,4-nitrophosphinyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, The term "3-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 3 to 10 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P. Non-limiting examples of "3-10 membered heterocycloalkyl" include, but are not limited to, the above-listed "3-6 membered heterocycloalkyl", azepanyl, oxepinyl, thiepanyl, etc.

[0094] The term "heterocycloalkenyl" refers to a monocyclic cyclic hydrocarbon group (which may be substituted or fused to other fragments) containing one or two double bonds on the ring but without aromaticity, wherein at least one (e.g., 1, 2, 3 or 4) ring atoms are heteroatoms selected from N, O, S and P, and the remaining ring atoms are C, for example, a 3- to 10-membered ring, or a 5- to 10-membered ring, or a 3- to 6-membered ring. The term "3- to 10-membered heterocycloalkenyl" refers to a heterocycloalkenyl group having 3 to 10 ring atoms, which may contain 1, 2, 3 or 4 heteroatoms selected from N, O, S and P. Non-limiting examples of "3- to 10-membered heterocycloalkenyl" include, but are not limited to

[0095] wait.

[0096] The term "heterospirocyclyl" refers to a fully saturated spirocyclic hydrocarbon group (which can be substituted or fused to other fragments), at least one (e.g., 1, 2, 3, or 4) of which is a heteroatom selected from N, O, S, and P, and the remaining ring atoms are C, for example, a 3- to 10-membered ring, or a 5- to 10-membered ring, or a 3- to 6-membered ring. The term "3-10-membered heterospirocyclyl" refers to a heterospirocyclyl having 3 to 10 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S, and P. Non-limiting examples of "3-10-membered heterospirocyclyl" include, but are not limited to, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, and the like.

[0097] The term "heterobridged ring group" refers to a group obtained by losing a hydrogen atom from a bridged ring compound in which at least one (e.g., 1, 2, 3 or 4) ring atom is a heteroatom (selected from N, O, S and P) (other fragments may be connected by substitution or fusion). The term "bridged ring compound" refers to a cyclic hydrocarbon in which any two rings in the compound share two carbon atoms that are not directly connected, and is divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. according to the number of constituent rings.

[0098] The term "heterocyclyl" includes, but is not limited to, "heterocycloalkyl", "heterocycloalkenyl", "heterospirocyclyl", "heterobridged cyclyl", etc. "3-10 membered heterocyclyl" includes, but is not limited to, "3-10 membered heterocycloalkyl", "3-10 membered heterocycloalkenyl", "3-10 membered heterospirocyclyl", "3-10 membered heterobridged cyclyl", etc.

[0099] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) which are located in Group VII of the Periodic Table of Elements.

[0100] The term "haloalkyl" refers to a linear or branched monovalent group formed by replacing at least one hydrogen atom in an alkyl group with a halogen atom, and does not contain unsaturation. 1-6 "Haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms. 1-6 Non-limiting examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, and the like.

[0101] The term "alkoxy" refers to an alkyl group attached to another moiety through an oxygen atom and contains no unsaturation. 1-6 "Alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms. 1-6 Non-limiting examples of alkoxy groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OC(CH3)3, and the like.

[0102] The term "haloalkoxy" refers to a haloalkyl group attached to another moiety through an oxygen atom and contains no unsaturation. 1-6 The term "haloalkoxy" refers to a haloalkoxy group having 1 to 6 carbon atoms. 1-6 Non-limiting examples of haloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, and the like.

[0103] The term "hydroxy" refers to a "-OH" group. The term "amino" refers to a "-NH2" group. The term "nitro" refers to a "-NO2" group. The term "cyano" refers to a "-CN" group. The term "carbonyl" refers to a "-C(=O)-" group. The term "aldehyde" refers to a "-C(=O)H" group. The term "carboxyl" refers to a "-C(=O)OH" group.

[0104] The term "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. When referring to a group as "optionally substituted", this means that the group is substituted or unsubstituted. For example, a heterocyclic group is "optionally" substituted with a halogen, which means that the heterocyclic group may be unsubstituted, or may be monosubstituted, polysubstituted or fully substituted with a halogen atom. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced. The term "independently" means that when one or more substituents are selected from a number of possible groups, the groups corresponding to these substituents may be the same or different.

[0105] The term "room temperature" means that the temperature may be 10-40°C, or 10-30°C, such as 25°C.

[0106] In this application, the terms "include", "comprises", and "contains" and their equivalents should be understood as open, non-exclusive meanings, i.e., "including but not limited to", meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included. In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents, and vice versa. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0107] Unless otherwise specified, in this article, the parameter values ​​representing the amount of ingredients or physicochemical properties or reaction conditions, etc. should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe the present application, the term "about" indicates the error value that exists, for example, it indicates a change within the range of ±5%, such as ±1% or ±0.1% of a particular value.

[0108] The term "subject" encompasses mammals, such as humans, non-human primates (eg, rhesus monkeys), pigs, cows, horses, sheep, dogs, rabbits, mice, and the like.

[0109] For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents.

[0110] [Compounds useful as PRMT5 inhibitors]

[0111] The present invention provides a novel compound that can be used as a PRMT5 inhibitor or a pharmaceutically acceptable form thereof, such as a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label (e.g., deuterated substance) or prodrug thereof.

[0112] In one embodiment of the present invention, a compound having a structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance (e.g., deuterated substance) or prodrug thereof is provided; the structure of such compound is shown in Formula I:

[0113]

[0114] in:

[0115] represents a single bond or a double bond;

[0116] X1 for CR 6 or N;

[0117] X2 for CR 4 or N;

[0118] X3 for CR 5 or N;

[0119] X4 for CR 3 or NR 3 ;

[0120] L is a single bond or oxygen;

[0121] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 3-6 membered heterocyclyl;

[0122] m is 0, 1, 2, 3, 4 or 5;

[0123] If present, each R 1 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C≡CR 1a , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0124] If present, each R 1a are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, 4 or 5 R # replace;

[0125] If present, each R # Each independently selected from halogen, cyano, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0126] R 2 is hydrogen or methyl;

[0127] R 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group and -(C 1-6 Alkylene)-NH2;

[0128] If present, R 4 is selected from the group consisting of hydrogen, amino, hydroxyl and carboxyl;

[0129] If present, R 5 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or, R 5 and R 3 Connected to each other 5-10 The ring B of the carbonyl group, the 5-10 membered heterocyclic group and the 5-10 membered heteroaryl group; 5-10 The carbocyclyl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-6 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0130] If present, R 6 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -(C 1-6 Alkylene)-NH2.

[0131] In one embodiment of the present invention, X1 in Formula I is N, and the structure of the compound is as shown in Formula I-1:

[0132]

[0133] Among them, ring A, L, m, R1~R2, X2~X4 and As defined in the compounds of formula I.

[0134] In one embodiment of the present invention, X2 in formula I-1 is CR 4 , at this time the structure of the compound is as shown in Formula I-2:

[0135]

[0136] Among them, ring A, L, m, R1~R2, R4, X3~X4 and As defined in the compound of formula I;

[0137] Preferably, R 4 is an amino group, and the structure of the compound is shown in Formula I-2':

[0138]

[0139] Among them, ring A, L, m, R1~R2, X3~X4 and As defined in the compounds of formula I.

[0140] In one embodiment of the present invention, X3 in Formula I-2 or Formula I-2' is CR 5 , X4 is CR 3 , in this case, the structure of the compound is as shown in Formula I-3A or Formula I-3A':

[0141]

[0142] Among them, R 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group and -(C 1-6 Alkylene)-NH2;

[0143] R 4 is selected from hydrogen, amino, hydroxyl and carboxyl (R in Formula I-3A' 4 is amino);

[0144] R 5 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Haloalkoxy;

[0145] Ring A, L, m and R1-R2 are as defined in the compound of formula I.

[0146] In one embodiment of the present invention, X3 in Formula I-2 or Formula I-2' is CR 5 , X4 is CR 3 , and R 5 and R 3 They are connected to form ring B. At this time, the structure of the compound is as shown in Formula I-3B or Formula I-3B':

[0147]

[0148] Wherein, ring B is selected from C 5-10 Carbocyclyl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl;

[0149] R 4 is selected from hydrogen, amino, hydroxyl and carboxyl (R in Formula I-3B' 4 is amino);

[0150] Ring A, L, m and R1-R2 are as defined in the compound of formula I.

[0151] In one embodiment of the present invention, X3 in Formula I-2 or Formula I-2' is CR 5 , X4 is NR 3 , and R 5 and R 3 They are connected to form ring B. At this time, the structure of the compound is as shown in Formula I-3C or Formula I-3C':

[0152]

[0153] in, represents a single bond or a double bond;

[0154] Ring B is selected from 5-10 membered heterocyclyl and 5-10 membered heteroaryl;

[0155] R 4 is selected from hydrogen, amino, hydroxyl and carboxyl (R in Formula I-3C' 4 is amino);

[0156] Ring A, L, m and R1-R2 are as defined in the compound of formula I.

[0157] In one embodiment of the present invention, R in the compound of formula I (or, formula I-3A or formula I-3A') 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl.

[0158] In a specific embodiment of the present invention, R in the compound of formula I (or, formula I-3A or formula I-3A') 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl, preferably hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl.

[0159] In a more specific embodiment of the present invention, R in the compound of formula I (or, formula I-3A or formula I-3A')3 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0160] In one embodiment of the present invention, R in the compound of formula I (or, formula I-3A or formula I-3A') 5 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Halogenated alkoxy.

[0161] In a specific embodiment of the present invention, R in the compound of formula I (or, formula I-3A or formula I-3A') 5 Selected from hydrogen, halogen, C 1-6 Alkyl and C 3-10 Cycloalkyl, preferably hydrogen, halogen, C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0162] In a more specific embodiment of the present invention, R in the compound of formula I (or, formula I-3A or formula I-3A') 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0163] In one embodiment of the present invention, R 5 and R 3 Connect to each other to form C 5-10 Carbocyclic groups, such as C 5-10 The cycloalkenyl group is preferably a cyclopentenyl group or a cyclohexenyl group.

[0164] In another embodiment of the present invention, R 5 and R 3 They are connected to each other to form a 5-10 membered heterocyclic group, such as a 5-10 membered heterocycloalkenyl group, preferably a dihydropyrrolyl group, a dihydrofuranyl group, a dihydrothiophenyl group, a dihydropyridinyl group, a pyranyl group, a thiopyranyl group, a tetrahydropyridinyl group, a dihydropyranyl group or a dihydrothiopyranyl group.

[0165] In another embodiment of the present invention, R 5 and R 3 They are connected to each other to form a 5-10 membered heteroaryl group, preferably a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a furanyl group, an oxazolyl group, an isoxazolyl group, a thienyl group, a thiazolyl group or an isothiazolyl group.

[0166] In one embodiment of the present invention, R in the compound of formula I (or, formula I-1, formula I-2, formula I-2', formula I-3A, formula I-3A', formula I-3B, formula I-3B', formula I-3C or formula I-3C') 2 For hydrogen.

[0167] In one embodiment of the present invention, ring A in the compound of formula I (or formula I-1, formula I-2, formula I-2', formula I-3A, formula I-3A', formula I-3B, formula I-3B', formula I-3C or formula I-3C') is selected from C 6-10 Aryl and 5-10 membered heteroaryl.

[0168] In a specific embodiment of the present invention, ring A in the compound of formula I (or, formula I-1, formula I-2, formula I-2', formula I-3A, formula I-3A', formula I-3B, formula I-3B', formula I-3C or formula I-3C') is selected from phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.

[0169] In one embodiment of the present invention, the compound of formula I (or, formula I-1, formula I-2, formula I-2', formula I-3A, formula I-3A', formula I-3B, formula I-3B', formula I-3C or formula I-3C') Any one selected from the following groups:

[0170]

[0171] wherein m and R1 are as defined in the compound of formula I.

[0172] In one embodiment of the invention, m in the compound of formula I (or, formula I-1, formula I-2, formula I-2', formula I-3A, formula I-3A', formula I-3B, formula I-3B', formula I-3C or formula I-3C') is 0, 1, 2, 3 or 4.

[0173] In one embodiment of the invention, each R in the compound of formula I (or, formula I-1, formula I-2, formula I-2', formula I-3A, formula I-3A', formula I-3B, formula I-3B', formula I-3C or formula I-3C') 1 are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C≡CC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 cycloalkyl)-O- or (3-10 membered heterocyclyl)-O-.

[0174] In a specific embodiment of the present invention, m is 0, in which case ring A has no substituents.

[0175] In another specific embodiment of the present invention, m is 1, in which case any one of the substitutable carbon atoms of ring A is connected to one R 1 , and R 1 C 1-6 Alkyl, preferably C 1-4 Alkyl, more preferably methyl.

[0176] In another specific embodiment of the present invention, m is 2, and any two substitutable carbon atoms of ring A are connected to two R 1 , and each R 1 Each independently selected from C 1-6 Alkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, 3-10 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C≡CC 1-6 Alkyl, (C 3-10 Preferably, each R 1 Each independently selected from C 1-4 Alkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-4 Alkyl, 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, C 1-4 Alkyl, C 1-4Alkoxy, -C≡CC 1-4 Alkyl, (C 3-6 More preferably, each R 1 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, naphthyl, indolyl, isoindolyl, benzofuranyl and benzothienyl; the methyl, ethyl, n-propyl, isopropyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, naphthyl, indolyl, isoindolyl, benzofuranyl and benzothienyl are each optionally substituted with one or more fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -C≡C-CH3, -C≡C-CH2-CH3, cyclopropyloxy, cyclobutyloxy, (cyclopentyl)oxy, (cyclohexyl)oxy, (oxetan-2-yl)oxy, (oxetan-2-yl)oxy or (oxetan-3-yl)oxy; further preferably, each R 1 Each is independently selected from any one of the following groups:

[0177]

[0178] The asterisk * indicates the site of attachment to ring A.

[0179] In another specific embodiment of the present invention, m is 4, and any 4 substitutable carbon atoms of ring A are connected to 4 R 1 (preferably in a 2,3,4,5-tetrasubstituted manner), and each R 1 are each independently selected from halogen, cyano, (C 3-10 Cycloalkyl)-O- and 5-10 membered heteroaryl; said (C 3-10 Cycloalkyl)-O- and 5-10 membered heteroaryl are each optionally substituted by one or more halogen or C 1-6 Alkyl substituted; preferably, each R 1 are each independently selected from halogen, cyano, (C 3-6 Cycloalkyl)-O- and 5-6 membered heteroaryl; said (C 3-6 cycloalkyl)-O- and 5-6 membered heteroaryl are each optionally substituted by one or more halogen or C 1-4 Alkyl substituted; more preferably, each R 1Each is independently selected from fluorine, chlorine, bromine, cyano, cyclopropyloxy, cyclobutyloxy, (cyclopentyl)oxy, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and isothiazolyl; and the cyclopropyloxy, cyclobutyloxy, (cyclopentyl)oxy, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and isothiazolyl are each optionally substituted with one or more fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl.

[0180] In another specific embodiment of the present invention, the compound of formula I (or, formula I-1, formula I-2, formula I-2', formula I-3A, formula I-3A', formula I-3B, formula I-3B', formula I-3C or formula I-3C') Any one selected from the following groups:

[0181]

[0182]

[0183] Where q is 0, 1, 2, 3, 4 or 5;

[0184] If present, each R 1b are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C≡CC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 cycloalkyl)-O- and (3-10 membered heterocyclyl)-O-.

[0185] In one embodiment of the present invention, under the premise of conforming to the valence bond theory, L in the compound of formula I is connected to any carbon atom of the benzene ring in the bicyclic fragment, and the structure of the compound is as shown in formula IIA, formula IIB or formula IIC:

[0186]

[0187] Among them, ring A, L, m, R1~R2, X1~X4 and As defined in the compounds of formula I.

[0188] In a specific embodiment of the present invention, L in the compound of formula I (or, formula IIA, formula IIB or formula IIC) is a single bond, and the structure of the compound is as shown in formula IIA', formula IIB' or formula IIC':

[0189]

[0190] Among them, ring A, m, R1~R2, X1~X4 and As defined in the compounds of formula I.

[0191] In another specific embodiment of the present invention, L in the compound of formula I (or, formula IIA, formula IIB or formula IIC) is oxygen, and the structure of the compound is as shown in formula IIA", formula IIB" or formula IIC":

[0192]

[0193] Among them, ring A, m, R1~R2, X1~X4 and As defined in the compounds of formula I.

[0194] In some embodiments of the present invention, in the compound of formula I,

[0195] represents a double bond;

[0196] X1 is N;

[0197] X2 for CR 4 ;

[0198] X3 for CR 5 ;

[0199] X4 for CR 3 ;

[0200] L is a single bond;

[0201] Ring A is a 5-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S (preferably a 5-membered heteroaryl group containing 1-2 N atoms; more preferably pyrazolyl, imidazolyl or pyrrolyl);

[0202] m is 0, 1, 2 or 3 (preferably m is 2);

[0203] R 1 Each independently selected from C 6-10 Aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with halogen, cyano or (C 3-10 One or more substitutions (preferably R 1 C 6-10 Aryl, C 6-10 The aryl group is optionally substituted with halogen, cyano or (C 3-6 cycloalkyl)-O-; more preferably R 1 is phenyl, the phenyl group is optionally substituted by halogen, cyano or (C 3-5 One or more substitutions in cycloalkyl)-O-; for example, R1 for Asterisk * indicates the site of attachment to loop A);

[0204] R 2 is hydrogen or methyl (preferably hydrogen);

[0205] R 3 Selected from hydrogen or C 1-6 Alkyl (preferably C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, more preferably methyl, ethyl, propyl);

[0206] R 4 is selected from hydrogen or amino (preferably amino);

[0207] R 5 Selected from hydrogen or C 1-6 Alkyl (preferably hydrogen).

[0208] Some embodiments of the present invention provide the following compounds or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopically labeled substances (e.g., deuterated substances), or prodrugs thereof:

[0209]

[0210] Wherein, ring A, m, R1~R2 and X2~X4 are defined as the corresponding groups in the above formula I compound (including formula I-1, formula I-2, formula I-2', formula I-3A, formula I-3A', formula I-3B, formula I-3B', formula I-3C or formula I-3C'; or, formula IIA, formula IIB, formula IIC, formula IIA', formula IIB' or formula IIC').

[0211] In some preferred embodiments, in the compounds represented by the above formula IIIA or IIIB, ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S (Ring A is preferably a 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, more preferably pyrazolyl, imidazolyl or pyrrolyl);

[0212] m is 0, 1, 2, 3, 4 or 5 (for example, m is 0, 1, 2 or 3, preferably m is 2);

[0213] R 1 are each independently selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl and 5-10 membered heteroaryl, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with halogen, cyano, 3-10 membered heterocyclic group or (C 3-10One or more substitutions (preferably R 1 C 6-10 Aryl, C 6-10 The aryl group is optionally substituted with halogen, cyano or (C 3-6 cycloalkyl)-O-; more preferably R 1 is phenyl, the phenyl group is optionally substituted by halogen, cyano or (C 3-5 cycloalkyl)-O-substituted with one or more);

[0214] R 2 is hydrogen or methyl (preferably hydrogen);

[0215] X2 for CR 4 ; X3 is CR 5 ; X4 is CR 3 ;

[0216] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 Cycloalkyl (preferably C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl, more preferably methyl, ethyl, propyl); R 5 Selected from hydrogen, halogen, C 1-6 Alkyl or C 3-10 Cycloalkyl, or, R 5 and R 3 Connect to each other to form C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl or 5-10 membered heteroaryl (preferably R 5 is hydrogen);

[0217] R 4 is selected from hydrogen or amino (preferably amino).

[0218] Specifically, the small molecule compounds used as PRMT5 inhibitors of the present invention include but are not limited to the following compounds:

[0219]

[0220]

[0221]

[0222]

[0223] [Drug composition]

[0224] The term "pharmaceutical composition" refers to a composition that can be used as a medicament, which comprises a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.

[0225] The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the active ingredient of the drug and is harmless to the subject, including but not limited to one or more of a diluent (or filler), a binder, a disintegrant, a lubricant, a wetting agent, a thickener, a glidant, a flavoring agent, an olfactory agent, a preservative, an antioxidant, a pH adjuster, a solvent, a cosolvent, a surfactant, a light-shielding agent (opacifying agent), etc.

[0226] The present invention provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance (eg, deuterated substance) or prodrug thereof.

[0227] In one embodiment of the present invention, the above pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0228] [Drug preparations]

[0229] The term "pharmaceutical preparation" refers to a finished drug prepared in a certain form for use by patients.

[0230] The present invention provides a pharmaceutical preparation, which is prepared from the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance (such as deuterated substance) or prodrug or the above-mentioned pharmaceutical composition.

[0231] In one embodiment of the present invention, the above-mentioned pharmaceutical preparation is a solid preparation for oral administration, including but not limited to pharmaceutically acceptable capsules, tablets, pills, powders, granules, etc. The solid preparation can be coated or microencapsulated with a coating or shell material (such as an enteric coating or other materials known in the art). The solid preparation can contain an opacifying agent, and the active ingredient therein can be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be adopted are polymeric substances and wax substances. In addition, the active ingredient can also be formed into a microcapsule form with one or more of the above-mentioned carriers.

[0232] In another embodiment of the present invention, the above-mentioned pharmaceutical preparation is a liquid dosage form for oral administration, including but not limited to pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc.

[0233] In another embodiment of the present invention, the above-mentioned pharmaceutical preparations may be in the form of dosage forms for parenteral injection, including but not limited to physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions.

[0234] In another embodiment of the present invention, the above-mentioned pharmaceutical preparation may be a dosage form for topical administration, including but not limited to ointments, powders, suppositories, drops, sprays, inhalants, and the like.

[0235] [Medical Use]

[0236] Whether it is the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, it can show inhibitory activity on PRMT5, so the present invention provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation in the preparation of a drug for preventing and / or treating a disease at least partially mediated by PRMT5. The present application also provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation for preventing and / or treating a disease at least partially mediated by PRMT5.

[0237] The present invention also provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation, which is used as a drug (especially PRMT5 inhibitor) or for preventing and / or treating diseases at least partially mediated by PRMT5.

[0238] The present invention also provides a method for preventing and / or treating a disease mediated at least in part by PRMT5, comprising administering a preventive and / or therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation to an individual in need thereof. In this article, the preventive and / or therapeutically effective amount refers to an amount sufficient to prevent, improve, inhibit, delay, slow down the progression of a disease or related symptoms mediated at least in part by PRMT5, which can be determined by a clinician based on the severity of the disease, the patient's physical condition, age, gender, weight, etc.

[0239] In one embodiment of the present invention, the above-mentioned disease mediated at least in part by PRMT5 is cancer, cardiovascular disease or myelofibrosis.

[0240] In a specific embodiment of the present invention, the above-mentioned disease mediated at least in part by PRMT5 is cancer or cardiovascular disease. The term "cancer" refers to a cell disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues and / or the ability to establish new growth ectopically. Non-limiting examples of cancer include, but are not limited to, glioblastoma, melanoma, blood tumors (such as leukemia, lymphoma and multiple myeloma), bladder urothelial carcinoma, colorectal cancer, lung cancer, gastric cancer, ovarian cancer, breast cancer, cervical cancer, squamous cell carcinoma, brain cancer, prostate cancer and myelodysplastic syndrome. The term "cardiovascular disease" is also called circulatory system disease, which is a series of diseases involving the circulatory system. The circulatory system refers to the organs and tissues that transport blood in the human body, mainly including the heart, blood vessels (arteries, veins, capillaries), which can be subdivided into acute and chronic, and are generally related to arteriosclerosis. These diseases have similar causes, pathogenesis and treatment methods. Non-limiting examples of cardiovascular diseases include, but are not limited to, myocardial hypertrophy, heart failure and arrhythmia.

[0241] [Combination medication]

[0242] The present invention provides a pharmaceutical combination comprising the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label (e.g., deuterated substance) or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation, and at least one additional therapeutic agent.

[0243] In one embodiment of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation can be administered alone or in combination with other therapeutic agents. The combined therapy can be achieved by administering different therapeutic agents simultaneously, sequentially or separately.

[0244] [Abbreviation and full name]

[0245] In this manual, the English abbreviations and their corresponding Chinese full names are shown in the following table:

[0246]

[0247] Example

[0248] Next, the present invention is further described in detail by examples, but the present invention is not limited to these examples. The following embodiments of the present invention will be described in detail in conjunction with examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. In the examples, those without specifying specific conditions are carried out according to normal conditions or the conditions recommended by the manufacturer. Reagents used or instruments without specifying manufacturers are all conventional products that can be obtained commercially.

[0249] Intermediate Preparation Example 1: Preparation of Compound 1-1

[0250]

[0251] Weigh 7-bromoquinolin-2(1H)-one (3 g) into a round-bottom flask, add phosphorus oxychloride (30 mL) and stir evenly, heat to 100°C and reflux for 3 h. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, pour into ice water and stir thoroughly, filter, wash the filter cake with water, and dry to obtain compound 1-1a (3.22 g, yield 99%). MS: m / z 241.8 [M+H] + .

[0252] Weigh compound 1-1a (3.2 g, 1.0 equiv.) into a reaction flask, add n-butanol (25 mL) and stir to dissolve, then weigh 4-methoxybenzylamine (1.3 equiv.) and triethylamine (2.0 equiv.) into the reaction system, and heat to 120°C and reflux for 24 h. After the reaction is completed, concentrate under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (PE:EA=15:1-5:1, v / v) to obtain a yellow solid compound 1-1b (2.96 g, yield 65%). MS: m / z 342.8[M+H] + .

[0253] Compound 1-1b (2.9 g, 1.0 equiv.), 1,4-dioxane (20 mL), bis(pinacolato)diboron (1.5 equiv.), potassium acetate (2.0 equiv.) and Pd(dppf)Cl2 (0.1 equiv.) were weighed in sequence and added to a round-bottom flask, nitrogen was replaced three times, and heated to reflux at 85°C for 6 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=5:1-3:1, v / v) to obtain a yellow solid compound 1-1 (3.2 g, yield 97%). MS: m / z 391.2 [M+H] + .

[0254] Intermediate Preparation Example 2: Preparation of Compound 1-2

[0255]

[0256] According to the operation basically similar to that of Intermediate Preparation Example 1, the compounds of each step were obtained: Compound 1-2a (3.8 g, yield 90%), MS: m / z 241.8 [M+H] + ; Compound 1-2b (2.3 g, yield 61%), MS: m / z 342.8 [M+H] + ; Compound 1-2 (1.8 g, yield 89%), MS: m / z 391.2 [M+H] + .

[0257] Intermediate Preparation Example 3: Preparation of Compound 1-3

[0258]

[0259] According to the operation basically similar to that of Intermediate Preparation Example 1, the compounds of each step were obtained: Compound 1-3a (2.7 g, yield 83%), MS: m / z 241.8 [M+H] + ; Compound 1-3b (1.8 g, yield 60%), MS: m / z 342.8 [M+H] + ; Compound 1-3 (1.3 g, yield 86%), MS: m / z 391.2 [M+H] + .

[0260] Example 1: Preparation of Compound 1

[0261]

[0262] Compound 1-1 (80 mg, 1.0 equiv.), bromobenzene (1.2 equiv.), Pd(PPh3)4 (0.2 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (6 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 90°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=3 / 1, v / v) to obtain a yellow solid compound 1a (32 mg, yield 46%). MS: m / z 341.1[M+H] + .

[0263] Compound 1a (32 mg, 1.0 equiv.) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (0.2 mm silica gel plate) (PE:EA=1 / 1, v / v) to obtain compound 1 (18 mg, yield 87%). MS: m / z 221.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=8.8Hz,1H),7.80–7.68(m,4H),7.56–7.45(m,3H),7.41(t,J=7.3Hz,1H),6.79(d,J=8.8Hz,1H),6.54(s,2H).

[0264] Example 2: Preparation of Compound 2

[0265]

[0266] According to the operation basically similar to Example 1, the compounds of each step were obtained: Compound 2a (88 mg, yield 53%), MS: m / z 342.2 [M+H] + ; Compound 2 (28 mg, yield 80%), MS: m / z 222.1 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.99(d,J=2.3Hz,1H),8.62-8.61(m,1H),8.21-8.14(m,1H),7.96(d ,J=8.8Hz,1H),7.77(d,J=8.2Hz,2H),7.57-7.49(m,2H),6.81(d,J=8.9Hz,1H),6.60(s,2H).

[0267] Example 3: Preparation of Compound 3

[0268]

[0269] According to the operation basically similar to Example 1, the compounds of each step were obtained: Compound 3a (78 mg, yield 55%), MS: m / z 342.2 [M+H] + ; Compound 3 (18 mg, yield 76%), MS: m / z 222.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.76-8.69(m,1H),8.15(d,J=1.7Hz,1H),8.09-8.03(m,1H),7.98- 7.88(m,3H),7.75(d,J=8.3Hz,1H),7.41-7.38(m,1H),6.82(d,J=8.8Hz,1H),6.59(s,2H).

[0270] Example 4: Preparation of Compound 4

[0271]

[0272] According to the operation basically similar to Example 1, the compounds of each step were obtained: Compound 4a (75 mg, yield 60%), MS: m / z 345.1 [M+H] + ; Compound 4 (25 mg, yield 81%), MS: m / z 225.1 [M+H] + .

[0273] Example 5: Preparation of Compound 5

[0274]

[0275] According to the operation basically similar to Example 1, the compounds of each step were obtained: Compound 5a (96 mg, yield 57%), MS: m / z 348.1 [M+H] + ; Compound 5 (24 mg, yield 88%), MS: m / z 228.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.44(s,1H),7.92(d,J=8.8Hz,1H),7.71(d,J=8.0Hz,2H),7.52-7.50(m,1H),6.79(d,J=8.8Hz,1H),6.59(s,2H).

[0276] Example 6: Preparation of Compound 6

[0277]

[0278] According to the operation basically similar to Example 1, the compounds of each step were obtained: Compound 6a (68 mg, yield 51%), MS: m / z 348.1 [M+H] + ; Compound 6 (15 mg, yield 82%), MS: m / z 228.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.48 (s, 1H), 9.17 (s, 1H), 7.92 (d, J = 8.9Hz, 1H), 7.90-7.87 (m, 1H ),7.72(d,J=8.2Hz,1H),7.60(dd,J=8.3,1.8Hz,1H),6.78(d,J=8.9Hz,1H),6.54(s,2H).

[0279] Example 7: Preparation of Compound 7

[0280]

[0281] According to the operation basically similar to Example 1, the compounds of each step were obtained: Compound 7a (45 mg, yield 50%), MS: m / z 359.2 [M+H] + ; Compound 7 (21 mg, yield 86%), MS: m / z 239.1 [M+H] + .

[0282] Example 8: Preparation of Compound 8

[0283]

[0284] 4-Bromo-1-methyl-1H-pyrazole (500 mg, 3.11 mmol, 1.0 equiv.), bromobenzene (1.2 equiv.), Pd(OAc)2 (0.01 equiv.), DavePhos (0.02 equiv.), tetrabutylammonium acetate (2.0 equiv.), pivalic acid (0.30 equiv.) and NMP (7 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 100°C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, and then ethyl acetate (100 mL) was added, and the mixture was washed with saturated brine (100 mL×3). The 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 thin layer chromatography (2.0 mm silica gel plate) (PE / EA=10 / 3, v / v) to obtain a white solid compound 8a (400 mg, yield 54%). MS: m / z 237.0[M+H] + .

[0285] Compound 1-1 (80 mg, 1.0 equiv.), compound 8a (1.2 equiv.), Pd(PPh3)4 (0.2 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (6 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 90°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=3 / 1, v / v) to obtain compound 8b (50 mg, yield 58%). MS: m / z 421.2[M+H] + .

[0286] Compound 8b (50 mg) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=1 / 1, v / v) to obtain compound 8 (33 mg, yield 92%). MS: m / z 301.1 [M+H] + .

[0287] Example 9: Preparation of Compound 9

[0288]

[0289] According to the operation basically similar to Example 8, the compound of each step was obtained: Compound 9a (365 mg, yield 50%), MS: m / z 262.0 [M+H] + ; Compound 9b (126 mg, yield 53%), MS: m / z 446.1 [M+H] + ; Compound 9 (16 mg, yield 86%), MS: m / z 326.1 [M+H] + .

[0290] Example 10: Preparation of Compound 10

[0291]

[0292] According to the operation basically similar to Example 8, the compounds of each step were obtained: Compound 10a (380 mg, yield 47%), MS: m / z 292.0 [M+H] + ; Compound 10b (103 mg, yield 51%), MS: m / z 476.2 [M+H] +; Compound 10 (24 mg, yield 87%), MS: m / z 356.1 [M+H] + .

[0293] Example 11: Preparation of Compound 11

[0294]

[0295] According to the operation basically similar to Example 8, the compounds of each step were obtained: Compound 11a (630 mg, yield 44%), MS: m / z 296.0 [M+H] + ; Compound 11b (240 mg, yield 53%), MS: m / z 480.2 [M+H] + ; Compound 11 (34 mg, yield 90%), MS: m / z 360.0 [M+H] + .

[0296] Example 12: Preparation of Compound 12

[0297]

[0298] According to the operation basically similar to Example 8, the compounds of each step were obtained: Compound 12a (185 mg, yield 51%), MS: m / z 276.0 [M+H] + ; Compound 12b (61 mg, yield 57%), MS: m / z 460.2 [M+H] + ; Compound 12 (12 mg, yield 81%), MS: m / z 340.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.85(d,J=8.8Hz,1H),7.80(t,J=7.7Hz,1H),7.68(d,J=7.8Hz,1H),7.55(d,J=8.0H z,2H),7.11(d,J=1.6Hz,1H),7.06(dd,J=8.3,1.8Hz,1H),6.71(d,J=8.8Hz,1H),6.66(bs,2H),3.68(s,3H),2.56(s,3H).

[0299] Example 13: Preparation of Compound 13

[0300]

[0301]

[0302] 2-Bromo-3-fluorobenzonitrile (0.60 g, 1.0 equiv.), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1.7 equiv.), Pd(dppf)Cl2 (0.1 equiv.), sodium carbonate (2.0 equiv.), 1,4-dioxane (10 mL) and water (2.5 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 80°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (20 mL) was added, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain a yellow solid compound 13a (320 mg, yield 53%). MS: m / z 202.1[M+H] + .

[0303] Weigh compound 13a (320 mg, 1.0 equiv.), NIS (2.0 equiv.) and acetic acid (10 mL), replace nitrogen three times, and react at 80 ° C for 3 h. After the reaction is completed, cool to room temperature and concentrate, then add water (20 mL), and extract with ethyl acetate (50 mL×3). Combine the organic phases, wash the organic phase with saturated sodium carbonate aqueous solution (50 mL×2), wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain a yellow solid compound 13b (203 mg, yield 39%). MS: m / z 328.0[M+H] + .

[0304] Compound 1-1 (80 mg, 1.0 equiv.), compound 13b (1.2 equiv.), Pd(PPh3)4 (0.2 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (6 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 90°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=3 / 1, v / v) to obtain compound 13c (35 mg, yield 37%). MS: m / z 464.2[M+H] + .

[0305] Compound 13c (35 mg, 1.0 equiv.) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=1 / 1, v / v) to obtain compound 13 (23 mg, yield 89%). MS: m / z 344.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.09(s,1H),7.99-7.97(m,1H),7.95-7.88(m,2H),7.85(d,J=8.9Hz,1H),7.57(d ,J=8.3Hz,1H),7.10-7.08(m,1H),7.05(d,J=1.6Hz,1H),6.71(d,J=8.8Hz,1H),6.60(s,2H),3.74(s,3H).

[0306] Example 14: Preparation of Compound 14

[0307]

[0308] Cyclopropanol (218 mg, 3.75 mmol, 1.25 equiv.), 2-bromo-6-fluorobenzonitrile (0.6 g, 3.0 mmol, 1.0 equiv.), cesium carbonate (1.47 g, 4.5 mmol, 1.5 equiv.) and DMF (10 mL) were weighed and placed in a round-bottom flask, nitrogen was replaced three times, and the temperature was raised to 75 ° C for 1 h. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added, and it was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain a white solid compound 14a (0.60 g, yield 84%). MS: m / z 238.0 [M+H] + .

[0309] Compound 14a (0.60 g, 2.25 mmol, 1.0 equiv.), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1.7 equiv.), Pd(dppf)Cl2 (0.1 equiv.), sodium carbonate (2.0 equiv.), 1,4-dioxane (15 mL) and water (5 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 80°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (50 mL) was added, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain a yellow solid compound 14b (330 mg, yield 54%). MS: m / z 240.1[M+H] + .

[0310] Weigh compound 14b (330 mg, 1.0 equiv.), NIS (2.0 equiv.) and acetic acid (20 mL), replace nitrogen three times, and react at 80 ° C for 3 h. After the reaction is completed, cool to room temperature and concentrate, then add water (20 mL), and extract with ethyl acetate (50 mL×3). Combine the organic phases, wash the organic phase with saturated sodium carbonate aqueous solution (50 mL×2), wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain a yellow solid compound 14c (285 mg, yield 56%). MS: m / z 366.0[M+H] + .

[0311] Compound 1-1 (80 mg, 1.0 equiv.), compound 14c (1.2 equiv.), Pd(PPh3)4 (0.2 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (6 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 90°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=2 / 1, v / v) to obtain compound 14d (28 mg, yield 27%). MS: m / z 502.2[M+H] + .

[0312] Compound 14d (28 mg, 1.0 equiv.) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (DCM: MeOH = 100 / 1, v / v) to obtain compound 14 (17 mg, yield 80%). MS: m / z 382.2 [M+H] + .

[0313] Example 15: Preparation of Compound 15

[0314]

[0315] Weigh 2,3-dibromonaphthalene (2.00 g, 6.99 mmol, 1.0 equiv.), cuprous cyanide (1.25 g, 14.0 mmol, 2.0 equiv.) and DMA (20 mL) in a round-bottom flask and heat to 130 °C for 12 h. After the reaction is completed, cool to room temperature, filter, dilute the filtrate with water (20 mL), and extract with ethyl acetate (40 mL × 3). Combine the organic phases, wash with saturated brine (80 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA = 100 / 1, v / v) to obtain compound 15a (340 mg, yield 21%). MS: m / z 232.0 [M+H] + .

[0316] 4-Bromo-1-methyl-1H-pyrazole (340 mg, 1.0 equiv.), compound 15a (1.2 equiv.), Pd(OAc)2 (0.01 equiv.), DavePhos (0.02 equiv.), tetrabutylammonium acetate (2.0 equiv.), pivalic acid (0.30 equiv.) and NMP (7 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 100°C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, and then ethyl acetate (100 mL) was added, and the mixture was washed with saturated brine (100 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (2.0 mm silica gel plate) (PE / EA=30 / 1, v / v) to obtain a white solid compound 15b (183 mg, yield 27%). MS: m / z 312.0 [M+H] + .

[0317] Compound 1-1 (80 mg, 1.0 equiv.), compound 15b (1.2 equiv.), Pd(PPh3)4 (0.2 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (6 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 90°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE / EA=15 / 1, v / v) to obtain compound 15c (26 mg, yield 26%). MS: m / z 496.2[M+H] + .

[0318] Compound 15c (26 mg, 1.0 equiv.) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=1 / 1, v / v) to obtain compound 15 (17 mg, yield 86%). MS: m / z 376.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.98(s,1H),7.96-7.94(m,2H),7.93-7.89(m,2H),7.55-7.52( m,2H),7.45-7.43(m,2H),7.32-7.30(m,2H),7.11-7.08(m,1H),6.83(d,J=9.0Hz,1H),3.76(s,3H).

[0319] Example 16: Preparation of Compound 16

[0320]

[0321] Benzo[b]thiophene-3-carbonitrile (500 mg, 1.26 mmol, 1.0 equiv.) was dissolved in anhydrous THF (2.0 mL) and cooled to -65 °C. A solution of lithium diisopropylamide in THF (2.0 M, 0.95 mL, 1.5 equiv.) was added to the above reaction system. After 1 h of reaction, a solution of iodine (383 mg, 1.51 mmol, 1.2 equiv.) in THF (0.5 mL) was added dropwise. After the addition was complete, the mixture was heated to room temperature and reacted for 1 h. A saturated aqueous solution of ammonium chloride (3.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (pure PE) to obtain a yellow solid compound 16a (330 mg, yield 37%). MS: m / z 285.0 [M+H] + .

[0322] Compound 16a (280 mg, 0.98 mmol, 1.0 equiv.), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (409 mg, 1.96 mmol, 2.0 equiv.), Pd(dppf)Cl2 (0.1 equiv.), sodium carbonate (312 mg, 2.95 mmol, 3.0 equiv.), 1,4-dioxane (4 mL) and water (1 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 80°C for 2 h. After the reaction was completed, water (5 mL) was added after cooling to room temperature, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=10 / 1, v / v) to obtain a yellow solid compound 16b (150 mg, yield 64%). MS: m / z 240.0[M+H] + .

[0323] Compound 16b (150 mg, 0.63 mmol, 1.0 equiv.), NBS (112 mg, 0.63 mmol, 1.0 equiv.) and acetonitrile (2 mL) were weighed in sequence and reacted at 25°C for 12 h. After the reaction was completed, saturated sodium carbonate (5 mL) was added to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA=10 / 1, v / v) to obtain compound 16c (160 mg, yield 80%). MS: m / z 318.0[M+H] + .

[0324] Compound 1-1 (80 mg, 1.0 equiv.), compound 16c (1.2 equiv.), Pd(PPh3)4 (0.2 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (6 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 90°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=3 / 1, v / v) to obtain compound 16d (29 mg, yield 28%). MS: m / z 502.2[M+H] + .

[0325] Compound 16d (29 mg, 1.0 equiv.) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (0.2 mm silica gel plate) (PE:EA=1 / 1, v / v) to obtain compound 16 (18 mg, yield 82%). MS: m / z 382.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.03 (s, 1H), 7.95 (d, J = 6.0Hz, 1H), 7.93-7.89 (m, 2H), 7.57-7.55 (m, 3H) ,7.43(d,J=8.6Hz,1H),7.38-7.35(m,1H),7.12-7.09(m,2H),6.83(d,J=9.0Hz,1H),3.76(s,3H).

[0326] Example 17: Preparation of Compound 17

[0327]

[0328] 5-iodo-1-methyl-1H-pyrazole (1.0 g, 1.0 equiv.), piperidine (5.0 equiv.), cuprous iodide (0.3 equiv.), potassium phosphate (3.0 equiv.), isopropanol (16 mL) and ethylene glycol (16 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 80°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=100 / 1, v / v) to obtain compound 17a (395 mg, yield 50%). MS: m / z 166.1[M+H] + .

[0329] Under ice-water cooling, NBS (1.2 equiv.) was added to a DMF (4 mL) solution of compound 17a (395 mg, 1.0 equiv.), and stirred at this temperature for 0.5 h. After the reaction was completed, ethyl acetate (20 mL) and 10% sodium bisulfite aqueous solution (50 mL) were added, and the liquids were separated. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA=100 / 1, v / v) to obtain compound 17b (364 mg, yield 62%). MS: m / z 244.0 [M+H] + .

[0330] Compound 1-1 (80 mg, 1.0 equiv.), compound 17b (1.2 equiv.), Pd(PPh3)4 (0.2 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (6 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 90°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE / EA=20 / 1, v / v) to obtain compound 17c (25 mg, yield 28%). MS: m / z 428.2[M+H] + .

[0331] Compound 17c (25 mg, 1.0 equiv.) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE / EA=5 / 1, v / v) to obtain compound 17 (13 mg, yield 72%). MS: m / z 308.2 [M+H] + .

[0332] Example 18: Preparation of Compound 18

[0333] (1) Preparation of Compound 18-1

[0334]

[0335] Cyclopropanol (14.3 g, 247 mmol, 1.0 equiv.) was dissolved in anhydrous THF (400 mL) and placed in an ice-water bath, and then sodium hydrogen (10.4 g, 259 mmol, 60%, 1.05 equiv.) was added. After reacting for 30 min, 4-chloro-2,5-difluorobenzonitrile (42.8 g, 247 mmol, 1.0 equiv.) was weighed and added to the reaction system, and then the temperature was raised to 60 ° C for 1 h. The reaction was cooled to room temperature, water (200 mL) was added, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA = 20 / 1, v / v) to obtain a white solid compound 18-1a (31.5 g, yield 61%). MS: m / z 212.0[M+H] + .

[0336] Compound 18-1a (12.8 g, 60.4 mmol, 1.0 equiv.) was dissolved in anhydrous THF (400 mL) and cooled to -78 °C. A THF solution of lithium diisopropylamide (2.0 M, 45.4 mL, 1.5 equiv.) was added to the above reaction system. After reacting for 30 min, a THF solution (400 mL) of iodine (30.8 g, 121 mmol, 2.0 equiv.) was added dropwise. After the addition was complete, the mixture was heated to room temperature and reacted for 12 h. Water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain a brown solid compound 18-1b (18.2 g, yield 89%). MS: m / z 338.0 [M+H] + .

[0337] Compound 18-1b (14.0 g, 41.5 mmol, 1.0 equiv.), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (14.7 g, 70.5 mmol, 1.7 equiv.), Pd(dppf)Cl2 (0.1 equiv.), sodium carbonate (8.79 g, 83.0 mmol, 2.0 equiv.), 1,4-dioxane (140 mL) and water (28 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 80°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (50 mL) was added and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA=20 / 1, v / v) to obtain a yellow solid compound 18-1c (8.5 g, yield 70%). MS: m / z 292.0 [M+H] + .

[0338] Weigh compound 18-1c (5.6 g, 19.2 mmol, 1.0 equiv.), NIS (8.6 g, 38.4 mmol, 2.0 equiv.) and acetic acid (60 mL), replace nitrogen three times, and react at 80 ° C for 3 h. After the reaction is completed, cool to room temperature and concentrate, then add water (20 mL), and extract with ethyl acetate (100 mL×3). Combine the organic phases, wash the organic phase with saturated sodium carbonate aqueous solution (50 mL×2), wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain a yellow solid compound 18-1 (5.0 g, yield 62%). MS: m / z 418.0[M+H] + .

[0339] (2) Preparation of Compound 18:

[0340]

[0341] Compound 1-1 (50 mg, 1.0 equiv.), compound 18-1 (1.2 equiv.), sodium carbonate (2.5 equiv.), Pd(PPh3)4 (0.15 equiv.) and dioxane: water (2 mL / 0.5 mL) were weighed in sequence and added to the reaction flask, nitrogen was replaced three times, and the mixture was heated to 85 °C for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=1:1, v / v) to obtain a yellow solid compound 18a (35 mg, yield 49%). MS: m / z 554.2 [M+H] + .

[0342] Weigh compound 18a (35 mg) and place it in a reaction bottle, add trifluoroacetic acid (1 mL) to dissolve, and heat to 65°C for 2 h. After the reaction is completed, concentrate under reduced pressure to obtain a crude product, which is purified by thin layer chromatography (1.0 mm silica gel plate) (DCM: MeOH = 100 / 1, v / v) to obtain compound 18 (17 mg, yield 62%). MS: m / z 434.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.95(d,J=6.0Hz,1H),7.91(d,J=9.0Hz,1H),7.53(d,J=2.0Hz,1H),7.43(d,J=8.6Hz,1H),7.2 8(dd,J=8.6,2.1Hz,1H),7.09(bs,2H),6.83(d,J=9.0Hz,1H),4.22-4.17(m,1H),3.76(s,3H),0.93-0.90m,2H),0.83-0.79(m,2H).

[0343] Example 19: Preparation of Compound 19

[0344]

[0345] According to the operation basically similar to Example 18, the compounds of each step were obtained: Compound 19a (86 mg, yield 51%), MS: m / z 554.1 [M+H] + ; Compound 19 (31 mg, yield 73%), MS: m / z 434.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.01(s,1H),7.98(d,J=6.0Hz,1H),7.93(d,J=9.0Hz,1H),7.53(d,J=2.0Hz,1H),7.43(d,J=8.6Hz,1H),7.2 8(dd,J=8.6,2.1Hz,1H),7.09(bs,2H),6.83(d,J=9.0Hz,1H),4.22-4.17(m,1H),3.76(s,3H),0.93-0.90m,2H),0.83-0.79(m,2H).

[0346] Example 20: Preparation of Compound 20

[0347]

[0348] According to the operation basically similar to Example 18, the compound of each step was obtained: Compound 20a (65 mg, yield 43%), MS: m / z 554.1 [M+H] + ; Compound 20 (15 mg, yield 70%), MS: m / z 434.1 [M+H] + .

[0349] Example 21: Preparation of Compound 21

[0350]

[0351] According to the operation basically similar to Example 18, the compound of each step was obtained: Compound 21-1a (2.6 g, yield 55%), MS: m / z 194.0 [M+H] + ; Compound 21-1b (1.8 g, yield 83%), MS: m / z 320.0 [M+H] + ; Compound 21-1c (350 mg, yield 69%), MS: m / z 274.0 [M+H] + ; Compound 21-1 (186 mg, yield 56%), MS: m / z 400.0 [M+H] + ; Compound 21a (54 mg, yield 51%), MS: m / z 536.1 [M+H] + ; Compound 21 (8 mg, yield 67%), MS: m / z 416.1 [M+H] + .

[0352] Example 22: Preparation of Compound 22

[0353]

[0354] According to the operation basically similar to Example 18, the compound of each step was obtained: Compound 22-1a (1.8 g, yield 50%), MS: m / z 178.0 [M+H] + ; Compound 22-1b (1.2 g, yield 79%), MS: m / z 304.0 [M+H] + ; Compound 22-1c (530 mg, yield 63%), MS: m / z 258.1 [M+H] + ; Compound 22-1 (360 mg, yield 51%), MS: m / z 384.0 [M+H] + ; Compound 22a (150 mg, yield 56%), MS: m / z 520.2 [M+H] + ; Compound 22 (23 mg, yield 69%), MS: m / z 400.1 [M+H] + .

[0355] Example 23: Preparation of Compound 23

[0356]

[0357] At 0°C, concentrated sulfuric acid (100 mL) was added dropwise to the stirred ice water (125 mL), and then 7-amino-4-methylquinolin-2(1H)-one (10.0 g) was added in batches. After the addition was completed, the mixture was stirred for 10 min, and then an aqueous solution (10 mL) of sodium nitrite (6.2 g) was added dropwise. After reacting for 20 min, an aqueous solution (10 mL) of sodium iodide (20.2 g) was added dropwise, stirred at 0°C for 30 min, and then heated to 60°C for 2 h. After the reaction was completed, water (150 mL) was added, and the pH value was adjusted to 8-9 with a 2N aqueous sodium hydroxide solution, and then extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=1 / 1, v / v) to obtain compound 23a (7.5 g, yield 46%). MS: m / z 286.0[M+H] + .

[0358] Weigh compound 23a (3.5 g) into a round-bottom flask, add phosphorus oxychloride (10 mL) and stir evenly, heat to 100°C and reflux for 3 h. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, pour into ice water and stir thoroughly, filter, wash the filter cake with water, and dry to obtain compound 23b (2.8 g, yield 75%). MS: m / z 304.0 [M+H] + .

[0359] Compound 23b (2.0 g, 1.0 equiv.) was weighed into a reaction bottle, dimethyl sulfoxide (DMSO) (10 mL) was added and stirred to dissolve, and then 4-methoxybenzylamine (1.3 equiv.) and triethylamine (2.0 equiv.) were weighed and added into the reaction system, and heated to 120°C and refluxed for 24 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE:EA=15:1-5:1, v / v) to obtain a yellow solid compound 23c (2.1 g, yield 79%). MS: m / z 405.0 [M+H] + .

[0360] Compound 23c (500 mg, 1.0 equiv.), 1,4-dioxane (10 mL), bis(pinacolato)diboron (1.5 equiv.), potassium acetate (2.0 equiv.) and Pd(dppf)Cl2 (0.1 equiv.) were weighed in sequence and added to a round-bottom flask, nitrogen was replaced three times, and heated to reflux at 85°C for 6 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE:EA=5:1-3:1, v / v) to obtain compound 23d (325 mg, yield 65%). MS: m / z405.2[M+H] + .

[0361] Compound 23d (50 mg, 1.0 equiv.), compound 18-1 (1.2 equiv.), sodium carbonate (2.5 equiv.), Pd(PPh3)4 (0.15 equiv.) and dioxane: water (2 mL / 0.5 mL) were weighed in sequence and added to a reaction flask, nitrogen was replaced three times, and the mixture was heated to 85°C for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) to obtain compound 23e (25 mg, yield 36%). MS: m / z 568.2 [M+H] + .

[0362] Compound 23e (25 mg) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (0.2 mm silica gel plate) (DCM: MeOH = 100 / 1, v / v) to obtain compound 23 (13 mg, yield 66%). MS: m / z 448.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.98(d,J=6.0Hz,1H),7.91(d,J=9.0Hz,1H),7.53(d,J=2.0Hz,1H),7.43(d,J=8.6Hz,1H),7. 10(s,1H),7.09(bs,2H),6.83(d,J=9.0Hz,1H),4.22-4.17(m,1H),3.76(s,3H),2.56(s,3H),0.93-0.90(m,2H),0.83-0.79(m,2H).

[0363] Example 24: Preparation of Compound 24

[0364]

[0365] According to the operation basically similar to Example 18, the compound of each step was obtained: Compound 24-1a (3.4 g, yield 57%), MS: m / z 226.0 [M+H] + ; Compound 24-1b (1.5 g, yield 81%), MS: m / z 352.0 [M+H] + ; Compound 24-1c (450 mg, yield 71%), MS: m / z 306.0 [M+H] + ; Compound 24-1 (287 mg, yield 60%), MS: m / z 432.0 [M+H] + ; Compound 24a (74 mg, yield 50%), MS: m / z 582.2 [M+H] + ; Compound 24 (13 mg, yield 61%), MS: m / z 462.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.98(d,J=6.0Hz,1H),7.91(d,J=9.0Hz,1H),7.53(d,J=2.0Hz,1H),7.43(d,J=8.6Hz,1H),7. 10(s,1H),7.09(bs,2H),6.83(d,J=9.0Hz,1H),4.32-4.27(m,1H),3.76(s,3H),2.56(s,3H),1.35-1.28(m,3H),1.15-1.08(m,3H).

[0366] Example 25: Preparation of Compound 25

[0367]

[0368] According to the operation basically similar to Example 18, the compound of each step was obtained: Compound 25-1a (3.6 g, yield 59%), MS: m / z 240.0 [M+H] + ; Compound 25-1b (1.1 g, yield 80%), MS: m / z 365.0 [M+H] + ; Compound 25-1c (630 mg, yield 69%), MS: m / z 320.0 [M+H] + ; Compound 25-1 (310 mg, yield 53%), MS: m / z 446.0 [M+H] + ; Compound 25a (158 mg, yield 43%), MS: m / z 596.2 [M+H] + ; Compound 25 (16 mg, yield 66%), MS: m / z 476.1 [M+H]+ .

[0369] Example 26: Preparation of Compound 26

[0370]

[0371] According to the operation basically similar to Example 18, the compound of each step was obtained: Compound 26-1a (3.9 g, yield 62%), MS: m / z 228.0 [M+H] + ; Compound 26-1b (1.7 g, yield 83%), MS: m / z 354.0 [M+H] + ; Compound 26-1c (568 mg, yield 65%), MS: m / z 308.0 [M+H] + ; Compound 26-1 (295 mg, yield 50%), MS: m / z 434.0 [M+H] + ; Compound 26a (130 mg, yield 47%), MS: m / z 584.1 [M+H] + ; Compound 26 (17 mg, yield 73%), MS: m / z 464.1 [M+H] + .

[0372] Example 27: Preparation of Compound 27

[0373]

[0374] Weigh benzene-1,3-diamine (1.0 g, 1.0 equiv.) and ethyl 2-fluoro-3-oxobutyrate (1.2 equiv.) and heat under reflux for 20 h. After the reaction is completed, pour it into ice water (100 mL) and filter to obtain a crude product, which is then purified by column chromatography (100-200 mesh silica gel) (PE / EA=1 / 1, v / v) to obtain compound 27a (1.06 g, yield 60%). MS: m / z 193.1 [M+H] + .

[0375] Referring to Example 23, the product in each step was obtained: Compound 27b (480 mg, yield 48%), MS: m / z 304.0 [M+H] + ; Compound 27c (410 mg, yield 70%), MS: m / z 322.0 [M+H] + ; Compound 27d (368 mg, yield 74%), MS: m / z 423.0 [M+H] + ; Compound 27e (188 mg, yield 69%), MS: m / z 423.2 [M+H] +; Compound 27f (96 mg, yield 33%), MS: m / z 586.1 [M+H] + ; Compound 27 (17 mg, yield 70%), MS: m / z 466.1 [M+H] + .

[0376] Example 28: Preparation of Compound 28

[0377]

[0378] Compound 23c (1.0 g, 1.0 equiv.) was weighed and dissolved in acetic acid (20 mL), and then NBS (2.0 equiv.) was added to the solution in batches, and the temperature was raised to 110°C for reaction for 2 h. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with methyl tert-butyl ether (50 mL×3) to obtain compound 28a (435 mg, yield 36%). MS: m / z 483.0 [M+H] + .

[0379] Compound 28a (435 mg, 1.0 equiv.), 1,4-dioxane (20 mL), bis(pinacolato)diboron (1.5 equiv.), potassium acetate (2.0 equiv.) and Pd(dppf)Cl2 (0.1 equiv.) were weighed in sequence and added to a round-bottom flask, nitrogen was replaced three times, and heated to reflux at 85°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1-5 / 1, v / v) to obtain compound 28b (260 mg, yield 60%). MS: m / z483.1[M+H] + .

[0380] Compound 28b (100 mg, 1.0 equiv.), compound 18-1 (1.2 equiv.), sodium carbonate (2.5 equiv.), Pd(PPh3)4 (0.15 equiv.) and dioxane: water (4 mL / 1 mL) were weighed and added to the reaction bottle, nitrogen was replaced three times, and the mixture was heated to 85 °C for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE / EA=3 / 1, v / v) to obtain compound 28c (35 mg, yield 26%). MS: m / z 646.1 [M+H] + .

[0381] Compound 28c (35 mg) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (0.2 mm silica gel plate) (DCM: MeOH = 80 / 1, v / v) to obtain compound 28 (20 mg, yield 70%). MS: m / z 526.0 [M+H] + .

[0382] Example 29: Preparation of Compound 29

[0383]

[0384] Except that 2-fluoro-3-oxobutyric acid ethyl ester was replaced by 2-oxocyclopentanecarboxylic acid ethyl ester, other conditions were the same as those in Example 27 to obtain the product in each step: Compound 29a (2.1 g, yield 63%), MS: m / z 201.0 [M+H] + ; Compound 29b (869 mg, yield 35%), MS: m / z 312.0 [M+H] + ; Compound 29c (489 mg, yield 55%), MS: m / z 329.8 [M+H] + ; Compound 29d (347 mg, yield 73%), MS: m / z 431.1 [M+H] + ; Compound 29e (315 mg, yield 68%), MS: m / z 431.0 [M+H] + ; Compound 29f (74 mg, yield 75%), MS: m / z 593.2 [M+H] + ; Compound 29 (18 mg, yield 67%), MS: m / z 474.1 [M+H] + .

[0385] Example 30: Preparation of Compound 30

[0386]

[0387] Compound 1-1 (200 mg, 1.0 equiv.) and acetonitrile (2 mL) were weighed in sequence, and hydrogen peroxide solution (1.2 equiv.) was added after mixing. After the reaction was completed, water (5 mL) was added, and the mixture was extracted with dichloromethane (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (20 mm silica gel plate) (PE:EA=3:1, v / v) to obtain compound 30a (130 mg, yield 90%). MS: m / z 281.1[M+H] + .

[0388] Weigh compound 30a (100 mg, 1.5 equiv.) and dissolve it in DMF (2 mL). Then add potassium carbonate (2.0 equiv.) in batches. After stirring at room temperature for 10 min, add compound 18-1 (1.0 equiv.). After the addition, heat to 140°C and react for 16 h. After the reaction is completed, add 10% citric acid solution (5 mL) and dichloromethane (20 mL). Separate the organic phase, dry it over anhydrous sodium sulfate, filter it, and concentrate it under reduced pressure to obtain a crude product. The crude product is purified by thin layer chromatography (1.0 mm silica gel plate) (PE: EA = 1: 1, v / v) to obtain compound 30b (56 mg, yield 50%). MS: m / z 662.1 [M+H] + .

[0389] Compound 30b (56 mg) was weighed and placed in a reaction bottle, trifluoroacetic acid (2 mL) was added to dissolve, and the reaction system was heated to 65°C for 2 h. After the reaction was completed, it was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (DCM: MeOH = 80 / 1, v / v) to obtain compound 30 (35 mg, yield 76%). MS: m / z 542.0 [M+H] + .

[0390] Example 31: Preparation of Compound 31

[0391]

[0392] 7-Bromoquinoxaline-2-amine (2.0 g, 1.0 equiv.) was weighed into a reaction bottle, dimethyl sulfoxide (DMSO) (10 mL) was added and stirred to dissolve, and then 4-methoxybenzyl chloride (1.3 equiv.) and triethylamine (2.0 equiv.) were weighed and added into the reaction system, and heated to 120°C and refluxed for 24 h. After the reaction was completed, water (50 mL) was added, and ethyl acetate (100 mL×3) was used for extraction, and the liquids were separated, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA=10 / 1, v / v) to obtain compound 31a (1.8 g, yield 58%). MS: m / z 344.0[M+H] + .

[0393] Compound 31a (1.0 g, 1.0 equiv.), 1,4-dioxane (20 mL), bis(pinacolato)diboron (1.5 equiv.), potassium acetate (2.0 equiv.) and Pd(dppf)Cl2 (0.1 equiv.) were weighed in sequence and added to a round-bottom flask, nitrogen was replaced three times, and the mixture was heated to reflux at 85°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=10 / 1, v / v) to obtain compound 31b (580 mg, yield 51%). MS: m / z 392.2 [M+H] + .

[0394] Compound 31b (200 mg, 1.0 equiv.), compound 18-1 (1.2 equiv.), sodium carbonate (2.5 equiv.), Pd(PPh3)4 (0.15 equiv.) and dioxane: water (4 mL: 1 mL) were weighed in sequence and added to the reaction flask, nitrogen was replaced three times, and the mixture was heated to 85°C for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE / EA=3 / 1, v / v) to obtain compound 31c (85 mg, yield 30%). MS: m / z 555.2 [M+H] + .

[0395] Weigh compound 31c (85 mg) into a reaction bottle, add trifluoroacetic acid (3 mL) to dissolve, and heat to 65°C for 2 h. After the reaction is completed, concentrate under reduced pressure to obtain a crude product, which is purified by thin layer chromatography (1.0 mm silica gel plate) (DCM: MeOH = 60 / 1, v / v) to obtain compound 31 (45 mg, yield 68%). MS: m / z 435.1 [M+H] + .

[0396] Example 32: Preparation of Compound 32

[0397]

[0398] 7-Nitroquinoline (23.0 g, 132 mmol) was weighed and dissolved in acetic acid (180 mL), and then NBS (30.2 g, 170 mmol) was added to the above solution in batches, and the temperature was raised to 110°C for reaction for 2 h. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with methyl tert-butyl ether (50 mL×3) to obtain compound 32a (16 g, yield 48%). MS: m / z 253.0 [M+H] + .

[0399] Compound 32a (15.0 g, 1.0 equiv.), cyclopropylboronic acid (2.0 equiv.), sodium carbonate (2.5 equiv.), Pd(PPh3)4 (0.15 equiv.) and dioxane: water (160 mL: 40 mL) were weighed in sequence and added to a reaction flask, nitrogen was replaced three times, and the mixture was heated to 85°C for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain compound 32b (8.5 g, yield 66%). MS: m / z 215.1 [M+H] + .

[0400] Weigh compound 32b (8.5 g, 1.0 equiv.) and dissolve it in ethanol (120 mL) and water (80 mL), then add ammonium chloride (8.7 g, 5.0 equiv.) and iron powder (10.5 g, 7.0 equiv.) to the solution, and heat to 80°C for 2 h. After the reaction is completed, cool to room temperature, filter, wash the filter cake with dichloromethane (150 mL×3), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 32c (5.3 g, yield 72%). MS: m / z185.1[M+H] + .

[0401] At 0°C, concentrated sulfuric acid (50 mL) was added dropwise to the stirred ice water (63 mL), and then compound 32c (5.0 g) was added in batches. After the addition was completed, the mixture was stirred for 10 min, and then an aqueous solution (5 mL) of sodium nitrite (3.1 g) was added dropwise. After reacting for 20 min, an aqueous solution (5 mL) of sodium iodide (10.2 g) was added dropwise, stirred at 0°C for 30 min, and then the mixture was heated to 60°C for 2 h. After the reaction was completed, water (75 mL) was added, and the pH value was adjusted to 8-9 with a 2N aqueous sodium hydroxide solution, and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=20 / 1, v / v) to obtain compound 32d (2.7 g, yield 34%). MS: m / z 296.0[M+H] + .

[0402] Weigh compound 32d (2.6 g) and dissolve it in dichloromethane (80 mL), and place it in an ice-water bath. Then, add m-CPBA (4.0 g) to the solution in batches, warm it to room temperature, and react overnight. After the reaction is completed, filter, dilute the filtrate with water (100 mL), adjust the pH value to 7-8 with saturated sodium bicarbonate aqueous solution, and then extract with dichloromethane (80 mL×3). Combine the organic phases, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA=50 / 1, v / v) to obtain compound 32e (2.5 g, yield 91%). MS: m / z 312.0[M+H] + .

[0403] Weigh compound 32e (2.5 g) and dissolve it in chloroform (60 mL), then add phosphorus oxychloride (7.7 g) dropwise to the solution, and heat to 80 ° C for 2 h. After the reaction is completed, cool to room temperature, place the reaction system in an ice-water bath, add water (80 mL), and adjust the pH value to 7-8 with saturated sodium bicarbonate aqueous solution, and then extract with dichloromethane (80 mL × 3). Combine the organic phases, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, filter it, and concentrate it under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA=30 / 1, v / v) to obtain compound 32f (0.3 g, yield 11%). MS: m / z 330.0 [M+H] + .

[0404] Weigh compound 32f (0.2 g) and dissolve it in DMSO (6 mL), then add 4-methoxybenzylamine (1.5 equiv.) and DIPEA (4.0 equiv.) to the solution, raise the temperature to 120°C, and react overnight. After the reaction is completed, cool to room temperature and extract with ethyl acetate (10 mL×3). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA=10 / 1, v / v) to obtain compound 32g (251 mg, yield 96%). MS: m / z 431.0[M+H] + .

[0405] Compound 32g (251 mg, 1.0 equiv.), 1,4-dioxane (5 mL), bis(pinacolato)diboron (1.5 equiv.), potassium acetate (2.0 equiv.) and Pd(dppf)Cl2 (0.1 equiv.) were weighed in sequence and added to a round-bottom flask, the nitrogen atmosphere was replaced three times, and the mixture was heated to reflux at 85°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA=10 / 1, v / v) to obtain compound 32h (130 mg, yield 52%). MS: m / z 431.2 [M+H] + .

[0406] Compound 32h (100 mg, 1.0 equiv.), compound 18-1 (1.2 equiv.), sodium carbonate (2.5 equiv.), Pd(PPh3)4 (0.15 equiv.) and dioxane: water (2 mL / 0.5 mL) were weighed in sequence and added to the reaction flask, nitrogen was replaced three times, and the mixture was heated to 85°C for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=1:1, v / v) to obtain compound 32i (26 mg, yield 19%). MS: m / z 594.2 [M+H] + .

[0407] Compound 32i (26 mg) was weighed and placed in a reaction bottle, trifluoroacetic acid (2 mL) was added to dissolve, and the mixture was heated to 65°C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (0.2 mm silica gel plate) (DCM: MeOH = 60 / 1, v / v) to obtain compound 32 (16 mg, yield 77%). MS: m / z 474.1 [M+H] + .

[0408] Example 33: Preparation of Compound 33

[0409]

[0410] According to the operation basically similar to Example 32, the product in each step was obtained: Compound 33a (10.8 g, yield 63%), MS: m / z 189.0 [M+H] + ; Compound 33b (8.3 g, yield 70%), MS: m / z 158.0 [M+H] + ; Compound 33c (3.9 g, yield 45%), MS: m / z 270.0 [M+H] + ; Compound 33d (2.2 g, yield 88%), MS: m / z 286.0 [M+H] +; Compound 33e (1.7 g, yield 20%), MS: m / z 304.0 [M+H] + ; Compound 33f (1.5 g, yield 90%), MS: m / z 405.0 [M+H] + ; Compound 33g (947 mg, yield 56%), MS: m / z 405.2 [M+H] + ; Compound 33h (68 mg, yield 23%), MS: m / z 568.1 [M+H] + ; Compound 33 (18 mg, yield 75%), MS: m / z 448.1 [M+H] + .

[0411] Example 34: Preparation of Compound 34

[0412]

[0413] According to the operation basically similar to Example 29, the product in each step was obtained: Compound 34a (3.8 g, yield 60%), MS: m / z 203.0 [M+H] + ; Compound 34b (1.2 g, yield 41%), MS: m / z 313.9 [M+H] + ; Compound 34c (650 mg, yield 69%), MS: m / z 331.8 [M+H] + , Compound 34d (580 mg, yield 85%), MS: m / z 433.1 [M+H] + ; Compound 34e (436 mg, yield 64%), MS: m / z 433.2 [M+H] + ; Compound 34f (67 mg, yield 75%), MS: m / z 596.2 [M+H] + ; Compound 34 (21 mg, yield 66%), MS: m / z 476.1 [M+H] + .

[0414] Example 35: Preparation of Compound 35

[0415]

[0416] 5-Bromo-2-iodoaniline (5.0mmol), 3-butyn-1-ol (0.42g, 6.0mmol), Pd(PPh3)2Cl2 (17.5mg, 5mmol%), cuprous iodide (10mg, 10mmol%) and triethylamine (15mL) were weighed and placed in a dry three-necked flask, nitrogen was replaced three times, and stirred at room temperature for 10h. After the reaction was completed, saturated aqueous ammonium chloride solution (10mL) was added to quench the reaction, and extracted with ethyl acetate (50mL×3). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA=20 / 1, v / v) to obtain compound 35a (0.56g, yield 70%). MS: m / z 241.0[M+H] + .

[0417] Compound 35a (322 mg, 1.0 equiv.), Pd(PPh3)4 (0.1 equiv.), dppp (0.2 equiv.), copper acetate (2.0 equiv.) and acetonitrile / toluene (10 mL, 1 / 1) were weighed and added to a reaction flask, and finally tert-butyl isocyanate (1.5 equiv) was added, and the temperature was raised to 110°C for 9 h. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was extracted (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA=30 / 1, v / v) to obtain compound 35b (220 mg, yield 51%). MS: m / z 321.0[M+H] + .

[0418] Compound 35b (220 mg, 1.0 equiv.), 1,4-dioxane (5 mL), bis(pinacolato)diboron (1.5 equiv.), potassium acetate (2.0 equiv.) and Pd(dppf)Cl2 (0.1 equiv.) were weighed in sequence and added to a round-bottom flask, nitrogen was replaced three times, and heated to reflux at 85°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=5:1-3:1, v / v) to obtain a yellow solid compound 35c (85 mg, yield 34%). MS: m / z 369.2[M+H] + .

[0419] Compound 35c (50 mg, 1.0 equiv.), compound 18-1 (1.2 equiv.), sodium carbonate (2.5 equiv.), Pd(PPh3)4 (0.15 equiv.) and dioxane: water (2 mL: 0.5 mL) were weighed in sequence and added to the reaction bottle, nitrogen was replaced three times, and the mixture was heated to 85 °C for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (PE: EA = 1: 1, v / v) to obtain a yellow solid compound 35d (18 mg, yield 25%). MS: m / z 532.2 [M+H] + .

[0420] Compound 35d (18 mg) was weighed and placed in a reaction bottle, trifluoroacetic acid (2 mL) was added to dissolve, and the mixture was heated to 80°C for 24 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (0.2 mm silica gel plate) (DCM: MeOH = 70 / 1, v / v) to obtain compound 35 (10 mg, yield 62%). MS: m / z 476.1 [M+H] + .

[0421] Example 36: Preparation of Compound 36

[0422]

[0423] Weigh 4-bromo-1-fluoro-2-nitrobenzene (1.18 g, 5.37 mmol), 1H-imidazole-2-carbonitrile (0.50 g, 5.37 mmol), DIPEA (2.35 mL, 13.43 mmol, 2.5 equiv.) and DMSO (5.0 mL) and stir at room temperature for 16 h. After the reaction is completed, add saturated saline solution (20 mL) and extract with ethyl acetate (50 mL×3). Combine the organic phases, wash with saturated saline (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA=5 / 1, v / v) to obtain compound 36a (1.27 g, yield 81%). MS: m / z 293.0[M+H] + .

[0424] Weigh compound 36a (0.90 g) and dissolve it in THF (10.0 mL) and water (2.0 mL), then add acetic acid (0.96 mL, 5.0 equiv.) and iron powder (1.85 g, 10.0 equiv.), and stir at room temperature for 16 h. After the reaction is completed, add ethyl acetate to extract and wash with saturated sodium bicarbonate solution. The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE / EA=5 / 1, v / v) to obtain compound 36b (350 mg, yield 44%). MS: m / z 263.0 [M+H] + .

[0425] Weigh compound 36b (350 mg, 1.0 equiv.), place in a reaction bottle, add DMSO (5 mL) and stir to dissolve, then weigh 4-methoxybenzyl chloride (1.3 equiv.) and triethylamine (2.0 equiv.), add to the reaction system, and heat to 120°C and reflux for 24 h. After the reaction is completed, add water (20 mL) and extract with ethyl acetate (50 mL×3). Combine the organic phases, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by column chromatography (100-200 mesh silica gel) (PE:EA=10:1-5:1, v / v) to obtain a yellow solid compound 36c (230 mg, yield 45%). MS: m / z 383.0[M+H] + .

[0426] Compound 36c (230 mg, 1.0 equiv.), 1,4-dioxane (5 mL), bis(pinacolato)diboron (1.5 equiv.), potassium acetate (2.0 equiv.) and Pd(dppf)Cl2 (0.1 equiv.) were weighed in sequence and added to a round-bottom flask, the nitrogen atmosphere was replaced three times, and the mixture was heated to reflux at 85°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE:EA=5:1-3:1, v / v) to obtain a yellow solid compound 36d (146 mg, yield 56%). MS: m / z 431.2 [M+H] + .

[0427] Compound 36d (50 mg, 1.0 equiv.), compound 18-1 (1.2 equiv.), sodium carbonate (2.5 equiv.), Pd(PPh3)4 (0.15 equiv.) and dioxane: water (2 mL / 0.5 mL) were weighed in sequence and added to a reaction flask, nitrogen was replaced three times, and the mixture was heated to 85°C for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=1:1, v / v) to obtain a yellow solid compound 36e (13 mg, yield 20%). MS: m / z 594.2 [M+H] + .

[0428] Compound 36e (13 mg) was weighed and placed in a reaction bottle, trifluoroacetic acid (2 mL) was added to dissolve, and the mixture was heated to 65°C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (0.2 mm silica gel plate) (DCM: MeOH = 50 / 1, v / v) to obtain compound 36 (8 mg, yield 77%). MS: m / z 474.1 [M+H] + .

[0429] Example 37: Preparation of Compound 37

[0430]

[0431] Except that 2-fluoro-3-oxobutyric acid ethyl ester was replaced by 2-methyl-3-oxobutyric acid ethyl ester, other conditions were the same as those in Example 27 to obtain the product in each step: compound 37a (2.7 g, yield 60%), MS: m / z 189.0 [M+H] + ; Compound 37b (1.6 g, yield 50%), MS: m / z 300.0 [M+H] + ; Compound 37c (1.1 g, yield 66%), MS: m / z 318.0 [M+H] + ; Compound 37d (930 mg, yield 77%), MS: m / z 419.1 [M+H] + ; Compound 37e (493 mg, yield 63%), MS: m / z 419.2 [M+H] + ; Compound 37f (124 mg, yield 39%), MS: m / z 582.1 [M+H] + ; Compound 37 (16 mg, yield 76%), MS: m / z 462.1 [M+H] + .

[0432] Example 38: Preparation of Compound 38

[0433]

[0434] Except that 2-fluoro-3-oxobutyric acid ethyl ester was replaced by 3-cyclopropyl-3-oxopropionic acid ethyl ester, other conditions were the same as those in Example 27 to obtain the product in each step: compound 38a (3.2 g, yield 67%), MS: m / z 201.0 [M+H] + ; Compound 38b (1.7 g, yield 48%), MS: m / z 312.0 [M+H] + ; Compound 38c (1.4 g, yield 70%), MS: m / z 330.0 [M+H] + ; Compound 38d (1.3 g, yield 80%), MS: m / z 431.0 [M+H] + ; Compound 38e (870 mg, yield 67%), MS: m / z 430.1 [M+H] + ; Compound 38f (104 mg, yield 41%), MS: m / z 594.2 [M+H] + ; Compound 38 (18 mg, yield 72%), MS: m / z 474.1 [M+H] + .

[0435] Example 39: Preparation of Compound 39

[0436]

[0437] Except that 2-fluoro-3-oxobutyric acid ethyl ester was replaced by 4,4-difluoro-3-oxobutyric acid ethyl ester, other conditions were the same as those in Example 27 to obtain the product in each step: compound 39a (2.9 g, yield 70%), MS: m / z 210.0 [M+H] + ; Compound 39b (1.6 g, yield 51%), MS: m / z 322.0 [M+H] + ; Compound 39c (1.3 g, yield 67%), MS: m / z 340.0 [M+H] + ; Compound 39d (885 mg, yield 81%), MS: m / z 441.0 [M+H] + ; Compound 39e (651 mg, yield 63%), MS: m / z 441.1 [M+H] + ; Compound 39f (107 mg, yield 46%), MS: m / z 604.2 [M+H] + ; Compound 39 (23 mg, yield 69%), MS: m / z 484.1 [M+H] + .

[0438] Example 40: Preparation of Compound 40

[0439]

[0440] Under nitrogen protection, compound 23e (50 mg, 1.0 equiv.) and tri-n-butyl propynyl stannane (4.0 equiv.) were dissolved in 1,4-dioxane (10 mL), and Pd(PPh3)4 (0.2 equiv.) was added, and the temperature was raised to 120°C for 72 h. After the reaction was completed, ice water (30 mL) was added to the system, and it was extracted with dichloromethane (20 mL×3). 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 (100-200 mesh silica gel) (DCM / MeOH=10 / 1, v / v) to obtain compound 40a (30 mg, yield 60%). MS: m / z 572.2[M+H] + .

[0441] Weigh compound 40a (30 mg) into a reaction bottle, add trifluoroacetic acid (2 mL) to dissolve, and heat to 65°C for 2 h. After the reaction is completed, concentrate under reduced pressure to obtain a crude product, which is purified by thin layer chromatography (1.0 mm silica gel plate) to obtain compound 40 (21 mg, yield 89%). MS: m / z 472.2 [M+H] + .

[0442] Example 41: Preparation of Compound 41

[0443]

[0444] Under nitrogen protection, compound 1,3-dibromo-2-chloro-5-fluorobenzene (61.0 g, 1.0 equiv.) and N-methylpyrrole (2.0 equiv.) were dissolved in toluene (1500 mL), cooled to -30 °C, and n-butyl lithium (2.5 M THF solution, 1.05 equiv.) was added dropwise. After the reaction was kept warm for 30 min, the temperature was raised to room temperature for 12 h. After the reaction was completed, water (20 mL) was added to the system, and the system was concentrated under reduced pressure. Ethyl acetate (1000 mL) was added to dilute the system, and then the system was washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA=10 / 1, v / v) to obtain compound 41a (30 g, yield 56%). MS: m / z 253.8 [M+H] + .

[0445] Compound 41a (30.0 g, 1.0 equiv.) was dissolved in chloroform (650 mL), and m-CPBA (2.0 equiv., 85% purity) was slowly added in batches (note: the temperature of the reaction system should not exceed 40°C). After 2 hours, the reaction system changed from brown to yellow, and the reaction was continued for 24 hours. After the reaction was completed, it was extracted with dichloromethane (500 mL), and washed with saturated sodium sulfate (750 mL×2) and saturated brine (750 mL) in sequence, and then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (100-200 mesh silica gel) (PE / EA=100 / 1-10-1) to obtain compound 41b (19 g, yield 70%). MS: m / z 225.9 [M+H] + .

[0446] Compound 41b (17.4 g, 1.0 equiv.), zinc cyanide (2.5 equiv.), Pd2(dba)3 (0.1 equiv.), DPPF (0.2 equiv.), zinc powder (0.1 equiv.) and DMF (200 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 115°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, and then ethyl acetate (500 mL) was added for dilution. The reaction system was washed with saturated brine (500 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA=100 / 1-20 / 1, v / v) to obtain compound 41c (10.7 g, yield 80%). MS: m / z 172.0[M+H] + .

[0447] Under nitrogen protection, diisopropylamine (845 mg, 1.3 equiv.) was dissolved in THF (15 mL) and cooled to -70 °C. n-Butyl lithium (2.5 M in n-hexane, 1.1 equiv.) was added to the above system and reacted for 15 min. Compound 41c (1.1 g, 1.0 equiv.) was weighed and dissolved in anhydrous THF (2 mL) and added to the above reaction system. After the reaction was kept warm for 30 min, a THF solution (2 mL) of iodine (2.12 g, 1.3 equiv.) was added dropwise. After the addition was completed and the reaction was continued for 30 min, the temperature was raised to room temperature and the reaction was continued for 10 h. After the reaction was completed, water (100 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated sodium sulfite (100 mL × 2) and saturated brine (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 mesh silica gel) (PE / EA = 100 / 1, v / v) to obtain compound 41d (1.7 g, yield 89%). MS: m / z 298.0 [M+H]+ .

[0448] Compound 41d (800 mg, 1.0 equiv.), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (2.2 equiv.), Pd(dppf)Cl2 (0.1 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (10 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 80°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE / EA=20 / 1-1 / 1, v / v) to obtain compound 41e (500 mg, yield 74%). MS: m / z 292.0[M+H] + .

[0449] Compound 41e (500 mg, 0.63 mmol, 1.0 equiv.), NIS (1.0 equiv.) and acetonitrile (8 mL) were weighed in sequence and reacted at 80°C for 12 h. After the reaction was completed, saturated sodium carbonate (5 mL) was added to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) (PE / EA=10 / 1-1 / 1, v / v) to obtain compound 41f (630 mg, yield 84%). MS: m / z 377.8[M+H] + .

[0450] Compound 1-1 (80 mg, 1.0 equiv.), compound 41f (1.2 equiv.), Pd(PPh3)4 (0.2 equiv.), sodium carbonate (3.0 equiv.), 1,4-dioxane (6 mL) and water (2 mL) were weighed in sequence, nitrogen was replaced three times, and the mixture was reacted at 90°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated, and then water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (1.0 mm silica gel plate) (PE:EA=3 / 1, v / v) to obtain compound 41g (29 mg, yield 28%). MS: m / z 514.2[M+H] + .

[0451] Compound 41g (29 mg, 1.0 equiv.) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) and reacted at 60°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was purified by thin layer chromatography (0.2 mm silica gel plate) (PE:EA=1 / 1, v / v) to obtain compound 41 (18 mg, yield 81%). MS: m / z 394.1 [M+H] + .

[0452] Experimental Example 1: PRMT5 enzyme inhibition activity test

[0453] 1.1 Experimental Materials

[0454]

[0455] 1.2 Experimental process

[0456] Step 1: Preparation of 1×PRMT5 assay buffer: Add 30 μL of 500 mM DTT to 4×PRMT5 assay buffer to prepare 1×PRMT5 assay buffer (add 3 volumes of distilled water to 4×PRMT5 assay buffer);

[0457] Step 2: Preparation of the working solution of the test compound: Take 45 μL DMSO, add 5 μL of 5 mM test compound stock solution to prepare a working solution with a concentration of 500 μM; take the 500 μM working solution as the initial working solution concentration, dilute it 3 times with DMSO, and obtain another 7 working solutions of different concentrations in turn;

[0458] Step 3: Preparation of test compounds containing MTA: add 28 μL of 1×PRMT5 assay buffer, 1 μL of test compound working solution and 1 μL of 200 μM MTA to each test compound;

[0459] Step 4: Preparation of 1×PRMT5 assay buffer containing MTA: Add 29 μL of 1×PRMT5 assay buffer and 1 μL of 200 μM MTA to each test compound;

[0460] Step 5: Preparation of the mixed solution: Take 2.0 μL of 4×PRMT5 assay buffer, 0.5 μL of 60 μM S-adenosylmethionine, 1 μL of biotin-labeled substrate, and 1.5 μL of water, and then add 5 μL of the mixed solution to the positive control well (without the test compound), the test well (with the test compound), and the blank well (without PRMT5 enzyme and test compound) in a 96-well plate;

[0461] Step 6: Take 3 μL of the test compound containing MTA and add it to the test well; take another 3 μL of 1×PRMT5 assay buffer containing MTA and add it to the positive control well and the blank well;

[0462] Step 7: Preparation of PRMT5 enzyme dilution: Take out PRMT5 enzyme from -80℃ freezer, thaw on ice, dilute the concentration of PRMT5 enzyme to 100 ng / μL with 1×PRMT5 assay buffer, then take 2μL of PRMT5 enzyme dilution and add it to the positive control well and test well; the final concentrations of the test compounds in the test wells are 5μM, 1.667μM, 0.556μM, 0.185μM, 0.0617μM, 0.0206μM, 0.0069μM and 0.0023μM;

[0463] The specific ratio is as follows:

[0464] / Positive control wells Test hole Blank hole 4×PRMT5 Assay Buffer 2μL 2μL 2μL 60 μM S-adenosylmethionine 0.5μL 0.5μL 0.5μL Biotinylated substrate 1μL 1μL 1μL water 1.5μL 1.5μL 1.5μL Test compounds containing MTA - 3μL - 1× PRMT5 Assay Buffer with MTA 3μL - 3μL PRMT5 enzyme (100 ng / μL) 2μL 2μL - 1×PRMT5 Assay Buffer - - 2μL total 10μL 10μL 10μL

[0465] Step 8: Preparation of 1× Assay Buffer: Take 550 μL of 4× Assay Buffer and add 1650 μL of water to obtain 1× Assay Buffer;

[0466] Step 9: Preparation of anti-rabbit IgG receptor microbead working solution: Take 498 μL of 1× detection buffer, add 2 μL of anti-rabbit IgG receptor microbeads, and mix well;

[0467] Step 10: Preparation of primary antibody 4-3 working solution: Take 522 μL of 1× detection buffer, add 18 μL of primary antibody 4-3 (PRMT5 homogeneous analysis kit), and mix well;

[0468] Step 11: Take 5 μL of the solutions prepared in step 9 and step 10, vortex mix, add to the wells to be tested in the above 96-well plate, and incubate at room temperature for 30 min;

[0469] Step 12: Preparation of Streptavidin-conjugated donor microbead working solution: Take 1054 μL of 1× detection buffer, add 8.5 μL of Streptavidin-conjugated donor microbeads, mix well, take 10 μL and add to the wells to be tested in the above 96-well plate, and incubate at room temperature for 30 minutes;

[0470] Step 13: Read the readings.

[0471] 1.3 Data Analysis

[0472] 1.3.1 Activity calculation formula

[0473] %Inhibition=(Signalpostive -Signal cmpd ) / (Signal postive -Signal PC )×100;

[0474] Among them: Signal cmpd Indicates the average signal of the test compound well (test well); Signal PC Indicates the average signal of blank wells; Signal postive Represents the average signal of positive control wells.

[0475] 1.3.2 Calculation of compound IC using GraphPad nonlinear fitting formula 50

[0476] The log value of compound concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis. The log (inhibitor) vs. response-variable slope function module of the analysis software GraphPad was used to fit the dose-effect curve to obtain the inhibitory activity of each compound on PRMT5.

[0477] The fitting formula is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope));

[0478] Among them: Top represents the percentage inhibition rate at the top platform, and the Top standard of the curve is generally between 80% and 120%; Bottom represents the percentage inhibition rate at the bottom platform, and the Bottom of the curve is generally between -20% and 20%, and HillSlope represents the slope of the percentage inhibition rate curve.

[0479] Table 1. In vitro activity test results (IC 50 express)

[0480] Compound <![CDATA[IC 50 (nM)]]> 15 61 16 86 18 131.5 23 34.8 24 31.5

[0481] It can be seen from the above experimental results that the compounds of the embodiments of the present invention have excellent in vitro inhibitory activity against PRMT5, so that they can be used as small molecule PRMT5 inhibitors, which have good anti-tumor effects and can be used to treat diseases such as cancer.

[0482] Experimental Example 2: Study on the metabolic stability of compounds in liver microsomes of different species

[0483] 2.1 Experimental Materials

[0484] Human liver microsomes, catalog number 452117, purchased from Corning;

[0485] Mouse liver microsomes, catalog number M1000, purchased from Xenotech;

[0486] NADPH, product number BD11658, was purchased from Bidler.

[0487] 2.2 Experimental methods

[0488] Microsomes (20 mg / mL) were stored in a -80°C freezer, thawed in a 37°C water bath before use, and then placed on ice until use.

[0489] 10 μL of microsomes (20 mg / mL, final concentration 0.5 mg / mL), 200 μL of phosphate buffer (200 mM, final concentration 100 mM), 40 μL of magnesium chloride (50 mM, final concentration 5 mM) and purified water (106 μL) were added to a 96-well plate, and the system was pre-incubated in a 37°C water bath for 10 minutes. 40 μL of NADPH solution (10 mM, final concentration 1 mM) was added to the reaction system; 40 μL of ultrapure water was used instead of NADPH solution as a negative control.

[0490] 4 μL of 100 mM test compound and control drug (Verapamil) were added to the reaction system to start the reaction, and the final concentration of the drug was 1 μM.

[0491] 50 μL of the reaction sample was taken out at 0, 5, 15, 30 and 60 min, and quenched with 4 times of cold acetonitrile containing internal standard (3% formic acid, 100 nM alprazolam, 200 nM labetalol, 2 μM ketoprofen, 200 nM caffeine). The sample was centrifuged at 3220 g for 45 min. After centrifugation, 100 μL of the supernatant was mixed with 100 μL of ultrapure water for LC-MS / MS analysis.

[0492] 2.3 Data Analysis

[0493] All data calculations were performed using Microsoft Excel. Peak areas were detected by extracting ion spectra. The in vitro half-life (t 1 / 2 ).

[0494] In vitro half-life (t 1 / 2 ) is calculated by the slope:

[0495] In vitro 1 / 2 =0.693 / k [k is the elimination rate constant (k = -slope value)];

[0496] The following formula is used to convert the in vitro t 1 / 2 Transformed into in vitro clearance (CL int)(μL / min / mg protein):

[0497]

[0498] Among them, the incubation volume is 400 μL and the protein amount is 0.2 mg.

[0499] 2.4 Conclusion

[0500] The results showed that the Example compounds of the present invention had low to moderate clearance rates in human and mouse liver microsomes, and the compounds had good stability.

[0501] Experimental Example 3: Inhibitory effects of compounds on cytochrome P450 enzymes CYP3A4, CYP2B6 and CYP1A2

[0502] 3.1 Experimental Materials

[0503] Human liver microsomes, catalog number 452117, purchased from Corning;

[0504] NADPH, product number BD11658, was purchased from Bidler.

[0505] 3.2 Experimental methods

[0506] 1 μL of 2 mM test compound or quality control inhibitor (ketoconazole for CYP3A4 and CYP2B6 inhibitors, furafylline for CYP1A2 inhibitor) was added, and the final concentration of the test compound or quality control inhibitor was 10 μM. DMSO was used as a solvent control, and all experiments were performed in duplicate.

[0507] A mixed solution system containing phosphate buffered saline, ultrapure water, MgCl2 and human liver microsomes was prepared according to the table below.

[0508] Reagents Stock solution concentration volume Final concentration <![CDATA[MgCl2 stock solution]]> 50mM 20μL 5mM Phosphate buffered saline 200mM 100μL 100mM Ultrapure water -- 56μL -- Human liver microsomes 20mg / mL 2μL 0.2mg / mL Test compound or quality control inhibitor 2mM 1μL 10μM

[0509] Take 1 μL of the substrate stock solution and add it to the above mixture.

[0510] CYP enzyme subtypes Substrate Stock solution concentration Final concentration Incubation time CYP3A4 Midazolam 1mM 5μM 5min CYP2B6 Bupropion 10mM 50μM 20min CYP1A2 Phenacetin 8mM 40μM 20min

[0511] Preheat the reaction system in a 37°C water bath for 5 min, then add 20 μL of 10 mM NADPH solution to start the reaction, with a final NADPH concentration of 1 mM, and incubate at 37°C for the time shown in the table above.

[0512] After the incubation, at the designated time point, the reaction was terminated with 400 μL of cold methanol (internal standard, 500 nM Labetalol, 100 nM Alprazolam and 2 μM Ketoprofen). The sample was centrifuged at 3220 g for 60 min to precipitate the protein. 100 μL of the supernatant was diluted with 100 μL of ultrapure water (based on the peak shape and signal intensity of LC-MS / MS) and analyzed by LC-MS / MS.

[0513] 3.3 Conclusion

[0514] The results showed that the compounds of the examples of the present invention had no strong inhibition on each CYP enzyme subtype at 10 μM, and the DDI risk was low.

[0515] Experimental Example 4: Compound Solubility Test

[0516] 4.1 Buffer preparation

[0517] Preparation of pH 6.8 phosphate buffer: measure 0.2 mol / L potassium dihydrogen phosphate solution (250 mL) and 0.2 mol / L sodium hydroxide solution (118 mL), dilute to 1000 mL with water, and degas by ultrasonication.

[0518] pH 4.5 acetate buffer: Weigh sodium acetate (18 g), add appropriate amount of water, slowly add glacial acetic acid (9.8 mL), stir evenly, dilute with water to 1000 mL, and degas by ultrasonication to obtain.

[0519] 4.2 Experimental methods

[0520] Take the sample into a transparent glass stopper tube (measure each compound twice), add an appropriate amount of pH 6.8 phosphate buffer or pH 4.5 acetate buffer (the solution temperature is controlled at 25±2°C), and observe the dissolution state of the sample. Take the dissolved sample solution, filter it, and perform HPLC analysis to obtain the solubility of each compound.

[0521] 4.3 Conclusion

[0522] The results showed that the compounds of the present invention had good solubility in both pH 4.5 and pH 6.8 buffers.

[0523] Experimental Example 5: Plasma kinetic study of compounds in CD-1 mice

[0524] 5.1 Experimental animals

[0525] CD-1 mice, SPF grade, male, were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.

[0526] 5.2 Experimental methods

[0527] The pharmacokinetic properties of compounds in rodents were tested following oral administration using standard protocols.

[0528] In the experiment, the candidate compound was prepared into a clear solution and given to mice by oral gavage once, and the oral gavage solvent was pH 4.5 acetate buffer. Six mice were gavaged for each compound, and the dosage was 10 mg / kg (the concentration of the drug solution was 1 mg / mL, and the administration volume was 10 μL / g).

[0529] Sampling was performed at 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after oral administration. Whole blood samples were immediately placed on ice and centrifuged at 4 °C and 2000 g for 5 min within 0.5 h after collection to separate plasma. The upper layer of samples was collected into sample tubes, frozen in a -10 to -30 °C refrigerator within 0.5 h, and transferred to a -60 to -90 °C refrigerator within 24 h.

[0530] The concentration of each prototype drug in plasma samples at each time point was detected by LC-MS / MS, and the peak concentration (C max ), half-life (t 1 / 2 ), area under the drug-time curve (AUC 0-t ), tissue distribution volume (Vd), plasma clearance (CL) and other PK parameters.

[0531] The results showed that the compounds of the embodiments of the present invention had the characteristics of low plasma clearance rate, long drug half-life and good exposure, indicating that the compounds had good pharmacokinetic properties.

[0532] Although the present invention has been described by way of specific examples above, it should not be construed as being limited thereto, but rather the invention encompasses the general aspects previously disclosed and is susceptible to numerous modifications and embodiments without departing from the spirit and scope of the invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, in: represents a single bond or a double bond; X1 for CR 6 or N; X2 for CR 4 or N; X3 for CR 5 or N; X4 for CR 3 or NR 3 ; L is a single bond or oxygen; Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 3-6 membered heterocyclyl; m is 0, 1, 2, 3, 4 or 5; If present, each R 1 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C≡CR 1a , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl or 5-10 membered heteroaryl substituted; If present, each R 1a are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3, 4 or 5 R # replace; If present, each R # Each independently selected from halogen, cyano, hydroxyl, amino, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 is hydrogen or methyl; R 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group and -(C 1-6 Alkylene)-NH2; If present, R 4 is selected from the group consisting of hydrogen, amino, hydroxyl and carboxyl; If present, R 5 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or, R 5 and R 3 Connected to each other 5-10 The ring B of the carbonyl group, the 5-10 membered heterocyclic group and the 5-10 membered heteroaryl group; 5-10 The carbocyclyl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more halogen, cyano, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-6 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl or 5-10 membered heteroaryl substituted; If present, R 6 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and -(C 1-6 Alkylene)-NH2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: The structure of the compound is shown in Formula I-1, Formula I-2 or Formula I-2':

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: The structure of the compound is shown in Formula I-3A or Formula I-3A': Among them, R 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group and -(C 1-6 Alkylene)-NH2; R 4 is selected from the group consisting of hydrogen, amino, hydroxyl and carboxyl; R 5 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Alternatively, the structure of the compound is as shown in Formula I-3B or Formula I-3B': Wherein, ring B is selected from C 5-10 Carbocyclyl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl; R 4 is selected from the group consisting of hydrogen, amino, hydroxyl and carboxyl; Alternatively, the structure of the compound is as shown in Formula I-3C or Formula I-3C': in, represents a single bond or a double bond; Ring B is selected from 5-10 membered heterocyclyl and 5-10 membered heteroaryl; R 4 Selected from hydrogen, amino, hydroxyl and carboxyl.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R 3 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; Preferably, R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-10 Cycloalkyl; More preferably, R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl; More preferably, R 3 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R 5 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; Preferably, R 5 Selected from hydrogen, halogen, C 1-6 Alkyl and C 3-10 Cycloalkyl; More preferably, R 5 Selected from hydrogen, halogen, C 1-4 Alkyl and C 3-6 Cycloalkyl; More preferably, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R 5 and R 3 Connect to each other to form C 5-10 Carbocyclic group; preferably, R 5 and R 3 Connected to each other to form cyclopentenyl or cyclohexenyl; Or, R 5 and R 3 are connected to form a 5-10 membered heterocyclic group; preferably, R 5 and R 3 are connected to each other to form dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, dihydropyridinyl, pyranyl, thiopyranyl, tetrahydropyridinyl, dihydropyranyl or dihydrothiopyranyl; Or, R 5 and R 3 are connected to each other to form a 5-10 membered heteroaryl group; preferably, R 5 and R 3 They are connected to each other to form pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or isothiazolyl.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R 2 For hydrogen.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: Ring A is selected from C 6-10 Aryl and 5-10 membered heteroaryl; Preferably, ring A is selected from phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: Any one selected from the following groups:

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: m is 0, 1, 2, 3 or 4.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: Every R 1 are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 Cycloalkyl)-O-, (3-10 membered heterocyclyl)-O-, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C≡CC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 cycloalkyl)-O- or (3-10 membered heterocyclyl)-O-.

12. The compound according to claim 11 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: m is 0; or, m is 1, and R 1 C 1-6 Alkyl; preferably, R 1 C 1-4 More preferably, R 1 is methyl; or, m is 2, each R 1 Each independently selected from C 1-6 Alkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-6 Alkyl, 3-10 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C≡CC 1-6 Alkyl, (C 3-10 cycloalkyl)-O- or (3-10 membered heterocyclyl)-O-; Preferably, each R 1 Each independently selected from C 1-4 Alkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; said C 1-4 Alkyl, 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, -C≡CC 1-4 Alkyl, (C 3-6 cycloalkyl)-O- or (3-6 membered heterocyclyl)-O-; More preferably, each R 1 each independently selected from methyl, ethyl, n-propyl, isopropyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, naphthyl, indolyl, isoindolyl, benzofuranyl and benzothienyl; the methyl, ethyl, n-propyl, isopropyl, pyrrolyl, piperidinyl, piperazinyl, phenyl, naphthyl, indolyl, isoindolyl, benzofuranyl and benzothienyl are each optionally substituted with one or more fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -C≡C-CH3, -C≡C-CH2-CH3, cyclopropyloxy, cyclobutyloxy, (cyclopentyl)oxy, (cyclohexyl)oxy, (oxetan-2-yl)oxy, (oxetan-2-yl)oxy or (oxetan-3-yl)oxy; Further preferably, each R 1 Each is independently selected from any one of the following groups: Among them, the asterisk * indicates the site of connection with ring A; or, m is 4, each R 1 are each independently selected from halogen, cyano, (C 3-10 Cycloalkyl)-O- and 5-10 membered heteroaryl; said (C 3-10 Cycloalkyl)-O- and 5-10 membered heteroaryl are each optionally substituted by one or more halogen or C 1-6 Alkyl substitution; Preferably, each R 1 are each independently selected from halogen, cyano, (C 3-6 Cycloalkyl)-O- and 5-6 membered heteroaryl; said (C 3-6 cycloalkyl)-O- and 5-6 membered heteroaryl are each optionally substituted by one or more halogen or C 1-4 Alkyl substitution; More preferably, each R 1 Each is independently selected from fluorine, chlorine, bromine, cyano, cyclopropyloxy, cyclobutyloxy, (cyclopentyl)oxy, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and isothiazolyl; and the cyclopropyloxy, cyclobutyloxy, (cyclopentyl)oxy, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and isothiazolyl are each optionally substituted with one or more fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl.

13. The compound according to any one of claims 9 to 12, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: Any one selected from the following groups: Where q is 0, 1, 2, 3, 4 or 5; If present, each R 1b are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C≡CC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, (C 3-10 cycloalkyl)-O- and (3-10 membered heterocyclyl)-O-.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: The structure of the compound is shown in Formula IIA, Formula IIB or Formula IIC: Alternatively, the structure of the compound is as shown in Formula IIA', Formula IIB' or Formula IIC': Alternatively, the structure of the compound is as shown in Formula IIA", Formula IIB" or Formula IIC":

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: represents a double bond; X1 is N; X2 for CR 4 ; X3 for CR 5 ; X4 for CR 3 ; L is a single bond; Ring A is a 5-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; m is 0, 1, 2 or 3; R 1 Each independently selected from C 6-10 Aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with halogen, cyano or (C 3-10 one or more substitutions in (cycloalkyl)-O-; R 2 is hydrogen or methyl; R 3 Selected from hydrogen or C 1-6 alkyl; R 4 is selected from hydrogen or amino; R 5 Selected from hydrogen or C 1-6 alkyl.

16. A compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: The compound is selected from the following compounds:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

18. A pharmaceutical preparation, which is prepared from the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, or the pharmaceutical composition according to claim 17.

19. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, or a pharmaceutical composition according to claim 17, or a pharmaceutical preparation according to claim 18 in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by PRMT5; Preferably, the disease at least partially mediated by PRMT5 is cancer, cardiovascular disease or myelofibrosis, preferably cancer or cardiovascular disease; More preferably, the cancer includes glioblastoma, melanoma, blood tumors, bladder urothelial carcinoma, colorectal cancer, lung cancer, gastric cancer, ovarian cancer, breast cancer, cervical cancer, squamous cell carcinoma, brain cancer, prostate cancer and myelodysplastic syndrome; and / or, the cardiovascular disease includes myocardial hypertrophy, heart failure and arrhythmia.

20. A pharmaceutical combination comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopically labeled or prodrug thereof, or a pharmaceutical composition according to claim 17 or a pharmaceutical preparation according to claim 18, and at least one additional therapeutic agent.

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