Quinoline compounds and their preparation, pharmaceutical compositions and uses

Abstract

The present invention provides quinoline compounds and their preparation methods, pharmaceutical compositions and uses. Specifically, the present invention provides a compound represented by formula (I) and its stereoisomers, deuterated compounds, solvates, metabolites, pharma- ceutically acceptable salts, cocrystals or prodrugs and its pharmaceutical compositions. The present invention also provides a preparation method for the above compounds and their use in the manufacture of drugs for diseases mediated by thyroid hormone receptors. Related diseases include, but are not limited to, non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type IA, hypothyroidism or thyroid cancer.

Description

[Technical field]

[0001] The present invention belongs to the field of medicines and relates to quinoline compounds and their stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals or prodrugs, as well as their pharmaceutical compositions, preparation methods and uses in the manufacture of medicines for diseases mediated by thyroid hormone receptors.Related diseases include but are not limited to non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type IA, hypothyroidism or thyroid cancer. [Background technology]

[0002] Thyroid hormones are important for normal growth and development and for maintaining metabolic balance. In the human circulatory system, thyroid hormones exist in two main forms: triiodothyronine (T3) and thyroxine (T4). T4 is the main form secreted by the thyroid gland, with T3 having higher biological activity. In the human body, T4 is secreted and released by the thyroid gland and enters the circulatory system where it is converted to T3 by tissue-specific deiodinase, which is present in all tissues but mainly in the liver and kidneys.

[0003] The thyroid hormone TH exerts its physiological effects mainly through the thyroid hormone receptor TR. TR is a member of the nuclear receptor superfamily and is a transcription factor induced by the ligand T3, and plays a key role in the action process mediated by the ligand T3. When TR is activated by T3, it has important effects on the physiological functions and basal metabolism of the human body. Among them, there are two subtypes of TR receptors, which differ in tissue and function in the human body. The α subtype is mainly distributed in the heart and is mainly responsible for regulating heart rate. The β subtype is mainly distributed in the liver and is related to cholesterol metabolism in the liver and thyroid-stimulating hormone (TSH) secretion in the pituitary gland.

[0004] In patients with hyperthyroidism, reductions in tachycardia, arrhythmia, heart failure and fatigue, accelerated breathing, skeletal muscle loss, osteoporosis, etc. were observed, while beneficial phenomena in metabolic diseases, such as a decrease in cholesterol content in the blood and an increase in the basal metabolic rate, were observed. In contrast, in patients with hypothyroidism due to pituitary disorders and congenital dysfunction, a decrease in heart rate, an increase in cholesterol in the blood, and an increase in body weight were observed. The cardiotoxicity of natural thyroid hormones is also a reason for the limited therapeutic use.

[0005] It has been demonstrated that thyroid hormone can lower serum low-density lipoprotein levels. Thyroid hormone stimulates the metabolism of cholesterol to bile acids by increasing the expression of hepatic LDL receptors. In animal models, thyroid hormone has shown beneficial effects in improving the conversion rate of LDL to HDL by increasing the expression of HDL cholesterol and apo A-1 (one of the main apolipoproteins of HDL).

[0006] Nonalcoholic fatty liver disease is also closely related to thyroid hormones. On the one hand, NAFLD patients may have affected functions such as inactivation of thyroid hormone conversion, leading to reduced levels of thyroid hormones in serum. On the other hand, reduced levels of thyroid hormones further lead to lipid and carbohydrate metabolic disorders, aggravating the disease course of NAFLD. In a study, the formation of fatty liver in rats was induced by a choline-methionine deficient diet, and the reversal of fatty liver was observed when T3 was administered.

[0007] However, endogenous thyroid hormones are non-selective and have side effects, especially those related to cardiovascular toxicity, which often lead to hyperthyroidism. Therefore, the development of thyroid hormone analogs that can avoid the side effects of hyperthyroidism is of great significance and can broaden the therapeutic approaches for hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic fatty liver disease, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease and other related diseases. Summary of the Invention

[0008] The present invention provides compounds having good agonistic activity on thyroid hormone β receptors, and such compounds and compositions thereof can be used to manufacture medicaments for preventing, treating or alleviating non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type IA, hypothyroidism or thyroid cancer in a patient.

[0009] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to any one of the above aspects of the present invention, its stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, cocrystal or prodrug, and a pharma- ceutically acceptable auxiliary and / or carrier.

[0010] The present invention also relates to the use of a compound according to the present invention or a pharmaceutical composition according to the present invention in the manufacture of a medicament, said medicament being for agonizing thyroid hormone receptors or for preventing, treating or alleviating a disease regulated by the thyroid hormone receptors, said disease mediated by the thyroid hormone receptors being non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type IA, hypothyroidism or thyroid cancer.

[0011] The present invention relates to a method for activating thyroid hormone receptors with the compounds or pharmaceutical compositions according to the present invention, or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors, by administering to an individual in need thereof an effective therapeutic amount of said compounds or pharmaceutical compositions. The compounds or pharmaceutical compositions provided by the present invention may be used together with other therapies or therapeutic agents, either simultaneously, sequentially or at a fixed time interval.

[0012] In a first aspect of the present invention, there is provided a compound having a structure represented by Formula (I), or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal, or prodrug thereof. [ka] (however, [ka] Rb, Rc and R7 are each independently located at any substitutable ring atom of the quinoline ring. Rb and Rc are each independently selected from the group consisting of deuterium, tritium, halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a phenyl group, a C5-C7 heteroaryl group, and a C5-C6 substituted heteroaryl group, and Rb and Rc are different substituents. R7 is one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl group, and C1-C6 haloalkyl located on the benzene ring of the quinoline. X is selected from the group consisting of -O-, -CH2-, -C(=O)-, -CH(OH)-, and -S-. R1, R2, R3 and R4 each independently represent H, D, F, Cl, Br, I, -CN, -OH, -NO2, -OR 1a , -NR 1b R 1c , -SR 1b , a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group. R5 is H, D, F, Cl, Br, I, -CN, -OH, -NO2, -OR 1a , -NR 1b R 1c , -SR 1b, -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1a R 1b , -S(O)NR 1a R 1b , -NHS(O)2R 1a , -C(O)R 1a , -OC(O)R 1a , -C(O)OR 1b , -C(O)NR 1b R 1c , -NHC(O)R 1a , a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group. R6 is H, deuterium, tritium, halogen, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with an amino group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, -SR 1b , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1a R 1b , -C(O)R 1a , -C(O)OR 1b , -C(O)NR 1b R 1c is selected from the group consisting of: Unless otherwise specified, each of the above alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be substituted with deuterium, tritium, halogen, -CN, -OH, oxo, -OR, -O- ... 1a , -NR 1b R 1c , -SR 1b , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1a R 1b , -S(O)NR 1a R 1b , -NHS(O)2R 1a , -C(O)R 1a , -OC(O)R 1a , -C(O)OR1b , -C(O)NR 1b R 1c , -NHC(O)R 1a , a C1-C6 alkyl group, and a C1-C6 haloalkyl group. R 1a , R 1b and R 1c are each independently selected from H, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group.

[0013] In another preferred embodiment, Rb is selected from the group consisting of a C1-C6 haloalkyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a phenyl group, and a C5-C7 heteroaryl group, and the phenyl group or heteroaryl group is optionally selected from the group consisting of deuterium, tritium, halogen, -CN, -OH, oxo, -OR 1a , -NR 1b R 1c , -C(O)R 1a , -C(O)OR 1b , -C(O)NR 1b R 1c , a C1-C6 alkyl group, and a C1-C6 haloalkyl group; The Rc is selected from the group consisting of halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C1-C6 deuterated alkyl group.

[0014] In another preferred embodiment, Rb is selected from the group consisting of a phenyl group and a C5-C7 heteroaryl group.

[0015] In another preferred embodiment, Rb is selected from the group consisting of a phenyl group and a pyridyl group; The Rc is selected from the group consisting of halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C1-C6 deuterated alkyl group.

[0016] In another preferred embodiment, the compound of formula I has the structure of formula Ia: [ka]

[0017] In another preferred embodiment, the compound of formula I has a structure represented by formula Ib or Ic: [ka]

[0018] In another preferred embodiment, R1, R2, R3, and R4 are each independently selected from H, D, halogen, and a C1-C4 alkyl group.

[0019] In another preferred embodiment, R3 and R4 are each independently selected from H and deuterium, and R1 and R2 are each independently selected from H, D, halogen, and a C1-C4 alkyl group.

[0020] In another preferred embodiment, R3 and R4 are each independently selected from, and R1 and R2 are each independently selected from halogen.

[0021] In another preferred embodiment, R6 is selected from H, deuterium, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, and a hydroxyl-substituted C1-C6 alkyl group.

[0022] In another preferred embodiment, R6 is selected from H, deuterium, a C1-C6 alkyl group, and a C1-C6 deuterated alkyl group.

[0023] In another preferred embodiment, R6 is selected from H, deuterium, and a C1-C6 alkyl group.

[0024] In another preferred embodiment, R6 is selected from H and deuterium.

[0025] In another preferred embodiment, R 1a , R 1b , R 1c are each independently selected from H, deuterium, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, and a 3- to 8-membered heterocycloalkyl group, and the alkyl, cycloalkyl, and heterocycloalkyl groups may be optionally substituted with one or more deuterium or halogen atoms.

[0026] In another preferred embodiment, R 1a , R 1b , R 1c are each independently selected from H, a C1-C6 alkyl group, said alkyl groups being optionally substituted with one or more deuteriums or halogens, preferably one or more deuteriums.

[0027] In another preferred embodiment, R5 is H, D, halogen, -CN, NHR 1b wherein said R 1b is selected from H, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C2-C6 alkynyl group, wherein R6 is H or D.

[0028] In another preferred embodiment, R5 is selected from H, D, halogen, and -CN.

[0029] In another preferred embodiment, R5 is selected from D, halogen.

[0030] In another preferred embodiment, R5 is selected from -CN.

[0031] In another preferred embodiment, each R7 is independently H.

[0032] In a second aspect of the present invention, there is provided a compound having a structure represented by Formula (II), or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal, or prodrug thereof. [ka] (however, Rd and Re are each independently selected from the group consisting of H, halogen, a C1-C6 alkyl group, and a C1-C6 haloalkyl group, and at least one of Rd and Re is a halogen. R7 is one or more (eg, 1, 2, 3, or 4) substituents selected from the group consisting of H, halogen, C1-C6 alkyl, and C1-C6 haloalkyl located on the benzene ring of the quinoline. X is selected from the group consisting of -O-, -CH2-, -C(=O)-, -CH(OH)-, and -S-. R1, R2, R3 and R4 each independently represent H, D, F, Cl, Br, I, -CN, -OH, -NO2, -OR 1a , -NR 1b R 1c , -SR 1b , a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group. R5 is H, D, F, Cl, Br, I, -CN, -OH, -NO2, -OR 1a , -NR 1b R 1c , -SR 1b , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1a R 1b , -S(O)NR 1a R 1b , -NHS(O)2R 1a , -C(O)R 1a , -OC(O)R 1a , -C(O)OR 1b , -C(O)NR 1b R1c , -NHC(O)R 1a , a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group. R6 is H, deuterium, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with an amino group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, -SR 1b , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1a R 1b , -C(O)R 1a , -C(O)OR 1b , -C(O)NR 1b R 1c is selected from the group consisting of: Unless otherwise specified, each of the above alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be substituted with deuterium, halogen, -CN, -OH, oxo, -OR, -O- ... 1a , -NR 1b R 1c , -SR 1b , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1a R 1b , -S(O)NR 1a R 1b , -NHS(O)2R 1a , -C(O)R 1a , -OC(O)R 1a , -C(O)OR 1b , -C(O)NR 1b R 1c , -NHC(O)R 1a , a C1-C6 alkyl group, and a C1-C6 haloalkyl group. R 1a , R 1b and R 1care each independently selected from H, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group.

[0033] In another preferred embodiment, R1, R2, R3, and R4 are each independently selected from H, D, halogen, and a C1-C4 alkyl group.

[0034] In another preferred embodiment, R3 and R4 are each independently selected from H and deuterium, and R1 and R2 are each independently selected from H, D, halogen, and a C1-C4 alkyl group.

[0035] In another preferred embodiment, R3 and R4 are each independently selected from, and R1 and R2 are each independently selected from halogen.

[0036] In another preferred embodiment, R6 is selected from H, deuterium, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, and a hydroxyl-substituted C1-C6 alkyl group.

[0037] In another preferred embodiment, R6 is selected from H, deuterium, a C1-C6 alkyl group, and a C1-C6 deuterated alkyl group.

[0038] In another preferred embodiment, R6 is selected from H, deuterium, and a C1-C6 alkyl group.

[0039] In another preferred embodiment, R6 is selected from H and deuterium.

[0040] In another preferred embodiment, R 1a , R 1b , R 1care each independently selected from H, deuterium, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, and a 3- to 8-membered heterocycloalkyl group, and the alkyl, cycloalkyl, and heterocycloalkyl groups may be optionally substituted with one or more deuterium or halogen atoms.

[0041] In another preferred embodiment, R 1a , R 1b , R 1c are each independently selected from H, a C1-C6 alkyl group, said alkyl groups being optionally substituted with one or more deuteriums or halogens, preferably one or more deuteriums.

[0042] In another preferred embodiment, R5 is H, D, halogen, -CN, NHR 1b wherein said R 1b is selected from H, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C2-C6 alkynyl group, wherein R6 is H or D.

[0043] In another preferred embodiment, R5 is selected from H, D, halogen, and -CN.

[0044] In another preferred embodiment, R5 is selected from D, halogen.

[0045] In another preferred embodiment, R5 is selected from -CN.

[0046] In another preferred embodiment, each R7 is independently H.

[0047] In a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first or second aspect of the invention, a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal or prodrug thereof, and a pharma- ceutically acceptable adjuvant and / or carrier.

[0048] In a fourth aspect of the invention there is provided the use of a compound according to the first or second aspect of the invention, or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal or prodrug thereof, in the manufacture of a medicament, wherein the medicament is for agonizing a thyroid hormone receptor or for preventing, treating or ameliorating a disease modulated by the thyroid hormone receptor.

[0049] In another preferred embodiment, the thyroid hormone receptor mediated disease is selected from the group consisting of alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type IA, hypothyroidism, or thyroid cancer.

[0050] The present invention relates to a method for activating thyroid hormone receptors with the compounds or pharmaceutical compositions according to the present invention, or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors, by administering to an individual in need thereof an effective therapeutic amount of said compounds or pharmaceutical compositions. The compounds or pharmaceutical compositions provided by the present invention may be used together with other therapies or therapeutic agents, either simultaneously, sequentially or at a fixed time interval.

[0051] Of course, it is understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (for example, in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described here one by one due to space limitations. [Brief description of the drawings]

[0052] [Figure 1] FIG. 1 shows a THRβ agonist curve in an in vitro evaluation system for a compound. [Diagram 2] FIG. 2 shows the results of expression of downstream genes of THRβ in liver tissue. [Diagram 3]FIG. 3 shows the results of expression of downstream genes of THRβ in cardiac tissue. [Figure 4] FIG. 4 shows the results of chronic administration of TC to mice. [Diagram 5] FIG. 5 shows the results of serum TC / TGL / DL-C following acute administration to golden hamsters. [Figure 6] FIG. 6 shows the results of DI01 gene expression in mouse liver after administration of Compound 3. [Figure 7] FIG. 7 shows the results of mouse cardiac MHC α expression after administration of Compound 3. [Figure 8] FIG. 8: Effect on thyroid hormone levels following administration of Compound 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] Specific embodiments The present inventors have conducted extensive research and found a quinoline compound represented by formula I and its preparation method. The compound can be used to prepare drugs for diseases mediated by thyroid hormone receptor, including but not limited to non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type IA, hypothyroidism or thyroid cancer. Based on the above findings, the present inventors have completed the present invention.

[0054] term In the present invention, unless otherwise specified, the terms of the present invention have the following meanings.

[0055] As used herein, "halogen" means F, Cl, Br, I, or an isotope thereof.

[0056] "Halo" or "halogen substituted" means substituted with one or more of F, Cl, Br, I, or isotopes thereof, where the upper limit of the number of halogen substituents is equal to the total number of hydrogens that can be replaced by the substituents, and unless otherwise specified, the number of halogen substituents can be any integer between 1 and the upper limit, and if the number of halogen substituents is more than 1, they may be substituted with the same or different halogens.

[0057] An "alkyl group" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the various branched isomers thereof, which may be further substituted with optional substituents.

[0058] "Deuterated" refers to a form in which hydrogen in an alkyl group, a cycloalkyl group, an alkylene group, an aryl group, a heteroaryl group, an alkenyl group, an alkynyl group, or the like is substituted with at least one isotope of neon, and the upper limit of the number of deuteration is equal to the total number of hydrogen that can be substituted by substituents. Unless otherwise specified, the number of deuteration is any integer between 1 and the upper limit, and is preferably substituted with 1 to 20 deuterium atoms, more preferably 1 to 10 deuterium atoms, even more preferably 1 to 6 deuterium atoms, and even more preferably 1 to 3 deuterium atoms.

[0059] An "alkynyl group" refers to a straight-chain or branched, monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds; unless otherwise specified, an alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms; non-limiting examples include ethynyl, propynyl, and propargyl.

[0060] An "alkenyl group" refers to a straight-chain or branched, monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds; unless otherwise specified, an alkenyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms; non-limiting examples include vinyl, propenyl, allyl, 2-butenyl, 1-butenyl, and the like.

[0061] An "alkoxy group" or "alkyloxy group" is an -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy groups.

[0062] A "haloalkoxy group" is an alkoxy group substituted with one or more halogens. Non-limiting examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0063] An "alkylamino group" or "alkylamino group" refers to an amino group substituted with one or two alkyl groups, which may also be designated as -N-(alkyl)2 or -NH-alkyl, the latter of which may also be designated as a monoalkylamino group. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0064] "Optional" or "optionally" means that a subsequent event or circumstance allows, but does not necessarily require, the occurrence of the event or circumstance described below, and includes cases where the event or circumstance described does or does not occur. For example, "an alkyl group optionally substituted with F" means that the alkyl group may be substituted with F, but is not necessarily substituted with F, and the description includes cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.

[0065] A "pharmaceutically acceptable salt" is a salt in which the compounds of the present invention retain the biological effectiveness and properties of the free acid or free base, and which is obtained by reacting said free acid with a non-toxic inorganic or organic base, or said free base with a non-toxic inorganic or organic acid.

[0066] A "pharmaceutical composition" is a mixture of one or more compounds described herein or stereoisomers, solvates, pharma- ceutically acceptable salts or co-crystals thereof with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0067] The term "carrier" refers to a system that can deliver a drug to a target organ without causing obvious irritation to the living body, without negating the biological activity and properties of the administered compound, and by changing the manner in which the drug enters the human body and its distribution within the body, and by controlling the release rate of the drug. Non-limiting examples of the carrier include microcapsules, microspheres, nanoparticles, liposomes, etc.

[0068] An "excipient" is an agent that is not itself a therapeutic agent, but is added to a drug composition as a diluent, adjuvant, binder and / or vehicle to improve its handling or storage properties, or to permit or facilitate the formation of the compound or drug composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients serve a variety of functions and may be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of pharmaceutical excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., croscarmellose sodium); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; and (8) excipients, such as cocoa butter and suppositories. Examples of suitable non-toxic compatible substances include, but are not limited to, waxes, (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, (10) glycols, such as propylene glycol, (11) polyhydric alcohols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl cinnamate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free distilled water, (17) isotonic saline, (18) Ringer's solution, (19) ethanol, (20) pH buffer solutions, (21) polyesters, polycarbonates, and / or polyanhydrides, and (22) other non-toxic compatible substances used in drug formulations.

[0069] "Stereoisomers" are isomers that differ in the way the atoms in a molecule are arranged in space, and include cis-trans isomers, enantiomers, and conformational isomers.

[0070] A "solvate" is a substance that the compound of the present invention or a salt thereof forms with a stoichiometric or non-stoichiometric amount of a solvent through intermolecular non-covalent bonding. When the solvent is water, it is a hydrate.

[0071] A "cocrystal" is a crystal formed by hydrogen bonding or other non-covalent association of an active pharmaceutical ingredient (API) and a co-crystal former (CCF), where the API and CCF are both solid in their pure form at room temperature and have a fixed stoichiometric ratio between the components. Cocrystals are multicomponent crystals, including binary cocrystals formed between two neutral solids and multiple cocrystals formed between a neutral solid and a salt or solvate.

[0072] Preparation of Formula I Compounds [ka]

[0073] All of the compounds according to the present invention can be prepared by the above-mentioned scheme, starting from the corresponding 6-methoxyquinoline compound or directly purchased commercially available 6-hydroxyquinoline compound, stirring with the corresponding p-fluoro-substituted nitrobenzene compound in DMF with potassium carbonate or cesium carbonate for several hours to obtain the material for step 2. Then, the nitro group is reduced under appropriate conditions to obtain the corresponding amino compound. The obtained amino compound is diazotized under hydrochloric acid and sodium nitrite conditions to couple with N-cyanoacetylurethane. Finally, the compound is refluxed in acetic acid and sodium acetate at high temperature to finally obtain each example.

[0074] Those skilled in the art can prepare the compounds of the present invention by combining the literature and known organic synthesis techniques. The starting materials are commercially available and commercial products and / or compounds described in the chemical literature. "Commercially available compounds" are obtained from regular commercial channels, and suppliers include companies such as BiDe Pharmaceutical, HaoHong Biologicals, TaiTan Technology, Sinopharm Group, Yaoming KangDe, BailingWei Technology and ShaoYuan Chemical Technology. Testing methods include nuclear magnetic resonance (NMR) and mass spectrometry (MS), etc.

[0075] Drug Compositions and Their Preparation In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of general formula I, their medicament salts, enantiomers, diastereomers or racemates, and optionally one or more medicament carriers, excipients, adjuvants, auxiliary agents and / or diluents, such as odorants, fragrances, sweeteners, etc.

[0076] The pharmaceutical composition provided by the present invention preferably contains 1-99% by weight of active ingredient, and the suitable ratio is that the compound of general formula I as the active ingredient accounts for 65wt%-99wt% of the total weight, and the rest is pharma- ceutically acceptable carrier, diluent or solution or salt solution.

[0077] The compounds and pharmaceutical compositions provided by the present invention may be in a variety of forms, for example, tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be present in suitable solid or liquid carriers or diluents, and in suitable sterile equipment for injection or infusion.

[0078] Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional manufacturing methods in the pharmaceutical field. The compound of formula I is contained in a unit dose of the preparation in a range of 1mg-700mg, preferably in a unit dose of the preparation in a range of 25mg-300mg.

[0079] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered via oral, nasal, cutaneous, pulmonary or gastrointestinal routes. Oral administration is the most preferred. The most preferred daily dose is 50-1400 mg / kg body weight, administered in one dose, or 25-700 mg / kg body weight, administered in several doses. Regardless of which administration method is used, the optimal dose for an individual is determined by the specific treatment. Usually, a small dose is administered first, and then gradually increased until the optimal dose is found.

[0080] The present invention will be further described below with reference to specific examples. It is understood that these examples are only used to explain the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which no specific conditions are described were usually carried out under normal conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0081] Example 1: 2-(3,5-dichloro-4-((2-(2-fluoropyridin-4-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka]

[0082] Step 1: Preparation of 6-methoxy-4-methyl-2-(4-fluoropyridyl)quinoline Using 6-methoxy-4-methyl-2-chloroquinoline (2g, 1eq) as a commercially available raw material, a catalytic amount of tetrakis(triphenylphosphine)palladium and an excess amount of 2-fluoropyridine 4-borate were added, and an excess amount of sodium carbonate was further added. The mixture was reacted overnight at 100°C in a mixed solution of 20ml of dioxane and 5ml of water under the protection of nitrogen gas. After the reaction was completed, the mixture was diluted with ethyl acetate and filtered to remove solids. The organic phase was washed three times with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain 6-methoxy-4-methyl-2-phenylquinoline as a white powder.

[0083] Step 2: Preparation of 6-hydroxy-4-methyl-2-(4-fluoropyridyl)quinoline 6-Methoxy-4-methyl-4-(2-fluoropyridyl)quinoline was placed in 20 ml of 48% aqueous hydrobromic acid and reacted at 90°C for three days. After the reaction was completed, the pH was adjusted to 8-9 with aqueous sodium bicarbonate, extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 6-hydroxy-4-methyl-2-(4-fluoropyridyl)quinoline as a yellow oily compound. This was used in the next step without purification.

[0084] Step 3: Preparation of 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-4-(2-fluoropyridyl)quinoline 6-Hydroxy-4-methyl-2-(4-fluoropyridyl)quinoline and 3,5-dichloro-p-fluoronitrobenzene (1.48g, 0.0070mol) were dissolved in 20ml of DMF, 5g of potassium carbonate was added, and the mixture was stirred at room temperature for 6 hours. Then, 200ml of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed three times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-2-(4-fluoropyridyl)quinoline as a pale yellow compound.

[0085] Step 4: Preparation of 3,5-dichloro-4-((4-methyl-2-(4-fluoropyridyl)quinolin-6-yl)oxy)aniline 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-2-phenylquinoline was added to 15ml of ethyl acetate and 15ml of ethanol, and then excess stannous chloride and catalytic amount of hydrochloric acid were added, and the mixture was stirred at room temperature overnight to completely react. The pH was adjusted to 9-10 with aqueous sodium carbonate solution, and the precipitate was removed by filtration. The mixture was extracted three times with ethyl acetate, and the organic phases were combined and washed three times with saturated saline, and anhydrous sodium sulfate was added, filtered, and concentrated under reduced pressure to obtain 3,5-dichloro-4-((4-methyl-2-(4-fluoropyridyl)quinolin-6-yl)oxy)aniline as a pale yellow solid.

[0086] Step 5: Preparation of ethyl (E)-(2-cyano-2-((3,5-dichloro-4-((4-methyl-2-(4-fluoropyridyl)quinolin-6-yl)oxy)phenyl)dienyl)acetyl)carbamate 10 ml of water and 10 ml of hydrochloric acid were added to a flask containing 3,5-dichloro-4-((4-methyl-2-(4-fluoropyridyl)quinolin-6-yl)oxy)aniline, and 3 ml of an aqueous solution of sodium nitrite was added dropwise at 0°C. In another round-bottom flask, 15 ml of pyridine and 10 ml of water were placed, and N-cyanoacetylurethane (483.93 mg, 0.0031 mol) was placed. Both phases were kept at 0°C for 30 minutes, and then the diazonium salt was added dropwise to the other phase. After the addition was completed, the mixture was kept warm for 30 minutes, and then extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated under reduced pressure to produce ethyl (E)-(2-cyano-2-((3,5-dichloro-4-((4-methyl-2-(4-fluoropyridyl)quinolin-6-yl)oxy)phenyl)dienyl)acetyl)carbamate (1.2 g, 83.8%) as a red solid. The crude product was used in the next step without purification.

[0087] Step 6: Preparation of 2-(3,5-dichloro-4-((2-trifluoromethyl-2-(4-fluoropyridyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Orange ethyl (E)-(2-cyano-2-((3,5-dichloro-4-((4-methyl-2-(4-fluoropyridyl)quinolin-6-yl)oxy)phenyl)dienyl)acetyl)carbamate (1.2 g, 83.8%) was added to 10 ml of acetic acid, 1 g of sodium acetate was added, and the mixture was heated at 120°C for 2 hours. Water was then added to precipitate a crude red compound, which was filtered and dried, and then separated and purified by preparative high performance liquid chromatography to obtain white 2-(3,5-dichloro-4-((2-(4-fluoropyridyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. 1H NMR (500 MHz, chloroform) δ 9.55 (s, 1H), 8.91 (s, 1H), 8.58 (s, 1H), 7.97 (d, J = 26.8 Hz, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0088] Example 2: 2-(3,5-dichloro-4-((2-phenyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced by the method described in Example 1 using phenylboronic acid ester, isolated and purified (total yield 22%). M / Z = 534.02 (M+1) 1H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 8.33 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 15.0 Hz, 4H), 7.49 (s, 2H), 6.63 (s, 1H), 2.69 (s, 3H).

[0089] Example 3: 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced by the method described in Example 1 using 4-fluorophenylboronic acid ester, isolated and purified (total yield 22%). M / Z = 534.02 (M+1) 1H NMR (500 MHz, chloroform) δ 9.53 (s, 2H), 8.25 (s, 4H), 7.92 (s, 2H), 7.67 (s, 2H), 7.58 (s, 4H), 7.49 (s, 3H), 7.31 (s, 3H), 6.63 (s, 2H), 2.69 (s, 6H).

[0090] Example 4: 2-(3,5-dichloro-4-((2-(4-trifluoromethylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced by the method described in Example 1 using 4-trifluoromethylphenylboronic acid ester, it was isolated and purified (total yield 18%). M / Z =538.04(M+1) 1H NMR (500 MHz, chloroform) δ 9.57 (s, 10H), 7.94 (d, J = 20.0 Hz, 31H), 7.74 (d, J = 1.8 Hz, 2H), 7.74 - 7.50 (m, 55H), 7.58 (s, 26H), 7.58 (s, 20H), 7.49 (s, 10H), 6.63 (s, 10H), 2.69 (s, 30H).

[0091] Example 5: 2-(3,5-dichloro-4-((2-(4-chlorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced by the method described in Example 1 using 4-chlorophenylboronic acid ester, isolated and purified (total yield 15%). M / Z = 550.02 1H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 8.36 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.59 (d, J = 10.0 Hz, 4H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0092] Example 6: 2-(3,5-dichloro-4-((2-(4-bromophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced by the method described in Example 1 using 4-bromophenylboronic acid ester, isolated and purified (total yield 23%). M / Z = 593.97 (M+1) 1H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 8.17 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 15.0 Hz, 4H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0093] Example 7: 2-(3,5-dichloro-4-((2-(4-cyanophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced by the method described in Example 1 using 4-cyanophenylboronic acid ester, isolated and purified (total yield 15%). M / Z =541.05(M+1) 1H NMR (500 MHz, chloroform) δ 9.57 (s, 1H), 8.34 (s, 2H), 7.91 (d, J = 5.0 Hz, 3H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0094] Example 8: 2-(3,5-dichloro-4-((2-(2-isopropylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced by the method described in Example 1 using 2-(3-chloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and isolated and purified (total yield 17%). M / Z =568.01(M+1) 1H NMR (500 MHz, chloroform) δ 9.56 (s, 16H), 8.13 (s, 16H), 7.92 (s, 18H), 7.88 (s, 13H), 7.73 (d, J = 60.0 Hz, 32H), 7.59 (s, 1H), 7.58 (s, 32H), 7.49 (s, 16H), 6.63 (s, 16H), 2.69 (s, 48H).

[0095] Example 9: 2-(3,5-dichloro-4-((2-(2-isopropylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-(2-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (total yield 16%). M / Z = 558.1 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.54 (s, 6H), 8.02 (s, 6H), 7.92 (s, 6H), 7.67 (s, 6H), 7.61 - 7.47 (m, 23H), 7.47 (s, 1H), 7.39 (s, 6H), 7.27 (s, 4H), 6.63 (s, 6H), 2.87 (s, 2H), 2.69 (s, 18H), 1.17 (s, 37H).

[0096] Example 10: 2-(3,5-dichloro-4-((2-(4-fluoro-3-methylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-(4-fluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (total yield 17%). M / Z = 548.06 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.57 (s, 1H), 8.34 (s, 2H), 7.91 (d, J = 5.0 Hz, 3H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H).

[0097] Example 11: 2-(3,5-dichloro-4-((2-(4-cyano-3-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (total yield 13%). M / Z = 559.04 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.57 (s, 1H), 8.34 (s, 2H), 7.91 (d, J = 5.0 Hz, 3H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H).

[0098] Example 12: 2-(3,5-dichloro-4-((2-(2-cyano-4-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 4-trifluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (total yield 18%). M / Z = 609.04 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.57 (s, 1H), 8.34 (s, 2H), 7.91 (d, J = 5.0 Hz, 3H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H).

[0099] Example 13: 2-(3,5-dichloro-4-((2-(4-fluoro-3,5-dichlorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and separated and purified according to the method described in Example 1 (total yield 22%). M / Z = 601.97 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.58 (s, 1H), 8.22 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0100] Example 14: 2-(3,5-dichloro-4-((2-(4-chloro-3,5-dimethylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-(3,5-dimethyl-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (total yield 19%). M / Z = 578.05 (M+1). 1H NMR (500 MHz, chloroform) δ 9.58 (s, 1H), 8.22 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0101] Example 15: 2-(3,5-dichloro-4-((2-(furan-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (total yield 20%). M / Z = 506.03 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.58 (s, 1H), 8.22 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0102] Example 16: 2-(3,5-dichloro-4-((4-methyl-2-(5-methylfuran-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-(4-methylfuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (total yield 22%). M / Z = 520.05 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.95 (d, J = 20.0 Hz, 2H), 5.94 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

[0103] Example 17: 2-(3,5-dichloro-4-((4-methyl-2-(5-cyclopropylfuran-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 2-(4-cyclopropylfuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and separated and purified according to the method described in Example 1 (total yield 21%). M / Z = 520.05 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.95 (d, J = 20.0 Hz, 2H), 5.94 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

[0104] Example 18: 2-(3,5-dichloro-4-((4-methyl-2-(2-cyano-5-methylfuran-3-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carbonitrile, and isolated and purified according to the method described in Example 1 (total yield 29%). M / Z = 545.05 (M+1) 1 H NMR (500 Mhz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.95 (d, J = 20.0 Hz, 2H), 5.94 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

[0105] Example 19: 2-(3,5-dichloro-4-((2-(thiophen-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (total yield 26%). M / Z = 522.01 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.95 (d, J = 20.0 Hz, 2H), 5.94 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

[0106] Example 20: 2-(3,5-dichloro-4-((4-methyl-2-(4-chlorothiophen-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-(4-chlorothiophene-2-group)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (total yield 13%). M / Z = 555.97 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.95 (d, J = 20.0 Hz, 2H), 5.94 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

[0107] Example 21: 2-(3,5-dichloro-4-((4-methyl-2-(5-cyanothiophen-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbonitrile, and separated and purified according to the method described in Example 1 (total yield 15%). M / Z = 547.01 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.95 (d, J = 20.0 Hz, 2H), 5.94 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

[0108] Example 22: 2-(3,5-dichloro-4-((4-methyl-2-(5-methylthiophen-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 using 2-(5-methylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (total yield 39%). M / Z = 536.03 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.02 (d, J = 55.0 Hz, 2H), 2.69 (s, 3H), 2.44 (s, 3H).

[0109] Example 23: 2-(3,5-dichloro-4-((4-methyl-2-(5-trifluoromethylthiophen-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 2-(5-trifluoromethylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and separated and purified according to the method described in Example 1 (total yield 17%). M / Z = 590.00 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.02 (d, J = 55.0 Hz, 2H), 2.69 (s, 3H), 2.44 (s, 3H).

[0110] Example 24: 2-(3,5-dichloro-4-((2-(pyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 16%). M / Z = 517.05 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.02 (d, J = 55.0 Hz, 2H), 2.69 (s, 3H), 2.44 (s, 3H).

[0111] Example 25: 2-(3,5-dichloro-4-((4-methyl-2-(5-methylpyridin-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 17%). M / Z = 531.07 (M+1) 1H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.02 (d, J = 55.0 Hz, 2H), 2.69 (s, 3H), 2.44 (s, 3H).

[0112] Example 26: 2-(3,5-dichloro-4-((4-methyl-2-(5-fluoropyridin-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 19%). M / Z = 535.04 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.02 (d, J = 55.0 Hz, 2H), 2.69 (s, 3H), 2.44 (s, 3H).

[0113] Example 27: 2-(3,5-dichloro-4-((4-methyl-2-(5-chloropyridin-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and following the procedure described in Example 1, it was isolated and purified (total yield 22%). M / Z = 551.01 (M+1) 1H NMR (500 MHz, chloroform) δ 9.54 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.77 (s, 1H), 2.69 (s, 3H).

[0114] Example 28: 2-(3,5-dichloro-4-((4-methyl-2-(5-bromopyridin-2-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 5-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 11%). M / Z = 594.96 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.54 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.77 (s, 1H), 2.69 (s, 3H).

[0115] Example 29: 2-(3,5-dichloro-4-((2-(pyridin-3-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 17%). M / Z = 517.05 (M+1). 1H NMR (500 MHz, chloroform) δ 9.54 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.77 (s, 1H), 2.69 (s, 3H).

[0116] Example 30: 2-(3,5-dichloro-4-((2-(6-methylpyridin-3-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 14%). M / Z = 531.07 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.54 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.77 (s, 1H), 2.69 (s, 3H).

[0117] Example 31: 2-(3,5-dichloro-4-((2-(6-fluoropyridin-3-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 15%). M / Z = 535.05 (M+1) 1H NMR (500 MHz, chloroform) δ 9.54 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.77 (s, 1H), 2.69 (s, 3H).

[0118] Example 32: 2-(3,5-dichloro-4-((2-(6-chloropyridin-3-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 6-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 11%). M / Z = 551.01 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 9.37 (s, 1H), 8.54 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.48 (d, J = 10.0 Hz, 2H), 6.97 (s, 1H), 2.69 (s, 3H).

[0119] Example 33: 2-(3,5-dichloro-4-((2-(6-bromopyridin-3-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 6-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 20%). M / Z = 594.96 (M+1) 1H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 9.37 (s, 1H), 8.54 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.48 (d, J = 10.0 Hz, 2H), 6.97 (s, 1H), 2.69 (s, 3H).

[0120] Example 34: 2-(3,5-dichloro-4-((2-(6-trifluoromethylpyridin-3-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 6-trifluoromethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 17%). M / Z = 585.04 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 9.37 (s, 1H), 8.54 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.48 (d, J = 10.0 Hz, 2H), 6.97 (s, 1H), 2.69 (s, 3H).

[0121] Example 35: 2-(3,5-dichloro-4-((2-(pyridin-4-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-4-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 18%). M / Z = 517.05 (M+1). 1H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 9.37 (s, 1H), 8.54 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.48 (d, J = 10.0 Hz, 2H), 6.97 (s, 1H), 2.69 (s, 3H).

[0122] Example 36: 2-(3,5-dichloro-4-((2-(2-methylpyridin-4-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-4-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 18%). M / Z = 531.07 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 9.37 (s, 1H), 8.54 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.48 (d, J = 10.0 Hz, 2H), 6.97 (s, 1H), 2.69 (s, 3H).

[0123] Example 37: 2-(3,5-dichloro-4-((2-(2-chloropyridin-4-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-4-yl)pyridine and following the procedure described in Example 1, it was isolated and purified (total yield 19%). M / Z = 551.01 (M+1) 1H NMR (500 MHz, chloroform) δ 9.55 (s, 1H), 9.08 (s, 1H), 8.91 (s, 1H), 8.37 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0124] Example 38: 2-(3,5-dichloro-4-((2-(2-fluoropyridin-4-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile [ka]

[0125] Step 1: Preparation of 6-methoxy-4-methyl-2-(trifluoromethyl)quinoline Commercially available p-methoxyaniline (10g, 0.0801mol) and trifluoroacetylacetone (15g, 0.9744mol) were added to a mixed solvent of polyphosphoric acid and toluene and reacted at 110°C for 48 hours. After the reaction was completed, the reaction solution was cooled and added to a 2L ice water mixture, and an aqueous sodium bicarbonate solution was added to adjust the pH to 8-9. The solution was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 6-methoxy-4-methyl-2-(trifluoromethyl)quinoline (9g, yield 45.95%) as white crystals.

[0126] Step 2: Preparation of 6-hydroxy-4-methyl-2-(trifluoromethyl)quinoline 6-Methoxy-4-methyl-2-(trifluoromethyl)quinoline (2g, 0.0083mol) was added to 20ml of 48% aqueous hydrobromic acid solution and refluxed at 90℃ for three days. After the reaction was completed, the pH was adjusted to 8-9 with aqueous sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 6-methoxy-4-methyl-2-(trifluoromethyl)quinoline (1.6g, 84%) as a yellow oily compound, which was used in the next step without purification.

[0127] Step 3: Preparation of 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-2-(trifluoromethyl)quinoline 6-Methoxy-4-methyl-2-(trifluoromethyl)quinoline (1.6g, 0.0070mol) and 3,5-dichloro-p-fluoronitrobenzene (1.48g, 0.0070mol) were dissolved in 20ml of DMF, 5g of potassium carbonate was added and stirred at room temperature for 6 hours, then 200ml of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate, and the organic phase was combined and washed three times with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain a pale yellow compound, 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-2-(trifluoromethyl)quinoline (1.5g, 51%).

[0128] Step 4: Preparation of 3,5-dichloro-4-((4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)aniline 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-2-(trifluoromethyl)quinoline (1.5g, 0.0031mol) was added to 15ml of ethyl acetate and 15ml of ethanol, and then an excess of stannous chloride and a catalytic amount of hydrochloric acid were added, and the mixture was stirred at room temperature overnight to completely react. The pH was adjusted to 9-10 with aqueous sodium carbonate solution, the precipitate was removed by filtration, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed three times with saturated brine, and anhydrous sodium sulfate was added, filtered, and concentrated under reduced pressure to obtain 3,5-dichloro-4-((4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)aniline (1g, 71.8%) as a pale yellow solid.

[0129] Step 5: Preparation of (E)-(2-cyano-2-((3,5-dichloro-4-((4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)phenyl)dienyl)acetyl)carbamate A flask containing 3,5-dichloro-4-((4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)aniline (1 g, 0.0026 mol) was charged with 10 ml of water and 10 ml of hydrochloric acid, and a 3 ml aqueous solution of sodium nitrite (213 mg, 0.0031 mol) was added dropwise at 0°C. In another round-bottom flask, 15 ml of pyridine and 10 ml of water were placed, and N-cyanoacetylurethane (483.93 mg, 0.0031 mol) was added. Both phases were kept at 0°C for 30 minutes, and then the diazonium salt was added dropwise to the other phase. After the addition was completed, the mixture was kept warm for 30 minutes, and then extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated under reduced pressure to produce ethyl (E)-(2-cyano-2-((3,5-dichloro-4-((4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)phenyl)dienyl)acetyl)carbamate (1.2 g, 83.8%) as a red solid. The crude product was used in the next step without purification.

[0130] Step 6: Preparation of 2-(3,5-dichloro-4-((2-trifluoromethyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Orange ethyl (E)-(2-cyano-2-((3,5-dichloro-4-((4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)phenyl)dienyl)acetyl)carbamate (1.2 g, 83.8%) was added to 10 ml of acetic acid, 1 g of sodium acetate was added, and the mixture was heated at 120° C. for 2 hours. Water was then added to precipitate a crude product of a red compound, which was filtered and dried, and then separated and purified by preparative high performance liquid chromatography to obtain white 2-(3,5-dichloro-4-((2-trifluoromethyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, i.e., Example 1 (200 mg). LCMS m / z =508.01 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 10.0 Hz, 3H), 7.31 (s, 1H).

[0131] Example 39: 2-(3,5-dichloro-4-((2-(2-bromopyridin-4-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 2-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-4-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 15%). M / Z = 594.96 (M+1) 1H NMR (500 MHz, chloroform) δ 9.55 (s, 1H), 9.08 (s, 1H), 8.91 (s, 1H), 8.37 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0132] Example 40: 2-(3,5-dichloro-4-((2-(2-trifluoromethylpyridin-4-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced using 2-trifluoromethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-4-yl)pyridine and separated and purified according to the method described in Example 1 (total yield 16%). M / Z = 585.04 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.55 (s, 1H), 9.08 (s, 1H), 8.91 (s, 1H), 8.37 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0133] Example 41: 2-(3,5-dichloro-4-((2-chloro-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Produced, isolated and purified by the method described in Example 1 (total yield 13%). M / Z = 473.98 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.93 (s, 1H), 7.58 (s, 2H), 7.51 (s, 1H), 7.42 (d, J = 15.0 Hz, 2H), 2.57 (s, 3H).

[0134] Example 42: 2-(3,5-dichloro-4-((4-chloroquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and was isolated and purified according to the method described in Example 1 (total yield 11%). M / Z = 459.97 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.53 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.58 (s, 2H), 7.52 (s, 1H), 7.42 (s, 1H).

[0135] Example 43: 2-(3,5-dichloro-4-((4-chloroquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and was isolated and purified by the method described in Example 1 (total yield 17%). M / Z = 503.92 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.54 (s, 1H), 8.64 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.79 - 7.37 (m, 4H).

[0136] Example 44: 2-(3,5-dichloro-4-((4-chloro-2-(trifluoromethyl)quinolin-6-yl))oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced from commercially available raw materials by the method described in Example 1, and was then isolated and purified (total yield 23%). M / Z = 527.96 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.54 (s, 1H), 7.99 (d, J = 20.0 Hz, 2H), 7.78 - 7.55 (m, 4H).

[0137] Example 45: 2-(3,5-dichloro-4-((2-methyl-4-phenylquinolin-6-yl)oxy)phenyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified by the method described in Example 1 (total yield 26%). M / Z = 516.06 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 4H), 7.97 (s, 4H), 7.79 (s, 8H), 7.58 (s, 8H), 7.43 (t, J = 12.5 Hz, 16H), 7.36 (s, 1H), 7.32 (d, J = 40.0 Hz, 7H), 2.69 (s, 12H).

[0138] Example 46: 2-(3,5-dichloro-4-((4-methyl-2-vinylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified according to the method described in Example 1 (total yield 22%). M / Z = 466.04 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 1H), 7.90 (s, 1H), 7.57 (d, J = 15.0 Hz, 3H), 7.41 (s, 1H), 7.32 (s, 1H), 7.21 (s, 1H), 6.50 (s, 1H), 5.71 (s, 1H), 2.69 (s, 3H).

[0139] Example 47: 2-(3,5-dimethyl-4-((4-methyl-2-phenylquinolin-6-yl)oxy)phenyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified by the method described in Example 1 (total yield 17%). M / Z = 476.16 (M+1) 1H NMR (500 MHz, chloroform) δ 9.57 (s, 1H), 8.33 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.55 (s, 2H), 7.49 (s, 2H), 7.43 (s, 2H), 6.63 (s, 1H), 2.69 (s, 3H), 2.15 (s, 6H).

[0140] Example 48: 2-(3,5-dichloro-4-((4-methyl-2-(pyrrolidin-1-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified according to the method described in Example 1 (total yield 17%). M / Z = 509.08 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.55 (s, 103H), 7.64 (d, J = 60.0 Hz, 321H), 7.56 - 7.44 (m, 4H), 7.31 (s, 105H), 7.08 (s, 108H), 6.88 (s, 103H), 3.51 (s, 355H), 2.55 (s, 309H), 1.90 (s, 289H).

[0141] Example 49: 2-(3,5-dichloro-4-((2-methyl-4-(pyrrolidin-1-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced from commercially available raw materials, and separated and purified according to the method described in Example 1 (total yield 11%). M / Z = 509.08 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.55 (s, 4H), 7.86 (s, 4H), 7.76 (s, 4H), 7.58 (s, 8H), 7.38 (s, 4H), 7.03 (s, 4H), 3.41 (s, 14H), 2.53 (s, 12H), 1.93 (s, 11H).

[0142] Example 50: 2-(3,5-dichloro-4-((2-methyl-4-vinylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified according to the method described in Example 1 (total yield 12%). M / Z = 466.04 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.54 (s, 2H), 7.92 (s, 2H), 7.58 (s, 4H), 7.44 - 7.36 (m, 6H), 7.08 (s, 1H), 6.19 (s, 2H), 5.68 (s, 2H), 2.68 (s, 6H).

[0143] Example 51: 2-(3,5-dichloro-4-((2-chloro-3-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified according to the method described in Example 1 (total yield 11%). M / Z = 476.16 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.57 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 10.0 Hz, 3H), 7.58 - 7.40 (m, 7H), 2.56 (s, 3H), 2.15 (s, 6H).

[0144] Example 52: 2-(3,5-dichloro-4-((2-chloro-3-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and was isolated and purified according to the method described in Example 1 (total yield 10%). M / Z = 473.98 (M+1). 1H NMR (500 MHz, chloroform) δ 9.56 (s, 9H), 7.79 (d, J = 55.0 Hz, 17H), 7.74 - 7.70 (m, 1H), 7.58 (s, 5H), 7.49 (d, J = 85.0 Hz, 21H), 7.34 (s, 9H), 2.40 (s, 26H).

[0145] Example 53: 2-(3,5-dichloro-4-((3-methyl-2-phenylquinolin-6-yl)oxy)phenyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified by the method described in Example 1 (total yield 27%). M / Z = 516.06 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.55 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 10.0 Hz, 3H), 7.58 (s, 2H), 7.58 - 7.41 (m, 5H), 2.56 (s, 3H).

[0146] Example 54: 2-(3,5-difluoro-4-((4-methyl-2-phenylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced from commercially available raw materials, and separated and purified according to the method described in Example 1 (total yield 15%). M / Z = 484.11 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.57 (s, 1H), 8.33 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.55 (s, 2H), 7.51 (dd, J = 3.4, 1.5 Hz, 1H), 7.41 (d, J = 80.0 Hz, 4H), 6.63 (s, 1H), 2.69 (s, 3H).

[0147] Example 55: 2-(3-bromo-5-methyl-4-((4-methyl-2-phenylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified according to the method described in Example 1 (total yield 16%). M / Z = 540.06 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.57 (s, 1H), 8.33 (s, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.64 - 7.43 (m, 5H), 7.40 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H), 2.15 (s, 3H).

[0148] Example 56: 2-(3-bromo-5-chloro-4-((3-chloro-4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The compound was produced using commercially available raw materials, and separated and purified by the method described in Example 1 (total yield 13%). M / Z = 560.00 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.56 (s, 40H), 8.33 (s, 83H), 7.92 (s, 42H), 7.67 (s, 41H), 7.65 (s, 3H), 7.56 (t, J = 37.5 Hz, 199H), 7.38 (s, 41H), 6.63 (s, 40H), 2.69 (s, 120H).

[0149] Example 57: 2-(3,5-dichloro-4-((4-chloroquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile Commercially available 4-bromo-6-methoxyquinoline was used as the raw material, and the compound was produced, separated, and purified by the method described in Example 1 (total yield 17%). M / Z = 585.92 (M+1). 1H NMR (500 MHz, chloroform) δ 9.54 (s, 1H), 7.90 (s, 1H), 7.60 (t, J = 37.5 Hz, 3H), 7.38 (s, 1H), 2.45 (s, 3H).

[0150] Example 58: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Step 1: Preparation of 2-(3,5-dichloro-4-((4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid After obtaining product Example 1 by the method described in Example 1, use Example 1 as raw material, put it into a mixed solution of acetic acid and concentrated hydrochloric acid, heat it at 120°C for one hour, cool it, add water and filter it, and the precipitated solid is vacuum dried to obtain 2-(3,5-dichloro-4-((4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid as white powder.

[0151] Step 2: Preparation of 6-amino-2-(3,5-dichloro-4-((2-(4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 2-(3,5-dichloro-4-((4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid is added to t-butanol, triethylamine and DPPA are added, and the mixture is heated at 80°C for 24 hours. After the reaction is completed, t-butanol is removed under reduced pressure, and the mixture is extracted three times with ethyl acetate. The organic phases are combined and washed with saturated saline, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then Trifluoroacetic acid was added to the mixture and stirred for one hour to remove the protecting group. Trifluoroacetic acid was then removed under reduced pressure, and the mixture was basified with an aqueous sodium hydroxide solution, extracted, concentrated under reduced pressure, and separated and purified by preparative high performance liquid chromatography to obtain a white powder compound, 6-amino-2-(3,5-dichloro-4-((2-(4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, i.e., Example 58. M / Z = 498.03 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.55 (s, 1H), 9.08 (s, 1H), 8.91 (s, 1H), 8.37 (s, 1H), 7.94 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0152] Example 59: 6-amino-2-(3,5-dichloro-4-((2-(4-chlorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 2 as the raw material, 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 506.07 (M+1) 1H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.33 (s, 2H), 7.76 (dd, J = 132.2, 37.9 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.56 (d, J = 15.0 Hz, 4H), 7.49 (s, 2H), 6.63 (s, 1H), 2.69 (s, 3H).

[0153] Example 60: 6-amino-2-(3,5-dichloro-4-((2-(4-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 3 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(4-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 524.06 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.33 (s, 2H), 7.76 (dd, J = 132.2, 37.9 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.56 (d, J = 15.0 Hz, 4H), 7.49 (s, 2H), 6.63 (s, 1H), 2.69 (s, 3H).

[0154] Example 61: 6-amino-2-(3,5-dichloro-4-((2-(4-trifluoromethylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 4 as the raw material, 6-amino-2-(3,5-dichloro-4-((2-(4-trifluoromethylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 574.06 (M+1) 1H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.33 (s, 2H), 7.76 (dd, J = 132.2, 37.9 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.56 (d, J = 15.0 Hz, 4H), 7.49 (s, 2H), 6.63 (s, 1H), 2.69 (s, 3H).

[0155] Example 62: 6-amino-2-(3,5-dichloro-4-((2-(4-chlorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 5 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(4-chlorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 540.03 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.33 (s, 2H), 7.76 (dd, J = 132.2, 37.9 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.56 (d, J = 15.0 Hz, 4H), 7.49 (s, 2H), 6.63 (s, 1H), 2.69 (s, 3H).

[0156] Example 63: 6-amino-2-(3,5-dichloro-4-((2-(4-bromophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 6 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(4-bromophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z =583.98(M+1) 1H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.33 (s, 2H), 7.76 (dd, J = 132.2, 37.9 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.56 (d, J = 15.0 Hz, 4H), 7.49 (s, 2H), 6.63 (s, 1H), 2.69 (s, 3H).

[0157] Example 64: 6-amino-2-(3,5-dichloro-4-((2-(4-cyanophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 7 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(4-cyanophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 531.07 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.07 (s, 1H), 8.34 (s, 2H), 7.94 - 7.85 (m, 5H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0158] Example 65: 6-amino-2-(3,5-dichloro-4-((2-(3-chloro-5-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 8 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(3-chloro-5-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 558.02 (M+1) 1H NMR (500 MHz, chloroform) δ 9.07 (s, 1H), 8.34 (s, 2H), 7.94 - 7.85 (m, 5H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0159] Example 66: 6-amino-2-(3,5-dichloro-4-((2-(2-isopropylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 9 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(2-isopropylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 548.12 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.07 (s, 1H), 8.34 (s, 2H), 7.94 - 7.85 (m, 5H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0160] Example 67: 6-amino-2-(3,5-dichloro-4-((2-(4-fluoro-3-methylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 10 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(4-fluoro-3-methylphenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 538.02 (M+1) 1H NMR (500 MHz, chloroform) δ 9.07 (s, 1H), 8.34 (s, 2H), 7.94 - 7.85 (m, 5H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0161] Example 68: 4-(6-(4-(6-amino-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2,6-dichlorophenoxy)-4-methylquinolin-2-yl)-2-fluorobenzonitrile Using Example 11 as the raw material, 4-(6-(4-(6-amino-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2,6-dichlorophenoxy)-4-methylquinolin-2-yl)-2-fluorobenzonitrile was obtained by the method described in Example 58. M / Z = 549.06 (M+1) 1 H NMR (500 Mhz, chloroform) δ 9.07 (s, 1H), 8.34 (s, 2H), 7.94 - 7.85 (m, 5H), 7.67 (s, 1H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0162] Example 69: 2-(6-(4-(6-amino-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2,6-dichlorophenoxy)-4-methylquinolin-2-yl)-5-(trifluoromethyl)benzonitrile Using Example 12 as the raw material, 2-(6-(4-(6-amino-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2,6-dichlorophenoxy)-4-methylquinolin-2-yl)-5-(trifluoromethyl)benzonitrile was obtained by the method described in Example 58. M / Z = 599.05 (M+1) 1H NMR (500 MHz, chloroform) δ 9.10 (s, 1H), 8.27 (d, J = 5.0 Hz, 2H), 8.00 (s, 1H), 7.75 (dd, J = 129.7, 40.4 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0163] Example 70: 6-amino-2-(3,5-dichloro-4-((2-(3,5-dichloro-4-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 13 as the raw material, 6-amino-2-(3,5-dichloro-4-((2-(3,5-dichloro-4-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 591.98 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.10 (s, 1H), 8.27 (d, J = 5.0 Hz, 2H), 8.00 (s, 1H), 7.75 (dd, J = 129.7, 40.4 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0164] Example 71: 6-amino-2-(3,5-dichloro-4-((2-(4-chloro-3,5-dimethylphenyl)-4-methylquinolin-6-yl)oxy)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 14 as the raw material, 6-amino-2-(3,5-dichloro-4-((2-(4-chloro-3,5-dimethylphenyl)-4-methylquinolin-6-yl)oxy)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 568.06 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.10 (s, 1H), 8.27 (d, J = 5.0 Hz, 2H), 8.00 (s, 1H), 7.75 (dd, J = 129.7, 40.4 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0165] Example 72: 6-amino-2-(3,5-dichloro-4-((2-(furan-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 15 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(furan-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 496.05 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.10 (s, 1H), 8.27 (d, J = 5.0 Hz, 2H), 8.00 (s, 1H), 7.75 (dd, J = 129.7, 40.4 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0166] Example 73: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(5-methylfuran-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 16 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(5-methylfuran-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 510.07 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.10 (s, 1H), 8.27 (d, J = 5.0 Hz, 2H), 8.00 (s, 1H), 7.75 (dd, J = 129.7, 40.4 Hz, 6H), 7.67 (s, 1H), 7.62 (d, J = 45.0 Hz, 3H), 7.58 (s, 2H), 7.49 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H).

[0167] Example 74: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(5-methylfuran-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 17 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(5-methylfuran-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 510.07(M+1) 1 H NMR (500 MHz, chloroform) δ 9.07 (s, 1H), 7.94 (s, 1H), 7.85 (s, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.27 (s, 1H), 6.97 (s, 1H), 6.42 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

[0168] Example 75: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(5-methylfuran-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 18 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(5-methylfuran-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 535.06 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.12 (s, 1H), 8.11 - 7.60 (m, 4H), 7.61 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 6.37 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

[0169] Example 76: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(thiophen-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 19 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(thiophen-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 512.03 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 2H), 8.12 - 7.56 (m, 16H), 7.66 (s, 2H), 7.74 - 7.56 (m, 8H), 7.60 (d, J = 15.0 Hz, 6H), 7.47 (s, 2H), 7.19 (s, 1H), 6.97 (s, 2H), 2.69 (s, 6H).

[0170] Example 77: 6-amino-2-(3,5-dichloro-4-((2-(4-chlorothiophen-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 20 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(4-chlorothiophen-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 545.99 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 2H), 8.12 - 7.56 (m, 16H), 7.66 (s, 2H), 7.74 - 7.56 (m, 8H), 7.60 (d, J = 15.0 Hz, 6H), 7.47 (s, 2H), 7.19 (s, 1H), 6.97 (s, 2H), 2.69 (s, 6H).

[0171] Example 78: 5-(6-(4-(6-amino-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2,6-dichlorophenoxy)-4-methylquinolin-2-yl)thiophene-2-carbonitrile Using Example 21 as the raw material, the compound was prepared according to the method described in Example 58 to obtain 5-(6-(4-(6-amino-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2,6-dichlorophenoxy)-4-methylquinolin-2-yl)thiophene-2-carbonitrile. M / Z = 537.02 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 2H), 8.12 - 7.56 (m, 16H), 7.66 (s, 2H), 7.74 - 7.56 (m, 8H), 7.60 (d, J = 15.0 Hz, 6H), 7.47 (s, 2H), 7.19 (s, 1H), 6.97 (s, 2H), 2.69 (s, 6H).

[0172] Example 79: 6-amino-2-(3,5-dichloro-4-((2-(5-methylthiophen-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 22 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(5-methylthiophen-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 526.04 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 2H), 8.12 - 7.56 (m, 16H), 7.66 (s, 2H), 7.74 - 7.56 (m, 8H), 7.60 (d, J = 15.0 Hz, 6H), 7.47 (s, 2H), 7.19 (s, 1H), 6.97 (s, 2H), 2.69 (s, 6H).

[0173] Example 80: 6-amino-2-(3,5-dichloro-4-((2-(5-trifluoromethylthiophen-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 23 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(5-trifluoromethylthiophen-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 580.01 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.12 - 7.61 (m, 5H), 7.61 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.02 (d, J = 55.0 Hz, 2H), 2.69 (s, 3H).

[0174] Example 81: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(pyridin-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 24 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(pyridin-2-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 507.07 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.18 (s, 1H), 9.09 (s, 1H), 8.55 (s, 1H), 7.94 (s, 1H), 7.86 (s, 2H), 7.74 (d, J = 5.0 Hz, 2H), 7.59 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.23 (s, 1H), 2.69 (s, 3H).

[0175] Example 82: 6-amino-2-(3,5-dichloro-4-((2-(5-methylpyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 25 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(5-methylpyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 521.08 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 7.94 (s, 1H), 7.84 (s, 2H), 7.75 (s, 1H), 7.59 (d, J = 15.0 Hz, 3H), 7.47 (d, J = 5.0 Hz, 2H), 2.69 (s, 3H), 2.32 (s, 3H).

[0176] Example 83: 6-amino-2-(3,5-dichloro-4-((2-(5-fluoropyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 26 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(5-fluoropyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 525.06 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.10 (s, 84H), 8.76 (s, 45H), 8.33 (s, 87H), 7.91 (d, J = 33.8 Hz, 252H), 7.86 - 7.85 (m, 6H), 7.75 (s, 84H), 7.60 (d, J = 15.0 Hz, 256H), 7.46 (d, J = 14.1 Hz, 166H), 2.69 (s, 251H).

[0177] Example 84: 6-amino-2-(3,5-dichloro-4-((2-(5-chloropyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 27 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(5-chloropyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 541.03 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.10 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 8.12 - 7.52 (m, 7H), 7.75 (s, 1H), 7.85 - 7.52 (m, 4H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.77 (s, 1H), 2.69 (s, 3H).

[0178] Example 85: 6-amino-2-(3,5-dichloro-4-((2-(5-bromopyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 28 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-(5-bromopyridin-2-yl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 584.98 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.11 (d, J = 11.3 Hz, 2H), 8.52 (s, 1H), 7.94 (s, 1H), 7.87 (s, 2H), 7.74 (d, J = 5.0 Hz, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 2.69 (s, 3H).

[0179] Example 86: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(pyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 29 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(pyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 507.07 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.63 (s, 2H), 9.08 (s, 2H), 8.71 (d, J = 10.0 Hz, 4H), 7.94 (s, 2H), 7.86 (s, 4H), 7.59 (d, J = 15.0 Hz, 6H), 7.47 (s, 3H), 6.97 (s, 2H), 2.69 (s, 6H).

[0180] Example 87: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-methylpyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 30 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-methylpyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 521.08 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.33 (s, 1H), 9.07 (s, 1H), 8.36 (s, 1H), 7.94 (s, 1H), 7.84 (s, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 7.20 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H), 2.61 (s, 3H).

[0181] Example 88: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-fluoropyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 31 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-fluoropyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 525.06 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.12 (d, J = 3.0 Hz, 8H), 8.64 (s, 4H), 7.94 (s, 4H), 7.85 (s, 8H), 7.60 (d, J = 15.0 Hz, 12H), 7.44 (d, J = 25.6 Hz, 8H), 7.39 (s, 1H), 6.97 (s, 4H), 2.69 (s, 12H).

[0182] Example 89: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-chloropyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 32 as the raw material, 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-chloropyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 541.03 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.38 (s, 1H), 9.09 (s, 1H), 8.52 (s, 1H), 7.94 (s, 1H), 7.86 (s, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.48 (d, J = 10.0 Hz, 2H), 6.97 (s, 1H), 2.69 (s, 3H).

[0183] Example 90: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-bromopyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 33 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-bromopyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 584.98 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.22 (s, 1H), 9.09 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.86 (s, 2H), 7.71 (s, 1H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0184] Example 91: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-bromopyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 34 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(6-bromopyridin-3-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 575.05 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.48 (s, 2H), 9.10 (s, 2H), 8.37 (s, 2H), 7.91 (d, J = 33.5 Hz, 7H), 7.61 (s, 1H), 7.60 (d, J = 15.0 Hz, 6H), 7.39 (d, J = 80.0 Hz, 4H), 6.97 (s, 2H), 2.69 (s, 6H).

[0185] Example 92: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(pyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 35 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(pyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 507.07 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.09 (s, 1H), 8.75 (s, 2H), 8.28 (s, 2H), 7.94 (s, 1H), 7.86 (s, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0186] Example 93: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-methylpyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 36 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-methylpyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 521.08 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.88 (s, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.86 (s, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 6H).

[0187] Example 94: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-chloropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 37 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-chloropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 541.03 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (d, J = 4.3 Hz, 2H), 8.91 (s, 1H), 8.37 (s, 1H), 7.90 (d, J = 35.0 Hz, 3H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0188] Example 95: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 38 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 525.06 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.07 (s, 3H), 8.91 (s, 3H), 8.58 (s, 3H), 8.15 - 7.61 (m, 13H), 7.61 (s, 1H), 7.60 (d, J = 15.0 Hz, 9H), 7.47 (s, 3H), 6.97 (s, 3H), 2.69 (s, 9H).

[0189] Example 96: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-bromopyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 39 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-bromopyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 584.98 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.03 (d, J = 49.6 Hz, 2H), 8.73 (s, 1H), 8.48 (s, 1H), 7.94 (s, 1H), 7.86 (s, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0190] Example 97: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-trifluoromethylpyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 40 as the raw material, 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-trifluoromethylpyridin-4-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 575.05 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.80 (d, J = 5.0 Hz, 2H), 8.33 (s, 1H), 7.94 (s, 1H), 7.86 (s, 2H), 7.60 (d, J = 15.0 Hz, 3H), 7.47 (s, 1H), 6.97 (s, 1H), 2.69 (s, 3H).

[0191] Example 98: 6-amino-2-(3,5-dichloro-4-((2-chloro-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 41 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-chloro-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 464.00 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 7.93 (s, 1H), 7.84 (s, 2H), 7.58 (s, 2H), 7.51 (s, 1H), 7.42 (d, J = 15.0 Hz, 2H), 2.57 (s, 3H).

[0192] Example 99: 6-Amino-2-(3,5-dichloro-4-((4-chloroquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 42 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(4-(4-bromoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 451.66 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.07 (s, 18H), 8.75 (s, 19H), 8.13 - 7.83 (m, 74H), 7.86 (s, 36H), 7.86 (s, 36H), 7.60 (s, 1H), 7.55 (d, J = 30.0 Hz, 55H), 7.42 (s, 18H).

[0193] Example 100: 6-amino-2-(4-(4-bromoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 43 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(4-(4-bromoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 493.93 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.07 (s, 1H), 8.64 (s, 1H), 7.96 (s, 1H), 7.86 (d, J = 15.5 Hz, 3H), 7.72 - 7.37 (m, 4H).

[0194] Example 101: 6-amino-2-(3,5-dichloro-4-((4-chloro-2-(trifluoromethyl)quinolin-6-yl))oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 44 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-chloro-2-(trifluoromethyl)quinolin-6-yl))oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 517.97 (M+1). 1H NMR (500 MHz, chloroform) δ 9.07 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.87 (s, 2H), 7.78 - 7.55 (m, 4H).

[0195] Example 102: 6-amino-2-(3,5-dichloro-4-((2-methyl-4-phenylquinolin-6-yl)oxy)phenyl-1,2,4-triazine-3,5(2H,4H)-dione Using Example 45 as the raw material, 6-amino-2-(3,5-dichloro-4-((2-methyl-4-phenylquinolin-6-yl)oxy)phenyl-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 506.07 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 7.97 (s, 1H), 7.84 (s, 2H), 7.79 (s, 2H), 7.58 (s, 2H), 7.56 - 7.39 (m, 4H), 7.36 (s, 1H), 7.28 (s, 1H), 2.69 (s, 3H).

[0196] Example 103: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-vinylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 46 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-vinylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 456.06 (M+1). 1H NMR (500 MHz, chloroform) δ 9.08 (s, 4H), 7.88 (d, J = 16.1 Hz, 12H), 7.57 (d, J = 15.0 Hz, 12H), 7.35 (d, J = 56.1 Hz, 9H), 7.27 (s, 1H), 7.21 (s, 2H), 6.50 (s, 4H), 5.71 (s, 4H), 2.69 (s, 12H).

[0197] Example 104: 6-amino-2-(3,5-dimethyl-4-((4-methyl-2-phenylquinolin-6-yl)oxy)phenyl-1,2,4-triazine-3,5(2H,4H)-dione Using Example 47 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dimethyl-4-((4-methyl-2-phenylquinolin-6-yl)oxy)phenyl-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 466.18 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.05 (s, 1H), 8.33 (s, 2H), 7.92 (s, 1H), 7.84 (s, 2H), 7.67 (s, 1H), 7.55 (s, 2H), 7.46 (d, J = 30.0 Hz, 4H), 6.63 (s, 1H), 2.69 (s, 3H), 2.15 (s, 6H).

[0198] Example 105: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(pyrrolidin-1-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 48 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(pyrrolidin-1-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 499.10 (M+1). 1H NMR (500 MHz, chloroform) δ 9.10 (s, 66H), 7.84 (s, 132H), 7.64 (d, J = 60.0 Hz, 208H), 7.39 (s, 3H), 7.31 (s, 67H), 7.08 (s, 69H), 6.88 (s, 66H), 3.51 (s, 227H), 2.55 (s, 198H), 1.90 (s, 185H).

[0199] Example 106: 6-amino-2-(3,5-dichloro-4-((2-methyl-4-(pyrrolidin-1-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 49 as the raw material, 6-amino-2-(3,5-dichloro-4-((2-methyl-4-(pyrrolidin-1-yl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 499.10 (M+1) 1 H NMR (500 MHz, chloroform) δ 9.07 (s, 2H), 7.86 (d, J = 3.1 Hz, 6H), 7.76 (s, 2H), 7.58 (s, 4H), 7.38 (s, 2H), 7.03 (s, 2H), 3.41 (s, 7H), 2.53 (s, 6H), 1.93 (s, 6H).

[0200] Example 107: 6-amino-2-(3,5-dichloro-4-((2-methyl-4-vinylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 50 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-methyl-4-vinylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 456.06 (M+1). 1H NMR (500 MHz, chloroform) δ 9.10 (s, 2H), 7.88 (d, J = 37.5 Hz, 6H), 7.58 (s, 4H), 7.44 - 7.36 (m, 6H), 7.08 (s, 1H), 6.19 (s, 2H), 5.68 (s, 2H), 2.68 (s, 6H).

[0201] Example 108: 6-amino-2-(3,5-dimethyl-4-((3-methyl-2-phenylquinolin-6-yl)oxy)phenyl-1,2,4-triazine-3,5(2H,4H)-dione Using Example 51 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dimethyl-4-((3-methyl-2-phenylquinolin-6-yl)oxy)phenyl-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 466.18 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.05 (s, 1H), 8.07 (s, 1H), 7.83 (t, J = 5.0 Hz, 5H), 7.58 - 7.40 (m, 7H), 2.56 (s, 3H), 2.15 (s, 6H).

[0202] Example 109: 6-amino-2-(3,5-dichloro-4-((2-chloro-3-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 52 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-chloro-3-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 464.00 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 7.84 (d, J = 6.6 Hz, 3H), 7.74 (s, 1H), 7.58 (s, 2H), 7.41 (s, 1H), 7.34 (s, 1H), 2.40 (s, 3H).

[0203] Example 110: 6-amino-2-(3,5-dichloro-4-((3-methyl-2-phenylquinolin-6-yl)oxy)phenyl-1,2,4-triazine-3,5(2H,4H)-dione Using Example 53 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((3-methyl-2-phenylquinolin-6-yl)oxy)phenyl-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 506.07 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.07 (s, 1H), 7.88 - 7.74 (m, 5H), 7.58 (s, 2H), 7.56 - 7.41 (m, 5H), 2.56 (s, 3H).

[0204] Example 111: 6-amino-2-(3,5-difluoro-4-((4-methyl-2-phenylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 54 as the starting material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-difluoro-4-((4-methyl-2-phenylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 474.13 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.10 (s, 2H), 8.33 (s, 4H), 7.92 (s, 2H), 7.84 (s, 4H), 7.67 (s, 2H), 7.55 (s, 4H), 7.52 - 7.51 (m, 1H), 7.41 (d, J = 80.0 Hz, 8H), 6.63 (s, 2H), 2.69 (s, 6H).

[0205] Example 112: 6-amino-2-(3-bromo-5-methyl-4-(4-methyl-2-phenylquinolin-6-yl)oxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 55 as the starting material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3-bromo-5-methyl-4-(4-methyl-2-phenylquinolin-6-yl)oxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 530.07 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.06 (s, 1H), 8.33 (s, 2H), 8.10 - 7.58 (m, 4H), 7.67 (s, 1H), 7.67 (s, 1H), 7.55 (s, 2H), 7.48 (d, J = 10.0 Hz, 3H), 7.40 (s, 1H), 6.63 (s, 1H), 2.69 (s, 3H), 2.15 (s, 3H).

[0206] Example 113: 6-amino-2-(3-bromo-5-chloro-4-(4-methyl-2-phenylquinolin-6-yl)oxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 56 as the starting material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3-bromo-5-chloro-4-(4-methyl-2-phenylquinolin-6-yl)oxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 550.02 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 2H), 8.33 (s, 4H), 8.10 - 7.56 (m, 11H), 7.65 (d, J = 15.0 Hz, 5H), 7.65 (d, J = 15.0 Hz, 4H), 7.55 (s, 3H), 7.49 (s, 5H), 7.38 (s, 2H), 6.63 (s, 2H), 2.69 (s, 6H).

[0207] Example 114: 6-amino-2-(3-bromo-5-chloro-4-((3-chloro-4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 57 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3-bromo-5-chloro-4-((3-chloro-4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 575.94 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0208] Example 115: 2-(3,5-dichloro-4-((2-ethyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((2-ethyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 468.03 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0209] Example 116: 2-(3,5-dichloro-4-((2-isopropyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((2-isopropyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 482.02 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0210] Example 117: 2-(3,5-dichloro-4-((2-cyclopropyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((2-cyclopropyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 480.01 (M+1). 1 H NMR (500 Mhz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0211] Example 118: 2-(3,5-dichloro-4-((2-cyclobutyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((2-cyclobutyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 494.01 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0212] Example 119: 2-(3,5-dichloro-4-((2-cyclopentyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((2-cyclopentyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 508.02 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0213] Example 120: 2-(3,5-dichloro-4-((2-cyclohexyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((2-cyclohexyl-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 521.11 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0214] Example 121: 2-(3,5-dichloro-4-((2-(4,4-dimethylcyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((2-(4,4-dimethylcyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 550.15 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0215] Example 122: 2-(3,5-dichloro-4-((2-(4,4-difluorocyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((2-(4,4-difluorocyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 558.04 (M+1). 1 H NMR (500 MHz, chloroform) δ 9.08 (s, 1H), 8.08 - 7.55 (m, 5H), 7.65 (d, J = 10.0 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 7.45 (d, J = 65.0 Hz, 2H), 2.45 (s, 3H).

[0216] Example 123: 2-(3,5-dichloro-4-((4-methyl-2-(4-(trifluoromethyl)cyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((4-methyl-2-(4-(trifluoromethyl)cyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 590.03 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.7 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.02 (d, J = 1.1 Hz, 1H), 2.96 - 2.88 (m, 1H), 2.71 (s, 3H), 2.37 - 2.25 (m, 1H), 2.18 - 2.06 (m, 2H), 2.00 - 1.81 (m, 4H), 1.78 - 1.67 (m, 2H).

[0217] Example 124: 2-(4-((2-(bicyclo[2.2.1]heptan-2-yl)-4-methylquinolin-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(4-((2-(bicyclo[2.2.1]heptan-2-yl)-4-methylquinolin-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 534.32 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.17 - 7.09 (m, 2H), 2.88 (dt, J = 6.0, 4.3 Hz, 1H), 2.71 (s, 3H), 2.26 (tt, J = 5.3, 3.5 Hz, 1H), 2.13 (dp, J = 6.0, 3.8 Hz, 1H), 2.01 (ddd, J = 12.5, 5.3, 4.5 Hz, 1H), 1.76 - 1.69 (m, 1H), 1.72 - 1.66 (m, 1H), 1.69 - 1.63 (m, 2H), 1.66 - 1.59 (m, 1H), 1.63 - 1.54 (m, 1H), 1.57 - 1.49 (m, 1H), 1.46 - 1.38 (m, 1H).

[0218] Example 125: 2-(3,5-dichloro-4-((4-methyl-2-(3-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((4-methyl-2-(3-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 536.39 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.2, 1.9 Hz, 1H), 7.12 - 7.09 (m, 1H), 2.98 - 2.90 (m, 1H), 2.71 (s, 3H), 1.91 - 1.82 (m, 1H), 1.78 - 1.70 (m, 1H), 1.73 - 1.67 (m, 1H), 1.70 - 1.63 (m, 2H), 1.66 - 1.55 (m, 1H), 1.57 - 1.48 (m, 1H), 1.47 - 1.31 (m, 4H), 0.93 (d, J = 6.2 Hz, 3H).

[0219] Example 126: 2-(3,5-dichloro-4-((4-methyl-2-(2-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((4-methyl-2-(2-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 536.40 (M+1). 1H NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.03 (s, 1H), 2.71 (s, 3H), 2.54 (dtd, J = 7.3, 6.0, 1.5 Hz, 1H), 2.21 (dddd, J = 12.6, 9.5, 6.8, 6.0 Hz, 1H), 1.99 - 1.85 (m, 2H), 1.74 - 1.30 (m, 6H), 0.95 (dd, J = 6.8, 1.5Hz, 3H).

[0220] Example 127: 2-(3,5-dichloro-4-((4-methyl-2-(4-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-((4-methyl-2-(4-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 536.41 (M+1). 1H NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.02 (d, J = 0.9 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.71 (s, 3H), 1.88 (ddt, J = 12.0, 8.8, 6.0 Hz, 2H), 1.78 (ddt, J = 12.3, 8.6, 5.9 Hz, 2H), 1.60 (ddt, J = 12.0, 8.6, 5.9Hz, 2H), 1.55 - 1.44 (m, 1H), 1.39 - 1.29 (m, 2H), 0.92 (d, J = 6.1 Hz, 3H).

[0221] Example 128: 2-(3,5-dichloro-4-(4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)quinolin-6-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile The corresponding boronic acid ester was used as the starting material to prepare the compound according to the method described in Example 1, to give 2-(3,5-dichloro-4-(4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)quinolin-6-yloxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. M / Z = 578.48 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 7.67 (s, 1H), 7.48 (d, J = 1.7 Hz, 0H), 7.20 - 7.11 (m, 1H), 3.15 - 3.07 (m, 0H), 2.71 (s, 1H), 1.86 (dd, J = 12.3, 5.5 Hz, 1H), 1.75 (dd, J = 12.3, 5.5 Hz, 1H), 0.94 (s, 2H), 0.89 (s, 2H).

[0222] Example 129: 6-amino-2-(3,5-dichloro-4-(2-ethyl-4-methylquinolin-6-yloxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 115 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-(2-ethyl-4-methylquinolin-6-yloxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 458.21 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.47 (d, J = 1.8 Hz, 1H), 7.17 - 7.11 (m, 2H), 5.17 (s, 2H), 2.82 (q, J = 7.1 Hz, 2H), 2.65 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0223] Example 130: 6-amino-2-(3,5-dichloro-4-(2-isopropyl-4-methylquinolin-6-yloxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 116 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-(2-isopropyl-4-methylquinolin-6-yloxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 472.28 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.17 - 7.11 (m, 2H), 5.17 (s, 2H), 3.15 (qd, J = 6.9, 6.3 Hz, 1H), 2.71 (s, 3H), 1.30 (d, J = 6.6 Hz, 6H).

[0224] Example 131: 6-amino-2-(3,5-dichloro-4-((2-cyclopropyl-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 117 as the starting material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-cyclopropyl-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 470.28 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 1.0 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 5.17 (s, 2H), 2.71 (s, 3H), 2.46 - 2.38 (m, 1H), 1.15 (dq, J = 5.6, 0.8 Hz, 4H).

[0225] Example 132: 6-amino-2-(3,5-dichloro-4-((2-cyclobutyl-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 118 as the starting material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-cyclobutyl-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 484.21 (M+1). 1H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.7 Hz, 1H), 7.18 - 7.11 (m, 2H), 5.17 (s, 2H), 3.08 - 3.01 (m, 1H), 2.71 (s, 3H), 2.03 - 1.80 (m, 6H), 1.83 - 1.69 (m, 1H).

[0226] Example 133: 6-amino-2-(3,5-dichloro-4-((2-cyclopentyl-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 119 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-cyclopentyl-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 498.14 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.02 (d, J = 1.1 Hz, 1H), 5.17 (s, 2H), 3.20 - 3.12 (m, 1H), 2.71 (s, 3H), 1.91 - 1.67 (m, 7H).

[0227] Example 134: 6-amino-2-(3,5-dichloro-4-((2-cyclohexyl-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 120 as the starting material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((2-cyclohexyl-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 512.29 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.02 (d, J = 1.1 Hz, 1H), 5.17 (s, 2H), 2.96 - 2.88 (m, 1H), 2.71 (s, 3H), 1.77 - 1.60 (m, 7H), 1.58 - 1.45 (m, 4H), 1.47 - 1.35 (m, 1H).

[0228] Example 135: 6-amino-2-(3,5-dichloro-4-((2-(4,4-dimethylcyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 121 as the raw material, 6-amino-2-(3,5-dichloro-4-((2-(4,4-dimethylcyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 540.35 (M+1) 1H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.2, 1.9 Hz, 1H), 7.02 (d, J = 0.9 Hz, 1H), 5.17 (s, 2H), 2.94 - 2.86 (m, 1H), 2.71 (s, 3H), 1.88 (dddd, J = 12.5, 9.9, 7.2, 5.5 Hz, 2H), 1.79 - 1.68 (m, 2H), 1.54 (ddd, J = 12.4, 9.7, 7.1 Hz, 2H), 1.44 (ddd, J = 12.5, 9.9, 7.2 Hz, 2H), 0.86 (s, 5H).

[0229] Example 136: 6-amino-2-(3,5-dichloro-4-((2-(4,4-difluorocyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 122 as the raw material, 6-amino-2-(3,5-dichloro-4-((2-(4,4-difluorocyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 548.27 (M+1) 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.02 (d, J = 0.9 Hz, 1H), 5.17 (s, 2H), 3.05 - 2.96 (m, 1H), 2.71 (s, 3H), 2.15 - 1.86 (m, 9H).

[0230] Example 137: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(4-(trifluoromethyl)cyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 123 as the raw material, 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(4-(trifluoromethyl)cyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 580.29 (M+1) 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.7 Hz, 1H), 7.14 (dd, J = 8.2, 1.9 Hz, 1H), 7.02 (d, J = 0.9 Hz, 1H), 5.17 (s, 2H), 2.96 - 2.88 (m, 1H), 2.71 (s, 3H), 2.37 - 2.25 (m, 1H), 2.18 - 2.06 (m, 2H), 2.00 - 1.81 (m, 4H), 1.78 - 1.67 (m, 2H).

[0231] Example 138: 6-amino-2-(4-(2-(bicyclo[2.2.1]heptan-2-yl)-4-methylquinolin-6-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 124 as the starting material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(4-(2-(bicyclo[2.2.1]heptan-2-yl)-4-methylquinolin-6-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 524.30 (M+1) 1H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.2, 1.9 Hz, 1H), 7.11 (d, J = 0.9 Hz, 1H), 5.17 (s, 2H), 2.88 (dt, J = 6.0, 4.3 Hz, 1H), 2.71 (s, 3H), 2.26 (tt, J = 5.3, 3.6 Hz, 1H), 2.13 (dp, J = 6.0, 3.8 Hz, 1H), 2.01 (ddd, J = 12.5, 5.3, 4.5 Hz, 1H), 1.76 - 1.69 (m, 1H), 1.72 - 1.66 (m, 1H), 1.69 - 1.63 (m, 2H), 1.66 - 1.59 (m, 1H), 1.63 - 1.54 (m, 1H), 1.57 - 1.49 (m, 1H), 1.47 - 1.38 (m, 1H).

[0232] Example 139: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(3-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 125 as the starting material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(3-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 526.32 (M+1). 1H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.12 - 7.09 (m, 1H), 5.17 (s, 2H), 2.99 - 2.90 (m, 1H), 2.71 (s, 3H), 1.91 - 1.82 (m, 1H), 1.78 - 1.49 (m, 6H), 1.47 - 1.32 (m, 3H), 0.93 (d, J = 6.2 Hz, 3H).

[0233] Example 140: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 126 as the raw material, 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 526.32 (M+1) 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.7 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.03 (s, 1H), 5.17 (s, 2H), 2.71 (s, 3H), 2.54 (dtd, J = 7.2, 5.9, 1.5 Hz, 1H), 2.21 (dddd, J = 12.6, 9.5, 6.8, 5.9 Hz, 1H), 1.99 - 1.85 (m, 2H), 1.74 - 1.40 (m, 5H), 1.35 (ddt, J = 11.8, 8.2, 5.8 Hz, 1H), 0.95 (dd, J = 6.8, 1.5 Hz, 3H).

[0234] Example 141: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(4-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 127 as the raw material, the compound was prepared by the method described in Example 58 to obtain 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(4-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione. M / Z = 526.32 (M+1). 1 H NMR (500 MHz, chloroform-d) δ 9.74 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J = 1.7 Hz, 1H), 7.14 (dd, J = 8.2, 1.9 Hz, 1H), 7.02 (d, J = 0.9 Hz, 1H), 5.17 (s, 2H), 2.93 - 2.84 (m, 1H), 2.71 (s, 3H), 1.88 (ddt, J = 12.0, 8.8, 5.9 Hz, 2H), 1.78 (ddt, J = 12.3, 8.6, 6.0Hz, 2H), 1.60 (ddt, J = 12.0, 8.6, 5.9 Hz, 2H), 1.54 - 1.44 (m, 1H), 1.39 - 1.29 (m, 2H), 0.92 (d, J = 6.1 Hz, 3H).

[0235] Example 142: 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione Using Example 128 as the raw material, 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)quinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione was obtained by the method described in Example 58. M / Z = 568.40 (M+1)1 H NMR (500 MHz, chloroform-d) δ 7.67 (s, 1H), 7.48 (d, J = 1.7 Hz, 0H), 7.20 - 7.11 (m, 1H), 5.17 (s, 1H), 3.15 - 3.07 (m, 0H), 2.71 (s, 1H), 1.86 (dd, J = 12.3, 5.5 Hz, 1H), 1.75 (dd, J = 12.3, 5.5 Hz, 1H), 0.94 (s, 2H), 0.89 (s, 2H).

[0236] Biological Test Experiment 1.1 Evaluation of THRβ agonist activity at the molecular level in vitro At the molecular level, the binding ability of compounds with thyroid hormone receptor beta (THRβ) was measured by means of AlphaScreen detection. First, recombinant GST-THRβ fusion protein was constructed, and then the compound-receptor binding reaction was carried out in a 384-well plate. The mixture of recombinant protein, agonist, coregulator, AlphaScreenR acceptor microbeads, and AlphaScreenR donor microbeads was reacted in Tris-HCl (pH 7.4) buffer. If the compound can bind to the receptor protein, the relative positions of AlphaScreenR acceptor microbeads and AlphaScreenR donor microbeads will change, and thus emit fluorescence of a specific wavelength. The binding activity of the compound with THRβ was characterized by detecting the intensity of the fluorescent signal with the fluorescent detection device Envision. Then, the EC50 of the compound was calculated by the software Graphpad Prism 7.

[0237] 1.2 Evaluation of THRβ agonist activity at the cellular level in vitro To detect the binding at the cellular level, FH-THRα / β expression plasmid, pal-luciferase reporter plasmid and RL-TK plasmid were used, and the three were co-transfected into 293T cells, then inoculated into a 96-well flat-bottom microplate, and the cells were cultured for 24 h to allow the plasmids to be expressed. After 18 h, the test TRα / β agonist was added and detected using a dual-luminescence detection kit (Dual-Luciferase Reporter Assay System), with firefly luciferase as the reporter gene and Renilla luciferase as the internal reference gene. The biofluorescence intensity was detected by the fluorescence detection device Envision, which could reflect the activation efficiency of the compound on the TRα / β receptor.

[0238] 1.3 Pharmacokinetic studies We will conduct preliminary pharmacokinetic studies in mice or rats for the target compounds with good activity obtained mainly from the above studies, and will consider in detail the pharmacokinetic properties of the compounds when administered orally, intraperitoneally, and intravenously, and will determine the area under exposure (AUC), peak concentration (Cmax), and time to peak (T max ), half-life (T 1 / 2 ) and its bioavailability (F) and other parameters were calculated, providing hints for further structural modification and optimization of the compound, while at the same time providing a basis for designing the internal dosage.

[0239] 1.4 In vivo drug efficacy evaluation 1.4.1 Acute pharmacodynamic evaluation A single oral administration was performed to mice or rats, and the liver and heart were harvested at three time points after administration to detect the expression of downstream genes of the THRβ receptor (DIO1, ME, CYP7α1, LDLR) in the liver, the target organ, and the expression of downstream genes of the THRβ receptor (DIO1, MHCα) in the heart, an organ involved in toxicity and side effects. 1.4.2 Chronic pharmacodynamic evaluation A high-fat diet-induced NAFLD model and a high-fat, high-pectin diet-induced NASH model were constructed in obob mice, and the test substances and the positive compound MGL-3196 were administered for a long period of three weeks, after which the TC and TG contents in the liver were detected.

[0240] 1.5 Evaluation of internal safety After the thyroid glands were removed from normal SD rats, they were allowed to recover for 1-2 weeks and then divided into groups based on body weight. The test substances and the positive compound MGL-3196 were then administered to the rats. Six hours after administration, the rats were euthanized and cardiac tissue was removed to examine the expression of the αMHC gene in the heart following a single administration.

[0241] Experimental Results 2.1 In vitro testing of THRβ agonist activity and selectivity The compounds synthesized above were subjected to preliminary in vitro THRβ agonist activity tests at the molecular and cellular levels. The results showed that most of the compounds had good THRβ agonist activity and good selectivity for THRα, among which the EC values ​​of compounds 38 and 95 were 100.0 and 100.0, respectively. 50 The agonist activity (EC 50 = 129.5nM), which was 2.5-fold and 39-fold higher than those of the control. Currently, three types of agonists have been obtained through in vitro activity evaluation and structure-effect relationship studies: 1) THRβ is a full agonist, THRα is a partial agonist, and has selectivity; 2) THRβ is a partial agonist, THRα is non-agonist, and has high selectivity; 3) THRβ is a full agonist, THRα is a full agonist, and has low selectivity. The molecular experimental results are shown in Figure 1.

[0242] We then tested the agonistic activity of these compounds against THRβ and THRα at the cellular level. As shown in Figure 2, the cellular results of these compounds were consistent with the molecular results. In the cell experiment, compounds 2, 3, and 38 had EC 50were found to have obvious agonistic activity, with 1026nM, 911nM and 165.9nM, respectively, compared with 3415nM of MGL-3196. Compounds 2 and 3 have particularly prominent characteristics, barely agonizing the THRα receptor, and have selectivity of more than 1000 times, far better than 17 times that of MGL-3196, while also possessing the characteristics of a partial agonist. Meanwhile, compound 38 has selectivity of up to 40 times, significantly better than MGL-3196, and maintains full agonistic ability. Such compounds have a promising future.

[0243] Among them, compounds 3, 42 and 43 were partial agonists with agonistic activity against THRβ of less than 70% and at the same time good selectivity, suggesting that such compounds are THRβ partial agonists with good THRα selectivity. [Table 1]

[0244] [Table 2]

[0245] 2.2 Pharmacokinetic testing Based on the good in vitro TRβ agonist activity and selectivity of compound 38, compound 38 was selected for preliminary drug-likeness evaluation and the study of its pharmacokinetic properties in mice was carried out. As shown in Table 3, compound 38 has good pharmacokinetic properties, with a half-life of 4.44 hours, high internal exposure of 156427h·ng / mL, and bioavailability of 75.8%. [Table 3]

[0246] To further evaluate the initial drug-likeness of the compound, a mouse tissue distribution study was conducted. As shown in Table 4, the tissue distribution data of compound 38 showed the characteristics of high distribution in the liver and low distribution in the heart, and the drug concentration in the liver was 23-fold higher than that in the heart, indicating good liver targeting and suggesting that the compound has a weak effect on cardiotoxicity. [Table 4]

[0247] In addition, compound 3 showed good activity and complete TRβ selectivity in in vitro experiments, and a preliminary evaluation of compound 3's drug-likeness was performed and a series of pharmacokinetic studies were conducted in mice, the results of which are shown in Table 5. Compound 3 has good pharmacokinetic properties, with a half-life of 4.71 hours, an internal exposure of 79362 h·ng / mL, and a bioavailability of 36.3%. [Table 5]

[0248] Compound 3 was further evaluated for its initial drug-likeness by conducting a tissue distribution study in mice, the results of which are shown in Table 6. The compound was distributed in the liver much more than in the heart, about 10 times, and the distribution of compound 3 in the liver was low, which has a positive effect on the occurrence of cardiotoxicity. [Table 6]

[0249] 2.3 Research into drug efficacy in the body Compound 38, which has high activity and good selectivity, was selected to evaluate its acute pharmacological efficacy in vivo. Using C57 mice, the expression of downstream genes of THRβ receptor in the target organ liver tissue after a single dose was examined. The results showed that in the positive control group, T3 (endogenous highly active and non-selective thyroid hormone, 0.5mg / kg) was administered 8h after, CYP7α1 and LDLR gene expression in the liver was significantly upregulated, and 8 and 24h after, DIO1 gene expression in the liver was significantly upregulated. Compound 38 (10mg / kg) was administered 24h after, CYP7α1, ME2, LDLR gene expression in the liver was significantly upregulated, and 8 and 24h after, DIO1 gene expression in the liver was significantly upregulated, which was better than MGL3196 at the same dose (see Figure 2).

[0250] In the expression of downstream genes in the hearts of thyroidectomized rats, neither compound 38 nor MGL3196 had any clear effect on the DIO1 and MHCα genes in the heart (see Figure 3), explaining the high safety of compound 38 to the heart.

[0251] In the pharmacological evaluation of the compounds in NAFLD model mice induced by CDAHFD feed, the test substance and the positive compound MGL-3196 both reduced the TC content in plasma after long-term administration for 2 and 4 weeks, and the TC content in plasma was also reduced in both the 1 mg / kg and 10 mg / kg dose groups of compound 38 (see Figure 4).

[0252] In an evaluation of the acute pharmacology of golden hamster model mice induced by a high-fat diet of the compound, after 21 days of administration of the test substance, compound 38 significantly reduced serum TC / TG and LCL-C levels at a dose of 10 mg / kg (see FIG. 5).

[0253] A preliminary in vivo acute pharmacological evaluation was also carried out for the partial agonist compound 3, but the experimental method was the same as that for compound 38. The results showed that compound 3 significantly upregulated the expression of DIO1 gene in the liver 3 hours after administration (see Figure 6), and the pharmacological effect appeared quickly, and the effect began to weaken 8 hours after administration, but still had an effect compared to the negative control group, and it may have different application scenarios compared to MGL-3196.

[0254] In C57 mice, a preliminary evaluation of the safety of compound 3 after administration was performed and it was found that compound 3 did not lead to upregulation of MHCα in the heart, and the overall trend was consistent with MGL-3196, and therefore has a high safety profile (Figure 7).

[0255] In C57 mice, the presence or absence of an inhibitory effect of compound 3 on the thyroid gland was also examined. As a result, as shown in FIG. 8, compound 3 had no effect on thyroid hormone levels when administered at high doses, indicating that its safety may be better than that of MGL-3196.

[0256] All documents related to the present invention are incorporated herein by reference as if each document were incorporated individually. After reading the above content of the present invention, it will be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalent forms thereof are within the scope of the claims of the present invention.

Claims

1. A compound having a structure represented by formula (I), or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal, or prodrug thereof. 【Chemistry 1】 (however, 【Chemistry 2】 Rb, Rc and R ７ are each independently located at any substitutable ring atom of the quinoline ring. Rb and Rc are each independently selected from the group consisting of deuterium, tritium, halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a phenyl group, a C5-C7 heteroaryl group, and a C5-C6 substituted heteroaryl group, and Rb and Rc are different substituents. R ７ is one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl group, and C1-C6 haloalkyl, located on the benzene ring of the quinoline. X is -O-, -CH ２ -C(=O)-, -CH(OH)-, and -S-. R １ , R ２ , R ３ and R ４ each independently represents H, D, F, Cl, Br, I, -CN, -OH, or -NO ２ , -OR １ａ , -NR １ｂ R １ｃ , -SR １ｂ , a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group. R ５ are H, D, F, Cl, Br, I, -CN, -OH, -NO ２ , -OR １ａ , -NR １ｂ R １ｃ , -SR １ｂ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ａ R １ｂ , -S(O) ２ N.R. １ａ R １ｂ , -NHS(O) ２ R １ａ , -C(O)R １ａ , -OC(O)R １ａ , -C(O)OR １ｂ , -C(O)NR １ｂ R １ｃ , -NHC(O)R １ａ , a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group. R ６ is H, deuterium, tritium, halogen, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with an amino group, a C3-C8 cycloalkyl group, a 3- to 8-membered heterocyclic group, -SR １ｂ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ａ R １ｂ , -C(O)R １ａ , -C(O)OR １ｂ , -C(O)NR １ｂ R １ｃ is selected from the group consisting of: Unless otherwise specified, each of the above alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally include deuterium, tritium, halogen, -CN, -OH, oxo, -OR, -O, -O- ... １ａ , -NR １ｂ R １ｃ , -SR １ｂ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ａ R １ｂ , -S(O) ２ N.R. １ａ R １ｂ , -NHS(O) ２ R １ａ , -C(O)R １ａ , -OC(O)R １ａ , -C(O)OR １ｂ , -C(O)NR １ｂ R １ｃ , -NHC(O)R １ａ , a C1-C6 alkyl group, and a C1-C6 haloalkyl group. R １ａ , R １ｂ and R １ｃ are each independently selected from H, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group.

2. The Rb is selected from the group consisting of a C1-C6 haloalkyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a phenyl group, and a C5-C7 heteroaryl group, and the phenyl group or the heteroaryl group is optionally selected from the group consisting of deuterium, tritium, halogen, -CN, -OH, oxo, -OR １ａ , -NR １ｂ R １ｃ , -C(O)R １ａ , -C(O)OR １ｂ , -C(O)NR １ｂ R １ｃ , a C1-C6 alkyl group, and a C1-C6 haloalkyl group; The compound according to claim 1, or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal or prodrug thereof, wherein Rc is selected from the group consisting of halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C1-C6 deuterated alkyl group.

3. 2. The compound of claim 1, wherein the compound of formula I has the structure represented by formula Ia: 【Chemistry 3】

4. 2. The compound of claim 1, wherein the compound of formula I has a structure represented by formula Ib or Ic: 【Chemistry 4】

5. R １ , R ２ , R ３ , R ４ are each independently selected from H, D, a halogen, and a C1-C4 alkyl group, or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal, or prodrug thereof.

6. The above R ５ is H, D, halogen, -CN, NHR １ｂ wherein R １ｂ is selected from H, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C2-C6 alkynyl group, ６ is H or D, or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal, or prodrug thereof.

7. 10. The compound of claim 1, including its stereoisomers, deuterated compounds, solvates, metabolites, pharma- ceutically acceptable salts, co-crystals or prodrugs. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】

8. A compound having a structure represented by formula (II), or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal, or prodrug thereof. 【Chemistry 5】 (however, Rd and Re are each independently selected from the group consisting of H, halogen, a C1-C6 alkyl group, and a C1-C6 haloalkyl group, and at least one of Rd and Re is halogen. R ７ is one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of H, halogen, C1-C6 alkyl group, and C1-C6 haloalkyl, located on the benzene ring of the quinoline. X is -O-, -CH ２ -C(=O)-, -CH(OH)-, and -S-. R １ , R ２ , R ３ and R ４ each independently represents H, D, F, Cl, Br, I, -CN, -OH, or -NO ２ , -OR １ａ , -NR １ｂ R １ｃ , -SR １ｂ , a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group. R ５ are H, D, F, Cl, Br, I, -CN, -OH, -NO ２ , -OR １ａ , -NR １ｂ R １ｃ , -SR １ｂ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ａ R １ｂ , -S(O) ２ N.R. １ａ R １ｂ , -NHS(O) ２ R １ａ , -C(O)R １ａ , -OC(O)R １ａ , -C(O)OR １ｂ , -C(O)NR １ｂ R １ｃ , -NHC(O)R １ａ , a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group. R ６ is H, deuterium, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with an amino group, a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, -SR １ｂ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ａ R １ｂ , -C(O)R １ａ , -C(O)OR １ｂ , -C(O)NR １ｂ R １ｃ is selected from the group consisting of: Unless otherwise specified, each of the above alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally include deuterium, halogen, -CN, -OH, oxo, -OR, -O, -O- ... １ａ , -NR １ｂ R １ｃ , -SR １ｂ , -S(O)R １ａ , -S(O) ２ R １ａ , -S(O)NR １ａ R １ｂ , -S(O) ２ N.R. １ａ R １ｂ , -NHS(O) ２ R １ａ , -C(O)R １ａ , -OC(O)R １ａ , -C(O)OR １ｂ , -C(O)NR １ｂ R １ｃ , -NHC(O)R １ａ , a C1-C6 alkyl group, and a C1-C6 haloalkyl group. R １ａ , R １ｂ and R １ｃ are each independently selected from H, deuterium, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C5-C6 aryl group, or a 5-6 membered heteroaryl group.

9. R １ , R ２ , R ３ , R ４ are each independently selected from H, D, a halogen, and a C1-C4 alkyl group, including stereoisomers, deuterated compounds, solvates, metabolites, pharma- ceutically acceptable salts, co-crystals, or prodrugs thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 or 8, its stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal or prodrug, and a pharma- ceutically acceptable adjuvant and / or carrier.

11. 13. Use of a compound according to any of claims 1 or 8, or a stereoisomer, deuterated compound, solvate, metabolite, pharma- ceutically acceptable salt, co-crystal or prodrug thereof, in the manufacture of a medicament, wherein the medicament is for agonizing a thyroid hormone receptor or for preventing, treating or ameliorating a disease modulated by the thyroid hormone receptor.

12. 12. The use of claim 11, wherein the thyroid hormone receptor mediated disease is selected from the group consisting of non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type IA, hypothyroidism, or thyroid cancer.

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