WO2023125716A1 - 一类喹啉类化合物及其制备方法、药物组合物和用途 - Google Patents

一类喹啉类化合物及其制备方法、药物组合物和用途 Download PDF

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WO2023125716A1
WO2023125716A1 PCT/CN2022/142988 CN2022142988W WO2023125716A1 WO 2023125716 A1 WO2023125716 A1 WO 2023125716A1 CN 2022142988 W CN2022142988 W CN 2022142988W WO 2023125716 A1 WO2023125716 A1 WO 2023125716A1
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alkyl
phenyl
dichloro
oxy
compound
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French (fr)
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柳红
李佳
王江
臧奕
陈飞扬
高立信
赵晶
孙丹丹
王珂安
蒋华良
谢蓉蓉
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中国科学院上海药物研究所
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Definitions

  • the invention belongs to the field of medicine, and relates to a quinoline compound and its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug, and its pharmaceutical composition and preparation method , and use in the preparation of medicines for diseases mediated by thyroid hormone receptors.
  • Related diseases include but not limited to non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, Disorders of lipid metabolism, glycogen storage disease type 1A, hypothyroidism or diseases such as thyroid cancer.
  • Thyroid hormones are critical for normal growth and development and for maintaining metabolic balance.
  • T3 triiodothyronine
  • T4 tetraiodothyronine
  • T3 has a higher physiological activity.
  • T4 is released into the circulatory system through thyroid secretion, and is converted to T3 by tissue-specific deiodinases, which are present in all tissues, but mainly in the liver and kidney.
  • Thyroid hormone TH plays its physiological role mainly through thyroid hormone receptor TR.
  • TR is a member of the nuclear receptor superfamily, a transcription factor induced by ligand T3, and plays a central role in mediating the action of ligand T3. After TR is activated by T3, it plays an important role in the physiological functions and basic metabolism of the human body.
  • the ⁇ subtype is mainly distributed in the heart and is mainly used to regulate heart rate.
  • the ⁇ subtype is mainly distributed in the liver and is related to the metabolism of cholesterol in the liver and the secretion of thyroid stimulating hormone (TSH) by the pituitary gland.
  • TSH thyroid stimulating hormone
  • Thyroid hormones have been shown to reduce serum LDL levels. Thyroid hormones stimulate the metabolism of cholesterol to bile acids by increasing the expression of hepatic LDL receptors. In animal models, thyroid hormones have been shown to have beneficial effects by increasing the expression of HDL cholesterol and apo A-1 (one of the major apolipoproteins of HDL) and increasing the conversion rate of LDL to HDL.
  • apo A-1 one of the major apolipoproteins of HDL
  • Nonalcoholic fatty liver disease is also closely related to thyroid hormones.
  • NAFLD patients have an impact on the transformation and inactivation of thyroid hormones, which may lead to a decrease in serum thyroid hormone levels; on the other hand, the decrease in thyroid hormone levels further causes lipid metabolism disorders, glucose metabolism disorders, and aggravates the course of NAFLD.
  • Studies have shown that fatty liver formation was induced in rats with a choline-methionine deficient diet, and reversal of fatty liver was observed with T3 administration.
  • thyroid hormone analogs that can avoid hyperthyroidism and avoid the side effects of hyperthyroidism, and can broaden the spectrum of hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic fatty liver disease, atherosclerosis Treatment pathways for sclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, and other related conditions.
  • the present invention provides a class of compounds with good agonistic activity on thyroid hormone ⁇ receptors.
  • Such compounds and their compositions can be prepared for the prevention and treatment of non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, etc.
  • Heart disease hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid Cancer Drugs.
  • the present invention also relates to a pharmaceutical composition, which is characterized in that it contains the compound of formula (I) described in any one of the preceding aspects of the present invention, its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, and pharmaceutically acceptable excipients and/or carriers.
  • the present invention also relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of medicaments, wherein the medicament is used to stimulate thyroid hormone receptors; or to prevent, treat or alleviate thyroid hormone receptors Body-regulated diseases.
  • the diseases mediated by thyroid hormone receptors are non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity , diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.
  • the present invention relates to a method of using the compound or pharmaceutical composition of the present invention to stimulate thyroid hormone receptors, or a method for preventing, treating or alleviating diseases regulated by thyroid hormone receptors, the method is to administer and A therapeutically effective amount of said compound or said pharmaceutical composition for an individual in need thereof.
  • the above-mentioned compounds or pharmaceutical compositions thereof provided by the present invention can be used together with other therapies or therapeutic agents. The usage can be performed simultaneously, sequentially or at certain time intervals.
  • the first aspect of the present invention provides a compound having the structure represented by formula (I), or its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or pro- medicine:
  • Rb, Rc and R are each independently located on any substitutable ring atom of the quinoline ring;
  • Rb and Rc are each independently selected from the group consisting of deuterium, tritium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3 -8-membered heterocyclic group, phenyl, C5-C7 heteroaryl, C5-C6 substituted heteroaryl; and Rb and Rc are different substituents;
  • R is one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, D, F, Cl, Br, I, -CN, -OH, -NO 2 , -OR 1a , -NR 1b R 1c , -SR 1b , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aromatic Base, or 5-6 membered heteroaryl;
  • R 5 is selected from the group consisting of 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 NR 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 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl , C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C5-C6 aryl or
  • R 6 is selected from the group consisting of H, deuterium, tritium, halogen, C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -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 ;
  • each of the above-mentioned alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally have 1-3 substituents selected from the following group : deuterium, tritium, halogen, -CN, -OH, oxo, -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 NR 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 , C1-C6 alkyl, C1-
  • R 1a , R 1b and R 1c are each independently selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl , C5-C6 aryl or 5-6 membered heteroaryl.
  • the Rb is selected from the group consisting of C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, C5-C7 heteroaryl; and the The phenyl or heteroaryl of may optionally have 1-3 substituents 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 , C1-C6 alkyl, C1-C6 haloalkyl;
  • the Rc is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl.
  • the Rb is selected from the following group: phenyl, C5-C7 heteroaryl.
  • the Rb is selected from the group consisting of phenyl, pyridyl
  • the Rc is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl.
  • the compound of formula I has the structure shown in the following formula Ia:
  • the compound of formula I has the structure shown in the following formula Ib or Ic:
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, halogen, and C1-C4 alkyl.
  • R 3 and R 4 are each independently selected from H and deuterium; and R 1 and R 2 are each independently selected from H, D, halogen, and C1-C4 alkyl.
  • R 3 and R 4 are independently selected from H, and R 1 and R 2 are independently selected from halogen.
  • R6 is selected from H, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, and C1-C6 alkyl substituted by hydroxyl.
  • R 6 is selected from H, deuterium, C1-C6 alkyl, and C1-C6 deuterated alkyl.
  • R 6 is selected from H, deuterium, and C1-C6 alkyl.
  • R 6 is selected from H and deuterium.
  • R 1a , R 1b , and R 1c are each independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, and the alkane
  • the radical, cycloalkyl, heterocycloalkyl is optionally substituted by one or more deuterium, halogen.
  • R 1a , R 1b , and R 1c are each independently selected from H, C1-C6 alkyl, and said alkyl is optionally substituted by one or more deuterium or halogen; preferably by One or more deuterium substitutions.
  • the R 5 is selected from the following group: H, D, halogen, -CN, NHR 1b ; wherein, the R 1b is selected from H, deuterium, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl; the R 6 is H or D.
  • R 5 is selected from H, D, halogen, -CN.
  • R 5 is selected from D and halogen.
  • R 5 is selected from -CN.
  • each R 7 is H independently.
  • the second aspect of the present invention provides a compound having the structure shown in formula (II), or its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or precursor medicine:
  • Rd and Re are each independently selected from the following group: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl; and at least one of Rd and Re is halogen;
  • R 7 is one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 haloalkane located on the quinoline benzene ring base;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, D, F, Cl, Br, I, -CN, -OH, -NO 2 , -OR 1a , -NR 1b R 1c , -SR 1b , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C6 aromatic Base, or 5-6 membered heteroaryl;
  • R 5 is selected from the group consisting of 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 NR 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 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl , C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C5-C6 aryl or
  • R 6 is selected from the group consisting of H, deuterium, C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -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 ;
  • each of the above-mentioned alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally have 1-3 substituents selected from the following group : Deuterium, halogen, -CN, -OH, oxo, -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 NR 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 , C1-C6 alkyl, C1-C6
  • R 1a , R 1b and R 1c are each independently selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl , C5-C6 aryl or 5-6 membered heteroaryl.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, D, halogen, and C1-C4 alkyl.
  • R 3 and R 4 are each independently selected from H and deuterium; and R 1 and R 2 are each independently selected from H, D, halogen, and C1-C4 alkyl.
  • R 3 and R 4 are independently selected from H, and R 1 and R 2 are independently selected from halogen.
  • R 6 is selected from H, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, and C1-C6 alkyl substituted by hydroxyl.
  • R 6 is selected from H, deuterium, C1-C6 alkyl, and C1-C6 deuterated alkyl.
  • R 6 is selected from H, deuterium, and C1-C6 alkyl.
  • R 6 is selected from H and deuterium.
  • R 1a , R 1b , and R 1c are each independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, and the alkane
  • the radical, cycloalkyl, heterocycloalkyl is optionally substituted by one or more deuterium, halogen.
  • R 1a , R 1b , and R 1c are each independently selected from H, C1-C6 alkyl, and said alkyl is optionally substituted by one or more deuterium or halogen; preferably by One or more deuterium substitutions.
  • the R 5 is selected from the following group: H, D, halogen, -CN, NHR 1b ; wherein, the R 1b is selected from H, deuterium, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl; the R 6 is H or D.
  • R 5 is selected from H, D, halogen, -CN.
  • R 5 is selected from D and halogen.
  • R 5 is selected from -CN.
  • each R 7 is H independently.
  • the third aspect of the present invention provides a pharmaceutical composition, which includes the compound as described in the first or second aspect of the present invention, its stereoisomers, deuterated compounds, solvates, Metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, and pharmaceutically acceptable excipients and/or carriers.
  • the fourth aspect of the present invention provides a compound as described in the first or second aspect of the present invention, or its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, co-
  • a crystal or a prodrug in the preparation of a medicament; wherein the medicament is used to stimulate thyroid hormone receptors, or to prevent, treat or alleviate diseases regulated by thyroid hormone receptors.
  • 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 mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer.
  • the present invention relates to a method of using the compound or pharmaceutical composition of the present invention to stimulate thyroid hormone receptors, or a method for preventing, treating or alleviating diseases regulated by thyroid hormone receptors, the method is to administer and A therapeutically effective amount of said compound or said pharmaceutical composition for an individual in need thereof.
  • the above-mentioned compounds or pharmaceutical compositions thereof provided by the present invention can be used together with other therapies or therapeutic agents. The usage can be performed simultaneously, sequentially or at certain time intervals.
  • Figure 1 is the THR ⁇ activation curve of the compound in vitro evaluation system
  • FIG. 1 shows the expression results of THR ⁇ downstream genes in liver tissue
  • FIG. 3 is the result of THR ⁇ downstream gene expression in heart tissue
  • Figure 4 is the result of chronic administration of TC in mice
  • Figure 5 is the result of acute administration of serum TC/TGL/DL-C in golden hamsters
  • Figure 6 is the result of DIO1 gene expression in mouse liver after compound 3 administration
  • Figure 7 is the expression result of mouse heart MHC ⁇ after compound 3 administration
  • Figure 8 is the effect of Compound 3 on the level of thyroid hormone after administration.
  • a quinoline compound represented by formula I can be used to prepare medicines for diseases mediated by thyroid hormone receptors, and related diseases include but not limited to non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia Lipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer and other diseases.
  • diseases mediated by thyroid hormone receptors include but not limited to non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia Lipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer and other diseases.
  • Halogen refers herein to F, Cl, Br, I, or isotopes thereof.
  • Halo or “halogen substitution” refers to being substituted by more than one selected from F, Cl, Br, I, or their isotopes.
  • the upper limit of the number of halogen substituents is equal to the sum of the hydrogen numbers that can be substituted by the substituted groups, Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, the same or different halogens can be used for substitution.
  • Alkyl means a monovalent straight chain or branched saturated aliphatic hydrocarbon group, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl , tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; said alkyl group can be further substituted by any substituent.
  • “Deuterated” refers to the situation that the hydrogen atoms on the alkyl group, cycloalkyl group, alkylene group, aryl group, heteroaryl group, alkenyl group, alkynyl group, etc. are replaced by at least one isotope neon, and the upper limit of the number of neon groups is It is equal to the sum of the number of hydrogens that can be replaced by the substituted group.
  • the number of neon generations is any integer between 1 and the upper limit, preferably 1-20 neon atoms, more preferably 1-10 neon atoms, more preferably 1-6 neon atoms, further preferably 1-3 neon atoms.
  • Alkynyl refers to a straight-chain or branched monovalent unsaturated hydrocarbon group containing more than one carbon-carbon triple bond. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms, Non-limiting examples are ethynyl, propynyl, propargyl, and the like.
  • alkenyl refers to a straight-chain or branched monovalent unsaturated hydrocarbon group containing more than one carbon-carbon double bond. Unless otherwise specified, an alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms, Non-limiting examples are vinyl, propenyl, allyl, 2-butenyl, 1-butenyl, and the like.
  • Alkoxy or "alkyloxy” means -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl Oxygen and cyclobutoxy, etc.
  • Haloalkoxy means an alkoxy group substituted with one or more halogens. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.
  • Alkylamino or “alkylamino” means an amino group substituted by a single or double alkyl group, also written as an N-(alkyl)z or an NH-alkyl, the latter also written as a monoalkylamino group.
  • Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, and the like.
  • Alkyl optionally substituted by F means that it may but not necessarily be substituted by F, and the description includes the case of being substituted by F and the case of not being substituted by F.
  • “Pharmaceutically acceptable salt” means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is mixed with a non-toxic inorganic base or organic base, and the free base is mixed with a non-toxic inorganic base or organic base.
  • Non-toxic salts obtained by reacting inorganic or organic acids.
  • “Pharmaceutical composition” means a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals thereof, with other constituents, wherein the other constituents comprise physiological/pharmaceutical acceptable carriers and/or excipients.
  • Carrier refers to: it will not cause significant irritation to the organism and will not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the human body and its distribution in the body, controls the release rate of the drug and releases the drug.
  • Non-limiting examples of systems for delivery to targeted organs include microcapsules and microspheres, nanoparticles, liposomes, and the like.
  • Excipient means: not itself a therapeutic agent, used as a diluent, adjuvant, binder and/or vehicle, for addition to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate The compound or pharmaceutical composition is presented in unit dosage form for administration.
  • pharmaceutical excipients can serve various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrating agents, absorbing agents, preservatives , surfactants, coloring agents, flavoring agents and sweeteners.
  • Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (such as croscarmellose sodium) (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, red Flower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as oil (13) a
  • Stepoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Solvate means a compound of the present invention or a salt thereof formed with a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces.
  • the solvent is water, it is a hydrate.
  • Co-crystal refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF are at room temperature All are solid, and there is a fixed stoichiometric ratio between the components.
  • API active pharmaceutical ingredient
  • CCF co-crystal former
  • the compounds involved in the present invention can be prepared using the route shown above, using the corresponding 6-methoxyquinoline compound to obtain or directly purchase the commercially available 6-hydroxyquinoline compound as the starting material, and potassium carbonate or carbonic acid Cesium was stirred in DMF with the corresponding p-fluorine-substituted nitrobenzene compound for several hours to obtain the starting material of step 2: subsequent nitro reduction under suitable conditions to obtain the corresponding amino compound: the resulting amino compound was dissolved in hydrochloric acid and sodium nitrite Diazotization under certain conditions and coupling with N cyanoacetylurethane: Finally, the compound was refluxed in acetic acid and sodium acetate at high temperature to finally obtain various examples.
  • compositions which contains a therapeutically effective amount of a compound selected from the above general formula I, its pharmaceutically acceptable salts, enantiomers, diastereoisomers or exosomes
  • a pharmaceutically acceptable carrier optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
  • the excipients are, for example, flavoring agents, flavoring agents, sweetening agents, and the like.
  • the pharmaceutical composition provided by the present invention preferably contains active ingredients in a weight ratio of 1-99%, and its preferred ratio is that the compound of general formula I accounts for 65wt%-99wt% of the total weight as the active ingredient, and the rest is pharmaceutically acceptable carrier, diluent or solution or saline solution.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents Neutralize in suitable sterile equipment for injection or infusion.
  • the unit dose of the preparation formula contains 1 mg-700 mg of the compound of general formula I, preferably, the unit dose of the preparation formula contains 25 mg-300 mg of the compound of general formula I.
  • the compounds and pharmaceutical compositions of the present invention can be clinically used in mammals, including humans and animals, and can be administered through oral, nasal, dermal, pulmonary or gastrointestinal routes. Oral administration is most preferred.
  • the most preferred daily dose is 50-1400 mg/kg body weight, taken once, or 25-700 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual should depend on the specific treatment. Usually, start with a small dose and gradually increase the dose until you find the most suitable dose.
  • Step 2 prepares 6-hydroxyl-4-methyl-2-(4-fluoropyridine) quinoline
  • 6-Hydroxy-4-methyl-2-(4-fluoropyridine) quinoline and 3,5-dichloro-p-fluoronitrobenzene (1.48g, 0.0070mol) were dissolved in 20mlDMF, and 5g of potassium carbonate was added with After stirring at room temperature for 6 hours, add 200ml of water to quench the reaction, extract three times with ethyl acetate, combine the organic phases and wash with saturated sodium chloride solution three times, dry the organic phases with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and use the column layer
  • the light yellow compound 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-2-(4-fluoropyridine)quinoline was obtained by analysis and purification
  • Example 12 2-(3,5-dichloro-4-((2-(2-cyano-4-fluorophenyl)-4-methylquinolin-6-yl)oxy)phenyl) -3,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 17 2-(3,5-Dichloro-4-((4-methyl-2-(5-cyclopropylfuran-2-yl)quinolin-6-yl)oxy)phenyl) -3,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 28 2-(3,5-Dichloro-4-((4-methyl-2-(5-bromopyridin-2-yl)quinolin-6-yl)oxy)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 32 2-(3,5-Dichloro-4-((2-(6-chloropyridin-3-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 38 2-(3,5-Dichloro-4-((2-(2-fluoropyridin-4-yl)-4-methylquinolin-6-yl)oxy)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-2-(trifluoromethyl)quinoline (1.5g, 0.0031mol) was added to 15ml of ethyl acetate and In 15ml of ethanol, add excess stannous chloride and catalytic amount of hydrochloric acid, and stir overnight at room temperature to complete the reaction.
  • 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
  • Example 48 2-(3,5-Dichloro-4-((4-methyl-2-(pyrrolidin-1-yl)quinolin-6-yl)oxy)phenyl)-3,5- Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 54 2-(3,5-Difluoro-4-((4-methyl-2-phenylquinolin-6-yl)oxy)phenyl)-3,5-dioxy-2, 3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 56 2-(3-Bromo-5-chloro-4-((3-chloro-4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxy)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 58 6-amino-2-(3,5-dichloro-4-((4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)benzene base)-1,2,4-triazine-3,5(2H,4H)-dione
  • Step 1 prepares 2-(3,5-dichloro-4-((4-methyl-2-(2-fluoropyridin-4-yl)quinolin-6-yl)oxy)phenyl)-3, 5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid
  • Example 1 was obtained by using the method described in Example 1. Using Example 1 as a raw material, it was added to a mixed solution of acetic acid and concentrated hydrochloric acid and heated at 120°C for one hour. After cooling, water was added to filter the precipitated solid, and vacuum drying was obtained.
  • 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
  • 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
  • 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
  • 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
  • Example 80 6-Amino-2-(3,5-dichloro-4-((2-(5-trifluoromethylthiophen-2-yl)-4-methylquinolin-6-yl)oxy yl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione
  • Example 84 6-amino-2-(3,5-dichloro-4-((2-(5-chloropyridin-2-yl)-4-methylquinolin-6-yl)oxy)benzene base)-1,2,4-triazine-3,5(2H,4H)-dione
  • Example 90 6-Amino-2-(3,5-dichloro-4-((4-methyl-2-(6-bromopyridin-3-yl)quinolin-6-yl)oxy)benzene base)-1,2,4-triazine-3,5(2H,4H)-dione
  • Example 102 6-Amino-2-(3,5-dichloro-4-((2-methyl-4-phenylquinolin-6-yl)oxy)phenyl-1,2,4-tris Oxazine-3,5(2H,4H)-dione
  • 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
  • Example 105 6-Amino-2-(3,5-dichloro-4-((4-methyl-2-(pyrrolidin-1-yl)quinoline-6-oxyl)phenyl)-1 ,2,4-Triazine-3,5(2H,4H)-dione
  • Example 106 6-amino-2-(3,5-dichloro-4-((2-methyl-4-(pyrrolidin-1-yl)quinoline-6-oxyl)phenyl)-1 ,2,4-Triazine-3,5(2H,4H)-dione
  • Example 109 6-Amino-2-(3,5-dichloro-4-((2-chloro-3-methylquinolin-6-yl)oxy)phenyl)-1,2,4-tris Oxazine-3,5(2H,4H)-dione
  • Example 110 6-amino-2-(3,5-dichloro-4-((3-methyl-2-phenylquinolin-6-yl)oxy)phenyl-1,2,4-tris Oxazine-3,5(2H,4H)-dione
  • Example 111 6-Amino-2-(3,5-difluoro-4-((4-methyl-2-phenylquinolin-6-yl)oxyphenyl)-1,2,4-tri Oxazine-3,5(2H,4H)-dione
  • Example 114 6-Amino-2-(3-bromo-5-chloro-4-((3-chloro-4-methyl-2-(trifluoromethyl)quinolin-6-yl)oxyphenyl )-1,2,4-triazine-3,5(2H,4H)-dione
  • 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
  • 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
  • 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
  • Example 121 2-(3,5-Dichloro-4-((2-(4,4-dimethylcyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)- 3,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 122 2-(3,5-Dichloro-4-((2-(4,4-difluorocyclohexyl)-4-methylquinolin-6-yl)oxy)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 123 2-(3,5-Dichloro-4-((4-methyl-2-(4-(trifluoromethyl)cyclohexyl)quinolin-6-yl)oxy)phenyl) -3,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 124 2-(4-((2-(bicyclo[2.2.1]heptan-2-yl)-4-methylquinolin-6-yl)oxy)-3,5-dichlorobenzene base)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 125 2-(3,5-Dichloro-4-((4-methyl-2-(3-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5 -Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 126 2-(3,5-Dichloro-4-((4-methyl-2-(2-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5 -Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 127 2-(3,5-Dichloro-4-((4-methyl-2-(4-methylcyclohexyl)quinolin-6-yl)oxy)phenyl)-3,5 -Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Example 128 2-(3,5-Dichloro-4-(4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)quinolin-6-yl)oxy)benzene base)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • 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
  • Example 136 6-Amino-2-(3,5-dichloro-4-((2-(4,4-difluorocyclohexyl)-4-methylquinolin-6-yl)oxy)benzene base)-1,2,4-triazine-3,5(2H,4H)-dione
  • 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
  • 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
  • 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
  • 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
  • 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
  • THR ⁇ thyroid hormone receptor ⁇
  • the recombinant GST-THR ⁇ fusion protein was constructed, and then the compound was combined with the receptor in a 384-well plate.
  • a single oral administration was performed in mice or rats, and the liver and heart were taken at 3 time points after the administration to detect the expression of target organs-liver THR ⁇ receptor downstream genes (DIO1, ME, CYP7 ⁇ 1, LDLR), and to detect toxic and side effects involving Organ-expression of cardiac THR ⁇ receptor downstream genes (DIO1, MHC ⁇ ).
  • DIO1, ME, CYP7 ⁇ 1, LDLR target organs-liver THR ⁇ receptor downstream genes
  • DIO1, MHC ⁇ Organ-expression of cardiac THR ⁇ receptor downstream genes
  • Obob mice were induced by high-fat diet to establish NAFLD model and NASH model induced by high-fat and high-fructose diet. After 3 weeks of long-term administration of the test substance and the positive compound MGL-3196, the contents of TC and TG in the liver were detected.
  • THR ⁇ agonistic activity tests were carried out on the compounds synthesized above at the molecular and cellular levels. As a result, it was found that many compounds had good THR ⁇ agonistic activity and good selectivity to THR ⁇ , among which the EC 50 values of compounds 38 and 95 were 13.2nM and 2.5nM respectively (as shown in Table 1), which were higher than those of Phase III clinical drugs.
  • compounds 3, 42 and 43 are partial agonists, with less than 70% agonistic activity on THR ⁇ and good selectivity, suggesting that these compounds are partial THR ⁇ agonists and have good THR ⁇ selectivity.
  • T3 Endogenous highly active non-selective thyroid hormone; 0.5mg/kg
  • T3 Endogenous highly active non-selective thyroid hormone
  • 38( 10 mg/kg) can significantly up-regulate the gene expression of CYP7 ⁇ 1, ME2, and LDLR in the liver after 24 hours of administration
  • it can significantly up-regulate the expression of DIO1 gene in the liver after 8 and 24 hours of administration, which is better than the same dose of MGL3196 (see Figure 2).

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Abstract

本发明提供了一类喹啉类化合物及其制备方法、药物组合物和用途，具体地，本发明提供了一种如式(I)所示的化合物，及其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药以及其药物组合物。本发明还提供了上述化合物的制备方法，以及在制备由甲状腺激素受体介导的疾病的药物中的用途。相关疾病包括但不限于非酒精性脂肪性肝病，动脉粥样硬化，冠心病，高血压，高胆固醇血症，高脂血症，高甘油三酯症，血脂异常，肥胖，糖尿病，代谢紊乱，脂质代谢紊乱，1A型糖原贮积病，甲状腺功能减退症或甲状腺癌等疾病。

Description

一类喹啉类化合物及其制备方法、药物组合物和用途 技术领域
本发明属于药物领域，涉及一种喹啉类化合物及其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药以及其药物组合物、制备方法，以及在制备由甲状腺激素受体介导的疾病的药物中的用途。相关疾病包括但不限于非酒精性脂肪性肝病，动脉粥样硬化，冠心病，高血压，高胆固醇血症，高脂血症，高甘油三酯症，血脂异常，肥胖，糖尿病，代谢紊乱，脂质代谢紊乱，1A型糖原贮积病，甲状腺功能减退症或甲状腺癌等疾病。
背景技术
甲状腺激素队友正常生长和发育以及维持代谢平衡是关键的。人体内循环系统中的甲状腺激素有两种主要的存在形式：三碘甲状腺原氨酸(T3)和四碘甲状腺原氨酸(T4)。尽管T4是甲状腺分泌的主要形式，但是T3具有更高的生理活性。在人体内，T4经由甲状腺分泌释放进入循环系统中后，通过组织特异性脱碘酶转化为T3，组织特异性脱碘酶存在于所有组织中，但是主要存在于肝和肾中。
甲状腺激素TH发挥其生理作用主要通过甲状腺激素受体TR进行。TR属于核受体超家族的一员，是配体T3诱导的转录因子，在介导配体T3的作用过程中处于核心地位。TR被T3激活后，对人体的生理功能和基础代谢产生重要作用。其中TR受体存在两种亚型，在人体内存在组织和功能差异，α亚型主要分布在心脏，主要用于调节心率。β亚型主要分布在肝脏，和肝脏胆固醇代谢以及垂体分泌促甲状腺激素(TSH)有关。
已经观察到在甲状腺功能亢进患者中，存在心动过速、心律不齐、心脏衰竭以及疲劳感、呼吸急促和骨骼肌减少、骨质疏松等现象，相对的还观察到对于代谢性疾病如血液中胆固醇含量降低和基础代谢率上升的有益现象。反之，在通过垂体障碍和先天性功能障碍引起的甲状腺功能减退中观察到心率下降、血液中胆固醇增加和体重增加。这也是天然的甲状腺激素存在心脏毒性使其治疗用途受限的原因。
甲状腺激素已经被证实可以降低血清低密度脂蛋白水平。甲状腺激素通过增加肝LDL受体的表达刺激胆固醇向胆汁酸代谢。在动物模型中，甲状腺激素已经显示出具有增加HDL胆固醇和apo A-1(HDL的主要脱辅基脂蛋白之一)的表达提高LDL向HDL的转化率的有益效果。
非酒精性脂肪性肝病与甲状腺激素也有密切关系。一方面，NAFLD患者对甲状腺激素的转化灭活等功能有影响，可能导致血清甲状腺激素水平下降；另一方面甲状腺激素水平的下降进一步造成脂质代谢紊乱，糖代谢紊乱，加重NAFLD的病程。研究表明，使用胆碱-蛋氨酸缺乏饮食诱导大鼠脂肪肝形成，再使用T3给药可以观察到脂肪肝的逆转。
然而内源性甲状腺激素是非选择性的，存在副作用，常见的会造成甲状腺功能亢进，特别是心血管毒性有关的副作用。因此开发能够避免甲状腺功能亢进，避免甲状腺功能亢进的副作用甲状腺激素类似物具有重要意义，能够拓宽高脂血症，高胆固醇血症，糖尿病，肝脂肪变性，非酒精性脂肪性肝病，动脉粥样硬化，心血管疾病，甲状腺功能减退，甲状腺癌，甲状腺疾病以及其他相关病症的治疗途径。
发明内容
本发明提供了一类对甲状腺激素β受体具有较好的激动活性的化合物，此类化合物及其组合物可以制备用于预防治疗或者减轻患者非酒精性脂肪性肝病，动脉粥样硬化，冠心病，高血压，高胆固醇血症，高脂血症，高甘油三酯症，血脂异常，肥胖，糖尿病，代谢紊乱，脂质代谢紊乱，1A型糖原贮积病，甲状腺功能减退症或甲状腺癌的药物。
本发明还涉及一种药物组合物，其特征在于，含有本发明前面任意一项所述的式(Ⅰ)化合物，其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，以及药学上可接受的辅料和\或载体。
本发明还涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用于激动甲状腺激素受体；或用于预防、治疗或减轻甲状腺激素受体调节的疾病。所述的甲状腺激素受体介导的疾病为非酒精性脂肪性肝病，动脉粥样硬化，冠心病，高血压，高胆固醇血症，高脂血症，高甘油三酯症，血脂异常，肥胖，糖尿病，代谢紊乱，脂质代谢紊乱,1A型糖原贮积病，甲状腺功能减退症或甲状腺癌。
本发明涉及一种使用本发明所述的化合物或药物组合物在激动甲状腺激素受体的方法，或用于预防、治疗或减轻由甲状腺激素受体调节的疾病的方法，所述方法是给予又需要的个体所述化合物或所述药物组合物的有效治疗量。并且，本发明提供的上述化合物或其药物组合物可以与其他疗法或治疗剂共同使用。使用方式可以为同时、顺序或以一定时间间隔进行。
本发明的第一方面，提供了一种具有式(Ⅰ)所示结构的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药：
Figure PCTCN2022142988-appb-000001
其中，
Figure PCTCN2022142988-appb-000002
Rb、Rc和R 7各自独立地位于喹啉环的任意可取代环原子上；
Rb和Rc各自独立地选自下组：氘，氚，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C1-C6烷氧基，C3-C8环烷基，3-8元杂环基，苯基，C5-C7杂芳基，C5-C6取代杂芳基；且Rb与Rc为不同取代基；
R 7为位于喹啉苯环上的一个或多个(如1个、2个、3个或4个)选自下组的取代基：H、氘、氚、卤素，C1-C6烷基，C1-C6卤代烷基；
X选自下组：-O-、-CH 2-、-C(＝O)-、-CH(OH)-、-S-；
R 1、R 2、R 3和R 4各自独立地选自下组：H、D、F、Cl、Br、I、-CN、-OH、-NO 2、-OR 1a、-NR 1bR 1c、-SR 1b、C1-C6烷基，C1-C6烷氧基、C2-C6烯基、C2-C6炔 基、C3-C8环烷基、3-8元杂环烷基、C5-C6芳基，或5-6元杂芳基；
R 5选自下组：H、D、F、Cl、Br、I、-CN、-OH、-NO 2、-OR 1a、-NR 1bR 1c、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-S(O) 2NR 1aR 1b、-NHS(O) 2R 1a、-C(O)R 1a、-OC(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、-NHC(O)R 1a、C1-C6烷基，C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环基、C5-C6芳基或5-6元杂芳基；
R 6选自下组：H、氘、氚、卤素、C1-C6烷基、氨基取代的C1-C6烷基、C3-C8环烷基、3-8元杂环基、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-C(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c；
除非特别说明，上述的各个烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基可任选地具有1-3个选自下组的取代基：氘、氚、卤素、-CN、-OH、氧代、-OR 1a、-NR 1bR 1c、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-S(O) 2NR 1aR 1b、-NHS(O) 2R 1a、-C(O)R 1a、-OC(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、-NHC(O)R 1a、C1-C6烷基、C1-C6卤代烷基；
R 1a、R 1b和R 1c各自独立地选自H、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C5-C6芳基或5-6元杂芳基。
在另一优选例中，所述的Rb选自下组：C1-C6卤代烷基，C3-C8环烷基，3-8元杂环基，苯基，C5-C7杂芳基；且所述的苯基或杂芳基可任选地具有1-3个选自下组的取代基：氘、氚、卤素、-CN、-OH、氧代、-OR 1a、-NR 1bR 1c、-C(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、C1-C6烷基、C1-C6卤代烷基；
所述的Rc选自下组：卤素，C1-C6烷基，C1-C6烷氧基，C1-C6卤代烷基，C1-C6氘代烷基。
在另一优选例中，所述的Rb选自下组：苯基，C5-C7杂芳基。
在另一优选例中，所述的Rb选自下组：苯基，吡啶基
所述的Rc选自下组：卤素，C1-C6烷基，C1-C6烷氧基，C1-C6卤代烷基，C1-C6氘代烷基。
在另一优选例中，所述的式I化合物具有如下式Ia所示的结构：
Figure PCTCN2022142988-appb-000003
在另一优选例中，所述的式I化合物具有如下式Ib或Ic所示的结构：
Figure PCTCN2022142988-appb-000004
在另一优选例中，R 1、R 2、R 3、R 4各自独立地选自H、D、卤素、C1-C4烷基。
在另一优选例中，R 3、R 4各自独立地选自H、氘；且R 1、R 2各自独立选自H、D、卤素、C1-C4烷基。
在另一优选例中，R 3、R 4各自独立地选自H，R 1、R 2各自独立地选自卤素。
在另一优选例中，R6选自H、氘、C1-C6烷基、C1-C6卤代烷基、C1-C6氘代烷基、羟基取代的C1-C6烷基。
在另一优选例中，R 6选自H、氘、C1-C6烷基、C1-C6氘代烷基。
在另一优选例中，R 6选自H、氘、C1-C6烷基。
在另一优选例中，R 6选自H、氘。
在另一优选例中，R 1a、R 1b、R 1c各自独立地选自H、氘、C1-C6烷基、C3-C8环烷基、3-8元杂环烷基，所述的烷基、环烷基、杂环烷基任选地被一个或多个氘、卤素取代。
在另一优选例中，R 1a、R 1b、R 1c各自独立地选自H、C1-C6烷基，所述的烷基任选地被一个或多个氘或卤素取代；较佳地被一个或多个氘取代。
在另一优选例中，所述的R 5选自下组：H、D、卤素、-CN、NHR 1b；其中，所述的R 1b选自H、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基；所述的R 6为H或D。
在另一优选例中，R 5选自H、D、卤素、-CN。
在另一优选例中，R 5选自D、卤素。
在另一优选例中，R 5选自-CN。
在另一优选例中，各个R 7各自独立地为H。
本发明的第二方面，提供了一种具有式(ⅠI)所示结构的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药：
Figure PCTCN2022142988-appb-000005
其中，
Rd和Re各自独立地选自下组：H、卤素，C1-C6烷基，C1-C6卤代烷基；且Rd和Re中至少一个为卤素；
R 7为位于喹啉苯环上的一个或多个(如1个、2个、3个或4个)选自下组的取代基：H、卤素，C1-C6烷基，C1-C6卤代烷基；
X选自下组：-O-、-CH 2-、-C(＝O)-、-CH(OH)-、-S-；
R 1、R 2、R 3和R 4各自独立地选自下组：H、D、F、Cl、Br、I、-CN、-OH、-NO 2、-OR 1a、-NR 1bR 1c、-SR 1b、C1-C6烷基，C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C5-C6芳基，或5-6元杂芳基；
R 5选自下组：H、D、F、Cl、Br、I、-CN、-OH、-NO 2、-OR 1a、-NR 1bR 1c、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-S(O) 2NR 1aR 1b、-NHS(O) 2R 1a、-C(O)R 1a、-OC(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、-NHC(O)R 1a、C1-C6烷基，C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环基、C5-C6芳基或5-6元杂芳基；
R 6选自下组：H、氘、C1-C6烷基、氨基取代的C1-C6烷基、C3-C8环烷基、3-8元杂环基、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-C(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c；
除非特别说明，上述的各个烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基可任选地具有1-3个选自下组的取代基：氘、卤素、-CN、-OH、氧代、- OR 1a、-NR 1bR 1c、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-S(O) 2NR 1aR 1b、-NHS(O) 2R 1a、-C(O)R 1a、-OC(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、-NHC(O)R 1a、C1-C6烷基、C1-C6卤代烷基；
R 1a、R 1b和R 1c各自独立地选自H、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C5-C6芳基或5-6元杂芳基。
在另一优选例中，R 1、R 2、R 3、R 4各自独立地选自H、D、卤素、C1-C4烷基。
在另一优选例中，R 3、R 4各自独立地选自H、氘；且R 1、R 2各自独立选自H、D、卤素、C1-C4烷基。
在另一优选例中，R 3、R 4各自独立地选自H，R 1、R 2各自独立地选自卤素。
在另一优选例中，R 6选自H、氘、C1-C6烷基、C1-C6卤代烷基、C1-C6氘代烷基、羟基取代的C1-C6烷基。
在另一优选例中，R 6选自H、氘、C1-C6烷基、C1-C6氘代烷基。
在另一优选例中，R 6选自H、氘、C1-C6烷基。
在另一优选例中，R 6选自H、氘。
在另一优选例中，R 1a、R 1b、R 1c各自独立地选自H、氘、C1-C6烷基、C3-C8环烷基、3-8元杂环烷基，所述的烷基、环烷基、杂环烷基任选地被一个或多个氘、卤素取代。
在另一优选例中，R 1a、R 1b、R 1c各自独立地选自H、C1-C6烷基，所述的烷基任选地被一个或多个氘或卤素取代；较佳地被一个或多个氘取代。
在另一优选例中，所述的R 5选自下组：H、D、卤素、-CN、NHR 1b；其中，所述的R 1b选自H、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基；所述的R 6为H或D。
在另一优选例中，R 5选自H、D、卤素、-CN。
在另一优选例中，R 5选自D、卤素。
在另一优选例中，R 5选自-CN。
在另一优选例中，各个R 7各自独立地为H。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括如本发明第一方面或第二方面所述的化合物，其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，以及药学上可接受的辅料和\或载体。
本发明的第四方面，提供了一种如本发明第一或第二方面所述的化合物，或其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药在制备药物中的用途；其中，所述药物用于激动甲状腺激素受体，或用于预防、治疗或减轻甲状腺激素受体调节的疾病。
在另一优选例中，所述的甲状腺激素受体介导的疾病选自下组：非酒精性脂肪性肝病，动脉粥样硬化，冠心病，高血压，高胆固醇血症，高脂血症，高甘油三酯症，血脂异常，肥胖，糖尿病，代谢紊乱，脂质代谢紊乱,1A型糖原贮积病，甲状腺功能减退症，或甲状腺癌。
本发明涉及一种使用本发明所述的化合物或药物组合物在激动甲状腺激素受体的方法，或用于预防、治疗或减轻由甲状腺激素受体调节的疾病的方法，所述方法是给予又需要的个体所述化合物或所述药物组合物的有效治疗量。并且，本发明提供的上述化合物或其药物组合物可以与其他疗法或治疗剂共同使用。使用方式可以为同时、顺序或以一定时间间隔进行。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为化合物体外评价体系THRβ激动曲线；
图2为肝脏组织中THRβ下游基因表达结果；
图3为心脏组织中THRβ下游基因表达结果；
图4为小鼠慢性给药TC结果；
图5为金黄地鼠急性给药血清TC/TGL/DL-C结果；
图6为化合物3给药后小鼠肝脏DIO1基因表达结果；
图7为化合物3给药后小鼠心脏MHCα表达结果；
图8为化合物3给药后对甲状腺激素水平的影响。
具体实施方式
本发明人经过长期而深入的研究，发现了一种式I所示的喹啉类化合物及其制备方法。所述的化合物可以用于制备由甲状腺激素受体介导的疾病的药物，相关疾病包括但不限于非酒精性脂肪性肝病，动脉粥样硬化，冠心病，高血压，高胆固醇血症，高脂血症，高甘油三酯症，血脂异常，肥胖，糖尿病，代谢紊乱，脂质代谢紊乱，1A型糖原贮积病，甲状腺功能减退症或甲状腺癌等疾。基于上述发现，发明人完成了本发明。
术语
在本发明未特殊说明的情况下，本发明的术语具有以下含义：
“卤素”在本文中是指F、Cl、Br、I，或者它们的同位素。
“卤代”或“卤素取代”是指被一个以上选自F、C1、Br、I，或者它们的同位素取代，卤素取代基数量的上限等于被取代基团可被取代的氢数之和，在未作特殊限定下，卤素取代基数量为1至该上限之间的任意整数，当卤素取代基数量大于1时，可以是相同或不同的卤素进行取代。
“烷基”是指一价的直链或支链饱和脂肪族烃基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；所述的烷基可以进一步被任意取代基取代。
“氘代”是指烷基、环烷基、亚烷基、芳基、杂芳基、烯基、炔基等基团上的氢原子被至少一个同位素氖取代的情形，氖代的数量上限等于被取代基团可被取代的氢数之和，在未作特殊限定下，氖代数量为1至该上限之间的任意整数，优选1-20个氖原子取代，更优选为1-10个氖原子取代，更优选为1-6个氖原子取代，进一步优选为1-3个氖原子取代。
“炔基”是指直链或支链的、含有一个以上碳碳三键的一价不饱和烃基，除非特殊说明，炔基含有2-6个碳原子，优选含有2-4个碳原子，非限制性地的实施例为乙炔基、丙炔基、炔丙基等。
“烯基”是指直链或支链的、含有一个以上碳碳双键的一价不饱和烃基，除非特殊说明，炔基含有2-6个碳原子，优选含有2-4个碳原子，非限制性地的实施例为乙烯 基、丙烯基、烯丙基、2-丁烯基、1-丁烯基等。
“烷氧基”或“烷基氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基等。
“卤代烷氧基”是指被一个或多个卤素取代的烷氧基。非限制性实施例包括一氟甲氧基、二氟甲氧基、三氟甲氧基、二氟乙基氧基等。
“烷基氨基”或“烷氨基”是指被单个或两个烷基取代的氨基，也写作一N-(烷基)z或一NH-烷基，后者也写作单烷基氨基。非限制实施例包括二甲氨基、单甲基氨基、二乙氨基、单乙氨基等。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指可以但不必须被F取代，说明包括被F取代的情形和不被F取代的情形。
“药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”表示一种或多种本文所述化合物或其立体异构体、溶剂化物、药学上可接受的盐或共晶，与其他组成成分的混合物，其中其他组分包含生理学/药学上可接受的载体和/赋形剂。
“载体”指的是:不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性，并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系，非限制性的实例包括微囊与微球、纳米粒、脂质体等。
“赋形剂”指的是:其本身并非治疗剂，用作稀释剂、辅料、粘合剂和/或媒介物，用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的，药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于:(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉及马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠)；(4)黄蓍胶粉；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格溶液(Ringer's solution)；(19)乙醇；(20)PH缓冲溶液；(21)聚酯、聚碳酸酯和/或聚酐；及(22)其他用于药物制剂中的无毒相容物质。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“溶剂化物”指本发明化合物或其盐与分子间非共价力结合的化学计量或非化学计量的溶剂形成的物质。当溶剂为水时，则为水合物。
“共晶”是指活性药物成分((API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中AP工和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共 晶，也包含中性固体与盐或溶剂化物形成的多元共晶。
式I化合物的制备
Figure PCTCN2022142988-appb-000006
本发明所涉及的化合物均可以使用以上所示路线进行制备，使用相应的6-甲氧基喹啉化合物获得或直接购买市售的6-羟基喹啉化合物为起始原料，与碳酸钾或碳酸铯在DMF中与相应的对氟取代硝基苯化合物搅拌数小时后获得步骤2的原料：随后在适合的条件下进行硝基还原获得相应的氨基化合物：所得的氨基化合物在盐酸和亚硝酸钠的条件下进行重氮化并与N氰基乙酰尿烷进行偶合：最后将化合物在醋酸和醋酸钠中在高温下进行回流，最终获得各实施例。
本领域技术人员可以结合文献以及已知的有机合成技术制备本发明的化合物。其起始原料为市售和货品和(或)化学文献中所述的化合物。“市售化合物”是从正规商业来源获得的，供应商包括：毕得医药，皓鸿生物，泰坦科技，国药集团，药明康德，百灵威科技以及韶远化学科技等公司。测试方法包括核磁(NMR)和质谱(MS)等。
药物组合物及其制备
本发明的另一方面提供了一种药物组合物，其含有治疗有效量的选自上述通式I的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种，以及任选地，一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。所述辅料例如为气味剂、香味剂、甜味剂等。
本发明所提供的药物组合物优选含有重量比为1-99％的活性成份，其优选的比例是，通式I化合物作为活性成分占总重量的65wt％～99wt％，其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
本发明所提供的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中包含1mg-700mg通式I化合物，优选地，制剂配方的单位计量中包含25mg-300mg通式I化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为50-1400mg/kg体重，一次性服用，或25-700mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：2-(3,5-二氯-4-((2-(2-氟吡啶-4-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
Figure PCTCN2022142988-appb-000007
步骤1制备6-甲氧基-4-甲基-2-(4-氟吡啶)喹啉
使用市售的原料6-甲氧基-4-甲基-2-氯喹啉(2g，1eq)加入催化量的四三苯基膦钯和过量的2-氟吡啶4-硼酸酯，再加入过量碳酸钠，在20ml的二氧六环和5ml的水的混合溶液中于氮气保护下在100℃下过夜，反应结束后用乙酸乙酯稀释，过滤除去固体，有机相用饱和食盐水洗涤三次，加入无水硫酸钠干燥过滤减压浓缩，柱层析得到白色粉末6-甲氧基-4-甲基-2-苯基喹啉
步骤2制备6-羟基-4-甲基-2-(4-氟吡啶)喹啉
将6-甲氧基-4-甲基-4-(2-氟吡啶)喹啉置于20ml的48％氢溴酸水溶液中于90℃下反应三天，反应结束后，使用碳酸氢钠水溶液调节PH至8-9，使用乙酸乙酯萃取三次，合并有机相用饱和食盐水洗涤，加入无水硫酸钠干燥过滤减压浓缩，获得黄色油状化合物6-羟基-4-甲基-2-(4-氟吡啶)喹啉，无需纯化直接进行下一步
步骤3制备6-(2,6-二氯-4-硝基苯氧基)-4-甲基-4-(2-氟吡啶)喹啉
将6-羟基-4-甲基-2-(4-氟吡啶)喹啉和3,5-二氯-对氟硝基苯(1.48g，0.0070mol)溶于20mlDMF中，加入5g碳酸钾与常温下搅拌6小时后，加入200ml水淬灭反应，使用乙酸乙酯萃取三次，合并有机相后使用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥过滤减压浓缩后使用柱层析纯化得淡黄色化合物6-(2,6-二氯-4-硝基苯氧基)-4-甲基-2-(4-氟吡啶)喹啉
步骤4制备3,5-二氯-4-((4-甲基-2-(4-氟吡啶)喹啉-6-基)氧基)苯胺
将6-(2,6-二氯-4-硝基苯氧基)-4-甲基-2-苯基喹啉加入到15ml的乙酸乙酯和15ml的乙醇中，再加入过量氯化亚锡和催化量盐酸，常温搅拌过夜后反应完成。使用碳酸钠水溶液调节PH至9-10，过滤除去沉淀，使用乙酸乙酯萃取三次，合并有机相用饱和食盐水洗涤三次，加入无水硫酸钠过滤减压浓缩获得淡黄色固体3,5-二氯-4-((4-甲基-2- (4-氟吡啶)喹啉-6-基)氧基)苯胺
步骤5制备(E)-(2-氰基-2-((3,5-二氯-4-((4-甲基-2-(4-氟吡啶)喹啉-6-基)氧基)苯基)二烯基)乙酰基)氨基甲酸乙酯
在装有3,5-二氯-4-((4-甲基-2-(4-氟吡啶)喹啉-6-基)氧基)苯胺的瓶中加入10ml水，以及10ml盐酸，于0℃下滴加亚硝酸钠的3ml水溶液；在另一个圆底烧瓶中加入15ml吡啶和10ml水，加入N-氰基乙酰尿烷(483.93mg，0.0031mol)，两相均在0℃下保温30分钟，随后将重氮盐滴加到另一相中，滴加完毕后保温30分钟后用乙酸乙酯萃取，有机相用食盐水洗涤干燥减压浓缩得红色固体制备(E)-(2-氰基-2-((3,5-二氯-4-((4-甲基-2-(4-氟吡啶)喹啉-6-基)氧基)苯基)二烯基)乙酰基)氨基甲酸乙酯(1.2g，83.8％)，粗品无须纯化直接用于下一步
步骤6制备2-(3,5-二氯-4-((2-三氟甲基-2-(4-氟吡啶)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
将橙色的(E)-(2-氰基-2-((3,5-二氯-4-((4-甲基-2-(4-氟吡啶)喹啉-6-基)氧基)苯基)二烯基)乙酰基)氨基甲酸乙酯(1.2g，83.8％)加入至10ml醋酸中，加入1g的乙酸钠，于120℃下加热2小时，随后加水析出红色的化合物粗品，过滤干燥后由高效制备液相分离纯化得到白色的2-(3,5-二氯-4-((2-(4-氟吡啶)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈，1H NMR(500MHz,Chloroform)δ9.55(s,1H),8.91(s,1H),8.58(s,1H),7.97(d,J＝26.8Hz,2H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例2：2-(3,5-二氯-4-((2-苯基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用苯硼酸酯，使用实施例1所述方法进行制备分离纯化(总产率22％)M/Z＝534.02(M+1)1H NMR(500MHz,Chloroform)δ9.56(s,1H),8.33(s,2H),7.92(s,1H),7.67(s,1H),7.57(d,J＝15.0Hz,4H),7.49(s,2H),6.63(s,1H),2.69(s,3H).
实施例3：2-(3,5-二氯-4-((2-(4-氟苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用4-氟苯硼酸酯，使用实施例1所述方法进行制备分离纯化(总产率22％)M/Z＝534.02(M+1)1H NMR(500MHz,Chloroform)δ9.53(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).
实施例4：2-(3,5-二氯-4-((2-(4-三氟甲基苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用4-三氟甲基苯硼酸酯，使用实施例1所述方法进行制备分离纯化(总产率18％)M/Z＝538.04(M+1)1H NMR(500MHz,Chloroform)δ9.57(s,10H),7.94(d,J＝20.0Hz,31H),7.74(d,J＝1.8Hz,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).
实施例5：2-(3,5-二氯-4-((2-(4-氯苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用4-氯苯硼酸酯，使用实施例1所述方法进行制备分离纯化(总产率15％)M/Z＝ 550.02 1H NMR(500MHz,Chloroform)δ9.53(s,1H),8.36(s,2H),7.92(s,1H),7.67(s,1H),7.59(d,J＝10.0Hz,4H),7.49(s,1H),6.63(s,1H),2.69(s,3H).
实施例6：2-(3,5-二氯-4-((2-(4-溴苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用4-溴苯硼酸酯，使用实施例1所述方法进行制备分离纯化(总产率23％)M/Z＝593.97(M+1)1H NMR(500MHz,Chloroform)δ9.53(s,1H),8.17(s,2H),7.92(s,1H),7.67(s,1H),7.57(d,J＝15.0Hz,4H),7.49(s,1H),6.63(s,1H),2.69(s,3H).
实施例7：2-(3,5-二氯-4-((2-(4-氰基苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用4-氰基苯硼酸酯，使用实施例1所述方法进行制备分离纯化(总产率15％)M/Z＝541.05(M+1)1H NMR(500MHz,Chloroform)δ9.57(s,1H),8.34(s,2H),7.91(d,J＝5.0Hz,3H),7.67(s,1H),7.58(s,2H),7.49(s,1H),6.63(s,1H),2.69(s,3H).
实施例8：2-(3,5-二氯-4-((2-(2-异丙基苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(3-氯-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝568.01(M+1)1H NMR(500MHz,Chloroform)δ9.56(s,16H),8.13(s,16H),7.92(s,18H),7.88(s,13H),7.73(d,J＝60.0Hz,32H),7.59(s,1H),7.58(s,32H),7.49(s,16H),6.63(s,16H),2.69(s,48H).
实施例9：2-(3,5-二氯-4-((2-(2-异丙基苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(2-异丙基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率16％)M/Z＝558.1(M+1) 1H NMR(500MHz,Chloroform)δ9.54(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).
实施例10：2-(3,5-二氯-4-((2-(4-氟-3-甲基苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(4-氟-3-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝548.06(M+1) 1H NMR(500MHz,Chloroform)δ9.57(s,1H),8.34(s,2H),7.91(d,J＝5.0Hz,3H),7.67(s,1H),7.58(s,2H),7.49(s,1H),6.63(s,1H).
实施例11：2-(3,5-二氯-4-((2-(4-氰基-3-氟苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苯腈，使用实施例1所述方法进行制备分离纯化(总产率13％)M/Z＝559.04(M+1) 1H NMR(500MHz,Chloroform)δ9.57(s,1H),8.34(s,2H),7.91(d,J＝5.0Hz,3H),7.67(s,1H),7.58(s,2H),7.49(s,1H),6.63(s,1H).
实施例12：2-(3,5-二氯-4-((2-(2-氰基-4-氟苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用4-三氟甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苯腈，使用实施例1所述方法进行制备分离纯化(总产率18％)M/Z＝609.04(M+1) 1H NMR(500MHz,Chloroform)δ9.57(s,1H),8.34(s,2H),7.91(d,J＝5.0Hz,3H),7.67(s,1H),7.58(s,2H),7.49(s,1H),6.63(s,1H).
实施例13：2-(3,5-二氯-4-((2-(4-氟-3,5-二氯苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(3,5-二氯-4-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率22％)M/Z＝601.97(M+1) 1H NMR(500MHz,Chloroform)δ9.58(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).
实施例14：2-(3,5-二氯-4-((2-(4-氯-3,5-二甲基苯基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(3,5-二甲基-4-氯苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率19％)M/Z＝578.05(M+1) 1H NMR(500MHz,Chloroform)δ9.58(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).
实施例15：2-(3,5-二氯-4-((2-(呋喃-2-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(呋喃-2-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率20％)M/Z＝506.03(M+1) 1H NMR(500MHz,Chloroform)δ9.58(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).
实施例16：2-(3,5-二氯-4-((4-甲基-2-(5-甲基呋喃-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(4-甲基呋喃-2-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率21％)M/Z＝520.05(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.95(d,J＝20.0Hz,2H),5.94(s,1H),2.69(s,3H),2.25(s,3H).
实施例17：2-(3,5-二氯-4-((4-甲基-2-(5-环丙基呋喃-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(4-环丙基呋喃-2-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率21％)M/Z＝520.05(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.95(d,J＝20.0Hz,2H),5.94(s,1H),2.69(s,3H),2.25(s,3H).
实施例18：2-(3,5-二氯-4-((4-甲基-2-(2-氰基-5甲基呋喃-3-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用5-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)呋喃-2-腈，使用实施例1所述方法进行制备分离纯化(总产率29％)M/Z＝545.05(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.95(d,J＝20.0Hz,2H),5.94(s,1H),2.69(s,3H),2.25(s,3H).
实施例19：2-(3,5-二氯-4-((2-(噻吩-2-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(呋喃-2-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率26％)M/Z＝522.01(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.95(d,J＝20.0Hz,2H),5.94(s,1H),2.69(s,3H),2.25(s,3H).
实施例20：2-(3,5-二氯-4-((4-甲基-2-(4-氯噻吩-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(4-氯噻吩-2-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率13％)M/Z＝555.97(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.95(d,J＝20.0Hz,2H),5.94(s,1H),2.69(s,3H),2.25(s,3H).
实施例21：2-(3,5-二氯-4-((4-甲基-2-(5-氰基噻吩-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)噻吩-2-腈，使用实施例1所述方法进行制备分离纯化(总产率15％)M/Z＝547.01(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.95(d,J＝20.0Hz,2H),5.94(s,1H),2.69(s,3H),2.25(s,3H).
实施例22：2-(3,5-二氯-4-((4-甲基-2-(5-甲基噻吩-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(5-甲基噻吩-2-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率39％)M/Z＝536.03(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.84(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),7.02(d,J＝55.0Hz,2H),2.69(s,3H),2.44(s,3H).
实施例23：2-(3,5-二氯-4-((4-甲基-2-(5-三氟甲基噻吩-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(5-三氟甲基噻吩-2-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝590.00(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.84(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),7.02(d,J＝55.0Hz,2H),2.69(s,3H),2.44(s,3H).
实施例24：2-(3,5-二氯-4-((2-(吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率16％)M/Z＝517.05(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.84(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),7.02(d,J＝55.0Hz,2H),2.69(s,3H),2.44(s,3H).
实施例25：2-(3,5-二氯-4-((4-甲基-2-(5-甲基吡啶-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用5-甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝531.07(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.84(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),7.02(d,J＝55.0Hz,2H),2.69(s,3H),2.44(s,3H).
实施例26：2-(3,5-二氯-4-((4-甲基-2-(5-氟吡啶-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用5-氟-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率19％)M/Z＝535.04(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.94(s,1H),7.84(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),7.02(d,J＝55.0Hz,2H),2.69(s,3H),2.44(s,3H).
实施例27：2-(3,5-二氯-4-((4-甲基-2-(5-氯吡啶-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用5-氯-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率22％)M/Z＝551.01(M+1) 1H NMR(500MHz,Chloroform)δ9.54(s,1H),8.97(s,1H),8.46(s,1H),7.94(s,1H),7.75(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.77(s,1H),2.69(s,3H).
实施例28：2-(3,5-二氯-4-((4-甲基-2-(5-溴吡啶-2-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用5-溴-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率11％)M/Z＝594.96(M+1) 1H NMR(500MHz,Chloroform)δ9.54(s,1H),8.97(s,1H),8.46(s,1H),7.94(s,1H),7.75(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.77(s,1H),2.69(s,3H).
实施例29：2-(3,5-二氯-4-((2-(吡啶-3-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝517.05(M+1) 1H NMR(500MHz,Chloroform)δ9.54(s,1H),8.97(s,1H),8.46(s,1H),7.94(s,1H),7.75(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.77(s,1H),2.69(s,3H).
实施例30：2-(3,5-二氯-4-((2-(6-甲基吡啶-3-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用6-甲基-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率14％)M/Z＝531.07(M+1) 1H NMR(500MHz,Chloroform)δ9.54(s,1H),8.97(s,1H),8.46(s,1H),7.94(s,1H),7.75(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.77(s,1H),2.69(s,3H).
实施例31：2-(3,5-二氯-4-((2-(6-氟吡啶-3-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用6-氟-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率15％)M/Z＝535.05(M+1) 1H NMR(500MHz,Chloroform)δ9.54(s,1H),8.97(s,1H),8.46(s,1H),7.94(s,1H),7.75(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.77(s,1H),2.69(s,3H).
实施例32：2-(3,5-二氯-4-((2-(6-氯吡啶-3-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用6-氯-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率11％)M/Z＝551.01(M+1) 1H NMR(500MHz,Chloroform)δ9.53(s,1H),9.37(s,1H),8.54(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.48(d,J＝10.0Hz,2H),6.97(s,1H),2.69(s,3H).
实施例33：2-(3,5-二氯-4-((2-(6-溴吡啶-3-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用6-溴-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率20％)M/Z＝594.96(M+1) 1H NMR(500MHz,Chloroform)δ9.53(s,1H),9.37(s,1H),8.54(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.48(d,J＝10.0Hz,2H),6.97(s,1H),2.69(s,3H).
实施例34：2-(3,5-二氯-4-((2-(6-三氟甲基吡啶-3-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用6-三氟甲基-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝585.04(M+1) 1H NMR(500MHz,Chloroform)δ9.53(s,1H),9.37(s,1H),8.54(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.48(d,J＝10.0Hz,2H),6.97(s,1H),2.69(s,3H).
实施例35：2-(3,5-二氯-4-((2-(吡啶-4-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-4-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率18％)M/Z＝517.05(M+1) 1H NMR(500MHz,Chloroform)δ9.53(s,1H),9.37(s,1H),8.54(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.48(d,J＝10.0Hz,2H),6.97(s,1H),2.69(s,3H).
实施例36：2-(3,5-二氯-4-((2-(2-甲基吡啶-4-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-甲基-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-4-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率18％)M/Z＝531.07(M+1) 1H NMR(500MHz,Chloroform)δ9.53(s,1H),9.37(s,1H),8.54(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.48(d,J＝10.0Hz,2H),6.97(s,1H),2.69(s,3H).
实施例37：2-(3,5-二氯-4-((2-(2-氯吡啶-4-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-氯-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-4-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率19％)M/Z＝551.01(M+1) 1H NMR(500MHz,Chloroform)δ9.55(s,1H),9.08(s,1H),8.91(s,1H),8.37(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例38：2-(3,5-二氯-4-((2-(2-氟吡啶-4-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
Figure PCTCN2022142988-appb-000008
步骤1：制备6-甲氧基-4-甲基-2-(三氟甲基)喹啉
使用市售的对甲氧基苯胺(10g，0.0801mol)，三氟乙酰丙酮(15g，0.9744mol)加入到多聚磷酸和甲苯的混合溶剂中在110℃下反应48小时。反应结束后，冷却反应液后加到2L的冰水混合物中，加入碳酸氢钠水溶液调节PH至8-9后用乙酸乙酯萃取，用无水硫酸钠干燥过滤减压浓缩后经柱层析纯化获得白色晶体6-甲氧基-4-甲基-2-(三氟甲基)喹啉(9g，产率45.95％)
步骤2：制备6-羟基-4-甲基-2-(三氟甲基)喹啉
将6-甲氧基-4-甲基-2-(三氟甲基)喹啉(2g，0.0083mol)加入20ml48％的氢溴酸的水溶液中在90℃下回流三天，反应结束后使用碳酸氢钠水溶液调节PH至8-9后使用乙酸乙酯萃取三次，合并有机相后使用无水硫酸钠干燥过滤减压浓缩得到黄色油状化合物6-甲氧基-4-甲基-2-(三氟甲基)喹啉(1.6g，84％)，粗品无需纯化直接用于下一步
步骤3：制备6-(2,6-二氯-4-硝基苯氧基)-4-甲基-2-(三氟甲基)喹啉
将6-甲氧基-4-甲基-2-(三氟甲基)喹啉(1.6g，0.0070mol)与3,5-二氯-对氟硝基苯(1.48g，0.0070mol)溶于20mlDMF中，加入5g碳酸钾与常温下搅拌6小时后，加入200ml水淬灭反应，使用乙酸乙酯萃取三次，合并有机相后使用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥过滤减压浓缩后使用柱层析纯化得淡黄色化合物6-(2,6-二氯-4-硝基苯氧基)-4-甲基-2-(三氟甲基)喹啉(1.5g,51％)
步骤4：制备3,5-二氯-4-((4-甲基-2-(三氟甲基)喹啉-6-基)氧基)苯胺
将6-(2,6-二氯-4-硝基苯氧基)-4-甲基-2-(三氟甲基)喹啉(1.5g,0.0031mol)加入到15ml的乙酸乙酯和15ml的乙醇中，再加入过量氯化亚锡和催化量盐酸，常温搅拌过夜后反应完成。使用碳酸钠水溶液调节PH至9-10，过滤除去沉淀，使用乙酸乙酯萃取三次，合并有机相用饱和食盐水洗涤三次，加入无水硫酸钠过滤减压浓缩获得淡黄色固体3,5-二氯-4-((4-甲基-2-(三氟甲基)喹啉-6-基)氧基)苯胺(1g,71.8％)
步骤5制备(E)-(2-氰基-2-((3,5-二氯-4-((4-甲基-2-(三氟甲基)喹啉-6-基)氧基)苯基)二烯基)乙酰基)氨基甲酸乙酯
在装有3,5-二氯-4-((4-甲基-2-(三氟甲基)喹啉-6-基)氧基)苯胺(1g，0.0026mol)的瓶中加入10ml水，以及10ml盐酸，于0℃下滴加亚硝酸钠(213mg，0.0031mol)的3ml水溶液；在另一个圆底烧瓶中加入15ml吡啶和10ml水，加入N-氰基乙酰尿烷(483.93mg，0.0031mol)，两相均在0℃下保温30分钟，随后将重氮盐滴加到另一相中，滴加完毕后保温30分钟后用乙酸乙酯萃取，有机相用食盐水洗涤干燥减压浓缩得红色固体制备(E)-(2-氰基-2-((3,5-二氯-4-((4-甲基-2-(三氟甲基)喹啉-6-基)氧基)苯基)二烯基)乙酰基)氨基甲酸乙酯(1.2g，83.8％)，粗品无须纯化直接用于下一步
步骤6制备2-(3,5-二氯-4-((2-三氟甲基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
将橙色的(E)-(2-氰基-2-((3,5-二氯-4-((4-甲基-2-(三氟甲基)喹啉-6-基)氧基)苯基)二烯基)乙酰基)氨基甲酸乙酯(1.2g，83.8％)加入至10ml醋酸中，加入1g的乙酸钠，于120℃下加热2小时，随后加水析出红色的化合物粗品，过滤干燥后由高效制备液相分离纯化得到白色的2-(3,5-二氯-4-((2-三氟甲基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈，即实施例1(200mg)LCMS m/z＝508.01(M+1) 1H NMR(500MHz,Chloroform)δ9.53(s,1H),8.00(s,1H),7.67(s,1H),7.57(d,J＝10.0Hz,3H),7.31(s,1H).
实施例39：2-(3,5-二氯-4-((2-(2-溴吡啶-4-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-溴-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-4-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率15％)M/Z＝594.96(M+1) 1H NMR(500MHz,Chloroform)δ9.55(s,1H),9.08(s,1H),8.91(s,1H),8.37(s,1H),7.94(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例40：2-(3,5-二氯-4-((2-(2-三氟甲基吡啶-4-基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用2-三氟甲基-3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-4-基)吡啶，使用实施例1所述方法进行制备分离纯化(总产率16％)M/Z＝585.04(M+1) 1H NMR(500MHz,Chloroform)δ9.55(s,1H),9.08(s,1H),8.91(s,1H),8.37(s,1H),7.94(s,1H),7.60(d,J＝ 15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例41：2-(3,5-二氯-4-((2-氯-4-甲基喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用实施例1所述方法进行制备分离纯化(总产率13％)M/Z＝473.98(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.93(s,1H),7.58(s,2H),7.51(s,1H),7.42(d,J＝15.0Hz,2H),2.57(s,3H).
实施例42：2-(3,5-二氯-4-((4-氯喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率11％)M/Z＝459.97(M+1) 1H NMR(500MHz,Chloroform)δ9.53(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).
实施例43：2-(3,5-二氯-4-((4-氯喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝503.92(M+1) 1H NMR(500MHz,Chloroform)δ9.54(s,1H),8.64(s,1H),7.96(s,1H),7.88(s,1H),7.79–7.37(m,4H).
实施例44：2-(3,5-二氯-4-((4-氯-2-(三氟甲基)喹啉-6-基)氧)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率23％)M/Z＝527.96(M+1) 1H NMR(500MHz,Chloroform)δ9.54(s,1H),7.99(d,J＝20.0Hz,2H),7.78–7.55(m,4H).
实施例45：2-(3,5-二氯-4-((2-甲基-4-苯基喹啉-6-基)氧)苯基-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率26％)M/Z＝516.06(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,4H),7.97(s,4H),7.79(s,8H),7.58(s,8H),7.43(t,J＝12.5Hz,16H),7.36(s,1H),7.32(d,J＝40.0Hz,7H),2.69(s,12H).
实施例46：2-(3,5-二氯-4-((4-甲基-2-乙烯基喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率22％)M/Z＝466.04(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,1H),7.90(s,1H),7.57(d,J＝15.0Hz,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).
实施例47：2-(3,5-二甲基-4-((4-甲基-2-苯基喹啉-6-基)氧)苯基-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝ 476.16(M+1) 1H NMR(500MHz,Chloroform)δ9.57(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).
实施例48：2-(3,5-二氯-4-((4-甲基-2-(吡咯烷-1-基)喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝509.08(M+1) 1H NMR(500MHz,Chloroform)δ9.55(s,103H),7.64(d,J＝60.0Hz,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).
实施例49：2-(3,5-二氯-4-((2-甲基-4-(吡咯烷-1-基)喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率11％)M/Z＝509.08(M+1) 1H NMR(500MHz,Chloroform)δ9.55(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).
实施例50：2-(3,5-二氯-4-((2-甲基-4-乙烯基喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率12％)M/Z＝466.04(M+1) 1H NMR(500MHz,Chloroform)δ9.54(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).
实施例51：2-(3,5-二氯-4-((2-氯-3-甲基喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率11％)M/Z＝476.16(M+1) 1H NMR(500MHz,Chloroform)δ9.57(s,1H),8.07(s,1H),7.83(d,J＝10.0Hz,3H),7.58–7.40(m,7H),2.56(s,3H),2.15(s,6H).
实施例52：2-(3,5-二氯-4-((2-氯-3-甲基喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率10％)M/Z＝473.98(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,9H),7.79(d,J＝55.0Hz,17H),7.74–7.70(m,1H),7.58(s,5H),7.49(d,J＝85.0Hz,21H),7.34(s,9H),2.40(s,26H).
实施例53：2-(3,5-二氯-4-((3-甲基-2-苯基喹啉-6-基)氧)苯基-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率29％)M/Z＝516.06(M+1) 1H NMR(500MHz,Chloroform)δ9.55(s,1H),8.07(s,1H),7.83(d,J＝10.0Hz,3H),7.58(s,2H),7.58–7.41(m,5H),2.56(s,3H).
实施例54：2-(3,5-二氟-4-((4-甲基-2-苯基喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率15％)M/Z＝484.11(M+1) 1H NMR(500MHz,Chloroform)δ9.57(s,1H),8.33(s,2H),7.92(s,1H),7.67(s,1H),7.55(s,2H),7.51(dd,J＝3.4,1.5Hz,1H),7.41(d,J＝80.0Hz,4H),6.63(s,1H),2.69(s,3H).
实施例55：2-(3-溴-5-甲基-4-((4-甲基-2-苯基喹啉-6-基)氧)苯基-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率16％)M/Z＝540.06(M+1) 1H NMR(500MHz,Chloroform)δ9.57(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).
实施例56：2-(3-溴-5-氯-4-((3-氯-4-甲基-2-(三氟甲基)喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的原料，使用实施例1所述方法进行制备分离纯化(总产率13％)M/Z＝560.00(M+1) 1H NMR(500MHz,Chloroform)δ9.56(s,40H),8.33(s,83H),7.92(s,42H),7.67(s,41H),7.65(s,3H),7.56(t,J＝37.5Hz,199H),7.38(s,41H),6.63(s,40H),2.69(s,120H).
实施例57：2-(3,5-二氯-4-((4-氯喹啉-6-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈
使用市售的4-溴-6甲氧基喹啉为原料，使用实施例1所述方法进行制备分离纯化(总产率17％)M/Z＝585.92(M+1) 1H NMR(500MHz,Chloroform)δ9.54(s,1H),7.90(s,1H),7.60(t,J＝37.5Hz,3H),7.38(s,1H),2.45(s,3H).
实施例58：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-氟吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
步骤1制备2-(3,5-二氯-4-((4-甲基-2-(2-氟吡啶-4-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸
使用实施例1所述的方法获得产物实施例1，以实施例1为原料，加入醋酸和浓盐酸的混合溶液中于120℃下加热一小时，冷却后加入水过滤析出的固体，真空干燥获得白色粉末2-(3,5-二氯-4-((4-甲基-2-(2-氟吡啶-4-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸
步骤2制备6-氨基-2-(3,5-二氯-4-((2-(4-甲基-2-(2-氟吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
将2-(3,5-二氯-4-((4-甲基-2-(2-氟吡啶-4-基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸加入叔丁醇中，加入三乙胺和DPPA，于80℃下加热24小时，反应结束后，减压除去叔丁醇，用乙酸乙酯萃取三次，合成有机相用饱和食盐水洗涤，加入无水硫酸钠干燥过滤减压浓缩，随后加入三氟乙酸搅拌一小时脱除保护基，减压除去三氟乙酸后用氢氧化钠水溶液碱化后萃取减压浓缩，由高效制备液相分离纯化获得白色粉末化合物：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-氟吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮，即实施例58M/Z＝498.03(M+1) 1H NMR(500MHz,Chloroform)δ9.55(s,1H),9.08(s,1H),8.91(s,1H),8.37(s,1H),7.94(s,1H), 7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例59：6-氨基-2-(3,5-二氯-4-((2-(4-氯苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例2为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(三氟甲基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝506.07(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.33(s,2H),7.76(dd,J＝132.2,37.9Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.56(d,J＝15.0Hz,4H),7.49(s,2H),6.63(s,1H),2.69(s,3H).
实施例60：6-氨基-2-(3,5-二氯-4-((2-(4-氟苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例3为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4-氟苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝524.06(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.33(s,2H),7.76(dd,J＝132.2,37.9Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.56(d,J＝15.0Hz,4H),7.49(s,2H),6.63(s,1H),2.69(s,3H).
实施例61：6-氨基-2-(3,5-二氯-4-((2-(4-三氟甲基苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例4为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4-三氟甲基苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝574.06(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.33(s,2H),7.76(dd,J＝132.2,37.9Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.56(d,J＝15.0Hz,4H),7.49(s,2H),6.63(s,1H),2.69(s,3H).
实施例62：6-氨基-2-(3,5-二氯-4-((2-(4-氯苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例5为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4-氯苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝540.03(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.33(s,2H),7.76(dd,J＝132.2,37.9Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.56(d,J＝15.0Hz,4H),7.49(s,2H),6.63(s,1H),2.69(s,3H).
实施例63：6-氨基-2-(3,5-二氯-4-((2-(4-溴苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例6为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4-溴苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝583.98(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.33(s,2H),7.76(dd,J＝132.2,37.9Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.56(d,J＝15.0Hz,4H),7.49(s,2H),6.63(s,1H),2.69(s,3H).
实施例64：6-氨基-2-(3,5-二氯-4-((2-(4-氰基苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例7为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4-氰基苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝531.07(M+1) 1H NMR(500MHz,Chloroform)δ9.07(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).
实施例65：6-氨基-2-(3,5-二氯-4-((2-(3-氯-5-氟苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例8为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(3-氯-5-氟苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝558.02(M+1) 1H NMR(500MHz,Chloroform)δ9.07(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).
实施例66：6-氨基-2-(3,5-二氯-4-((2-(2-异丙基苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例9为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(2-异丙基苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝548.12(M+1) 1H NMR(500MHz,Chloroform)δ9.07(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).
实施例67：6-氨基-2-(3,5-二氯-4-((2-(4-氟-3-甲基苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例10为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4-氟-3-甲基苯基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝538.02(M+1) 1H NMR(500MHz,Chloroform)δ9.07(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).
实施例68：4-(6-(4-(6-氨基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)-2,6-二氯苯氧基)-4-甲基喹啉-2-基)-2-氟苯腈
以实施例11为原料，使用实施例58所述方法进行制备得到4-(6-(4-(6-氨基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)-2,6-二氯苯氧基)-4-甲基喹啉-2-基)-2-氟苄腈M/Z＝549.06(M+1) 1H NMR(500MHz,Chloroform)δ9.07(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).
实施例69：2-(6-(4-(6-氨基-3,5-二氧基-4,5-二氢-1,2,4-三嗪-2(3H)基)-2,6-二氯苯氧基)-4-甲基喹啉-2-基)-5-(三氟甲基)苯腈
以实施例12为原料，使用实施例58所述方法进行制备得到2-(6-(4-(6-氨基-3,5-二氧基-4,5-二氢-1,2,4-三嗪-2(3H)基)-2,6-二氯苯氧基)-4-甲基喹啉-2-基)-5-(三氟甲基)苯腈M/Z＝599.05(M+1) 1H NMR(500MHz,Chloroform)δ9.10(s,1H),8.27(d,J＝5.0Hz,2H),8.00(s,1H),7.75(dd,J＝129.7,40.4Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.58(s,2H),7.49(s,1H),6.63(s,1H),2.69(s,3H).
实施例70：6-氨基-2-(3,5-二氯-4-((2-(3,5-二氯-4-氟苯基)-4-甲基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)二酮
以实施例13为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(3,5-二氯-4-氟苯基)-4-甲基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)二酮M/Z＝591.98(M+1) 1H NMR(500MHz,Chloroform)δ9.10(s,1H),8.27(d,J＝5.0Hz,2H),8.00(s,1H),7.75(dd,J＝129.7,40.4Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.58(s,2H),7.49(s,1H),6.63(s,1H),2.69(s,3H).
实施例71：6-氨基-2-(3,5-二氯-4-((2-(4-氯-3,5-二甲基苯基)-4-甲基喹啉-6-基)氧基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例14为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4-氯-3,5-二甲基苯基)-4-甲基喹啉-6-基)氧基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝568.06(M+1) 1H NMR(500MHz,Chloroform)δ9.10(s,1H),8.27(d,J＝5.0Hz,2H),8.00(s,1H),7.75(dd,J＝129.7,40.4Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.58(s,2H),7.49(s,1H),6.63(s,1H),2.69(s,3H).
实施例72：6-氨基-2-(3,5-二氯-4-((2-(呋喃-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3，5(2H,4H)-二酮
以实施例15为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(呋喃-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3，5(2H,4H)-二酮M/Z＝496.05(M+1) 1H NMR(500MHz,Chloroform)δ9.10(s,1H),8.27(d,J＝5.0Hz,2H),8.00(s,1H),7.75(dd,J＝129.7,40.4Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.58(s,2H),7.49(s,1H),6.63(s,1H),2.69(s,3H).
实施例73：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(5-甲基呋喃-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例16为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(5-甲基呋喃-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝510.07(M+1) 1H NMR(500MHz,Chloroform)δ9.10(s,1H),8.27(d,J＝5.0Hz,2H),8.00(s,1H),7.75(dd,J＝129.7,40.4Hz,6H),7.67(s,1H),7.62(d,J＝45.0Hz,3H),7.58(s,2H),7.49(s,1H),6.63(s,1H),2.69(s,3H).
实施例74：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(5-甲基呋喃-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例17为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(5-甲基呋喃-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝510.07(M+1) 1H NMR(500MHz,Chloroform)δ9.07(s,1H),7.94(s,1H),7.85(s,2H),7.60(d,J＝15.0Hz,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).
实施例75：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(5-甲基呋喃-2-基)喹啉-6-基)氧基)苯 基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例18为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(5-甲基呋喃-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝535.06(M+1) 1H NMR(500MHz,Chloroform)δ9.12(s,1H),8.11–7.60(m,4H),7.61(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),6.37(s,1H),2.69(s,3H),2.25(s,3H).
实施例76：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(噻吩-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例19为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(噻吩-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝512.03(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,2H),8.12–7.56(m,16H),7.66(s,2H),7.74–7.56(m,8H),7.60(d,J＝15.0Hz,6H),7.47(s,2H),7.19(s,1H),6.97(s,2H),2.69(s,6H).
实施例77：6-氨基-2-(3,5-二氯-4-((2-(4-氯噻吩-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例20为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4-氯噻吩-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝545.99(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,2H),8.12–7.56(m,16H),7.66(s,2H),7.74–7.56(m,8H),7.60(d,J＝15.0Hz,6H),7.47(s,2H),7.19(s,1H),6.97(s,2H),2.69(s,6H).
实施例78：5-(6-(4-(6-氨基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)-2,6-二氯苯氧基)-4-甲基喹啉-2-基)噻吩-2-腈
以实施例21为原料，使用实施例58所述方法进行制备得到5-(6-(4-(6-氨基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)-2,6-二氯苯氧基)-4-甲基喹啉-2-基)噻吩-2-腈M/Z＝537.02(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,2H),8.12–7.56(m,16H),7.66(s,2H),7.74–7.56(m,8H),7.60(d,J＝15.0Hz,6H),7.47(s,2H),7.19(s,1H),6.97(s,2H),2.69(s,6H).
实施例79：6-氨基-2-(3,5-二氯-4-((2-(5-甲基噻吩-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例22为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(5-甲基噻吩-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝526.04(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,2H),8.12–7.56(m,16H),7.66(s,2H),7.74–7.56(m,8H),7.60(d,J＝15.0Hz,6H),7.47(s,2H),7.19(s,1H),6.97(s,2H),2.69(s,6H).
实施例80：6-氨基-2-(3,5-二氯-4-((2-(5-三氟甲基噻吩-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例23为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4- ((2-(5-三氟甲基噻吩-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝580.01(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.12–7.61(m,5H),7.61(s,1H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),7.02(d,J＝55.0Hz,2H),2.69(s,3H).
实施例81：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(吡啶-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例24为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(吡啶-2-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝507.07(M+1) 1H NMR(500MHz,Chloroform)δ9.18(s,1H),9.09(s,1H),8.55(s,1H),7.94(s,1H),7.86(s,2H),7.74(d,J＝5.0Hz,2H),7.59(d,J＝15.0Hz,3H),7.47(s,1H),7.23(s,1H),2.69(s,3H).
实施例82：6-氨基-2-(3,5-二氯-4-((2-(5-甲基吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例25为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(5-甲基吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝521.08(M+1) 1H NMR(500MHz,Chloroform)δ9.08(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＝15.0Hz,3H),7.47(d,J＝5.0Hz,2H),2.69(s,3H),2.32(s,3H).
实施例83：6-氨基-2-(3,5-二氯-4-((2-(5-氟吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例26为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(5-氟吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝525.06(M+1) 1H NMR(500MHz,Chloroform)δ9.10(s,84H),8.76(s,45H),8.33(s,87H),7.91(d,J＝33.8Hz,252H),7.86–7.85(m,6H),7.75(s,84H),7.60(d,J＝15.0Hz,256H),7.46(d,J＝14.1Hz,166H),2.69(s,251H).
实施例84：6-氨基-2-(3,5-二氯-4-((2-(5-氯吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例27为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(5-氯吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝541.03(M+1) 1H NMR(500MHz,Chloroform)δ9.10(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＝15.0Hz,3H),7.47(s,1H),6.77(s,1H),2.69(s,3H).
实施例85：6-氨基-2-(3,5-二氯-4-((2-(5-溴吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例28为原料，使用实施例58所述方法进行制备得到即6-氨基-2-(3,5-二氯-4-((2-(5-溴吡啶-2-基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝584.98(M+1) 1H NMR(500MHz,Chloroform)δ9.11(d,J＝11.3Hz,2H),8.52(s,1H),7.94(s,1H),7.87(s,2H),7.74(d,J＝5.0Hz,2H),7.60(d,J＝15.0Hz,3H),7.47(s,1H), 2.69(s,3H).
实施例86：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例29为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝507.07(M+1) 1H NMR(500MHz,Chloroform)δ9.63(s,2H),9.08(s,2H),8.71(d,J＝10.0Hz,4H),7.94(s,2H),7.86(s,4H),7.59(d,J＝15.0Hz,6H),7.47(s,3H),6.97(s,2H),2.69(s,6H).
实施例87：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-甲基吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例30为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-甲基吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝521.08(M+1) 1H NMR(500MHz,Chloroform)δ9.33(s,1H),9.07(s,1H),8.36(s,1H),7.94(s,1H),7.84(s,2H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),7.20(s,1H),6.97(s,1H),2.69(s,3H),2.61(s,3H).
实施例88：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-氟吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例31为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-氟吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝525.06(M+1) 1H NMR(500MHz,Chloroform)δ9.12(d,J＝3.0Hz,8H),8.64(s,4H),7.94(s,4H),7.85(s,8H),7.60(d,J＝15.0Hz,12H),7.44(d,J＝25.6Hz,8H),7.39(s,1H),6.97(s,4H),2.69(s,12H).
实施例89：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-氯吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例32为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-氯吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝541.03(M+1) 1H NMR(500MHz,Chloroform)δ9.38(s,1H),9.09(s,1H),8.52(s,1H),7.94(s,1H),7.86(s,2H),7.60(d,J＝15.0Hz,3H),7.48(d,J＝10.0Hz,2H),6.97(s,1H),2.69(s,3H).
实施例90：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-溴吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例33为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-溴吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝584.98(M+1) 1H NMR(500MHz,Chloroform)δ9.22(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＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例91：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-溴吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例34为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(6-溴吡啶-3-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝575.05(M+1) 1H NMR(500MHz,Chloroform)δ9.48(s,2H),9.10(s,2H),8.37(s,2H),7.91(d,J＝33.5Hz,7H),7.61(s,1H),7.60(d,J＝15.0Hz,6H),7.39(d,J＝80.0Hz,4H),6.97(s,2H),2.69(s,6H).
实施例92：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例35为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝507.07(M+1) 1H NMR(500MHz,Chloroform)δ9.09(s,1H),8.75(s,2H),8.28(s,2H),7.94(s,1H),7.86(s,2H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例93：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-甲基吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例36为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-甲基吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝521.08(M+1) 1H NMR(500MHz,Chloroform)δ9.08(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＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,6H).
实施例94：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-氯吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例37为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-氯吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝541.03(M+1) 1H NMR(500MHz,Chloroform)δ9.08(d,J＝4.3Hz,2H),8.91(s,1H),8.37(s,1H),7.90(d,J＝35.0Hz,3H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例95：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-氟吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例38为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-氟吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝525.06(M+1) 1H NMR(500MHz,Chloroform)δ9.07(s,3H),8.91(s,3H),8.58(s,3H),8.15–7.61(m,13H),7.61(s,1H),7.60(d,J＝15.0Hz,9H),7.47(s,3H),6.97(s,3H),2.69(s,9H).
实施例96：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-溴吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例39为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4- ((4-甲基-2-(2-溴吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝584.98(M+1) 1H NMR(500MHz,Chloroform)δ9.03(d,J＝49.6Hz,2H),8.73(s,1H),8.48(s,1H),7.94(s,1H),7.86(s,2H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例97：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-三氟甲基吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例40为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-三氟甲基吡啶-4-基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝575.05(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.80(d,J＝5.0Hz,2H),8.33(s,1H),7.94(s,1H),7.86(s,2H),7.60(d,J＝15.0Hz,3H),7.47(s,1H),6.97(s,1H),2.69(s,3H).
实施例98：6-氨基-2-(3,5-二氯-4-((2-氯-4-甲基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例41为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-氯-4-甲基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝464.00(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),7.93(s,1H),7.84(s,2H),7.58(s,2H),7.51(s,1H),7.42(d,J＝15.0Hz,2H),2.57(s,3H).
实施例99：6-氨基-2-(3,5-二氯-4-((4-氯喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例42为原料，使用实施例58所述方法进行制备得到6-氨基-2-(4-(4-溴喹啉-6-基)氧)-3,5-二氯苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝451.66(M+1) 1H NMR(500MHz,Chloroform)δ9.07(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＝30.0Hz,55H),7.42(s,18H).
实施例100：6-氨基-2-(4-(4-溴喹啉-6-基)氧)-3,5-二氯苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例43为原料，使用实施例58所述方法进行制备得到6-氨基-2-(4-(4-溴喹啉-6-基)氧)-3,5-二氯苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝493.93(M+1) 1H NMR(500MHz,Chloroform)δ9.07(s,1H),8.64(s,1H),7.96(s,1H),7.86(d,J＝15.5Hz,3H),7.72–7.37(m,4H).
实施例101：6-氨基-2-(3,5-二氯-4-((4-氯-2-(三氟甲基)喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例44为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-氯-2-(三氟甲基)喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝517.97(M+1) 1H NMR(500MHz,Chloroform)δ9.07(s,1H),8.01(s,1H),7.97(s,1H),7.87(s,2H),7.78–7.55(m,4H).
实施例102：6-氨基-2-(3,5-二氯-4-((2-甲基-4-苯基喹啉-6-基)氧)苯基-1,2,4-三嗪- 3,5(2H,4H)-二酮
以实施例45为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-甲基-4-苯基喹啉-6-基)氧)苯基-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝506.07(M+1) 1H NMR(500MHz,Chloroform)δ9.08(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).
实施例103：6-氨基-2-(3,5-二氯-4-((4-甲基-2-乙烯基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例46为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-乙烯基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝456.06(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,4H),7.88(d,J＝16.1Hz,12H),7.57(d,J＝15.0Hz,12H),7.35(d,J＝56.1Hz,9H),7.27(s,1H),7.21(s,2H),6.50(s,4H),5.71(s,4H),2.69(s,12H).
实施例104：6-氨基-2-(3,5-二甲基-4-((4-甲基-2-苯基喹啉-6-基)氧)苯基-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例47为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二甲基-4-((4-甲基-2-苯基喹啉-6-基)氧)苯基-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝466.18(M+1) 1H NMR(500MHz,Chloroform)δ9.05(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＝30.0Hz,4H),6.63(s,1H),2.69(s,3H),2.15(s,6H).
实施例105：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(吡咯烷-1-基)喹啉-6-氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例48为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(吡咯烷-1-基)喹啉-6-氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝499.10(M+1) 1H NMR(500MHz,Chloroform)δ9.10(s,66H),7.84(s,132H),7.64(d,J＝60.0Hz,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).
实施例106：6-氨基-2-(3,5-二氯-4-((2-甲基-4-(吡咯烷-1-基)喹啉-6-氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例49为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-甲基-4-(吡咯烷-1-基)喹啉-6-氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝499.10(M+1) 1H NMR(500MHz,Chloroform)δ9.07(s,2H),7.86(d,J＝3.1Hz,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).
实施例107：6-氨基-2-(3,5-二氯-4-((2-甲基-4-乙烯基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例50为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-甲基-4-乙烯基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝456.06(M+1) 1H NMR(500MHz,Chloroform)δ9.10(s,2H),7.88(d,J＝37.5Hz,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).
实施例108：6-氨基-2-(3,5-二甲基-4-((3-甲基-2-苯基喹啉-6-基)氧)苯基-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例51为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二甲基-4-((3-甲基-2-苯基喹啉-6-基)氧)苯基-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝466.18(M+1) 1H NMR(500MHz,Chloroform)δ9.05(s,1H),8.07(s,1H),7.83(t,J＝5.0Hz,5H),7.58–7.40(m,7H),2.56(s,3H),2.15(s,6H).
实施例109：6-氨基-2-(3,5-二氯-4-((2-氯-3-甲基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例52为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-氯-3-甲基喹啉-6-基)氧)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝464.00(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),7.84(d,J＝6.6Hz,3H),7.74(s,1H),7.58(s,2H),7.41(s,1H),7.34(s,1H),2.40(s,3H).
实施例110：6-氨基-2-(3,5-二氯-4-((3-甲基-2-苯基喹啉-6-基)氧)苯基-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例53为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((3-甲基-2-苯基喹啉-6-基)氧)苯基-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝506.07(M+1) 1H NMR(500MHz,Chloroform)δ9.08(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).
实施例111：6-氨基-2-(3,5-二氟-4-((4-甲基-2-苯基喹啉-6-基)氧苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例54为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氟-4-((4-甲基-2-苯基喹啉-6-基)氧苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝474.13(M+1) 1H NMR(500MHz,Chloroform)δ9.10(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＝80.0Hz,8H),6.63(s,2H),2.69(s,6H).
实施例112：6-氨基-2-(3-溴-5-甲基-4-(4-甲基-2-苯基喹啉-6-基)氧苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例55为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3-溴-5-甲基-4-(4-甲基-2-苯基喹啉-6-基)氧苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝530.07(M+1) 1H NMR(500MHz,Chloroform)δ9.06(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＝10.0Hz,3H),7.40(s,1H),6.63(s,1H),2.69(s,3H),2.15(s,3H).
实施例113：6-氨基-2-(3-溴-5-氯-4-(4-甲基-2-苯基喹啉-6-基)氧苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例56为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3-溴-5-氯-4-(4-甲基-2-苯基喹啉-6-基)氧苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝550.02(M+1) 1H  NMR(500MHz,Chloroform)δ9.08(s,2H),8.33(s,4H),8.10–7.56(m,11H),7.65(d,J＝15.0Hz,5H),7.65(d,J＝15.0Hz,4H),7.55(s,3H),7.49(s,5H),7.38(s,2H),6.63(s,2H),2.69(s,6H).
实施例114：6-氨基-2-(3-溴-5-氯-4-((3-氯-4-甲基-2-(三氟甲基)喹啉-6-基)氧苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例57为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3-溴-5-氯-4-((3-氯-4-甲基-2-(三氟甲基)喹啉-6-基)氧苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝575.94(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例115：2-(3,5-二氯-4-((2-乙基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((2-乙基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈M/Z＝468.03(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例116：2-(3,5-二氯-4-((2-异丙基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((2-异丙基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈M/Z＝482.02(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例117：2-(3,5-二氯-4-((2-环丙基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((2-环丙基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈M/Z＝480.01(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例118：2-(3,5-二氯-4-((2-环丁基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((2-环丁基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈M/Z＝494.01(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例119：2-(3,5-二氯-4-((2-环戊基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((2-环戊 基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈M/Z＝508.02(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例120：2-(3,5-二氯-4-((2-环己基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((2-环己基-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈M/Z＝521.11(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例121：2-(3,5-二氯-4-((2-(4,4-二甲基环己基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((2-(4,4-二甲基环己基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈M/Z＝550.15(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例122：2-(3,5-二氯-4-((2-(4,4-二氟环己基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((2-(4,4-二氟环己基)-4-甲基喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈M/Z＝558.04(M+1) 1H NMR(500MHz,Chloroform)δ9.08(s,1H),8.08–7.55(m,5H),7.65(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.45(d,J＝65.0Hz,2H),2.45(s,3H).
实施例123：2-(3,5-二氯-4-((4-甲基-2-(4-(三氟甲基)环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((4-甲基-2-(4-(三氟甲基)环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-碳腈M/Z＝590.03(M+1) 1H NMR(500MHz,Chloroform-d)δ7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.7Hz,1H),7.14(dd,J＝8.1,1.9Hz,1H),7.02(d,J＝1.1Hz,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).
实施例124：2-(4-((2-(双环[2.2.1]庚烷-2-基)-4-甲基喹啉-6-基)氧基)-3,5-二氯苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(4-((2-(双环[2.2.1]庚烷-2-基)-4-甲基喹啉-6-基)氧基)-3,5-二氯苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-碳腈M/Z＝534.32(M+1) 1H NMR(500MHz,Chloroform-d)δ7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.17–7.09(m,2H),2.88(dt,J＝6.0,4.3Hz,1H),2.71(s,3H),2.26(tt,J＝5.3,3.5Hz,1H),2.13(dp,J＝6.0,3.8Hz,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).
实施例125：2-(3,5-二氯-4-((4-甲基-2-(3-甲基环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((4-甲基-2-(3-甲基环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-碳腈M/Z＝536.39(M+1) 1H NMR(500MHz,Chloroform-d)δ7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.2,1.9Hz,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＝6.2Hz,3H).
实施例126：2-(3,5-二氯-4-((4-甲基-2-(2-甲基环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((4-甲基-2-(2-甲基环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-碳腈M/Z＝536.40(M+1) 1H NMR(500MHz,Chloroform-d)δ7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.1,1.9Hz,1H),7.03(s,1H),2.71(s,3H),2.54(dtd,J＝7.3,6.0,1.5Hz,1H),2.21(dddd,J＝12.6,9.5,6.8,6.0Hz,1H),1.99–1.85(m,2H),1.74–1.30(m,6H),0.95(dd,J＝6.8,1.5Hz,3H).
实施例127：2-(3,5-二氯-4-((4-甲基-2-(4-甲基环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-((4-甲基-2-(4-甲基环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-碳腈M/Z＝536.41(M+1) 1H NMR(500MHz,Chloroform-d)δ7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.1,1.9Hz,1H),7.02(d,J＝0.9Hz,1H),2.93–2.84(m,1H),2.71(s,3H),1.88(ddt,J＝12.0,8.8,6.0Hz,2H),1.78(ddt,J＝12.3,8.6,5.9Hz,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＝6.1Hz,3H).
实施例128：2-(3,5-二氯-4-(4-甲基-2-(3,3,5,5-四甲基环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
以相应的硼酸酯为原料使用实施例1所述方法进行制备得到2-(3,5-二氯-4-(4-甲基-2-(3,3,5,5-四甲基环己基)喹啉-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-碳腈M/Z＝578.48(M+1) 1H NMR(500MHz,Chloroform-d)δ7.67(s,1H),7.48(d,J＝1.7Hz,0H),7.20–7.11(m,1H),3.15–3.07(m,0H),2.71(s,1H),1.86(dd,J＝12.3,5.5Hz,1H),1.75(dd,J＝12.3,5.5Hz,1H),0.94(s,2H),0.89(s,2H).
实施例129：6-氨基-2-(3,5-二氯-4-(2-乙基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例115为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-(2-乙基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝458.21(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.82(d,J＝8.2Hz,1H),7.67(s,2H),7.47(d,J＝1.8Hz,1H),7.17–7.11(m,2H),5.17(s,2H),2.82(q,J＝7.1Hz,2H),2.65(s,2H),1.29(t,J＝7.1Hz,3H).
实施例130：6-氨基-2-(3,5-二氯-4-(2-异丙基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例116为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-(2-异丙基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝472.28(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.17–7.11(m,2H),5.17(s,2H),3.15(qd,J＝6.9,6.3Hz,1H),2.71(s,3H),1.30(d,J＝6.6Hz,6H).
实施例131：6-氨基-2-(3,5-二氯-4-((2-环丙基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例117为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-环丙基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝470.28(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.7Hz,1H),7.23(d,J＝1.0Hz,1H),7.14(dd,J＝8.1,1.9Hz,1H),5.17(s,2H),2.71(s,3H),2.46–2.38(m,1H),1.15(dq,J＝5.6,0.8Hz,4H).
实施例132：6-氨基-2-(3,5-二氯-4-((2-环丁基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例118为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-环丁基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝484.21(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.7Hz,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).
实施例133：6-氨基-2-(3,5-二氯-4-((2-环戊基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例119为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-环戊基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝498.14(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.1,1.9Hz,1H),7.02(d,J＝1.1Hz,1H),5.17(s,2H),3.20–3.12(m,1H),2.71(s,3H),1.91–1.67(m,7H).
实施例134：6-氨基-2-(3,5-二氯-4-((2-环己基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例120为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-环己基-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝ 512.29(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.1,1.9Hz,1H),7.02(d,J＝1.1Hz,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).
实施例135：6-氨基-2-(3,5-二氯-4-((2-(4,4-二甲基环己基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例121为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4,4-二甲基环己基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝540.35(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.2,1.9Hz,1H),7.02(d,J＝0.9Hz,1H),5.17(s,2H),2.94–2.86(m,1H),2.71(s,3H),1.88(dddd,J＝12.5,9.9,7.2,5.5Hz,2H),1.79–1.68(m,2H),1.54(ddd,J＝12.4,9.7,7.1Hz,2H),1.44(ddd,J＝12.5,9.9,7.2Hz,2H),0.86(s,5H).
实施例136：6-氨基-2-(3,5-二氯-4-((2-(4,4-二氟环己基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例122为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((2-(4,4-二氟环己基)-4-甲基喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝548.27(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.1,1.9Hz,1H),7.02(d,J＝0.9Hz,1H),5.17(s,2H),3.05–2.96(m,1H),2.71(s,3H),2.15–1.86(m,9H).
实施例137：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(4-(三氟甲基)环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例123为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(4-(三氟甲基)环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝580.29(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.7Hz,1H),7.14(dd,J＝8.2,1.9Hz,1H),7.02(d,J＝0.9Hz,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).
实施例138：6-氨基-2-(4-(2-(双环[2.2.1]庚烷-2-基)-4-甲基喹啉-6-基)氧基)-3,5-二氯苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例124为原料，使用实施例58所述方法进行制备得到6-氨基-2-(4-(2-(双环[2.2.1]庚烷-2-基)-4-甲基喹啉-6-基)氧基)-3,5-二氯苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝524.30(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.2,1.9Hz,1H),7.11(d,J＝0.9Hz,1H),5.17(s,2H),2.88(dt,J＝6.0,4.3Hz,1H),2.71(s,3H),2.26(tt,J＝5.3,3.6Hz,1H),2.13(dp,J＝6.0,3.8Hz,1H),2.01(ddd,J＝12.5,5.3,4.5Hz,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).
实施例139：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(3-甲基环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例125为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(3-甲基环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝526.32(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.8Hz,1H),7.14(dd,J＝8.1,1.9Hz,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＝6.2Hz,3H).
实施例140：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-甲基环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例126为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(2-甲基环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝526.32(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.7Hz,1H),7.14(dd,J＝8.1,1.9Hz,1H),7.03(s,1H),5.17(s,2H),2.71(s,3H),2.54(dtd,J＝7.2,5.9,1.5Hz,1H),2.21(dddd,J＝12.6,9.5,6.8,5.9Hz,1H),1.99–1.85(m,2H),1.74–1.40(m,5H),1.35(ddt,J＝11.8,8.2,5.8Hz,1H),0.95(dd,J＝6.8,1.5Hz,3H).
实施例141：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(4-甲基环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例127为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(4-甲基环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝526.32(M+1) 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),7.85(d,J＝8.2Hz,1H),7.67(s,2H),7.48(d,J＝1.7Hz,1H),7.14(dd,J＝8.2,1.9Hz,1H),7.02(d,J＝0.9Hz,1H),5.17(s,2H),2.93–2.84(m,1H),2.71(s,3H),1.88(ddt,J＝12.0,8.8,5.9Hz,2H),1.78(ddt,J＝12.3,8.6,6.0Hz,2H),1.60(ddt,J＝12.0,8.6,5.9Hz,2H),1.54–1.44(m,1H),1.39–1.29(m,2H),0.92(d,J＝6.1Hz,3H).
实施例142：6-氨基-2-(3,5-二氯-4-((4-甲基-2-(3,3,5,5-四甲基环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮
以实施例128为原料，使用实施例58所述方法进行制备得到6-氨基-2-(3,5-二氯-4-((4-甲基-2-(3,3,5,5-四甲基环己基)喹啉-6-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮M/Z＝568.40(M+1) 1H NMR(500MHz,Chloroform-d)δ7.67(s,1H),7.48(d,J＝1.7Hz,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＝12.3,5.5Hz,1H),1.75(dd,J＝12.3,5.5Hz,1H),0.94(s,2H),0.89(s,2H).
生物测试实验
1.1体外分子水平THRβ激动活性评价
在分子水平，我们通过AlphaScreen检测方式来测定化合物与甲状腺激素受体β(THRβ)的结合能力。首先，构建重组GST-THRβ融合蛋白，后在384孔板中进行化合 物与受体结合的反应。将重组蛋白、激动剂、辅调节因子、
Figure PCTCN2022142988-appb-000009
受体微珠和
Figure PCTCN2022142988-appb-000010
供体微珠的混合液在Tris-HCl(pH7.4)缓冲液中进行反应，若化合物能够与受体蛋白发生结合，
Figure PCTCN2022142988-appb-000011
受体微珠和
Figure PCTCN2022142988-appb-000012
供体微珠的相对位置发生改变，则会发出特定波长的荧光。我们通过荧光检测仪Envision检测荧光信号强度以表征化合物与THRβ的结合活性。并通过软件Graphpad Prism 7计算化合物EC50。
1.2体外细胞水平THRβ激动活性评价
在细胞水平检测其结合时，利用FH-THRα/β表达质粒、pal-luciferase报告质粒和RL-TK质粒，将三者共转染至293T细胞后接种于96孔平底微孔板，培养细胞24h确保质粒表达。加入待测TRα/β激动剂，18h后利用双荧光试剂检测试剂盒(Dual-Luciferase Reporter Assay System)检测，以萤火虫荧光素酶为报告基因，以海肾荧光素酶为内参基因。通过荧光检测仪Envision检测生物荧光强度，即可反映化合物对TRα/β受体的激活效率。
1.3药代动力学研究
主要是对上述研究获得的活性优良的目标化合物进行小鼠或大鼠的初步药代动力学研究，详细考察化合物口服、腹腔和静脉给药下的药代动力学性质，计算其体内暴露量(AUC)、峰浓度(Cmax)、达峰时间(T max)、半衰期(T 1/2)和其生物利用度(F)等参数，为化合物的进一步结构修饰与优化提供线索，同时为体内给药剂量设计提供依据。
1.4体内药效评价
1.4.1急性药效学评价
采用小鼠或大鼠单次口服给药，给药后3个时间点取肝脏和心脏，检测靶器官-肝脏THRβ受体下游基因(DIO1、ME、CYP7α1、LDLR)的表达，检测毒副作用涉及器官-心脏THRβ受体下游基因(DIO1、MHCα)的表达。
1.4.2慢性药效学评价
采用高脂饲料诱导obob小鼠建立NAFLD模型及高脂高果糖饮食诱导的NASH模型，受试物及阳性化合物MGL-3196长期给药3周后，检测肝脏中TC、TG含量。
1.5体内安全性评价
正常SD大鼠，进行甲状腺切除后，恢复1-2周，按体重分组后给予受试物及阳性化合物MGL-3196，于给药6h后安乐死后取心脏组织，考察单次给药心脏αMHC基因的表达。
实验结果
2.1体外THRβ激动活性及选择性测试
在分子水平和细胞水平分别对上述合成的化合物进行了初步的体外THRβ激动活性测试。结果发现多个化合物均具有良好的THRβ激动活性，并且对THRα有较好的选择性，其中化合物38和95的EC 50值分别为13.2nM和2.5nM(如表1)，比Ⅲ期临床药物Resmetirom(MGL-3196)激动活性(EC 50＝129.5nM)提高2.5倍和39倍。目前我们通过体外活性评价以及构效关系研究已获得三类激动剂：1)THRβ全激动，THRα部分激动，有选择性，2)THRβ部分激动，THRα不激动，高选择性，3)THRβ全激动，THRα全激动，低选择性。分子实验结果如图1所示。
随后在细胞水平测试该类化合物对THRβ和THRα的激动活性，结果如图2所示，该类化合物的细胞结果与分子结果一致，在细胞实验中发现，化合物2、3和38细胞的EC 50分别为1026nM、911nM和165.9nM，对比MGL-3196的3415nM具有明显的激动活性。化合物2与化合物3的特点尤为突出，几乎完全不激活THRα受体， 选择性在1000倍以上，远远优于MGL-3196的17倍，同时具有部分激动剂的特征。而化合物38的选择性达到了40倍，也显著优于MGL-3196，并且保持了完全激动能力。该类化合物极具开发前景。
其中化合物3，42和43是部分激动剂，对THRβ的激动活性小于70％，同时具有良好的选择性，提示该类化合物是THRβ部分激动剂并具有良好的THRα选择性。
表1化合物体外分子评价体系活性数据
Figure PCTCN2022142988-appb-000013
表2化合物体外细胞评价体系活性数据
Figure PCTCN2022142988-appb-000014
2.2药代动力学测试
基于化合物38良好的体外TRβ激动活性和选择性，我们选择38进行初步成药性 评价，开展小鼠药代动力学性质的研究。如表3所示，化合物38具有良好的药代动力学性质，其半衰期达到4.44小时，体内暴露量较高，达到156427h*ng/mL，生物利用度达到75.8％。
表3. 38药代动力学数据
Figure PCTCN2022142988-appb-000015
为了进一步评价化合物的初步成药性，我们开展小鼠的组织分布研究，如表4所示，化合物38组织分布数据显示出肝里分布多，且心脏里分布少的特点,肝脏中药物浓度是心脏中药物浓度的23倍，体现出良好的肝脏靶向性，提示该化合物对心脏毒性的影响较弱。
表4.小鼠10mg/kg口服给药化合物38，组织分布数据
Figure PCTCN2022142988-appb-000016
另外由于化合物3在体外实验中呈现的良好的活性与完全的TRβ选择性，我们对化合物3也进行了初步的成药性评价，在小鼠中进行了一系列药代动力学研究，结果如图表5所示。化合物3具有优良的药代动力学性质，半衰期为4.71小时，体内暴露量达到79362h*ng/mL，生物利用度为36.3％。
表5.化合物3药代动力学数据
Figure PCTCN2022142988-appb-000017
Figure PCTCN2022142988-appb-000018
我们也进一步对化合物3进行了小鼠体内组织分布研究以进一步评价其初步成药性，结果如表6所示。可以看到化合物在肝脏中的分布远大于心脏中的分布，大约为10倍，并且在肝脏中化合物3分布很少，这对于心脏毒性的产生具有积极影响。
表6.小鼠10mg/kg口服给药化合物38，组织分布数据
Figure PCTCN2022142988-appb-000019
2.3体内药效研究
我们选择高活性选择性好化合物38进行体内的急性药效学评价，采用C57小鼠，考察单次给药后靶器官-肝脏组织内THRβ受体下游基因的表达，结果显示，阳性对照组T3(内源性的高活性无选择性甲状腺激素；0.5mg/kg)给药8h后能显著上调肝脏中CYP7α1及LDLR基因表达；给药8、24h后能显著上调肝脏中DIO1基因表达；38(10mg/kg)给药24h后能显著上调肝脏中CYP7α1、ME2、LDLR基因表达；给药8、24h后能显著上调肝脏中DIO1基因表达，优于同剂量MGL3196(见图2)。
甲状腺摘除大鼠中心脏下游基因表达，化合物38和MGL3196对心脏DIO1及MHCα基因作用均不明显(见图3)，说明化合物38对心脏的安全性较高。
化合物对CDAHFD饲料诱导的NAFLD模型小鼠的药效学评价，受试物及阳性化合物MGL-3196长期给药2周和4周后，血浆中TC含量均下降，化合物38的1mg/kg和10mg/kg剂量组均能下降血浆中TC含量(见图4)。
化合物对高脂饲料诱导的金黄地鼠模型小鼠的急性药效学评价,受试物给药21天后，化合物38在10mg/kg剂量下使得血清TC/TG水平及LCL-C水平显著下降(见图 5)。
我们也对部分激动剂化合物3进行了初步的体内极性药效学评价，实验方法同化合物38。结果显示，化合物3在给药后3h后显著上调肝脏DIO1基因表达(见图6)，药效凸显快，在给药8h后作用开始减弱，但相对于阴性对照组仍具有作用，相比于MGL-3196可能具有不同的应用场景。。
在C57小鼠中，对化合物3给药后的安全性进行了初步评估，发现化合物3并不会导致心脏的MHCα的上调，整体趋势与MGL-3196一致，因此具有较高的安全性(图7)。
我们也在C57小鼠中对化合物3是否对甲状腺轴存在抑制作用进行了验证，结果见图8，化合物3在高剂量给药的情况下并未对甲状腺激素水平产生影响，说明其安全性可能优于MGL-3196。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种具有式(Ⅰ)所示结构的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药：
    Figure PCTCN2022142988-appb-100001
    其中，
    Figure PCTCN2022142988-appb-100002
    Rb、Rc和R 7各自独立地位于喹啉环的任意可取代环原子上；
    Rb和Rc各自独立地选自下组：氘，氚，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C1-C6烷氧基，C3-C8环烷基，3-8元杂环基，苯基，C5-C7杂芳基，C5-C6取代杂芳基；且Rb与Rc为不同取代基；
    R 7为位于喹啉苯环上的一个或多个(如1个、2个、3个或4个)选自下组的取代基：H、氘、氚、卤素，C1-C6烷基，C1-C6卤代烷基；
    X选自下组：-O-、-CH 2-、-C(＝O)-、-CH(OH)-、-S-；
    R 1、R 2、R 3和R 4各自独立地选自下组：H、D、F、Cl、Br、I、-CN、-OH、-NO 2、-OR 1a、-NR 1bR 1c、-SR 1b、C1-C6烷基，C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C5-C6芳基，或5-6元杂芳基；
    R 5选自下组：H、D、F、Cl、Br、I、-CN、-OH、-NO 2、-OR 1a、-NR 1bR 1c、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-S(O) 2NR 1aR 1b、-NHS(O) 2R 1a、-C(O)R 1a、-OC(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、-NHC(O)R 1a、C1-C6烷基，C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环基、C5-C6芳基或5-6元杂芳基；
    R 6选自下组：H、氘、氚、卤素、C1-C6烷基、氨基取代的C1-C6烷基、C3-C8环烷基、3-8元杂环基、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-C(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c；
    除非特别说明，上述的各个烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基可任选地具有1-3个选自下组的取代基：氘、氚、卤素、-CN、-OH、氧代、-OR 1a、-NR 1bR 1c、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-S(O) 2NR 1aR 1b、-NHS(O) 2R 1a、-C(O)R 1a、-OC(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、-NHC(O)R 1a、C1-C6烷基、C1-C6卤代烷基；
    R 1a、R 1b和R 1c各自独立地选自H、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C5-C6芳基或5-6元杂芳基。
  2. 如权利要求1所述的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药，其特征在于，所述的Rb选自下组：C1-C6卤代烷基，C3-C8环烷基，3-8元杂环基，苯基，C5-C7杂芳基；且所述的苯基或杂芳基可任选地具有1-3个选自下组的取代基：氘、氚、卤素、-CN、-OH、氧代、-OR 1a、- NR 1bR 1c、-C(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、C1-C6烷基、C1-C6卤代烷基；
    所述的Rc选自下组：卤素，C1-C6烷基，C1-C6烷氧基，C1-C6卤代烷基，C1-C6氘代烷基。
  3. 如权利要求1所述的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药，其特征在于，所述的式I化合物具有如下式Ia所示的结构：
    Figure PCTCN2022142988-appb-100003
  4. 如权利要求1所述的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药，其特征在于，所述的式I化合物具有如下式Ib或Ic所示的结构：
    Figure PCTCN2022142988-appb-100004
  5. 如权利要求1所述的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药，其特征在于，R 1、R 2、R 3、R 4各自独立地选自H、D、卤素、C1-C4烷基。
  6. 如权利要求1所述的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药，其特征在于，所述的R 5选自下组：H、D、卤素、-CN、NHR 1b；其中，所述的R 1b选自H、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基；所述的R 6为H或D。
  7. 如权利要求1所述的化合物，包含其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药：
    Figure PCTCN2022142988-appb-100005
    Figure PCTCN2022142988-appb-100006
    Figure PCTCN2022142988-appb-100007
    Figure PCTCN2022142988-appb-100008
    Figure PCTCN2022142988-appb-100009
    Figure PCTCN2022142988-appb-100010
    Figure PCTCN2022142988-appb-100011
    Figure PCTCN2022142988-appb-100012
    Figure PCTCN2022142988-appb-100013
    Figure PCTCN2022142988-appb-100014
    Figure PCTCN2022142988-appb-100015
    Figure PCTCN2022142988-appb-100016
    Figure PCTCN2022142988-appb-100017
    Figure PCTCN2022142988-appb-100018
    Figure PCTCN2022142988-appb-100019
    Figure PCTCN2022142988-appb-100020
  8. 一种具有式(ⅠI)所示结构的化合物，或其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药：
    Figure PCTCN2022142988-appb-100021
    其中，
    Rd和Re各自独立地选自下组：H、卤素，C1-C6烷基，C1-C6卤代烷基；且Rd和Re中至少一个为卤素；
    R 7为位于喹啉苯环上的一个或多个(如1个、2个、3个或4个)选自下组的取代基：H、卤素，C1-C6烷基，C1-C6卤代烷基；
    X选自下组：-O-、-CH 2-、-C(＝O)-、-CH(OH)-、-S-；
    R 1、R 2、R 3和R 4各自独立地选自下组：H、D、F、Cl、Br、I、-CN、-OH、-NO 2、-OR 1a、-NR 1bR 1c、-SR 1b、C1-C6烷基，C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C5-C6芳基，或5-6元杂芳基；
    R 5选自下组：H、D、F、Cl、Br、I、-CN、-OH、-NO 2、-OR 1a、-NR 1bR 1c、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-S(O) 2NR 1aR 1b、-NHS(O) 2R 1a、-C(O)R 1a、-OC(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、-NHC(O)R 1a、C1-C6烷基，C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环基、C5-C6芳基或5-6元杂芳基；
    R 6选自下组：H、氘、C1-C6烷基、氨基取代的C1-C6烷基、C3-C8环烷基、3-8元杂环基、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-C(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c；
    除非特别说明，上述的各个烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基可任选地具有1-3个选自下组的取代基：氘、卤素、-CN、-OH、氧代、-OR 1a、-NR 1bR 1c、-SR 1b、-S(O)R 1a、-S(O) 2R 1a、-S(O)NR 1aR 1b、-S(O) 2NR 1aR 1b、-NHS(O) 2R 1a、-C(O)R 1a、-OC(O)R 1a、-C(O)OR 1b、-C(O)NR 1bR 1c、-NHC(O)R 1a、C1-C6烷基、C1-C6卤代烷基；
    R 1a、R 1b和R 1c各自独立地选自H、氘、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、C5-C6芳基或5-6元杂芳基。
  9. 如权利要求1所述的化合物，包含其立体异构体，氘代化合物，溶剂化物，代谢产物，药学上可接受的盐，共晶或前药，其特征在于，R 1、R 2、R 3、R 4各自独立地选自H、D、卤素、C1-C4烷基。
  10. 一种药物组合物，其特征在于，所述的药物组合物包括如权利要求1或8任一所述的化合物，其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药，以及药学上可接受的辅料和\或载体。
  11. 如权利要求1或8任一所述的化合物，或其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药在制备药物中的用途；其中，所述药物用于激动甲状腺激素受体，或用于预防、治疗或减轻甲状腺激素受体调节的疾病。
  12. 如权利要求11所述的用途，其特征在于，所述的甲状腺激素受体介导的疾病 选自下组：非酒精性脂肪性肝病，动脉粥样硬化，冠心病，高血压，高胆固醇血症，高脂血症，高甘油三酯症，血脂异常，肥胖，糖尿病，代谢紊乱，脂质代谢紊乱，1A型糖原贮积病，甲状腺功能减退症，或甲状腺癌。
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