Compounds as thyroid hormone beta receptor agonists and their uses

Abstract

The present invention relates to compounds and their uses as thyroid hormone β receptor agonists, and also to pharmaceutical compositions containing said compounds. The compounds or pharmaceutical compositions of the present invention can be used in the manufacture of a medicament for preventing, treating, or alleviating diseases regulated by thyroid hormone β receptors, in particular for the manufacture of a medicament for treating non-alcoholic fatty liver disease.

Description

[Technical Field]

[0001] The present invention relates to the field of medicines, specifically to compounds and their uses as thyroid hormone beta receptor agonists, and to pharmaceutical compositions containing said compounds. The present invention further relates to the use of said compounds and pharmaceutical compositions in the manufacture of medicaments for preventing, treating, or alleviating diseases regulated by thyroid hormone beta receptors, particularly in the manufacture of medicaments for treating non-alcoholic fatty liver disease. [Background technology]

[0002] Thyroid hormones (THs) play crucial roles in growth, differentiation, development, and maintaining metabolic balance. They are synthesized by the thyroid gland and secreted into the circulation in two major forms: triiodothyronine (T3) and tetraiodothyronine (T4). T4 is the primary form secreted by the thyroid gland, but T3 is the physiologically more active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues but primarily in the liver and kidney.

[0003] The physiological actions of thyroid hormones are primarily mediated by thyroid hormone receptors (TRs). TRs are members of the nuclear receptor superfamily and are transcription factors induced by the ligand T3, playing a central role in mediating the role of the ligand T3. TRs are primarily located in the cell nucleus and form heterodimers with the retinoic acid X receptor (RXR) and other nuclear receptors to bind to the thyroid hormone response element (TRE) in the promoter of target genes, thereby regulating gene transcription. There are two subtypes of TRs: TRα and TRβ. TRα is further divided into TRα1 and TRα2, and TRβ is further divided into TRβ1 and TRβ2. Of these, only TRα1, TRβ1, and TRβ2 can bind to the ligand T3. TRα primarily regulates heart rate, while TRβ plays an important role in regulating hepatic cholesterol metabolism and suppressing thyroid-stimulating hormone (TSH) release, which may be related to the high expression of TRβ in the liver and pituitary gland.

[0004] If side effects can be minimized or eliminated, THs have a certain therapeutic effect (Paul M. Yen et al., Physiological Reviews, Vol. 81(3): pp. 1097-1126 (2001); Paul Webb et al., Expert Opin. Investig. Drugs, Vol. 13(5): pp. 489-500 (2004)). For example, THs can reduce body weight by increasing metabolic rate, oxygen consumption, and heat production. Weight reduction has beneficial effects on obese patients by improving obesity-related complications, and has beneficial effects on glycemic control in obese patients with type 2 diabetes.

[0005] TH can also reduce serum low-density lipoprotein (LDL) (Eugene Morkin et al., Journal of Molecular and Cellular Cardiology, Vol. 37: pp. 1137-1146 (2004)). It has been discovered that hyperthyroidism is associated with low serum total cholesterol, which is due to TH increasing hepatic LDL receptor expression and stimulating cholesterol metabolism into bile acids (JJ Abrams et al., J. Lipid Res., Vol. 22: pp. 323-38 (1981)). It has been reported that hypothyroidism is associated with hypercholesterolemia and that TH replacement therapy reduces total cholesterol (M. Aviram et al. Clin. Biochem., Vol. 15: pp. 62-66 (1982), JJ. Abrams et al. J. Lipid Res., Vol. 22: pp. 323-38 (1981)). In animal models, TH has shown beneficial effects by increasing HDL cholesterol and improving the conversion rate of LDL to HDL by increasing the expression of apo A-1 (one of the major apolipoproteins in HDL) (Gene C. Ness et al., Biochemical Pharmacology, Vol. 56: pp. 121-129 (1998); GJ. Grover et al., Endocrinology, Vol. 145: pp. 1656-1661 (2004); GJ. Grover et al., Proc. Natl. Acad. Sci. USA, Vol. 100: pp. 10067-10072 (2003)). The incidence of atherosclerotic vascular disease is directly related to LDL cholesterol levels, and TH, through its regulatory effects on LDL and HDL, may also reduce the risk of atherosclerosis and other cardiovascular diseases.There is also evidence that TH reduces lipoprotein(a), an important risk factor that is elevated in patients with atherosclerosis (Paul Webb et al. Expert Opin. Investig. Drugs, Vol. 13(5): pp. 489-500 (2004); de Bruin et al. J. Clin. Endo. Metab., Vol. 76: pp. 121-126 (1993)).

[0006] TH is also an important signal for oligodendrocyte differentiation and myelination during development and stimulates remyelination in adult models of multiple sclerosis (MS) (Calza et al., Brain Res Revs 48:339-346, 2005). However, TH cannot be applied for long-term treatment due to the limited therapeutic window for achieving remyelination while avoiding the cardiotoxicity and bone demineralization associated with chronic hyperthyroidism. Some TH analogs can activate TH-responsive genes while utilizing the molecular and physiological characteristics of the TH receptor to avoid the associated drawbacks of TH (Malm et al., Mini Rev Med Chem 7:79-86, 2007).

[0007] Nonalcoholic fatty liver disease (NAFLD) is also closely related to TH. NAFLD affects the conversion and inactivation of TH, resulting in decreased serum TH levels. Decreased TH levels, in turn, cause lipid and glucose metabolism disorders, contributing to the development of NAFLD. One study showed that fatty liver was induced in rats using a choline-methionine deficient diet, and subsequent feeding of T3 reversed the fatty liver (Perra A, et al., Faseb, 2008, 22(8):2981).

[0008] However, endogenous TH is nonselective and has side effects such as hyperthyroidism, particularly those related to cardiovascular toxicity. Therefore, the development of TH analogs (e.g., thyroid hormone β receptor agonists) that avoid the adverse effects of hyperthyroidism while retaining the beneficial effects of TH would provide a new approach to treating patients suffering from obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic fatty liver disease, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disorders, and related diseases and disorders. [Prior art documents] [Patent documents]

[0009] [Non-Patent Document 1] Paul M.Yen et.al.Physiological Reviews, Vol.81(3):pp.1097-1126(2001) [Non-patent document 2] Paul Webb et.al.Expert Opin.Investig.Drugs, Vol.13(5):pp.489-500(2004) [Non-patent document 3] Eugene Morkin et.al.Journal of Molecular and Cellular Cardiology, Vol.37:pp.1137-1146(2004) [Non-patent document 4] J. Abrams et.al. J. Lipid Res., Vol.22:pp.323-38(1981) [Non-Patent Document 5] M.Aviram et.al.Clin.Biochem., Vol.15:pp.62-66(1982) [Non-patent document 6] J. Abrams et.al. J. Lipid Res., Vol.22:pp.323-38(1981) [Non-Patent Document 7] Gene C.Ness et.al.Biochemical Pharmacology, Vol.56:pp.121-129(1998) [Non-patent document 8] G.J.Grover et.al.Endocrinology, Vol.145:pp.1656-1661(2004) [Non-Patent Document 9] GJ.Grover et.al.Proc.Natl.Acad.Sci.USA, Vol.100:pp.10067-10072(2003) [Non-Patent Document 10] Paul Webb et.al.Expert Opin.Investig.Drugs, Vol.13(5):pp.489-500(2004) [Non-Patent Document 11] de Bruin et.al.J.Clin.Endo.Metab., Vol.76:pp.121-126(1993) [Non-Patent Document 12] Calza et al., Brain Res Revs 48:339-346,2005 [Non-Patent Document 13] Malm et.al.Mini Rev Med Chem 7:79-86, 2007 [Non-Patent Document 14] Perra A, et al.Faseb, 2008,22(8):2981 Summary of the Invention

[0010] The present invention provides compounds that have excellent agonist activity against thyroid hormone β receptors, and such compounds and pharmaceutical compositions thereof can be used to manufacture medicaments for preventing, treating, or alleviating non-alcoholic fatty liver disease, hepatic fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism, or thyroid cancer in patients.

[0011] In one aspect, the present invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (I): [ka] (In the formula, Y is -O-, -S-, or -NR 0 -, -C(=O)-, C 1-6 Alkylene group, C 2-6 Alkenylene group, C 2-6 Alkynylene group, -NR 0 C(=O)- or -C(=O)NR 0 -, wherein Y is 1, 2 or 3 R x may be substituted with R 0 are H, deuterium, and C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl or cyano C 1-6 is an alkyl group, R 3a , R 3b , R 3c and R 3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl or cyano C 1-6 is an alkyl group, R 1 are H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl group, C 2-6 Alkenyl group, C2-6 Alkynyl group, -C(=O)-C 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkylamino group, -C(=O)NH2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylamino group, -S(=O)2NH2, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl or cyano C 1-6 is an alkyl group, R 2 are H, deuterium, and C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 an aryl group or a 5- to 6-membered heteroaryl group, Ring A is [ka] wherein ring A is selected from the group consisting of 1, 2 or 3 R y may be substituted with E1, U1 and Z1 each independently represent -(CR 4a R 4b ) q -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR a - and E2, U2 and Z2 each independently represent -CR 4c R 4d -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR b - and E3, E6, U3 and Z3 each independently represent -CR 4e R 4f-, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR c - and E4 is -CR 4g = or -N =, and E5 is -CR 4h = or -N =, q is 0, 1, 2 or 3. R a , R b , R c and R 5 are independently H, deuterium, and C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 an aryl group or a 5- to 6-membered heteroaryl group, among which the R a , R b , R c and R 5 independently, 1, 2 or 3 R y1 may be substituted with R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h are each independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyl-C 1-4 Alkylene group, 5- to 6-membered heterocyclic group, (5- to 6-membered heterocyclic group)-C 1-4 Alkylene group, C 6-10 Aryl group, C 6-10Aryl-C 1-4 Alkylene group, 5- to 6-membered heteroaryl group, or (5- to 6-membered heteroaryl group)-C 1-4 alkylene groups, among which the R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h independently, 1, 2 or 3 R y2 may be substituted with Or, R 4a , R 4b C along with the carbon atoms to which they are attached 3-8 forming a carbocyclic ring or a 5- to 6-membered heterocyclic ring, or R 4c , R 4d C along with the carbon atoms to which they are attached 3-8 forming a carbocyclic ring or a 5- to 6-membered heterocyclic ring, or R 4e , R 4f C along with the carbon atoms to which they are attached 3-8 forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, 3-8 The carbocycle and the 5- to 6-membered heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 R y3 may be substituted with Each R x are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy group or C 1-6 is an alkylamino group, Each R y are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy group or C 1-6 alkylamino group, or two R on adjacent atoms y C along with the atoms to which they are attached3-8 forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, 3-8 The carbocycle and the 5- to 6-membered heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 R y4 may be substituted with Each R y1 are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkylamino group, -C(=O)NH2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylamino group, -S(=O)2NH2, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 is an aryl group or a 5- to 6-membered heteroaryl group, y1 is one, two or three R z may be substituted with R z , R y2 , R y3 and R y4 are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -COOH, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy group, C 1-6 Alkylthio group or C 1-6 It is an alkylamino group. In some embodiments, R 3a , R 3b , R 3c and R 3dare each independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a methylthio group, a methylamino group, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, a hydroxymethyl group, an aminomethyl group, or a cyanomethyl group.

[0012] In some embodiments, R 1 stands for H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl group, ethyl group, n-propyl group, isopropyl group, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C(=O)-OCH3, -C(=O)-OCH2CH3, -C(=O)-OCH(CH3)2, -C(=O)-OCH2CH2CH3, -C(=O)-O(CH2)3CH3, -C(=O)-OCH2CH(CH3)2, -C(=O)-CH3, -C(= O)-CH2CH3, -C(=O)-NHCH3, -C(=O)-N(CH3)2, -C(=O)NH2, -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-NHCH3, -S(=O)2NH2, methylamino group, ethylamino group, methoxy group, ethoxy group, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, hydroxymethyl group, aminomethyl group, carboxymethyl group or cyanomethyl group.

[0013] In some embodiments, R a , R b , R c and R 5 are independently H, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 is an aryl group or a 5- to 6-membered heteroaryl group,a , R b , R c and R 5 is unsubstituted or contains 1, 2 or 3 R y1 and R y1 is as defined in the present invention.

[0014] In some embodiments, R a , R b , R c and R 5 are each independently H, deuterium, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyrrolidinyl group, a pyrazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a piperazinyl group, a phenyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrimidinyl group, a pyridyl group, a pyrrolyl group, a pyrazinyl group, a thiazolyl group, or an oxazolyl group; a , R b , R c and R 5 independently, 1, 2 or 3 R y1 and R y1 is as defined in the present invention.

[0015] In some embodiments, each R y1 are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-C 1-4 Alkyl group, -C(=O)-C 1-4 Alkoxy group, -C(=O)-C 1-4 Alkyl group, -C(=O)-C 1-4 Alkylamino group, -C(=O)NH2, -S(=O)2-C 1-4 Alkyl group, -S(=O)2-C 1-4Alkylamino group, -S(=O)2NH2, C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy group, C 1-4 Alkylthio group, C 1-4 Alkylamino group, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 an aryl group or a 5- to 6-membered heteroaryl group, and each R y1 independently, 1, 2 or 3 R z and R z is as defined in the present invention.

[0016] In some embodiments, each R y1 are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-methyl, -OC(=O)-ethyl, -OC(=O)-n-propyl, -OC(=O)-isopropyl, -OC(=O)-n-butyl, -OC(=O)-tert-butyl, -OC(=O)-isobutyl, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl -propyl group, -C(=O)O-butyl group, -C(=O)O-tert-butyl group, -C(=O)O-isobutyl group, -C(=O)-methyl group, -C(=O)-ethyl group, -C(=O)-n-propyl group, -C(=O)-isopropyl group, -C(=O)-n-butyl group, -C(=O)-tert-butyl group, -C(=O)-isobutyl group, -C(=O)-methylamino group, -C(=O)-ethylamino group, -C(=O)NH2, -S(=O)2-C 1-3 Alkyl group, -S(=O)2-C 1-3Alkylamino group, -S(=O)2NH2, methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCHFCH3, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, methylthio group, ethylthio group, methylamino group, ethylamino group, cyclo propyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, pyrazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyranyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, phenylfuranyl group, thienyl group, imidazolyl group, pyrimidinyl group, pyridyl group, pyrrolyl group, pyridazinyl group, pyrazinyl group, thiazolyl group or oxazolyl group, y1 independently, 1, 2 or 3 R z and R z is as defined in the present invention.

[0017] In some embodiments, R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4hare each independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, methoxy group, ethoxy group, methylamino group, ethylamino group, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, pyrrolidinyl group, pyrazolidinyl group, tetrahydrofuran R is a phenyl group, a tetrahydrothienyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a piperazinyl group, a pyrrolidinyl-CH2-, a pyrazolidinyl-CH2-, a tetrahydrofuranyl-CH2-, a tetrahydrothienyl-CH2-, a piperidinyl-CH2-, a morpholinyl-CH2-, a thiomorpholinyl-CH2-, a piperazinyl-CH2-, a phenyl group, a phenyl-CH2-, a phenyl-CH2CH2-, a furanyl group, a thienyl group, an imidazolyl group, a pyrimidinyl group, a pyridyl group, a pyrrolyl group, a pyridazinyl group, a pyrazinyl group, a thiazolyl group, an oxazolyl group, a furanyl-CH2-, a thienyl-CH2-, an imidazolyl-CH2-, a pyrimidinyl-CH2-, a pyridyl-CH2-, or a pyrrolyl-CH2-; 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h independently, 1, 2 or 3 R y2 may be substituted with Or, R 4a , R 4b C along with the carbon atoms to which they are attached 3-6 forming a carbocyclic ring or a 5- to 6-membered heterocyclic ring, or R 4c , R 4d C along with the carbon atoms to which they are attached 3-6 forming a carbocyclic ring or a 5- to 6-membered heterocyclic ring, or R4e , R 4f C along with the carbon atoms to which they are attached 3-6 forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, 3-6 The carbocycle and the 5- to 6-membered heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 R y3 may be substituted with, among which R y2 and R y3 is as defined in the present invention.

[0018] In some embodiments, R z , R y2 , R y3 and R y4 are each independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -COOH, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, a methoxy group, an ethoxy group, or a methylamino group.

[0019] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention and optionally any one or any combination of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle.

[0020] In one aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament for agonizing thyroid hormone receptors or for preventing, treating or ameliorating a disease modulated by thyroid hormone receptors.

[0021] In some embodiments, the thyroid hormone receptor according to the present invention is a thyroid hormone beta receptor.

[0022] In some embodiments, the disease modulated by thyroid hormone receptors according to the present invention is a neurodegenerative disease, non-alcoholic fatty liver disease, idiopathic pulmonary fibrosis (IPF), atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism, or thyroid cancer.

[0023] In another aspect the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament for the prevention, treatment or amelioration of neurodegenerative diseases, non-alcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism or thyroid cancer.

[0024] In some embodiments, the non-alcoholic fatty liver disease according to the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated cryptogenic cirrhosis or primary liver cancer.

[0025] In some embodiments, the neurodegenerative disease described herein is demyelination, chronic demyelination, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD), amyotrophic lateral sclerosis (ALS), or Alzheimer's disease.

[0026] The foregoing outlines some aspects of the present invention, but the present invention is not limited to these aspects. These and other aspects are described in more detail and more fully below. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention provides a compound having excellent agonistic activity against thyroid hormone β receptors, a method for producing the compound, a pharmaceutical composition thereof, and use thereof. Those skilled in the art can realize the compound by appropriately improving process parameters based on the contents of this specification. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and are considered to be within the scope of the present invention. Definitions and General Terms

[0028] Some embodiments of the present invention are described in detail below, and examples thereof are illustrated by the accompanying structural and chemical formulae. The present invention is intended to include all alternatives, modifications, and equivalent technical solutions, all of which are within the scope of the present invention. It will be apparent to those skilled in the art that numerous methods and materials similar or equivalent to those described herein can all be applied to the practice of the present invention. The present invention is not limited to the methods and materials described herein, and in the event that one or more of the referenced literature, patents, or similar materials differs or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this application shall control.

[0029] It should be noted that some features of the invention are, for clarity, described in the context of separate embodiments, but may also be provided in combination in a single example. Conversely, various features of the invention may, for convenience, be described in a single embodiment, but may also be provided alone or in any suitable subcombination.

[0030] Unless otherwise specified, all scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All references and publications related to this invention are incorporated herein by reference in their entirety.

[0031] Unless otherwise specified, the following definitions are used herein. For purposes of this invention, the chemical elements are defined in accordance with the CAS version of the Periodic Table of the Elements and the Handbook of Chemistry and Physics, 75th Edition, 1994. For general principles of organic chemistry, reference may also be made to "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0032] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," "one," and "said," as used herein, are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more (i.e., at least one) of the object article. For example, "a component" means one or more components, i.e., one or more components may be employed or used in the embodiments.

[0033] Unless otherwise stated, terms used in the present specification and claims have the following definitions.

[0034] The term "comprising" is an open-ended expression, ie, including the content specified in the present invention, but not excluding other content.

[0035] As described in the present invention, the compounds of the present invention are compounds that may be optionally substituted with one or more substituents, such as compounds of the general formula above, or specific examples, subclasses, and compounds included in the examples. The term "optionally substituted" can be interchanged with the term "unsubstituted or optionally substituted with ...". The terms "may," "optionally," or "optionally" mean that the following event or circumstance may occur, but does not necessarily occur, and the description includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. Generally, unless otherwise specified, one optional substituent can be substituted at each substitutable position of the group. In a given structural formula, when one or more positions can be substituted with one or more substituents selected from a specific group, the substituents substituted at each position can be the same or different. The substituents can be, but are not limited to, H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, alkyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogenated alkyl groups, halogenated alkoxy groups, hydroxyalkyl groups, aminoalkyl groups, cyanoalkyl groups, carboxylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkyl-alkylene groups, heterocyclic-alkylene groups, carbocyclic groups, heterocyclic groups, aryl groups, aryl-alkylene groups, heteroaryl groups, heteroaryl-alkylene groups, and the like.

[0036] Unless otherwise clearly stated, the phrases "each...independently", "...respectively independently", and "...independently" used in the present invention may be used interchangeably, and may mean that specific objects represented by the same symbol in different groups do not affect each other, or may mean that specific objects represented by the same symbol in the same group do not affect each other, and should all be understood in a broad sense.

[0037] In various parts of this specification, substituents for compounds disclosed in the present invention are disclosed according to group types or ranges. It should be noted that the present invention includes all independent subcombinations of each member of these group types and ranges. For example, the term "C 1-6 The term "alkyl group" refers specifically to the independently disclosed C1 alkyl group (methyl group), C2 alkyl group (ethyl group), C3 alkyl group, C4 alkyl group, C5 alkyl group, and C6 alkyl group, and "C 3-8 "Cycloalkyl" particularly refers to the independently disclosed C3 cycloalkyl group, C4 cycloalkyl group, C5 cycloalkyl group, C6 cycloalkyl group, C7 cycloalkyl group, and C8 cycloalkyl group, and "3- to 6-membered heterocyclic group" refers to a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, and a 6-membered heterocyclic group.

[0038] Each part of this specification describes a linking substituent.When the structure clearly requires a linking group, the Markush variable listed for the group should be understood to be a linking group.For example, when the structure requires a linking group and an "alkyl group" or an "aryl group" is listed for the definition of the Markush group of the variable, the "alkyl group" or the "aryl group" should be understood to represent a linking alkylene group or an arylene group, respectively.

[0039] The term "alkylene group" means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon group. Unless otherwise specified, an alkylene group contains 1 to 12 carbon atoms. In some embodiments, an alkylene group contains 1 to 6 carbon atoms, i.e., C 1-6 In some embodiments, the alkylene group contains 1-4 carbon atoms, i.e., C 1-4It is an alkylene group, examples of which include, but are not limited to, a methylene group (-CH-), an ethylene group (including -CHCH- or -CH(CH)-), an isopropylene group (including -CH(CH)CH- or -C(CH)-), an n-propylene group (including -CHCHCH-, -CH(CHCH)-, or -CHCH(CH)-), etc. The alkylene group may be substituted with one or more substituents described in the present invention.

[0040] The term "alkyl" or "alkyl group" refers to a saturated, straight- or branched-chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, which alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, an alkyl group contains 1 to 10 carbon atoms, and in some embodiments, an alkyl group contains 1 to 8 carbon atoms, i.e., C 1-8 is an alkyl group, and in some embodiments, the alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 is an alkyl group, and in some embodiments, the alkyl group contains 1 to 4 carbon atoms, i.e., C 1-4 It is an alkyl group.

[0041] Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), s-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH 2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH2CH(CH3)CH2CH3), n-heptyl group, n-octyl group, and the like.

[0042] The term "alkenyl group" refers to a straight or branched chain monovalent hydrocarbon group containing 2 to 12 carbon atoms, in which at least one site of unsaturation is a carbon-carbon sp 2 The alkenyl group may be substituted with one or more substituents as described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In some embodiments, the alkenyl group contains 2-8 carbon atoms, and in some embodiments, the alkenyl group contains 2-6 carbon atoms, i.e., C 2-6 In some embodiments, the alkenyl group contains 2 to 4 carbon atoms, i.e., C 2-4 It becomes an alkenyl group.

[0043] Examples of alkenyl groups include, but are not limited to, vinyl groups (-CH=CH), allyl groups (-CH2CH=CH2), propenyl groups (-CH=CHCH3), butenyl groups (-CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=C(CH3)2, -CH=C(CH3)2, -CH2C(CH3)=CH2), pentenyl groups (-CH2CH2CH2CH=CH2, -CH2CH2CH=CHCH3, -CH2CH2CH=CHCH3, -CH2CH2CH=CHCH3, -CH2CH=CHCH2CH3, -CH2CH2CH=CHCH2, -CH2CH2C(CH3)=CH2, -CH2CH=C(CH3)2, -CH=CHCH(CH3)2, -C(CH2CH3)=CHCH3, -CH(CH2CH3)CH=CH2), and the like.

[0044] The term "alkynyl group" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, in which at least one site of unsaturation is a carbon-carbon sp triple bond, and which is optionally substituted with one or more substituents described herein. In some embodiments, an alkynyl group contains 2 to 8 carbon atoms, and in some embodiments, an alkynyl group contains 2 to 6 carbon atoms, i.e., C 2-6 In some embodiments, the alkynyl group contains 2 to 4 carbon atoms, i.e., C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡CH-CH), propargyl (-CHC≡CH), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, and 1-octynyl groups.

[0045] The term "alkoxy group" refers to an alkyl group attached to the rest of the molecule through an oxygen atom, i.e., -O-alkyl group, wherein alkyl is as defined herein, and the alkoxy group may be substituted with one or more substituents as described herein. In some embodiments, an alkoxy group contains 1 to 20 carbon atoms, in some embodiments, an alkoxy group contains 1 to 10 carbon atoms, in some embodiments, an alkoxy group contains 1 to 8 carbon atoms, and in some embodiments, an alkoxy group contains 1 to 6 carbon atoms, i.e., C 1-6 In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, i.e., C 1-4 It becomes an alkoxy group.

[0046] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH), ethoxy (EtO, -OCHCH), n-propyloxy (n-PrO, -OCHCHCH), isopropyloxy (i-PrO, -OCH(CH)), 1-butoxy (n-BuO, -OCHCHCHCH), 2-methyl-l-propoxy (i-BuO, -OCHCH(CH)), 2-butoxy (s-BuO, -OCH(CH)CHCH), 2-methyl-isopropyloxy (t-BuO, -OC(CH)), and the like.

[0047] The term "alkylamino group" includes "N-alkylamino group" and "N,N-dialkylamino group," and refers to an amino group that is independently substituted with one or two alkyl groups, where the alkyl groups are as defined herein. The alkylamino group may be substituted with one or more substituents as described herein. In some embodiments, the alkylamino group may be substituted with one or two C 1-6 An alkylamino group in which the alkyl group is attached to a nitrogen atom, i.e., C 1-6In some embodiments, the alkylamino group is an alkylamino group having one or two C 1-4 An alkylamino group in which the alkyl group is attached to a nitrogen atom, i.e., C 1-4 Examples of alkylamino groups include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), dimethylamino (N,N-dimethylamino), diethylamino (N,N-diethylamino), n-propylamino (Nn-propylamino), and isopropylamino (N-isopropylamino).

[0048] The term "alkylthio group" refers to an alkyl group attached to the rest of the molecule through a sulfur atom, i.e., -S-alkyl group, wherein alkyl is as defined herein, and said alkylthio group may be substituted with one or more substituents as described herein. In some embodiments, alkylthio groups contain 1 to 10 carbon atoms, in some embodiments, alkylthio groups contain 1 to 8 carbon atoms, and in some embodiments, alkylthio groups contain 1 to 6 carbon atoms, i.e., C 1-6 In some embodiments, the alkylthio group contains 1 to 4 carbon atoms, i.e., C 1-4 In some embodiments, the alkylthio group contains 1 to 3 carbon atoms, i.e., C 1-3 Examples of alkylthio groups include, but are not limited to, methylthio and ethylthio groups.

[0049] The term "halogenated alkyl group" refers to an alkyl group having one or more halogen substituents, which may be substituted with one or more substituents as described herein. In some embodiments, the halogenated alkyl group contains 1 to 10 carbon atoms, in some embodiments, the halogenated alkyl group contains 1 to 8 carbon atoms, and in some embodiments, the halogenated alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 In some embodiments, the halogenated alkyl group contains 1 to 4 carbon atoms, i.e., C 1-4 In some embodiments, the halogenated alkyl group contains 1 to 3 carbon atoms, i.e., C 1-3 Examples of halogenated alkyl groups include, but are not limited to, a fluoromethyl group (-CHF), a difluoromethyl group (-CHF), a trifluoromethyl group (-CF), a fluoroethyl group (-CHFCH, -CHCHF), a difluoroethyl group (-CFCH, -CFHCFH, -CHCHF), a perfluoroethyl group, and a fluoropropyl group (-CHFCHCH, -CHCHFCH, -CHCHCHF, -CHCHCHF).

[0050] The term "halogenated alkoxy group" refers to an alkoxy group substituted with one or more halogen substituents, which may be substituted with one or more substituents as described herein. In some embodiments, the halogenated alkoxy group contains 1 to 10 carbon atoms, in some embodiments, the halogenated alkoxy group contains 1 to 8 carbon atoms, and in some embodiments, the halogenated alkoxy group contains 1 to 6 carbon atoms, i.e., C 1-6 In some embodiments, the halogenated alkoxy group contains 1 to 4 carbon atoms, i.e., C 1-4 In some embodiments, the halogenated alkoxy group contains 1 to 3 carbon atoms, i.e., C 1-3Examples of halogenated alkoxy groups include, but are not limited to, -OCF3, -OCHF2, and -OCH2F.

[0051] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups (-OH), wherein the alkyl group is as defined herein, and the hydroxyalkyl group may be substituted with one or more substituents as described herein. In some embodiments, the hydroxyalkyl group as described herein refers to a C substituted with one or more hydroxy groups (-OH). 1-6 Alkyl groups, i.e., hydroxy C 1-6 In some embodiments, a hydroxyalkyl group refers to a C alkyl group substituted with one or more hydroxy groups (—OH). 1-4 Alkyl groups, i.e., hydroxy C 1-4 refers to an alkyl group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl groups (e.g., —CHOH), hydroxyethyl groups (e.g., 2-hydroxyethyl groups), and the like.

[0052] The term "aminoalkyl group" refers to an alkyl group substituted with one or more amino groups (-NH), wherein the alkyl group is as defined herein, and the aminoalkyl group may be substituted with one or more substituents as described herein. In some embodiments, the aminoalkyl group as described herein is a C substituted with one or more amino groups (-NH). 1-6 Alkyl groups, i.e., amino C 1-6 In some embodiments, an aminoalkyl group refers to a C alkyl group substituted with one or more amino groups (—NH). 1-4 Alkyl groups, i.e., amino C 1-4 Alkyl groups, i.e., amino C 1-2It refers to an alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl groups (-CHNH), diaminomethyl groups (-CH(NH)), aminoethyl groups (e.g., 2-aminoethyl groups), and the like.

[0053] The term "cyanoalkyl group" refers to an alkyl group substituted with one or more cyano groups (-CN), wherein the alkyl group is as defined herein, and the cyanoalkyl group may be substituted with one or more substituents as described herein. In some embodiments, the cyanoalkyl group described herein is a C substituted with one or more cyano groups (-CN). 1-6 Alkyl groups, i.e., cyano C 1-6 In some embodiments, a cyanoalkyl group refers to a C alkyl group substituted with one or more cyano groups (—CN). 1-4 Alkyl groups, i.e., cyano C 1-4 Examples of cyanoalkyl groups include, but are not limited to, cyanomethyl groups (e.g., —CHCN), cyanoethyl groups (e.g., 2-cyanoethyl groups), and the like.

[0054] The term "carboxyalkyl group" refers to an alkyl group substituted with one or more carboxyl groups (-COOH), wherein the alkyl group is as defined herein, and the carboxyalkyl group may be substituted with one or more substituents as described herein. In some embodiments, the carboxyalkyl group described herein is a C substituted with one or more carboxyl groups (-COOH). 1-6 Alkyl groups, i.e., carboxy C 1-6 In some embodiments, a carboxyalkyl group refers to a C alkyl group substituted with one or more carboxyl groups (—COOH). 1-4 Alkyl groups, i.e., carboxy C 1-4 It refers to an alkyl group. Examples of a carboxyalkyl group include, but are not limited to, a carboxymethyl group, a carboxyethyl group (e.g., a 2-carboxyethyl group), and the like.

[0055] The term "cycloalkyl group" or "carbocyclic group" refers to a monocyclic, bicyclic, or tricyclic ring system that has one or more points of attachment to the rest of the molecule, is saturated or partially unsaturated, and contains 3 to 14 ring carbon atoms, and the cycloalkyl group may be optionally substituted with substituents as described herein. In some embodiments, a cycloalkyl group refers to a ring system that contains 3 to 10 ring carbon atoms, i.e., C 3-10 In some embodiments, a cycloalkyl group is a ring system containing 3 to 8 ring carbon atoms, i.e., C 3-8 In some embodiments, a cycloalkyl group is a ring system containing 3 to 6 ring carbon atoms, i.e., C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopentadienyl groups.

[0056] The term "heterocyclic group" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 atoms, in which at least one ring atom is selected from heteroatoms such as nitrogen, sulfur, oxygen, and phosphorus atoms. The heterocyclic group is non-aromatic and does not contain any aromatic rings. The ring system has one or more points of attachment to the rest of the molecule. The heterocyclic group may be substituted with one or more substituents as described herein. The term "heterocyclic group" includes monocyclic, bicyclic, or polycyclic fused, spiro, or bridged heterocyclic ring systems. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. The terms "heterocyclic group" and "heterocycle" may be used interchangeably herein. Unless otherwise specified, heterocyclic groups are carbon or nitrogen groups, and -CH- groups may be replaced with -C(=O)-. The sulfur atoms in the ring may be optionally oxidized to S-oxides. The nitrogen atoms in the ring may be optionally oxidized to N-oxides. The phosphorus atoms in the ring may be optionally oxidized to P-oxygen compounds. In some embodiments, the heterocyclic groups are 3- to 10-membered ring systems, in some embodiments, the heterocyclic groups are 5- to 10-membered ring systems, in some embodiments, the heterocyclic groups are 5- to 8-membered ring systems, in some embodiments, the heterocyclic groups are 6- to 8-membered ring systems, in some embodiments, the heterocyclic groups are 5- to 6-membered ring systems, i.e., 5- to 6-membered heterocyclic groups, in some embodiments, the heterocyclic groups are 3- to 6-membered ring systems, i.e., 3- to 6-membered heterocyclic groups, in some embodiments, the heterocyclic groups are 3-membered ring systems, in some embodiments, the heterocyclic groups are 4-membered ring systems, in some other embodiments, the heterocyclic groups are 5-membered ring systems, and in some other embodiments, the heterocyclic groups are 6-membered ring systems.

[0057] Examples of heterocyclic groups include an ethylene oxide group, an azetidinyl group, an oxetanyl group, a thietanyl group, a pyrrolidinyl group, a 2-pyrrolinyl group, a 3-pyrrolinyl group, a pyrazolinyl group, a pyrazolidinyl group, an imidazolinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a dihydrofuranyl group, a tetrahydrothienyl group, a dihydrothienyl group, a 1,3-dioxolanyl group, a dithiolanyl group, a tetrahydropyranyl group, a dihydropyranyl group, a 2H-pyranyl group, a 4H-pyranyl group, Examples of heterocyclic groups in which a -CH- group is replaced with -C(=O)- include, but are not limited to, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a piperazinyl group, a dioxanyl group, a thioxanyl group, a homopiperazinyl group, a homopiperidinyl group, an oxepanyl group, a thiepanyl group, a tetrahydropyrrolyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydropyrimidyl group, a tetrahydropyrazinyl group, a tetrahydropyridazinyl group, an indoline group, a 1,2,3,4-tetrahydroisoquinolinyl group, etc. Examples of heterocyclic groups in which a -CH- group is replaced with -C(=O)- include, but are not limited to, a 2-oxopyrrolidinyl group, an oxo-1,3-thiazolidinyl group, a 2-piperidinone group, a 3,5-dioxopiperidinyl group, a pyrimidinedione group, and a 3,4-dihydroisoquinolin-1(2H)-one. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. Examples of bridged heterocyclic groups include, but are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.1]octyl.

[0058] The term "m-membered" refers to an integer that typically describes the number of ring atoms in a molecule, where m is the number of ring atoms in the molecule. For example, a piperidinyl group is a 6-membered heterocyclic group, and a furanyl group is a 5-membered heteroaryl group. Also, for example, a "3- to 6-membered heterocyclic group" refers to a 3-, 4-, 5-, or 6-membered heterocyclic group.

[0059] The term "aryl group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 10 ring atoms, in which each ring contains 3 to 7 ring atoms and has one or more points of attachment to other parts of the molecule. The aryl group may be substituted with one or more substituents as described herein. The term "aryl group" can be used interchangeably with the term "aromatic ring" or "aromatic ring." Examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, and anthracene groups.

[0060] The term "heteroaryl group" refers to monocyclic, bicyclic, and tricyclic aromatic ring systems containing 5 to 14 ring atoms, in which at least one ring contains one or more heteroatoms, so that the entire ring system is aromatic, and the heteroaryl group has one or more points of attachment to other parts of the molecule. The heteroaryl group may be substituted with one or more substituents as described herein. Unless otherwise specified, the heteroaryl group may be connected to other parts of the molecule (e.g., the main structure in a general formula) by any reasonable position (e.g., C in CH or N in NH). If a -CH2- group is present in the heteroaryl group, the -CH2- group may be replaced by -C(=O)-. The term "heteroaryl group" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." In some embodiments, the heteroaryl group is a 5- to 8-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, the heteroaryl group is a 5- to 7-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, the heteroaryl group is a 5-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; and in some embodiments, the heteroaryl group is a 6-membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0061] Examples of heteroaryl groups include furanyl groups (2-furanyl groups, 3-furanyl groups), imidazolyl groups (N-imidazolyl groups, 2-imidazolyl groups, 4-imidazolyl groups, 5-imidazolyl groups), isoxazolyl groups (3-isoxazolyl groups, 4-isoxazolyl groups, 5-isoxazolyl groups), oxazolyl groups (2-oxazolyl groups, 4-oxazolyl groups, 5-oxazolyl groups), pyrrolyl groups (N-pyrrolyl groups, 2-pyrrolyl groups, 3-pyrrolyl groups), pyridine groups (2-pyridyl groups, 3-pyridyl groups, 4-pyridyl groups), pyrimidinyl groups (2-pyrimidinyl groups, 4-pyrimidinyl groups, 5-pyrimidinyl groups), Examples of monocyclic groups include, but are not limited to, pyridazinyl groups (e.g., 3-pyridazinyl groups), thiazolyl groups (e.g., 2-thiazolyl groups, 4-thiazolyl groups, 5-thiazolyl groups), thienyl groups (e.g., 2-thienyl groups, 3-thienyl groups), pyrazolyl groups (e.g., 2-pyrazolyl groups, 3-pyrazolyl groups), isothiazolyl groups, 1,2,3-oxadiazolyl groups, 1,2,5-oxadiazolyl groups, 1,2,4-oxadiazolyl groups, 1,3,4-oxadiazolyl groups, 1,2,3-thiodiazolyl groups, 1,3,4-thiodiazolyl groups, 1,2,5-thiodiazolyl groups, pyrazinyl groups, and 1,3,5-triazinyl groups. Examples of heteroaryl groups also include, but are not limited to, bicyclic or tricyclic groups such as benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, or 4-quinolyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), dibenzimidazolyl, dibenzofuranyl, and dibenzothienyl.

[0062] The term "cycloalkyl-alkylene group" indicates that a cycloalkyl group is bonded to the other part of the molecule via an alkylene group, and the cycloalkyl group and the alkylene group are as defined in the present invention. The cycloalkyl-alkylene group may be substituted with one or more substituents as described in the present invention. 3-6 Cycloalkyl-C 1-4The alkylene group is C 3-6 Cycloalkyl group is C 1-4 It indicates that the compound is bonded to another part of the molecule via an alkylene group. 3-6 Cycloalkyl-C 1-2 The alkylene group is C 3-6 Cycloalkyl group is C 1-2 Indicates attachment to the rest of the molecule via an alkylene group, examples of which include, but are not limited to, cyclopropyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl-CH2-, cyclobutyl-CH2CH2-, cyclopentyl-CH2-, cyclopentyl-CH2CH2-, cyclohexyl-CH2-, cyclohexyl-CH2CH2-, and the like.

[0063] The term "heterocyclic-alkylene group" indicates that a heterocyclic group is bonded to another part of the molecule via an alkylene group, and the heterocyclic group and the alkylene group are as defined in the present invention. The heterocyclic-alkylene group may be substituted with one or more substituents as described in the present invention. The "(5- to 6-membered heterocyclic group)-C" in the present invention is a heterocyclic group. 1-4 The alkylene group is a 5- to 6-membered heterocyclic group having C 1-4 The above "(5- to 6-membered heterocyclic group)-C" in the present invention indicates that the alkylene group is bonded to another part of the molecule via the alkylene group. 1-2 The alkylene group is a 5- to 6-membered heterocyclic group having C 1-2 Indicates attachment to another portion of the molecule via an alkylene group, such as, but not limited to, tetrahydropyranyl-CH2-, tetrahydropyranyl-CH2CH2-, tetrahydrofuranyl-CH2-, tetrahydrofuranyl-CH2CH2-, pyrrolidinyl-CH2-, piperidinyl-CH2-, piperidinyl-CH2CH2-, morpholinyl-CH2-, morpholinyl-CH2CH2-, and the like.

[0064] The term "aryl-alkylene group" indicates that an aryl group is bonded to another part of the molecule via an alkylene group, and the aryl group and the alkylene group are as defined in the present invention. The aryl-alkylene group may be substituted with one or more substituents as defined in the present invention. For example, the "C 6-10 Aryl-C 1-4 The alkylene group is C 6-10 The aryl group is C 1-4 It indicates that the compound is bonded to another part of the molecule via an alkylene group. 6-10 Aryl-C 1-2 The alkylene group is C 6-10 The aryl group is C 1-2 Indicates attachment to the rest of the molecule via an alkylene group, such as, but not limited to, phenyl-CH2-, phenyl-CH2CH2-, naphthyl-CH2-, and the like.

[0065] The term "heteroaryl-alkylene group" indicates that a heteroaryl group is bonded to another part of the molecule via an alkylene group, and the heteroaryl group and the alkylene group are as defined in the present invention. The heteroaryl-alkylene group may be substituted with one or more substituents as described in the present invention. The "(5- to 6-membered heteroaryl group)-C" in the present invention is a substituted or unsubstituted heteroaryl group. 1-4 The alkylene group is a 5- to 6-membered heteroaryl group. 1-4 The above-mentioned "(5- to 6-membered heteroaryl group)-C" in the present invention indicates that the group is bonded to another part of the molecule via an alkylene group. 1-2 The alkylene group is a 5- to 6-membered heteroaryl group. 1-2 Indicates attachment to the rest of the molecule via an alkylene group, examples of which include, but are not limited to, pyridyl-CH2-, pyrrolyl-CH2CH2-, quinolyl-CH2-, thienyl-CH2-, furanyl-CH2-, pyrimidinyl-CH2-, pyridyl-CH2-, and the like.

[0066] The term "heteroatom" refers to O, S, N, P, and Si in the form of primary, secondary, and tertiary amines and quaternary ammonium salts, or in the form of a replacement of a hydrogen atom on a nitrogen atom in a heterocycle, such as N (N in a 3,4-dihydro-2H-pyrrolyl group), NH (NH in a pyrrolidinyl group), or NR T (NR in N-substituted pyrrolidinyl groups T , R T is a substituent on N), including forms of S, N, and P in any oxidation state.

[0067] The term "carbonyl group", whether used alone or in combination with other terms such as "aminocarbonyl group" or "acyloxy group", refers to --(C.dbd.O)--.

[0068] The term "deuterium" refers to deuteration, i.e. 2 Point to H.

[0069] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or the mammal being treated therewith. Preferably, "pharmacologically acceptable" according to the present invention refers to a substance or composition that is approved by a federal regulatory agency or national government or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0070] The term "carrier" includes any solvent, dispersion medium, coating agent, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combinations thereof, all of which are known to those skilled in the art (e.g., as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0071] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, including auxiliary materials such as physiologically / pharmaceutically acceptable carriers, excipients, diluents, binders, fillers, and additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate administration of a compound to a living organism.

[0072] The term "prodrug" as used in the present invention means that a compound is converted in the body to a compound represented by formula (I). Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention may be esters, and in previous inventions, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, the compounds of the present invention contain a hydroxy group, and thus, by acylation, a prodrug form of the compound can be obtained. Other prodrug forms include phosphate esters, and these phosphate ester compounds can be obtained, for example, by phosphorylating the parent hydroxy group. For a complete discussion of prodrugs, see Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270; and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0073] The term "metabolite" refers to a product produced by in vivo metabolism of a specific compound or salt thereof. Metabolic products of a compound can be identified using techniques known in the art, and their activity can be characterized by test methods as described herein. Such products can be obtained by subjecting an administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, or enzymatic cleavage. Correspondingly, the present invention includes metabolic products of a compound, including metabolic products produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

[0074] The term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art and are described, for example, in Berge et al., "Describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci., 1997, 66, 1-19."

[0075] The term "solvate" refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

[0076] The term "nitrogen oxide" refers to a compound containing multiple amine functional groups, in which one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides include the N-oxides of tertiary amines or N-oxides containing nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., a carboxylic acid peroxide) (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages 1977-1989). In particular, N-oxides can be prepared by the LWDready method (Syn. Comm. 1977, 7, 509-514), for example, by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).

[0077] Any asymmetric atom (e.g., carbon) of the compounds of the present invention can exist in a racemic or enantiomerically enriched form, such as the (R)-, (S)-, or (R,S)-configuration. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Where possible, substituents on atoms having unsaturated double bonds can exist in cis-(Z)- or trans-(E)-form.

[0078] Thus, as described in the present invention, the compounds of the present invention may exist in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, e.g. in the form of essentially pure geometric (cis or trans) isomers, diastereoisomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0079] Any mixture of isomers obtained based on the physical and chemical differences of the components can be separated into pure or essentially pure geometric or optical isomers, diastereoisomers, racemates, for example, by chromatographic techniques and / or stepwise crystallization.

[0080] Any racemic final product or intermediate obtained can be resolved into its optical antipodes by methods known to those skilled in the art, for example, by separation of the resulting diastereoisomeric salts. Racemic products can be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) on a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis (see, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) or Principles of Asymmetric Synthesis (2 ndEd. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012), Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972)).

[0081] The present invention further includes isotopically labeled compounds of the present invention, which are identical to those compounds described in the present invention except that one or more atoms are replaced with atoms whose atomic mass or mass number differs from the common atomic mass or mass number in nature. Exemplary isotopes that can be introduced into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 16 O. 17 O. 31 P, 32 P, 36 S, 18 F and 37 Contains Cl.

[0082] Compounds of the present invention and pharmaceutically acceptable salts of the compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are all within the scope of the present invention. 3 H and 14 C can be incorporated into the compounds of the present invention and used for drug and / or substrate tissue distribution analysis. 3 H and carbon-14, i.e. 14 C is a particularly preferred isotope because it is easy to produce and detect. 2Substitution with higher mass isotopes, such as H, may offer therapeutic advantages of greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some cases.

[0083] The stereochemistry definitions and rules used in the present invention generally follow those set forth in S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. As expected, all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereoisomers, enantiomers, and atropisomers, and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active forms, i.e., have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes d and l or (+) and (-) are symbols used to designate the rotation of plane-polarized light by a compound, with (-) or l indicating that the compound is levorotatory. Compounds with a (+) or d prefix are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers can be referred to as enantiomers, and mixtures of such isomers are commonly referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate; such a racemic mixture or racemate occurs where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0084] Depending on the selection of raw materials and methods, the compounds of the present invention can exist in the form of one of the possible isomers or a mixture thereof, for example, as a pure optical isomer or as a mixture of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or can be resolved using conventional techniques. When the compound contains one double bond, the substituents can be in the E- or Z-configuration, and when the compound contains a disubstituted cycloalkyl group, the cycloalkyl group substituents can be in the cis- or trans-configuration.

[0085] Unless otherwise indicated, structures depicted in the present invention further represent all isomeric (e.g., enantiomers, diastereomers, atropisomers, and geometric (or conformational)) forms encompassing the structure, including, for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers and enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present invention are all within the scope of the invention.

[0086] The term "tautomer" or "tautomeric form" refers to structural isomers that have different energies and are interchangeable through a low energy barrier. When tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include tautomers via proton transfer, such as ketone-enol isomerization and imine-enamine isomerization. Valence tautomers include tautomers via recombination of some bonding electrons. A specific example of ketone-enol tautomerism is the tautomerism between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-ketone tautomerism is the tautomerism of pyridine-4-alcohol and pyridine-4(1H)-one. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0087] The term "geometric isomers", also called "cis-trans isomers", are isomers that result from the inability to freely rotate about double bonds (including olefinic double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms.

[0088] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. Subject also refers to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0089] As used herein, the terms "subject" and "patient" can be used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds or mammals such as chickens, quails, or turkeys), particularly "mammals" including non-primate animals (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), more particularly humans. In one embodiment, the subject is a non-human animal, such as a livestock animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In some other embodiments, "patient" refers to a human.

[0090] Unless otherwise stated, the structural formulae of the compounds described herein also include enriched isotopes of one or more different atoms.

[0091] The term "treatment" as used herein refers to any disease or disorder, and in one embodiment, refers to ameliorating the disease or disorder (i.e., alleviating, inhibiting, or reducing the worsening of the disease or at least one clinical symptom thereof). In another embodiment, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters imperceptible to the patient. In another embodiment, "treatment" refers to modulating the disease or disorder physically (e.g., stable detectable symptoms) or physiologically (e.g., stable physical parameters), or both. In another embodiment, "treatment" refers to preventing or delaying the onset, onset, or worsening of the disease or disorder. Description of the compounds of the present invention

[0092] The present invention provides compounds with excellent agonistic activity against thyroid hormone β receptors, which can be used to prepare drugs for treating neurodegenerative diseases, non-alcoholic fatty liver disease, hepatic fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism, or thyroid cancer. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for preparing drugs for treating the above-mentioned diseases in mammals, particularly humans, using these compounds and pharmaceutical compositions. Compared with conventional similar compounds, the compounds of the present invention not only have good pharmacological activity and selectivity, but also excellent in vivo metabolic kinetics and pharmacodynamic properties. The preparation method of the compounds of the present invention is simple, easy to implement, stable, and suitable for industrial production. Therefore, the compounds of the present invention have better drug discovery potential than conventional similar compounds.

[0093] in particular, In one aspect, the present invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (I): [ka] (In the formula, rings A, Y, R 1 , R 2 , R 3a , R 3b , R 3c and R 3d is as defined in the present invention.

[0094] In some embodiments, Y is —O—, —S—, —NR 0 -, -C(=O)-, C 1-6 Alkylene group, C 2-6 Alkenylene group, C 2-6 Alkynylene group, -NR 0 C(=O)- or -C(=O)NR0 wherein Y is one, two or three R x may be substituted with the above R 0 and R x is as defined in the present invention.

[0095] In some embodiments, R 0 are H, deuterium, and C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl or cyano C 1-6 It is an alkyl group.

[0096] In some embodiments, R 0 is H, deuterium, methyl group, ethyl group, n-propyl group, isopropyl group, C 1-4 The alkyl group may be a halogenated alkyl group, a hydroxymethyl group, a hydroxyethyl group, an aminomethyl group, or a cyanomethyl group.

[0097] In some embodiments, R 3a , R 3b , R 3c and R 3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl or cyano C 1-6 It is an alkyl group.

[0098] In some embodiments, R 1 are H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl group, C 2-6Alkenyl group, C 2-6 Alkynyl group, -C(=O)-C 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkylamino group, -C(=O)NH2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylamino group, -S(=O)2NH2, C 1-6 Alkylamino group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, hydroxy C 1-6 Alkyl group, amino C 1-6 Alkyl group, carboxy C 1-6 Alkyl or cyano C 1-6 It is an alkyl group.

[0099] In some embodiments, R 2 are H, deuterium, and C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 It is an aryl group or a 5- to 6-membered heteroaryl group.

[0100] In some embodiments, R 2 is H, deuterium, methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 It is a cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group.

[0101] In some embodiments, ring A is [ka] wherein ring A is selected from the group consisting of 1, 2 or 3 R yand may be substituted with the above-mentioned E1, E2, E3, E4, E5, E6, U1, U2, U3, Z1, Z2, Z3, R 5 and R y is as defined in the present invention.

[0102] In some embodiments, E1, U1, and Z1 are each independently -(CR 4a R 4b ) q -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR a - and the above R 4a , R 4b , R a and q is as defined in the present invention.

[0103] In some embodiments, E2, U2, and Z2 are each independently -CR 4c R 4d -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR b - and the above R 4c , R 4d and R b is as defined in the present invention.

[0104] In some embodiments, E3, E6, U3, and Z3 are each independently -CR 4e R 4f -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR c - and the above R 4e , R 4f and R c is as defined in the present invention.

[0105] In some embodiments, E4 is -CR 4g = or -N =, and the above R 4g is as defined in the present invention.

[0106] In some embodiments, E5 is -CR 4h= or -N =, and the above R 4h is as defined in the present invention.

[0107] In some embodiments, q is 0, 1, 2, or 3.

[0108] In some embodiments, R a , R b , R c and R 5 are independently H, deuterium, and C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 an aryl group or a 5- to 6-membered heteroaryl group, among which the above R a , R b , R c and R 5 independently, 1, 2 or 3 R y1 may be substituted with the above R y1 is as defined in the present invention.

[0109] In some embodiments, R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h are each independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyl-C 1-4Alkylene group, 5- to 6-membered heterocyclic group, (5- to 6-membered heterocyclic group)-C 1-4 Alkylene group, C 6-10 Aryl group, C 6-10 Aryl-C 1-4 Alkylene group, 5- to 6-membered heteroaryl group, or (5- to 6-membered heteroaryl group)-C 1-4 alkylene groups, among which the above R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h is unsubstituted or contains 1, 2 or 3 R y2 may be substituted with the above R y2 is as defined in the present invention.

[0110] In some embodiments, R 4a , R 4b C along with the carbon atoms to which they are attached 3-8 Forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, and 3-8 The carbocycle and the 5- to 6-membered heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 R y3 may be substituted with the above R y3 is as defined in the present invention.

[0111] In some embodiments, R 4c , R 4d C along with the carbon atoms to which they are attached 3-8 Forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, and 3-8 The carbocyclic or 5- to 6-membered heterocyclic rings are each independently unsubstituted or substituted with 1, 2, or 3 R y3 may be substituted with the above R y3 is as defined in the present invention.

[0112] In some embodiments, R 4e , R 4f C along with the carbon atoms to which they are attached 3-8Forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, and 3-8 The carbocyclic or 5- to 6-membered heterocyclic rings are each independently unsubstituted or substituted with 1, 2, or 3 R y3 may be substituted with the above R y3 is as defined in the present invention.

[0113] In some embodiments, two R on adjacent atoms y C along with the atoms to which they are attached 3-8 Forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, and 3-8 The carbocycle and the 5- to 6-membered heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 R y4 may be substituted with the above R y4 is as defined in the present invention.

[0114] In some embodiments, each R x are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy group or C 1-6 It is an alkylamino group.

[0115] In some embodiments, each R x are independently deuterium, F, Cl, Br, I, —CN, —OH, —NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, isopropoxy, methylamino, or dimethylamino.

[0116] In some embodiments, each R y are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6Halogenated alkoxy groups, C 1-6 Alkoxy group or C 1-6 It is an alkylamino group.

[0117] In some embodiments, each R y are independently deuterium, F, Cl, Br, I, —CN, —OH, —NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, isopropoxy, methylamino, or dimethylamino.

[0118] In some embodiments, each R y1 are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkylamino group, -C(=O)NH2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylamino group, -S(=O)2NH2, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 An aryl group or a 5- to 6-membered heteroaryl group, and each of the R y1 independently represent one, two or three R z may be substituted with the above R z is as defined in the present invention.

[0119] In some embodiments, R z , R y2 , R y3 and Ry4 are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -COOH, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy group, C 1-6 Alkylthio group or C 1-6 It is an alkylamino group.

[0120] In some embodiments, R 3a , R 3b , R 3c and R 3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a methylthio group, a methylamino group, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, a hydroxymethyl group, an aminomethyl group, or a cyanomethyl group.

[0121] In some embodiments, R 1stands for H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl group, ethyl group, n-propyl group, isopropyl group, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -C(=O)-OCH3, -C(=O)-OCH2CH3, -C(=O)-OCH(CH3)2, -C(=O)-OCH2CH2CH3, -C(=O)-O(CH2)3CH3, -C(=O)-OCH2CH(CH3)2, -C(=O)-CH3, -C(= O)-CH2CH3, -C(=O)-NHCH3, -C(=O)-N(CH3)2, -C(=O)NH2, -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-NHCH3, -S(=O)2NH2, methylamino group, ethylamino group, methoxy group, ethoxy group, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, hydroxymethyl group, aminomethyl group, carboxymethyl group or cyanomethyl group.

[0122] In some embodiments, R a , R b , R c and R 5 are independently H, deuterium, and C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 an aryl group or a 5- to 6-membered heteroaryl group, among which the above R a , R b , R c and R 5 independently, 1, 2 or 3 R y1 may be substituted with the above R y1 is as defined in the present invention.

[0123] In some embodiments, R a , R b , R c and R 5are each independently H, deuterium, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyrrolidinyl group, a pyrazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a piperazinyl group, a phenyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrimidinyl group, a pyridyl group, a pyrrolyl group, a pyrazinyl group, a thiazolyl group, or an oxazolyl group, among which the above R a , R b , R c and R 5 independently, 1, 2 or 3 R y1 may be substituted with the above R y1 is as defined in the present invention.

[0124] In some embodiments, each R y1 are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-C 1-4 Alkyl group, -C(=O)-C 1-4 Alkoxy group, -C(=O)-C 1-4 Alkyl group, -C(=O)-C 1-4 Alkylamino group, -C(=O)NH2, -S(=O)2-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkylamino group, -S(=O)2NH2, C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy group, C 1-4 Alkylthio group, C 1-4 Alkylamino group, C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups, C 6-10 an aryl group or a 5- to 6-membered heteroaryl group, among which the above R y1is one, two or three R z may be substituted with the above R z is as defined in the present invention.

[0125] In some embodiments, each R y1 are independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-methyl, -OC(=O)-ethyl, -OC(=O)-n-propyl, -OC(=O)-isopropyl, -OC(=O)-n-butyl, -OC(=O)-tert-butyl, -OC(=O)-isobutyl, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl -propyl group, -C(=O)O-butyl group, -C(=O)O-tert-butyl group, -C(=O)O-isobutyl group, -C(=O)-methyl group, -C(=O)-ethyl group, -C(=O)-n-propyl group, -C(=O)-isopropyl group, -C(=O)-n-butyl group, -C(=O)-tert-butyl group, -C(=O)-isobutyl group, -C(=O)-methylamino group, -C(=O)-ethylamino group, -C(=O)NH2, -S(=O)2-C 1-3 Alkyl group, -S(=O)2-C 1-3 Alkylamino group, -S(=O)2NH2, methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCHFCH3, methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, methylthio group, ethylthio group, methylamino group, ethylamino group, cyclopropyl a propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyrrolidinyl group, a pyrazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a piperazinyl group, a phenyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrimidinyl group, a pyridyl group, a pyrrolyl group, a pyridazinyl group, a pyrazinyl group, a thiazolyl group, or an oxazolyl group, among whichy1 is unsubstituted or contains 1, 2 or 3 R z may be substituted with the above R z is as defined in the present invention.

[0126] In some embodiments, R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h are each independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, oxy group, ethoxy group, methylamino group, ethylamino group, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, pyrrolidinyl group, pyrazolidinyl group, or tetrahydrofuranyl group. , tetrahydrothienyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, pyrrolidinyl-CH2-, pyrazolidinyl-CH2-, tetrahydrofuranyl-CH2-, tetrahydrothienyl-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, thiomorpholinyl-CH2-, piperazinyl-CH2-, phenyl group, phenyl-CH2-, phenyl-CH2CH2-, furanyl group, thienyl group, imidazolyl group, pyrimidinyl group, pyridyl group, pyrrolyl group, pyridazinyl group, pyrazinyl group, thiazolyl group, oxazolyl group, furanyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, pyridyl-CH2-, or pyrrolyl-CH2-, among which, 4a , R 4b , R 4c , R 4d , R 4e , R4f , R 4g and R 4h independently, 1, 2 or 3 R y2 may be substituted with the above R y2 is as defined in the present invention.

[0127] In some embodiments, R 4a , R 4b C along with the carbon atoms to which they are attached 3-6 Forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, and 3-6 The carbocycle and the 5- to 6-membered heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 R y3 may be substituted with the above R y3 is as defined in the present invention.

[0128] In some embodiments, R 4c , R 4d C along with the carbon atoms to which they are attached 3-6 Forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, and 3-6 The carbocycle and the 5- to 6-membered heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 R y3 may be substituted with the above R y3 is as defined in the present invention.

[0129] In some embodiments, R 4e , R 4f C along with the carbon atoms to which they are attached 3-6 Forms a carbocyclic ring or a 5- to 6-membered heterocyclic ring, and 3-6 The carbocycle and the 5- to 6-membered heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 R y3 may be substituted with the above R y3 is as defined in the present invention.

[0130] In some embodiments, R z , R y2 , R y3 and R y4are each independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -COOH, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, a methoxy group, an ethoxy group, or a methylamino group.

[0131] In other aspects, the invention relates to one of the following structures: or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof: [ka] [ka] [ka] [ka] [ka] In another aspect, the present invention relates to pharmaceutical compositions comprising the compounds according to the present invention.

[0132] In some embodiments, the pharmaceutical compositions of the present invention optionally comprise any one or any combination of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle.

[0133] In another aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament, wherein said medicament agonizes thyroid hormone receptors or prevents, treats or alleviates a disease modulated by thyroid hormone receptors.

[0134] In another aspect, the present invention relates to a method for agonizing thyroid hormone receptors or for preventing, treating, or alleviating diseases regulated by thyroid hormone receptors using a compound or pharmaceutical composition according to the present invention, comprising administering to an individual in need thereof an effective therapeutic amount of the compound or pharmaceutical composition. The compound or pharmaceutical composition according to the present invention can be administered together with other therapies or therapeutic agents. The administration can be simultaneous, sequential, or at a fixed time interval.

[0135] In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention to agonize thyroid hormone receptors or to prevent, treat or alleviate diseases modulated by thyroid hormone receptors.

[0136] In some embodiments, the thyroid hormone receptor according to the present invention is a thyroid hormone beta receptor.

[0137] In some embodiments, the disease modulated by thyroid hormone receptors according to the present invention is a neurodegenerative disease, non-alcoholic fatty liver disease, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism, or thyroid cancer.

[0138] In one aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for preventing, treating or alleviating neurodegenerative diseases, non-alcoholic fatty liver disease, hepatic fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism or thyroid cancer.

[0139] In one aspect, the invention relates to a compound or pharmaceutical composition according to the invention for preventing, treating or alleviating neurodegenerative diseases, non-alcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism or thyroid cancer.

[0140] In one aspect, the present invention relates to a method of preventing, treating or alleviating neurodegenerative diseases, non-alcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism or thyroid cancer using a compound or pharmaceutical composition according to the present invention, said method comprising administering to an individual in need thereof an effective therapeutic amount of said compound or said pharmaceutical composition.

[0141] In some embodiments, the non-alcoholic fatty liver disease according to the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated cryptogenic cirrhosis or primary liver cancer.

[0142] In some embodiments, the neurodegenerative disease described herein is demyelination, chronic demyelination, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD), amyotrophic lateral sclerosis (ALS), or Alzheimer's disease.

[0143] The dosage of the compound or pharmaceutical composition required to perform the effects of treatment, prevention, or delay generally depends on the specific compound administered, the patient, the specific disease or condition and its severity, the route and frequency of administration, etc., and must be determined by the attending physician based on the specific situation. For example, when the compound or pharmaceutical composition of the present invention is administered via the intravenous route, it can be administered once a week or at longer intervals.

[0144] In some embodiments, the salts refer to pharmaceutically acceptable salts. The term "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or the mammal being treated therewith.

[0145] The compounds of the present invention further include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and which may be used as enantiomeric intermediates for preparing and / or purifying the compounds of the present invention and / or for separating the compounds of the present invention.

[0146] The compounds of the present invention and their salts or other solvents for crystallization may also be obtained in the form of their hydrates. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water), and therefore the present invention is intended to encompass both solvated and unsolvated forms. Pharmaceutical Compositions, Formulations and Administration of Compounds of the Invention

[0147] The present invention relates to pharmaceutical compositions comprising a compound of the present invention or a compound of the structure shown in the Examples, or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof. The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof, and other therapeutic and / or prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention and at least one pharmaceutically acceptable carrier, excipient, adjuvant, or vehicle. The amount of compound in the pharmaceutical composition of the present invention is sufficient to effectively and detectably agonize thyroid hormone beta receptors in a biological sample or in a patient.

[0148] Pharmaceutically acceptable carriers may contain inactive ingredients that do not unduly inhibit the biological activity of the compound. Pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or have no other untoward or adverse effects when administered to a patient. Standard pharmaceutical techniques can be used.

[0149] As described herein, the pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, or vehicle, which may be any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, or lubricant, etc., suitable for a particular target dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, discloses the preparation of various carriers used in pharmaceutically acceptable compositions and known methods for their manufacture. Any conventional carrier medium and its use are within the scope of the present invention, except insofar as it is incompatible with the compounds of the present invention, such as to produce adverse biological effects or to interact adversely with any other ingredients in the pharmaceutically acceptable composition.

[0150] Some examples of substances that can be used as pharmaceutically acceptable carriers include ion exchange agents, aluminum oxide, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (e.g., lactose, PEG-10 ... starch (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth gum, malt, gel, talc, excipients (e.g., cocoa oil and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), ethylene glycols (e.g., propylene glycol or polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution These include, but are not limited to, aqueous solutions, ethanol, and phosphate buffers, and other non-toxic, compatible lubricants (e.g., sodium lauryl sulfate, and magnesium stearate); coloring agents, release agents, coating agents, sweetening agents, flavoring agents, preservatives, and antioxidants can also be present in the composition, at the discretion of the formulator.

[0151] It is known in the art that the pharmaceutical compositions of the present invention can be administered directly or in the form of pharmaceutical compositions or drugs together with suitable carriers or excipients. The therapeutic methods of the present invention comprise administering an effective amount of a compound of the present invention to an individual in need thereof. In some embodiments, the individual is a mammal, and in other embodiments, the individual is a human.

[0152] The effective amount of the compound, pharmaceutical composition or drug according to the present invention can be easily determined by conventional methods and tests, and the most effective and convenient route of administration and the optimum formulation can also be determined by conventional tests.

[0153] The compounds or compositions of the present invention can be administered in any suitable manner, including orally, rectally, parenterally, intracerebrally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, or drops), or as nasal drops, to humans or other animals, and the compounds and pharmaceutically acceptable compositions described above can be administered in any suitable manner, depending on the severity of the disease.

[0154] Oral liquid dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.

[0155] Injectable preparations, for example, sterile injectable aqueous or oil suspensions, can be prepared using suitable dispersing or wetting agents and suspending agents based on known techniques. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. Conventionally, sterile, fixed oils are used as solvents or suspending media. For this purpose, any odorless, fixed oil, such as synthetic monoglycerides or diglycerides, can be used. Fatty acids, such as oleic acid, are also used in the preparation of injectables.

[0156] The injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0157] To prolong the effect of a compound or composition according to the present invention, it is always desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compounds can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0158] For compositions administered rectally or vaginally, particularly suppositories prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa oil, polyethylene glycol or a suppository wax, the excipient or carrier is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity, releasing the active compound.

[0159] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose, and gum arabic, c) humectants, such as glycerol, and d) disintegrants. Examples of suitable additives include, for example, agar-agar, calcium carbonate, potato or cassava starch, alginic acid, some silicates and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and monostearate glyceride, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. When the dosage form is a capsule, tablet or pill, the dosage form can also contain a buffering agent.

[0160] Solid compositions of a similar type can also be employed as fillers in soft and hard gel capsules, using excipients such as lactose or caramel and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. These materials can optionally contain emulsifying agents and have compositional properties so that they release the active ingredient only, optionally in a delayed manner, or preferably in a certain part of the intestinal tract. Examples of filler compositions that can be used include polymers, waxes, and the like.

[0161] The active compound can be in a microencapsulated form with one or more of the above-mentioned excipients. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Generally, such dosage forms may contain other substances in addition to the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. These substances may optionally contain an emulsifier and have the properties of a composition, so that the active ingredient is released only, optionally in a delayed manner, or preferably in a certain part of the intestinal tract. Examples of usable filling compositions include polymers, waxes, etc.

[0162] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is combined under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. The present invention also contemplates the use of skin patches, which have the added advantage of controlling delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0163] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an indwelling reservoir. As used herein, the term "parenteral" includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In particular, compositions are administered orally, intraperitoneally, or intravenously.

[0164] The sterile injectable form of the composition of the present invention can be an aqueous or oil suspension. These suspensions can be prepared using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. Sterile, fixed oils can also be used as solvents or suspending media according to the regulations. For this purpose, any odorless, fixed oil can be used, such as synthetic mono- or diglycerides. Natural pharmaceutically acceptable oils, particularly those in polyoxyethylated form, such as olive oil or castor oil, and fatty acids such as octadecenoic acid and its glyceride derivatives can also be used to prepare injectables. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersants commonly used in pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other common surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for the formulation.

[0165] The pharmaceutical composition of the present invention can be orally administered in any orally administrable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For oral tablets, common carriers include, but are not limited to, lactose and starch. Lubricants such as magnesium stearate are generally added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and suspending agent. If necessary, some sweeteners, flavor enhancers, or coloring agents can be further added.

[0166] Alternatively, the pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared using mixed reagents and non-irritating excipients, including, but not limited to, cocoa oil, beeswax, and polyethylene glycol.

[0167] In particular, the pharmaceutical compositions of the present invention can be administered topically when the area or organ to be treated includes areas or organs that are easily accessible by topical instillation, such as the eye, skin, or lower intestinal diseases, etc. It is easy to prepare topical formulations suitable for each of these areas or organs.

[0168] Local instillation into the lower intestinal tract can be accomplished in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical skin patches may also be used.

[0169] For topical application, the pharmaceutical composition can be prepared into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum oil, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be prepared into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0170] For ophthalmic use, the pharmaceutical composition can be prepared as a micronized suspension in sterile saline at an isotonic pH without the use of preservatives such as benzalkonium chloride, or as a solution in sterile saline at an isotonic pH, among others. Alternatively, for ophthalmic use, the pharmaceutical composition can be prepared in a topical agent such as petrolatum.

[0171] The pharmaceutical composition may also be administered by nasal gas spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art, and are prepared in solution in saline using benzyl alcohol and other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents. Uses of the Compounds and Pharmaceutical Compositions of the Invention

[0172] The compounds or pharmaceutical compositions according to the present invention can be used in the manufacture of a medicament for agonizing thyroid hormone receptors or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

[0173] The compounds or pharmaceutical compositions of the present invention can be used to agonize thyroid hormone receptors or to prevent, treat or alleviate diseases modulated by thyroid hormone receptors.

[0174] The present invention provides a method for agonizing thyroid hormone receptors or for preventing, treating, or alleviating diseases regulated by thyroid hormone receptors, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound or a pharmaceutical composition thereof. The compound or pharmaceutical composition according to the present invention can be administered together with other therapies or therapeutic agents. The administration can be simultaneous, sequential, or at a fixed time interval.

[0175] The thyroid hormone receptor according to the present invention is the thyroid hormone β receptor.

[0176] The diseases described in the present invention are non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type I, hypothyroidism, or thyroid cancer, among which the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated idiopathic cirrhosis, or primary liver cancer.

[0177] The compounds or pharmaceutical compositions according to the present invention can be used to treat fibrotic diseases, including, but not limited to, liver fibrosis, idiopathic pulmonary fibrosis, and the like.

[0178] The compounds of the present invention are not only useful in human therapy, but can also be applied in veterinary therapy in mammals, rodents, pets, introduced breeds, and farm animals. Examples of other animals include horses, dogs, and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0179] An "effective amount," "effective therapeutic amount," or "effective dosage" of a compound or pharmaceutically acceptable pharmaceutical composition of the present invention refers to an amount effective in treating or reducing the severity of one or more of the diseases mentioned in the present invention. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective within a very wide dosage range. For example, a daily dosage range may range from about 0.1 mg to 1000 mg per person, administered as a single or multiple doses. The methods, compounds, and pharmaceutical compositions of the present invention can be applied to any dosage and any route of administration, and therefore can be effectively used to treat or reduce the severity of diseases. The exact amount required will vary depending on the patient's circumstances, which may depend on the race, age, general condition of the patient, the severity of the infection, specific factors, the mode of administration, etc. As discussed herein, the compounds or pharmaceutical compositions of the present invention can be administered in combination with one or more other therapeutic agents. General synthesis and detection methods

[0180] To illustrate the present invention, the following examples are provided, but it should be understood that the invention is not limited to these examples, which merely provide methods of practicing the invention.

[0181] In this specification, if there is any discrepancy between the chemical name and the chemical structure, the structure is the control.

[0182] In general, the compounds of the present invention can be prepared by the methods described herein, and the substituents are as defined in formula (I) unless further specified. The following reaction schemes and examples are used to further illustrate the subject matter of the present invention.

[0183] Those skilled in the art will recognize that the chemical reactions of the present invention can be adapted to the preparation of many other compounds of the present invention, and other methods for preparing the compounds of the present invention are all considered to be within the scope of the present invention. For example, those skilled in the art can successfully synthesize the compounds of the present invention by modifying the method, for example, by appropriately protecting the blocking groups, by using known drugs other than those described in the present invention, or by making routine changes to the reaction conditions. It is also believed that the reactions disclosed in the present invention or known reaction conditions can be applied to the preparation of other compounds of the present invention.

[0184] The structure of the compound was determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or / and 19 F-NMR). 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR, 19F-NMR measurements were performed using a Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and a Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, using deuterated chloroform (CDCl), deuterated methanol (CDOD or MeOH-d), or deuterated dimethyl sulfoxide (DMSO-d). TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiplets appear, the abbreviations s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), ddd (doublet doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and brs (broadened singlet) are used. Coupling constants, J, are given in units of hertz (Hz).

[0185] Preparative purification or separation typically uses a Novasep pump 250 high performance liquid chromatograph.

[0186] LC-MS measurements are performed using an Agilen-6120 Quadrupole LC / MS mass spectrometer.

[0187] Column chromatography generally uses 300 to 400 mesh silica gel manufactured by Qingdao Kaiyo Kagaku Co., Ltd. as a carrier.

[0188] The starting materials of the present invention are known and commercially available, such as from Shanghai Accela Company, Ananji Energy Company, J&K, Tianjin Alfa Company, etc., or can be synthesized according to methods known in the art.

[0189] Unless otherwise stated in the examples, all reactions are carried out under a nitrogen atmosphere.

[0190] Nitrogen atmosphere refers to connecting a nitrogen gas balloon or steel kettle with a volume of approximately 1 L to the reaction flask. The hydrogen gas atmosphere refers to connecting a hydrogen gas balloon with a volume of about 1 L or a stainless steel high-pressure reactor with a volume of about 1 L to the reaction flask; Unless otherwise stated in the examples, the solutions are aqueous solutions. Unless otherwise specified in the examples, the reaction temperature was room temperature. In the examples, unless otherwise specified, the room temperature is 20°C to 40°C.

[0191] In the examples, the reaction process was monitored by thin layer chromatography (TLC), and the developer systems used in the reaction included dichloromethane and methanol, dichloromethane and ethyl acetate, and petroleum ether and ethyl acetate, with the volume ratio of the solvents adjusted according to the polarity of the compounds.

[0192] The eluent systems for column chromatography include A: petroleum ether and ethyl acetate, B: dichloromethane and ethyl acetate, and C: dichloromethane and methanol. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and can also be adjusted by adding a small amount of aqueous ammonia, acetic acid, etc.

[0193] HPLC refers to high performance liquid chromatography. The HPLC measurement is carried out using an Agilent 1260 high performance liquid chromatograph (chromatographic column: Agilent ZORBAX Eclipse Plus C18 4.6 mm x 150 mm, 3.5 μm). HPLC measurement conditions: Run time: 25 min; Column temperature: 35°C; Detection wavelengths: 210 nm, 245 nm Mobile phase: Phase A: 0.05% phosphoric acid solution; Phase B: acetonitrile; Flow rate: 1.0 ml / min The mobile phase gradient is shown in Table A.

[0194] Table A [Table 1]

[0195] The LC / MS / MS system for analysis in the bioassay study included an Agilent 1200 series vacuum degassing oven, a two-dimensional syringe pump, an orifice autosampler, a column thermostat, and an Agilent G6430 triple quadrupole mass spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed in MRM mode, and the MRM conversion parameters are listed in Table B.

[0196] Table B [Table 2]

[0197] The analysis was performed using an Agilent XDB-C18, 2.1 x 30 mm, 3.5 μm column, with a 5 μL sample injection. The analysis conditions were: the mobile phase was 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4 mL / min. The mobile phase gradient is shown in Table C.

[0198] Table C [Table 3]

[0199] Low-resolution mass spectral (MS) data were measured using an Agilent 6120 Quadropole HPLC-MS (column: Zorbax SB-C18, 2.1 × 30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min, mobile phase: 5%-95% (CHCN containing 0.1% formic acid) in HO containing 0.1% formic acid), with UV detection at 210 nm / 254 nm and electrospray ionization (ESI) mode.

[0200] The following abbreviations are used throughout this specification: DMSO-d6: Deuterated dimethyl sulfoxide TFA: trifluoroacetic acid μL, μl: microliter mol: mole μmol / L, μmol / l, μM: micromoles per liter g: grams mg: milligram ng: nanogram μm: micron min: minutes Me: methyl group; DMSO: dimethyl sulfoxide mL, ml: milliliter mol / L, mol / l: moles per liter mmol / L, mmol / l, mM: millimoles per liter nmol / L, nmol / l, nM: nanomoles per liter h: time μg: microgram %wt,mass%: Weight percentage MPa: Megapascal ACN: acetonitrile; Et ethyl group General synthesis method

[0201] Typical synthetic steps for preparing the compounds disclosed in the present invention are as shown in the following synthetic scheme. Unless otherwise specified, each ring A, R 1 , R3a , R 3b , R 3c and R 3d is as defined in the present invention and X is a halogen.

[0202] Synthetic Scheme 1: [ka] The compound having the structure represented by general formula (IA) can be produced by the general synthesis method described in Synthesis Scheme 1, and the specific steps can be seen in the Examples. First, compound (Ia) and compound (Ib) are reacted with a base (e.g., potassium carbonate) to obtain compound (Ic), and compound (Id) is obtained from compound (Ic) by nitro group reduction. The amino group of compound (Id) is diazotized and reacted with compound (Ie) to obtain compound (If), and compound (If) is ring-closed with a base (e.g., sodium acetate) to obtain the target compound represented by general formula (IA).

[0203] Synthetic Scheme 2: [ka] The compound having the structure represented by general formula (IB) can be produced by the general synthesis method illustrated in Synthesis Scheme 2, and the specific steps can be seen in the Examples. First, compound (II-a) is hydrolyzed under acidic conditions (e.g., concentrated hydrochloric acid) to obtain compound (II-b), which is then decarboxylated to obtain the target compound represented by general formula (IB). Manufacturing Example

[0204] Example 1 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b

[0205] 6-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one 1a (1.00 g, 6.13 mmol) and 1,2,3-trichloro-5-nitrobenzene (1.39 g, 6.14 mmol) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (2.14 g, 15.3 mmol) was added, and the mixture was reacted at 120 °C for 16 h. The reaction mixture was cooled to room temperature, water (20 mL) was added, stirred for 15 min, filtered, and the filter cake was collected. The recrystallization was performed with ethanol / ethyl acetate / petroleum ether (1 / 2 / 4, 35 mL), filtered, and the filter cake was collected and dried to give a yellow solid 1b (1.41 g, 65% yield).

[0206] MS (ESI, pos. ion) m / z: 353.1 [M+H] + .

[0207] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1c

[0208] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.4 g, 4.0 mmol) was dissolved in acetic acid (8 mL), iron powder (0.22 g, 3.9 mmol) was added, and the reaction was carried out at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, the iron powder was removed, water (30 mL) was added, the mixture was stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to give a yellow solid 1c (1.0 g, 78% yield).

[0209] MS (ESI, pos. ion) m / z: 323.2 [M+H] + .

[0210] Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetraisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 1d

[0211] 6-(4-Amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1c (0.20 g, 0.62 mmol) and N-cyanoacetylurethane (0.11 g, 0.69 mmol) were dissolved in acetic acid (4 mL), and a solution of sodium nitrite (65 mg, 0.93 mmol) in water (2 mL) was added at 0° C. and the mixture was allowed to react for 4.5 hours. Water (10 mL) was added to the reaction mixture at 0° C., and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (2 mL), and the filter cake was collected and dried to give an orange solid 1d (0.30 g, 99% yield).

[0212] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1

[0213] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetraisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 1d (0.30 g, 0.61 mmol) was dissolved in N,N-dimethylformamide (3 mL), and sodium acetate (55 mg, 0.67 mmol) was added. The mixture was allowed to react at 120°C for 5 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added to precipitate a solid. After stirring for 10 minutes, the solid was filtered and rinsed with water (5 mL). The filter cake was collected and dried, and the resulting reddish-brown solid was recrystallized (acetonitrile / ethanol / N,N-dimethylformamide / water = 10 / 5 / 2 / 20, 37 mL), filtered, rinsed with water (2 mL), and the filter cake was collected and dried to give an orange solid 1 (0.13 g, 48% yield, 91.86% purity).

[0214] MS (ESI, negative ion) m / z: 442.0 [MH] - . 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.27(s,1H),7.85(d,J=6.4Hz,4H),6.87(s,1H),6.81(dd,J=8.6, 2.3Hz,1H),3.32(s,2H),2.90(t,J=6.2Hz,2H).

[0215] Example 2 2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one 2a

[0216] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.0 g, 2.8 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydride (0.23 g, 5.8 mmol, 60% in oil) and iodomethane (0.26 mL, 4.2 mmol) were added, and the mixture was allowed to react at room temperature for 2.5 h. The reaction was quenched by the addition of water (10 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phase was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a yellow solid 2a (1.0 g, 99% yield).

[0217] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one 2b

[0218] 6-(2,6-Dichloro-4-nitrophenoxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one 2a (1.0 g, 2.7 mmol) was dissolved in acetic acid (8 mL), iron powder (0.30 g, 5.4 mmol) was added, and the reaction was carried out at 70 °C. The reaction mixture was cooled to room temperature, and after removing the iron powder, water (30 mL) was added and stirred for 10 min. The mixture was filtered and rinsed with water (10 mL). The filter cake was collected and dried, and the resulting solid was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid 2b (0.40 g, 44% yield).

[0219] Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 2c

[0220] 6-(4-Amino-2,6-dichlorophenoxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one 2b (0.40 g, 1.2 mmol) and N-cyanoacetylurethane (0.21 g, 1.3 mmol) were dissolved in acetic acid (8 mL), and a solution of sodium nitrite (0.17 g, 2.4 mmol) in water (4 mL) was added at 0° C. and the mixture was allowed to react for 4 hours. Water (10 mL) was added to the reaction mixture at 0° C., and the mixture was stirred for 10 minutes. The mixture was filtered, rinsed with water (2 mL), and the filter cake was collected and dried to give a red solid 2c (0.62 g, 99% yield).

[0221] Step 4: 2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2

[0222] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 2c (0.62 g, 1.2 mmol) was dissolved in N,N-dimethylformamide (6 mL), and sodium acetate (0.11 g, 1.3 mmol) was added. The mixture was reacted at 120°C for 6 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3). The resulting solid was recrystallized (acetonitrile / ethyl acetate / ethanol / petroleum ether = 3 / 10 / 15 / 30, 58 mL) to give a pale red solid 2 (0.21 g, yield 38%, purity: 97.61%).

[0223] MS (ESI, negative ion) m / z: 456.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.29(s,1H),8.11-7.63(m,3H),6.91-6.76(m,2H),3.53(t,J=6.6Hz,2H),3.00(s,3H),2.97(t,J=6.6Hz,2H).

[0224] Example 3 2-(3,5-dichloro-4-((2-(methoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 3 [ka] 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.10 g, 0.23 mmol) was dissolved in methanol (4 mL), and 37% formaldehyde (0.37 mL, 5.0 mmol) was added. The reaction mixture was then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). The resulting solid was recrystallized (methanol / ethyl acetate / petroleum ether = 1 / 6 / 12, 9.5 mL) to give 3 (50 mg, 45% yield, HPLC purity: 97.51%) as a white solid.

[0225] MS (ESI, negative ion) m / z: 486.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.91(d,J=8.6Hz,1H),7.84(s,2H),6.95 -6.81(m,2H),4.86(s,2H),3.56(t,J=6.4Hz,2H),3.22(s,3H),2.98(t,J=6.2Hz,2H).

[0226] Example 4 2-(3,5-dichloro-4-((2-(ethoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 4 [ka] 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.40 g, 0.90 mmol) was dissolved in ethanol (10 mL), 37% formaldehyde (2.0 mL, 27 mmol) was added, and the reaction was carried out at 100 °C in a sealed test tube for 48 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). The resulting solid was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 5 / 3, 18 mL) to give 4 (0.28 g, 62% yield, HPLC purity: 96.19%) as a white solid.

[0227] MS (ESI, negative ion) m / z: 500.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.31(s,1H),8.06-7.74(m,3H),6.99-6.74(m,2H),4.90(s, 2H),3.56(t,J=6.1Hz,2H),3.49-3.43(m,2H),2.98(t,J=5.8Hz,2H),1.11(t,J=6.9Hz,3H).

[0228] Example 5 2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5 [ka] Step 1: Synthesis of 2-ethyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 5b

[0229] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (2.05 g, 11.6 mmol) was dissolved in a mixture of tetrahydrofuran (40 mL) and N,N-dimethylacetamide (15 mL). Sodium hydride (0.58 g, 14.5 mmol, 60% in oil) was added in several portions at 0°C, followed by dropwise addition of iodoethane (1.13 mL, 13.8 mmol), and the mixture was allowed to react at 50°C for 24 hours. The reaction mixture was cooled to room temperature, quenched by adding ice water (40 mL), concentrated under reduced pressure to remove tetrahydrofuran, and the remaining solution was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (45 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give pale yellow oil 5b (2.30 g, yield 97%).

[0230] MS (ESI, pos. ion) m / z: 206.2 [M+H] + .

[0231] Step 2: Synthesis of 2-ethyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 5c

[0232] 2-Ethyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 5b (2.40 g, 11.7 mmol) was dissolved in dichloromethane (50 mL) and boron tribromide (2.28 mL, 23.4 mmol) was added dropwise at 0 °C, followed by stirring for 3.5 h. The reaction was quenched by the dropwise addition of methanol (10 mL) at 0 °C, concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give a tan solid 5c (2.01 g, 90% yield).

[0233] MS (ESI, negative ion) m / z: 190.1 [MH] - .

[0234] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one 5d

[0235] 2-Ethyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 5c (2.00 g, 10.5 mmol) was dissolved in N,N-dimethylacetamide (25 mL), and 1,2,3-trichloro-5-nitrobenzene (2.37 g, 10.5 mmol) and potassium carbonate (5.61 g, 40.2 mmol) were added sequentially. The mixture was reacted at 80 °C for 7 h. The reaction mixture was cooled to room temperature, poured into water (50 mL), stirred for 20 min, and then hydrochloric acid (3N, 15 mL) was added dropwise. The mixture was filtered, and the solid was collected and dried. The resulting solid was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 5d (3.42 g, 86% yield) as a white solid.

[0236] MS (ESI, pos. ion) m / z: 381.0 [M+H] + .

[0237] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one 5e

[0238] 6-(2,6-Dichloro-4-nitrophenoxy)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one 5d (2.05 g, 5.38 mmol) was dissolved in acetic acid (25 mL), iron powder (1.23 g, 21.6 mmol) was added, and the reaction was carried out at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, the iron powder was removed, water (50 mL) was added, the mixture was stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to give a white solid 5e (1.80 g, 95% yield).

[0239] MS (ESI, pos. ion) m / z: 351.1 [M+H] + .

[0240] Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 5f

[0241] 6-(4-Amino-2,6-dichlorophenoxy)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one 5e (0.80 g, 2.28 mmol) and N-cyanoacetylurethane (0.40 g, 2.50 mmol) were dissolved in acetic acid (15 mL), and a solution of sodium nitrite (0.24 g, 3.42 mmol) in water (2 mL) was added at 0 °C and reacted for 3 h. Water (35 mL) was added to the reaction mixture at 0 °C, stirred for 10 min, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to give a yellow solid 5f (1.10 g, 93% yield).

[0242] MS (ESI, negative ion) m / z: 515.9 [MH] - .

[0243] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5

[0244] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 5f (1.10 g, 2.12 mmol) was dissolved in N,N-dimethylformamide (25 mL), and sodium acetate (0.88 g, 12.9 mmol) was added thereto, followed by reaction at 120° C. for 6 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), stirred for 30 minutes, filtered, and the filter cake was collected and dried. The resulting pale yellow solid was purified by preparative separation [50% ACN / 50% HO (0.1% TFA), Kromasil standard: C18 10 μm × 50 mm × 250 mm, flow rate: 100 mL / min] to give a white solid 5 (0.56 g, yield: 54%, HPLC purity: 99.80%).

[0245] MS (ESI, negative ion) m / z: 470.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)13.29(s,1H),7.92-7.81(m,3H),6.82(dd,J=13.1, 4.5Hz,2H),3.55-3.50(m,2H),3.50-3.45(m,2H),2.95(t,J=6.4Hz,2H),1.10(t,J=7.1Hz,3H).

[0246] Example 6 Methyl 2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formate 6 [ka] 2-(3,5-Dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2 (0.30 g, 0.66 mmol) was dissolved in a solution of hydrogen chloride in methanol (10 mL, 40 mmol, 4.0 mol / L) and reacted at 70 °C for 48 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give a pale yellow solid 6 (35 mg, 11% yield, HPLC purity: 98.29%).

[0247] MS(ESI,pos.ion)m / z:492.00[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.87(d,J=8.7Hz,3H),6.87-6.76(m,2H),4.13(d,J=5.0H z,1H),3.85(s,3H),3.52(t,J=6.6Hz,2H),3.17(d,J=4.1Hz,3H),2.97(t,J=6.7Hz,2H).

[0248] Example 7 2-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-2H-benzo[c]azepin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 7 [ka] Step 1: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 7b

[0249] 7-Hydroxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 7a (0.60 g, 3.4 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.77 g, 3.4 mmol) were dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (1.2 g, 8.6 mmol) was added, and the mixture was reacted at 120 °C for 16 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, stirred for 15 min, filtered, and the collected filter cake was pulped with ethanol / ethyl acetate / petroleum ether (1 / 2 / 4, 28 mL), filtered, and the collected filter cake was dried to give brown solid 7b (0.90 g, 72% yield).

[0250] Step 2: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 7c

[0251] 7-(2,6-Dichloro-4-nitrophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 7b (0.50 g, 1.4 mmol) was dissolved in acetic acid (5 mL), iron powder (91 mg, 1.63 mmol) was added, and the reaction was carried out at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, the iron powder was removed, water (48 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, rinsed with water (10 mL), and the solid was collected and dried to give a yellow solid 7c (0.36 g, 78% yield).

[0252] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 7d

[0253] 7-(4-Amino-2,6-dichlorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 7c (0.26 g, 0.77 mmol) and N-cyanoacetylurethane (0.14 g, 0.88 mmol) were dissolved in acetic acid (8 mL), and a solution of sodium nitrite (0.11 g, 1.6 mmol) in water (4 mL) was added at 0 °C and reacted for 2 h. Water (10 mL) was added to the reaction mixture at 0 °C, stirred for 10 min, filtered, rinsed with water (2 mL), and the filter cake was collected and dried to give a yellow solid 7d (0.39 g, 100% yield).

[0254] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-2H-benzo[c]azepin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 7

[0255] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate 7d (0.39 g, 0.77 mmol) was dissolved in N,N-dimethylformamide (4 mL), and sodium acetate (70 mg, 0.85 mmol) was added, followed by reaction at 120°C for 5 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 5). The combined organic phase was washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate). The solid was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 5 / 6, 12 mL) to give a reddish-brown solid 7 (26 mg, yield 7.3%, HPLC purity: 82.24%).

[0256] MS (ESI, negative ion) m / z: 456.5 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)7.99(t,J=5.7Hz,1H),7.84(s,2H),7.51(d,J=8.5Hz,1H),6.87(d,J=2.4Hz,1H),6.76(dd,J=8.5, 2.5Hz, 1H), 2.97-2.89 (m, 2H), 2.74 (t, J=6.9Hz, 2H), 1.93-1.81 (m, 2H).

[0257] Example 8 2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8 [ka] Step 1: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroquinolin-2(1H)-one 8b

[0258] 7-Hydroxy-3,4-dihydroquinolin-2(1H)-one 8a (1.20 g, 7.35 mmol) was dissolved in N,N-dimethylformamide (15 mL), and 1,2,3-trichloro-5-nitrobenzene (1.67 g, 7.38 mmol) and potassium carbonate (2.46 g, 17.6 mmol) were added, followed by reaction at 80° C. for 4 h. The reaction mixture was cooled to room temperature, poured into water (50 mL), stirred for 30 min, filtered, and the filter cake was collected and dried to give pale yellow solid 8b (2.46 g, 95% yield).

[0259] MS (ESI, negative ion) m / z: 351.0 [MH] - .

[0260] Step 2: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroquinolin-2(1H)-one 8c

[0261] 7-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroquinolin-2(1H)-one 8b (2.00 g, 5.66 mmol) was dissolved in acetic acid (40 mL), iron powder (1.29 g, 22.6 mmol) was added, and the reaction was carried out at 60 °C for 4.5 h. The reaction mixture was cooled to room temperature, the iron powder was removed, and water (100 mL) was added dropwise. The mixture was stirred for 30 min, filtered, and the filter cake was collected and dried to give a light gray solid 8c (1.71 g, 93% yield).

[0262] MS (ESI, pos. ion) m / z: 323.0 [M+H] + .

[0263] Step 3: Synthesis of ethyl 2-cyano-2-(2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate 8d

[0264] 7-(4-Amino-2,6-dichlorophenoxy)-3,4-dihydroquinolin-2(1H)-one 8c (0.70 g, 2.17 mmol) and N-cyanoacetylurethane (0.38 g, 2.39 mmol) were dissolved in acetic acid (10 mL), and a solution of sodium nitrite (0.23 g, 3.25 mmol) in water (3 mL) was added at 0° C. and the mixture was allowed to react for 3 h. Water (20 mL) was added to the reaction mixture at 0° C., and the mixture was stirred for 10 min, filtered, rinsed with water (4 mL), and the filter cake was collected and dried to give a yellow solid 8d (0.88 g, 83% yield).

[0265] MS (ESI, negative ion) m / z: 488.1 [MH] - .

[0266] Step 4: Synthesis of 2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8

[0267] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate 8d (0.85 g, 1.73 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium acetate (0.72 g, 8.65 mmol) was added. The mixture was reacted at 120° C. for 6 hours. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the mixture was stirred for 10 minutes. Then, hydrochloric acid (2 N, 3 mL) was added and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was collected and dried to give a gray solid 8 (0.56 g, 73% yield, 89.58% HPLC purity).

[0268] MS (ESI, negative ion) m / z: 442.1 [MH] - ; 1 H NMR(600MHz,DMSO-d6)δ(ppm)13.29(s,1H),9.98(s,1H),7.82(s,2H),7.14(d,J=8.3Hz,1H),6.44(dd,J=8.2, 2.6Hz,1H),6.40(d,J=2.5Hz,1H),2.83(t,J=7.5Hz,2H),2.45(t,J=7.5Hz,2H).

[0269] Example 9 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 9 [ka] Step 1: Synthesis of 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 9b

[0270] Boron tribromide (5.5 mL, 57 mmol) was added dropwise to a solution of 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one 9a (5.0 g, 28 mmol) in dichloromethane (30 mL) at 0 °C, followed by reaction for 3.5 h. The reaction mixture was poured into ice water (40 mL) to quench the reaction, stirred for 30 min, filtered, washed with water (5 mL × 2), and dried. The solid obtained was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 3 / 3, 42 mL) to give brown solid 9b (5.0 g, 100% yield).

[0271] Step 2: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 9c

[0272] 7-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one 9b (1.5 g, 9.2 mmol) and 1,2,3-trichloro-5-nitrobenzene (2.3 g, 10 mmol) were dissolved in N,N-dimethylformamide (40 mL), potassium carbonate (2.6 g, 19 mmol) was added, and the mixture was reacted at 80 °C for 4 h. The reaction mixture was cooled to room temperature, water (80 mL) was added, stirred for 15 min, filtered, and the filter cake was collected to give a yellow solid, which was pulped with ethanol / ethyl acetate / petroleum ether (1 / 3 / 6, 50 mL), filtered, and the filter cake was collected and dried to give a gray solid 9c (2.4 g, 74% yield).

[0273] Step 3: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 9d

[0274] 7-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 9c (2.4 g, 6.8 mmol) was dissolved in acetic acid (15 mL), iron powder (1.5 g, 3.9 mmol) was added, and the reaction was carried out at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, the iron powder was removed, water (30 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, rinsed with water (10 mL), and the solid was collected and dried to give a white solid 9d (1.00 g, 46% yield).

[0275] Step 4: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate 9e

[0276] 7-(4-Amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 9d (0.20 g, 0.62 mmol) and N-cyanoacetylurethane (0.11 g, 0.69 mmol) were dissolved in acetic acid (4 mL), and a solution of sodium nitrite (65 mg, 0.93 mmol) in water (2 mL) was added at 0° C. and the mixture was reacted for 3.5 h. Water (10 mL) was added to the reaction mixture at 0° C., and the mixture was stirred for 10 min. The mixture was filtered, washed with water (2 mL), and the filter cake was collected and dried to give a yellow solid 9e (0.30 g, 99% yield).

[0277] Step 5: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 9

[0278] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)phenyl)hydrazono)acetyl)carbamate 9e (0.30 g, 0.61 mmol) was dissolved in N,N-dimethylformamide (4 mL), sodium acetate (55 mg, 0.67 mmol) was added, and the mixture was reacted at 120 °C for 5 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 7 / 11, 19 mL) to give off-white solid 9 (0.18 g, 66% yield, HPLC purity: 98.20%).

[0279] MS (ESI, negative ion) m / z: 442.0 [MH] - ; 1 H NMR(600MHz,DMSO-d6)δ(ppm)13.30(s,1H),8.06(s,1H),7.85(s,2H),7.35(d,J=8.4Hz,1H),7.16(dd,J=8.3, 2.8Hz, 1H), 7.09 (d, J = 2.8Hz, 1H), 3.36 (d, J = 2.3Hz, 2H), 2.87 (t, J = 6.5Hz, 2H).

[0280] Example 10 2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 10 [ka] Step 1: Synthesis of 6-(benzyloxy)-3,4-dihydroisoquinolin-1(2H)-one 10a

[0281] 6-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one 1a (5.0 g, 31 mmol) was dissolved in N,N-dimethylformamide (50 mL), potassium carbonate (6.4 g, 46 mmol) was added, and the mixture was allowed to react at room temperature for 15 minutes. Benzyl bromide (4.4 mL, 37 mmol) was added dropwise and the mixture was allowed to react at room temperature for 48 hours. Water (100 mL) was added to quench the reaction, and the mixture was stirred for 20 minutes. The solid was collected by filtration and dried to give 10a (6.2 g, 80% yield) as a white solid.

[0282] Step 2: Synthesis of 6-(benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10b

[0283] 6-(Benzyloxy)-3,4-dihydroisoquinolin-1(2H)-one 10a (3.0 g, 12 mmol) was dissolved in tetrahydrofuran (24 mL) and N,N-dimethylformamide (6 mL). Sodium hydride (1.4 g, 35 mmol, 60% in oil) was added and the mixture was stirred at room temperature for 15 minutes. 1-Bromo-2-methoxyethane (1.7 mL, 18 mmol) was added dropwise and the mixture was stirred at 60°C for 4 hours. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated sodium chloride (20 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give yellow oil 10b (3.7 g, 100% yield).

[0284] Step 3: Synthesis of 6-hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10c

[0285] 6-(Benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10b (3.7 g, 12 mmol) was dissolved in ethanol (30 mL), and 10% palladium-carbon (0.37 g) was added. The mixture was then hydrogenated under hydrogen gas (3 MPa) for 16 hours. The reaction mixture was filtered, and the filtrate was collected and concentrated to give a yellow solid 10c (2.6 g, 99% yield).

[0286] Step 4: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10d

[0287] 6-Hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10c (0.50 g, 2.3 mmol) and 1,2,3-trichloro-5-nitro-benzene (0.56 g, 2.5 mmol) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (0.63 g, 4.5 mmol) was added, and the mixture was reacted at 70 °C for 3 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, stirred for 15 min, filtered, and the filter cake was collected and recrystallized (ethyl acetate / petroleum ether = 3 / 5, 12 mL) to give yellow solid 10d (0.49 g, 53% yield).

[0288] Step 5: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10e

[0289] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10d (0.40 g, 0.97 mmol) was dissolved in acetic acid (4 mL), iron powder (0.14 g, 2.48 mmol) was added, and the reaction was allowed to proceed at 60 °C for 5 h. The reaction was cooled to room temperature and quenched by the addition of water (12 mL), stirred for 10 min, filtered, rinsed with water (20 mL), and the solid was collected and dried to give white solid 10e (0.33 g, 89% yield).

[0290] Step 6: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 10f

[0291] 6-(4-Amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10e (0.33 g, 0.87 mmol) was dissolved in acetic acid (6.6 mL), and a solution of sodium nitrite (90 mg, 1.29 mmol) in water (3.3 mL) was added at 0 °C. The mixture was reacted for 10 minutes. N-Cyanoacetylurethane (0.17 g, 1.1 mmol) was added, followed by reaction at 0 °C for 1 hour. Water (12 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred for 10 minutes. The mixture was filtered, rinsed with water (10 mL), and the filter cake was collected and dried to give a yellow solid 10f (0.47 g, 99% yield).

[0292] Step 7: Synthesis of 2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 10

[0293] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 10f (0.47 g, 0.86 mmol) was dissolved in N,N-dimethylformamide (3 mL), and sodium acetate (0.77 g, 0.94 mmol) was added. The reaction mixture was heated to 120° C. The mixture was cooled to room temperature, and water (10 mL) was added. The mixture was stirred for 10 minutes, filtered, and the solid was collected and recrystallized (ethanol / ethyl acetate / petroleum ether = 7.5 / 20 / 10, 37.5 mL). The filter cake was collected and dried to give a white solid 10 (0.23 g, 53% yield, 96.55% HPLC purity).

[0294] MS (ESI, negative ion) m / z: 500.1 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.28(s,1H),7.86(d,J=12.5Hz,3H),6.82(d,J=10.8Hz,2H),3. 61(d,J=5.3Hz,2H),3.59-3.54(m,2H),3.52-3.49(m,2H),3.26(s,3H),2.93(t,J=5.7Hz,2H).

[0295] Example 11 Methyl 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formate 11 [ka] A solution of hydrogen chloride in methanol (5 mL, 4.5 mol / L) was added to 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.10 g, 0.23 mmol) and reacted at 70 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give 11 (45 mg, 42% yield, HPLC purity: 95.69%) as a white solid.

[0296] MS (ESI, pos. ion) m / z: 477.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.79(s,1H),7.86(s,3H),7.84(s,1H),6.87(d,J=2.2Hz,1H),6.81(dd,J=8.6, 2.5Hz, 1H), 3.85 (s, 3H), 3.45 (d, J = 9.4Hz, 2H), 2.90 (t, J = 6.4Hz, 2H).

[0297] Example 12 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 12 [ka] Step 1: Synthesis of 6-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12a

[0298] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (3.0 g, 16.9 mmol) was dissolved in tetrahydrofuran (30 mL) and N,N-dimethylformamide (30 mL). Sodium hydride (0.85 g, 21.2 mmol, 60% in oil) was added in portions at 0 °C, followed by the dropwise addition of bromomethylpyran (1.13 mL, 13.8 mmol). After the dropwise addition was completed, the reaction was continued at room temperature for 24 h. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (40 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 12a (4.35 g, 93% yield) as a pale yellow oil.

[0299] MS (ESI, pos. ion) m / z: 276.2 [M+H] + .

[0300] Step 2: Synthesis of 6-hydroxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12b

[0301] 6-Methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12a (0.81 g, 2.94 mmol) was dissolved in dichloromethane (20 mL), and boron tribromide (0.57 mL, 5.89 mmol) was added dropwise at 0 °C. The mixture was allowed to react for 2.5 h at 0 °C. The reaction was quenched by the addition of methanol (5 mL) at 0 °C, concentrated, and water (50 mL) was added. The mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a pale yellow solid 12b (0.42 g, 55% yield).

[0302] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12c

[0303] 6-Hydroxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12b (0.33 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1,2,3-trichloro-5-nitrobenzene (0.39 g, 1.7 mmol) and potassium carbonate (0.55 g, 3.9 mmol) were added. The mixture was then heated at 80 °C for 5 h. The reaction mixture was cooled to room temperature, and water (15 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 12c (0.31 g, 54% yield) as a yellow solid.

[0304] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12d

[0305] 6-(2,6-Dichloro-4-nitrophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12c (0.31 g, 0.69 mmol) was dissolved in acetic acid (10 mL), iron powder (0.19 g, 3.3 mmol) was added, and the mixture was reacted at 60 °C for 3.5 h. The reaction mixture was cooled to room temperature, the iron powder was removed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 12d (0.18 g, 62% yield) as a pale yellow solid.

[0306] MS (ESI, pos. ion) m / z: 421.1 [M+H] + .

[0307] Step 5: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazino)acetyl)carbamate ethyl 12e

[0308] 6-(4-Amino-2,6-dichlorophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12d (0.18 g, 0.43 mmol) was dissolved in acetic acid (8 mL) and a solution of sodium nitrite (46 mg, 0.65 mmol) in water (0.5 mL) was added dropwise at 0 °C. After reacting for 20 min, N-cyanoacetylurethane (75 mg, 0.47 mmol) was added and reacted for 4.5 h. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give yellow solid 12e (0.25 g, 99% yield).

[0309] MS (ESI, negative ion) m / z: 586.1 [MH] - .

[0310] Step 6: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 12

[0311] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazino)acetyl)carbamate 12e (0.25 g, 0.43 mmol) was dissolved in N,N-dimethylformamide (8 mL), and sodium acetate (0.18 g, 2.2 mmol) was added, followed by reaction at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1). The resulting solid was recrystallized (petroleum ether / ethyl acetate = 3 / 1, 5 mL) to give a white solid 12 (0.21 g, yield 89%, HPLC purity: 97.04%).

[0312] MS (ESI, negative ion) m / z: 540.1 [MH] - . 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.29(s,1H),7.88-7.80(m,3H),6.85-6.78(m,2H),3.86-3.80(m,2H),3.53(t,J=6.4Hz,2H) ,3.35(s,2H),3.25(t,J=11.2Hz,2H),2.95(t,J=6.3Hz,2H),1.95-1.85(m,1H),1.53(d,J=11.6Hz,2H),1.21(ddd,J=16.5, 12.4, 5.4Hz, 2H).

[0313] Example 13 2-(3,5-dichloro-4-((2-(isopropoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 13 [ka] 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.30 g, 0.68 mmol) was dissolved in isopropanol (10 mL), 37% formaldehyde (1.5 mL, 20 mmol) was added, and the reaction was carried out in a sealed tube at 100 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). The resulting solid was recrystallized (ethyl acetate / petroleum ether = 1 / 2, 6 mL) to give 13 (85 mg, 24% yield, HPLC purity: 99.85%) as a white solid.

[0314] MS (ESI, negative ion) m / z: 514.1 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.97-7.79(m,3H),6.87(dd,J=17.0, 4.9Hz,2H),4.92(s,2H),3.67(dt,J=12.2, 6.1Hz, 1H), 3.56 (t, J=6.5Hz, 2H), 2.97 (t, J=6.3Hz, 2H), 1.10 (d, J=6.1Hz, 6H).

[0315] Example 14 2-(3,5-dichloro-4-((1-oxo-2-((2,2,2-trifluoroethoxy)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 14 [ka] 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.48 g, 1.08 mmol) was dissolved in trifluoroethanol (8 mL), 37% formaldehyde (1.60 mL, 22 mmol) was added, and the reaction was carried out at 100 °C in a sealed test tube for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2). The resulting solid was recrystallized (ethyl acetate / petroleum ether = 1 / 2, 6 mL) to give 14 (0.23 g, 38% yield, HPLC purity: 96.05%) as a white solid.

[0316] MS (ESI, negative ion) m / z: 554.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.93(d,J=8.6Hz,1H),7.90-7.79(m,2H),6.93-6 .83(m,2H),5.07(s,2H),4.12(q,J=9.4Hz,2H),3.63(t,J=6.4Hz,2H),3.01(t,J=6.4Hz,2H); 19 F NMR(376MHz,DMSO-d6)δ(ppm)-73.04.

[0317] Example 15 2-(3,5-dichloro-4-((1-oxo-2-((2,2-difluoroethoxy)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 15 [ka] 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.30 g, 0.68 mmol) was dissolved in 2,2-difluoroethanol (6 mL), 37% formaldehyde (1.0 mL, 14 mmol) was added, and the reaction was carried out at 100 °C in a sealed test tube for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2). The resulting solid was recrystallized (ethyl acetate / petroleum ether = 1 / 2, 6 mL) to give 15 (85 mg, 23% yield, HPLC purity: 97.53%) as a white solid.

[0318] MS (ESI, negative ion) m / z: 536.1 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)13.31(s,1H),7.89(dd,J=27.8, 8.3Hz,3H),6.95-6.78(m,2H),6.14(t,J=55.1Hz,1H),5.01(s,2H),3.74(t,J=14.8Hz,2H),3.61(s,2H),3.00(s,2H); 19 F NMR(376MHz,DMSO-d6)δ(ppm)-125.56.

[0319] Example 16 2-(3,5-dichloro-4-((2-(1-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 16 [ka] 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.20 g, 0.45 mmol) was dissolved in ethanol (4 mL), acetaldehyde (0.8 mL, 14 mmol) was added, and the reaction was carried out at 90 °C for 48 h in a sealed test tube. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2). The resulting solid was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 7 / 10, 18 mL) to give 16 (60 mg, 26% yield, HPLC purity: 87.08%) as a yellow solid.

[0320] MS (ESI, negative ion) m / z: 514.1 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.90(d,J=8.6Hz,1H),7.85(s,2H),6.93-6.78(m,2H),5.89(q,J=6. 0Hz,1H),3.41(s,2H),3.39(d,J=7.0Hz,2H),2.95(t,J=6.5Hz,2H),1.26(d,J=6.1Hz,3H),1.11(t,J=7.0Hz,3H).

[0321] Example 17 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 17 [ka] Step 1: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 17a

[0322] Concentrated hydrochloric acid (1.5 mL) was added to a solution of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.20 g, 0.45 mmol) in acetic acid (4 mL), and the reaction was carried out at 120° C. for 16 hours. The reaction mixture was cooled to room temperature, and water (6 mL) was added. The mixture was stirred for 5 minutes, filtered, and the filter cake was collected and dried to give a yellow solid 17a (90 mg, 87% yield).

[0323] MS (ESI, negative ion) m / z: 463.0 [MH] - .

[0324] Step 2: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 17

[0325] 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 17a (175 mg, 0.38 mmol) was dissolved in thioglycolic acid (2.5 mL) and reacted at 140 °C for 17 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give 17 (63 mg, 40% yield, HPLC purity: 95.58%) as a pale red solid.

[0326] MS (ESI, negative ion) m / z: 418.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),7.85(d,J=10.5Hz,4H),7.73(s,1H),6.85(d,J=2.6Hz,1H),6.78(dd,J=8.6, 2.6Hz,1H),3.57- 3.38(m,2H),2.89(t,J=6.6Hz,2H).

[0327] Example 18 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 18 [ka] Step 1: Synthesis of 2-benzyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 18a

[0328] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (3.0 g, 17 mmol) was added to a solution of sodium hydride (0.81 g, 20 mmol, 60% in oil) in N,N-dimethylformamide (24 mL) and tetrahydrofuran (18 mL) at 0 °C, and benzyl bromide (2.2 mL, 19 mmol) was added dropwise. The mixture was allowed to react at room temperature for 6 h. The reaction was quenched by the addition of water (120 mL), extracted with ethyl acetate (200 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give 18a (4.51 g, 100% yield) as a pale yellow oil.

[0329] Step 2: Synthesis of 2-benzyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 18b

[0330] Boron tribromide (3.2 mL, 34 mmol) was added dropwise to a solution of 2-benzyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 18a (4.5 g, 17 mmol) in dichloromethane (36 mL) at 0°C, followed by reaction at room temperature for 5 h. The reaction was quenched by pouring into ice water (100 mL), stirring for 10 min, filtering, and washing the filter cake with water (20 mL × 2). The filter cake was collected and dried to give a white solid 18b (3.8 g, 89% yield).

[0331] Step 3: Synthesis of 2-benzyl-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 18c

[0332] 2-Benzyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 18b (3.80 g, 15.0 mmol) and 1,2,3-trichloro-5-nitrobenzene (3.74 g, 16.5 mmol) were dissolved in N,N-dimethylformamide (23 mL), potassium carbonate (3.14 g, 22.5 mmol) was added, and the mixture was reacted at 70 °C for 7 h. The reaction mixture was cooled to room temperature, water (50 mL) was added, stirred for 10 min, filtered, and the filter cake was washed with water (20 mL × 2). The filter cake was collected and recrystallized (ethyl acetate / petroleum ether = 1 / 2, 30 mL) to give 18c (6.10 g, 92% yield) as a white solid.

[0333] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-benzyl-3,4-dihydroisoquinolin-1(2H)-one 18d

[0334] The synthesized 2-benzyl-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 18c (3.0 g, 6.8 mmol) was dissolved in acetic acid (18 mL), iron powder (1.1 g, 20 mmol) was added, and the mixture was reacted at 60 °C for 3 h. The reaction mixture was cooled to room temperature, water (40 mL) was added, stirred for 10 min, filtered, and the filter cake was washed with water (20 mL × 2). The filter cake was collected and recrystallized (ethyl acetate / petroleum ether = 2 / 1, 15 mL) to give brown solid 18d (1.1 g, 39% yield).

[0335] Step 5: Synthesis of ethyl (2-(2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)hydrazono)-2-cyanoacetyl)carbamate 18e

[0336] 6-(4-Amino-2,6-dichlorophenoxy)-2-benzyl-3,4-dihydroisoquinolin-1(2H)-one 18d (1.0 g, 2.4 mmol) and N-(2-cyanoacetyl)carbamate (0.45 g, 2.9 mmol) were dissolved in acetic acid (20 mL), and an aqueous solution (10 mL) of sodium nitrite (0.33 g, 4.8 mmol) was added at 0 °C. The mixture was then reacted for 2 h at 0 °C. Water (30 mL) was added to the reaction mixture at 0 °C, stirred for 10 min, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 18e (0.60 g, 43% yield).

[0337] Step 6: Synthesis of 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 18

[0338] Ethyl (2-(2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)hydrazono)-2-cyanoacetyl)carbamate 18e (0.70 g, 1.2 mmol) was dissolved in N,N-dimethylformamide (7 mL), and sodium acetate (0.11 g, 1.3 mmol) was added. The mixture was then heated at 120 °C for 4 h. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate / petroleum ether (2 / 1, 30 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was recrystallized from ethanol / ethyl acetate / petroleum ether (1 / 3 / 6, 50 mL) to give 18 (0.26 g, 40% yield, HPLC purity: 98.24%) as a red solid.

[0339] MS (ESI, negative ion) m / z: 533.4 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.94(d,J=8.6Hz,1H),7.84(s,2H),7.32(dq,J=19.3, 11.0, 9.3Hz, 5H), 6.85 (d, J=6.9Hz, 2H), 4.70 (s, 2H), 3.47 (s, 3H), 2.95 (s, 2H).

[0340] Example 19 2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 19 [ka] Step 1: 6-(2,6-dichloro-4-nitrophenoxy) )Isoquinoline-1 Synthesis of (2H)-one 19b

[0341] 6-Hydroxyisoquinolin-1(2H)-one 19a (0.92 g, 5.7 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 1,2,3-trichloro-5-nitrobenzene (1.40 g, 6.18 mmol) and potassium carbonate (1.90 g, 13.6 mmol) were added. The mixture was then reacted at 80 °C for 3 h. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (35 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (35 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give yellow solid 19b (1.83 g, 91% yield).

[0342] MS (ESI, pos. ion) m / z: 351.1 [M+H] + .

[0343] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)isoquinolin-1(2H)-one 19c

[0344] 6-(2,6-Dichloro-4-nitrophenoxy)isoquinolin-1(2H)-one 19b (0.45 g, 1.30 mmol) was dissolved in acetic acid (15 mL), iron powder (0.29 g, 5.1 mmol) was added, and the reaction was carried out at 60° C. for 2.5 hours. The reaction mixture was cooled to room temperature, the iron powder was removed, water (30 mL) was added, the mixture was stirred for 10 minutes, filtered, and the filter cake was collected and dried to give a pale yellow solid 19c (0.38 g, 92% yield).

[0345] Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 19d

[0346] 6-(4-Amino-2,6-dichlorophenoxy)isoquinolin-1(2H)-one 19c (0.40 g, 1.20 mmol) was dissolved in acetic acid (12 mL) and a solution of sodium nitrite (0.13 g, 1.8 mmol) in water (1.5 mL) was added dropwise at 0 °C for 20 min. N-Cyanoacetylurethane (0.22 g, 1.40 mmol) was added and the mixture was allowed to react for 4 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (35 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give yellow solid 19d (0.60 g, 99% yield).

[0347] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 19

[0348] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 19d (0.45 g, 0.92 mmol) was dissolved in N,N-dimethylformamide (15 mL), sodium acetate (0.38 g, 4.61 mmol) was added, and the mixture was reacted at 120 °C for 3 h. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give a white solid 19 (0.23 g, 55% yield, HPLC purity: 96.04%).

[0349] MS (ESI, negative ion) m / z: 440 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.32(s,1H),11.20(d,J=3.8Hz,1H),8.21(d,J= 8.8Hz, 1H), 7.86 (s, 2H), 7.24-7.10 (m, 2H), 7.02 (s, 1H), 6.52 (d, J=7.1Hz, 1H).

[0350] Example 20 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 20 [ka] Step 1: 6-(2,6-Dichloro-4-nitrophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 20a

[0351] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (0.50 g, 1.4 mmol) was dissolved in tetrahydrofuran (20 mL) and added with sodium hydride (85 mg, 2.1 mmol, 60 mass% in oil) at 0 °C. After 20 min, 1-bromomethyl-4-fluorobenzene (0.55 g, 2.8 mmol) and N,N-dimethylformamide (5 mL) were added dropwise and the mixture was allowed to react at room temperature for 15 h. The reaction was quenched with ice water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 20a (0.65 g, 99% yield) as a pale yellow oil.

[0352] MS (ESI, pos. ion) m / z: 461.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ(ppm)8.35(s,2H),8.14(d,J=8.6Hz,1H),7.37-7.30(m,2H),7.07-7.00(m,2H),6.79(dd,J=8.7, 2.6Hz,1H), 6.64(d,J=2.5Hz,1H),4.76(s,2H),3.51(t,J=6.6Hz,2H),2.93(t,J=6.6Hz,2H).

[0353] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 20b

[0354] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 20a (0.65 g, 1.4 mmol) was dissolved in acetic acid (10 mL), iron powder (0.16 g, 2.8 mmol) was added, and the mixture was reacted at 50 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (30 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 20b (0.37 g, 61% yield) as a pale yellow oil.

[0355] MS (ESI, pos. ion) m / z: 431.0 [M+H] + .

[0356] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 20c

[0357] 6-(4-Amino-2,6-dichlorophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 20b (0.37 g, 0.86 mmol) was dissolved in acetic acid (12 mL), and a solution of sodium nitrite (0.12 g, 1.7 mmol) in water (6 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.20 g, 1.3 mmol). The reaction was allowed to react for 3 h. The reaction was quenched by the addition of water (30 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (5 mL). The filter cake was collected and dried to give a pale yellow solid 20c (0.50 g, 97% yield).

[0358] MS (ESI, pos. ion) m / z: 596.0 [M+H] + .

[0359] Step 4: 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 20d

[0360] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 20c (0.50 g, 0.84 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium acetate (0.15 g, 1.1 mmol) was added. The mixture was reacted at 120 °C for 6 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), stirred for 15 min, filtered, and the filter cake was collected, dried, and then recrystallized at 60 °C (ethyl acetate / petroleum ether = 2 / 1, 15 mL) to give yellow solid 20d (0.28 g, 61% yield, 100% HPLC purity).

[0361] MS (ESI, negative ion) m / z: 550.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.94(dd,J=9.0, 6.2Hz,1H),7.84(s,2H),7.36(dd,J=8.4, 5.5Hz,2H),7.16(t,J=8.7Hz,2H),6.85(d,J=6.7Hz,2H),4.67(s,2H),3.47(t,J=6.6Hz,2H),2.95(t,J=6.6Hz,2H); 19 F NMR(376MHz,DMSO-d6)δ(ppm)-115.68.

[0362] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 20e

[0363] 2-(3,5-Dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 20d (0.17 g, 0.31 mmol) was dissolved in acetic acid (4 mL), concentrated hydrochloric acid (2 mL) was added, and the reaction was carried out at 100° C. for 18 hours. The reaction mixture was cooled to room temperature, water (18 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 20e (0.15 g, 85% yield).

[0364] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 20

[0365] 2-(3,5-Dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 20e (0.15 g, 0.26 mmol) was dissolved in thioglycolic acid (3 mL) and reacted at 150 °C for 24 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 20 (90 mg, 65% yield, HPLC purity: 98.12%) as a white solid.

[0366] MS (ESI, negative ion) m / z: 525.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),7.93(d,J=8.6Hz,1H),7.87(s,2H),7.73(s,1H),7.36(dd,J=8.5, 5.6Hz,2H),7.16(dd,J=10.1, 7.6Hz,2H),6.83(s,1H),6.81(d,J=2.6Hz,1H),4.67(s,2H),3.47(t,J=6.6Hz,2H),2.95(t,J=6.6Hz,2H).

[0367] Example 21 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 21 [ka] Step 1: 6-(2,6-Dichloro-4-nitrophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 21a

[0368] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (0.50 g, 1.4 mmol) was dissolved in tetrahydrofuran (20 mL) and added with sodium hydride (85 mg, 2.1 mmol, 60 mass% in oil) at 0 °C. After 20 min, 1-bromomethyl-4-toluene (0.54 g, 2.8 mmol) and N,N-dimethylformamide (5 mL) were added dropwise and the mixture was allowed to react at room temperature for 14 h. The reaction was quenched with ice water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 21a (0.63 g, 98% yield) as a pale yellow oil.

[0369] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 21b

[0370] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 21a (0.63 g, 1.4 mmol) was dissolved in acetic acid (10 mL), iron powder (0.16 g, 2.8 mmol) was added, and the mixture was reacted at 50 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (30 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 21b (0.46 g, 78% yield) as a pale yellow oil.

[0371] MS (ESI, pos. ion) m / z: 428.1 [M+H] + .

[0372] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 21c

[0373] 6-(4-Amino-2,6-dichlorophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 21b (0.46 g, 1.1 mmol) was dissolved in acetic acid (16 mL), and an aqueous solution (8 mL) of sodium nitrite (0.15 g, 2.1 mmol) was added at 0 °C, followed by N-cyanoacetylurethane (0.25 g, 1.6 mmol), and the reaction was allowed to proceed for 2.5 h. The reaction was quenched by the addition of water (30 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (5 mL). The filter cake was collected and dried to give a pale yellow solid 21c (0.48 g, 75% yield).

[0374] MS (ESI, pos. ion) m / z: 595.0 [M+H] + .

[0375] Step 4: 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 21d

[0376] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 21c (0.48 g, 0.81 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium acetate (0.14 g, 1.0 mmol) was added. The mixture was reacted at 120 °C for 8 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 60 °C (ethyl acetate / petroleum ether = 2 / 1, 15 mL) to give yellow solid 21d (0.41 g, 93% yield, HPLC purity: 98.71%).

[0377] MS (ESI, negative ion) m / z: 547.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.33(s,1H),7.97-7.89(m,1H),7.84(s,2H),7.20(d,J=7.7Hz,2H),7.14(d,J=7.8Hz,2H),6.85(dd,J=5.8, 2.9Hz,2H),4.64(s,2H),3.44(t,J=6.5Hz,2H),2.93(t,J=6.6Hz,2H),2.28(s,3H).

[0378] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 21e

[0379] 2-(3,5-Dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 21d (0.21 g, 0.37 mmol) was dissolved in acetic acid (4 mL), concentrated hydrochloric acid (2 mL) was added, and the reaction was carried out at 100° C. for 18 hours. The reaction mixture was cooled to room temperature, water (18 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 21e (0.20 g, 93% yield).

[0380] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 21

[0381] 2-(3,5-Dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 21e (0.20 g, 0.35 mmol) was dissolved in thioglycolic acid (3 mL) and reacted at 150 °C for 24 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid 21 (96 mg, 52% yield, HPLC purity: 96.18%).

[0382] MS (ESI, negative ion) m / z: 521.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.53(s,1H),7.93(d,J=9.2Hz,1H),7.86(s,2H),7.72(s,1H),7.23-7.11(m,4H) ),6.82(s,1H),6.80(d,J=2.6Hz,1H),4.64(s,2H),3.44(d,J=6.5Hz,2H),2.92(t,J=6.6Hz,2H),2.27(s,3H).

[0383] Example 22 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione 22 [ka] Step 1: Synthesis of 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 22a

[0384] 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 18 (0.21 g, 0.37 mmol) was dissolved in acetic acid (4 mL), concentrated hydrochloric acid (1.5 mL) was added, and the reaction was carried out at 120 °C for 24 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 22a (0.20 g, 100% yield).

[0385] Step 2: Synthesis of 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione 22

[0386] 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 22a (0.20 g, 0.36 mmol) was dissolved in thioglycolic acid (4 mL) and reacted at 160 °C for 24 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a pale yellow solid 22 (0.13 g, 68% yield, HPLC purity: 98.02%).

[0387] MS (ESI, negative ion) m / z: 507.5 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.51(s,1H),7.92(d,J=8.7Hz,1H),7.85(s,2H),7.72(s,1H),7.35- 7.22(m,5H),6.81(d,J=7.6Hz,2H),4.68(s,2H),3.45(t,J=6.4Hz,2H),2.93(t,J=6.2Hz,2H).

[0388] Example 23 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5( 2H , 4H )-Zion 23 [ka] Step 1: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 23a

[0389] 2-(3,5-Dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 12 (1.3 g, 2.4 mmol) was dissolved in acetic acid (20 mL), concentrated hydrochloric acid (6 mL) was added, and the mixture was reacted at 120°C for 4.5 hours. The reaction mixture was cooled to room temperature, concentrated, and then water (25 mL), saturated sodium bicarbonate solution (30 mL), and ethyl acetate (30 mL) were added. The mixture was separated and the organic phase was extracted with water (25 mL × 2). The aqueous phase was collected and adjusted to pH 2-3 with dilute hydrochloric acid (4N). The organic phase was further extracted with ethyl acetate (25 mL × 3). The combined and acidified organic phases were washed with saturated sodium chloride solution (25 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give a yellow solid 23a (0.87 g, 65% yield).

[0390] Step 2: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 23

[0391] 2-(3,5-Dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 23a (0.85 g, 1.5 mmol) was dissolved in thioglycolic acid (4 mL) and reacted at 160° C. for 24 hours. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate solution (15 mL) was slowly added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give a pale yellow solid 23 (0.42 g, yield 54%, HPLC purity: 96.10%).

[0392] MS (ESI, negative ion) m / z: 515.2 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.51(s,1H),7.94-7.82(m,3H),7.72(s,1H),6.87-6.75(m,2H),3.83(d,J=8.9Hz,2H),3.53(t,J=6 .4Hz,2H),3.35(s,2H),3.25(t,J=11.1Hz,2H),2.94(t,J=6.2Hz,2H),1.96-1.85(m,1H),1.53(d,J=11.9Hz,2H),1.24(dd,J=11.7, 4.0Hz,2H).

[0393] Example 24 2-(3,5-dichloro-4-((1-oxo-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 24 [ka] Step 1: 6-(2,6-Dichloro-4-nitrophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 24a

[0394] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (2.0 g, 5.7 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (0.80 g, 20 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 20 min, 4-(bromomethyl)pyridine hydrobromide (1.5 g, 8.7 mmol) and N,N-dimethylformamide (3 mL) were added, followed by reacting for 2 h at 5 °C. The reaction was quenched by adding water (70 mL), stirred for 10 min, filtered, and the filter cake was rinsed with water (20 mL × 3). The filter cake was collected and dried to give yellow solid 24a (2.3 g, 91% yield).

[0395] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 24b

[0396] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 24a (1.9 g, 4.3 mmol) was dissolved in acetic acid (25 mL), iron powder (0.60 g, 11 mmol) was added, and the mixture was reacted at 55 °C for 8 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (120 mL). The mixture was extracted with ethyl acetate (150 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give a gray solid 24b (1.8 g, 100% yield).

[0397] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 24c

[0398] 6-(4-Amino-2,6-dichlorophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 24b (1.8 g, 4.3 mmol) was dissolved in acetic acid (27 mL) and added with an aqueous solution (14 mL) of sodium nitrite (0.60 g, 8.7 mmol) at 0 °C, followed by N-cyanoacetylurethane (0.81 g, 5.3 mmol) for 2 h. The reaction was quenched by adding water (80 mL), extracted with ethyl acetate (150 mL × 2), and the combined organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give 24c (2.5 g, 99% yield) as a red foamy solid.

[0399] Step 4: 2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 24d

[0400] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 24c (1.8 g, 3.1 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium acetate (0.28 g, 3.4 mmol) was added. The mixture was reacted at 120 °C for 6 h. The reaction mixture was cooled to room temperature and quenched by adding water (100 mL). The mixture was stirred for 15 min, filtered, and the filter cake was collected, dried, and then recrystallized at 85 °C (N,N-dimethylformamide / ethanol / ethyl acetate / petroleum ether = 4 / 25 / 15 / 20, 128 mL) to give yellow solid 24d (0.90 g, 53% yield, HPLC purity: 82.28%).

[0401] MS (ESI, pos. ion) m / z: 536.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.56(s,2H),7.92(d,J=8.4Hz,1H),7.84(s,2H) ,7.33(s,2H),6.86(d,J=13.0Hz,2H),4.71(s,2H),3.54(s,2H),3.01(s,2H).

[0402] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 24e

[0403] 2-(3,5-Dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 24d (0.45 g, 0.84 mmol) was dissolved in acetic acid (8 mL), concentrated hydrochloric acid (3 mL) was added, and the reaction was carried out at 120 °C for 24 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a pale yellow solid 24e (0.45 g, 97% yield).

[0404] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 24

[0405] 2-(3,5-Dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 24e (0.37 g, 0.67 mmol) was dissolved in thioglycolic acid (5 mL) and reacted at 120 °C for 36 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (80 mL) was added. The mixture was washed successively with water (40 mL), saturated sodium bicarbonate solution (20 mL), and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give 24 (0.20 g, 59% yield, HPLC purity: 92.08%) as a pale yellow solid.

[0406] MS (ESI, negative ion) m / z: 511.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ(ppm)12.53(s,1H),8.77(s,2H),7.92(d,J=8.5Hz,1H),7.87(s,2H),7.73(s,1H), 7.65(s,2H),6.87(s,1H),6.83(d,J=7.6Hz,1H),4.82(s,2H),3.59(d,J=6.2Hz,2H),3.03(d,J=6.5Hz,2H).

[0407] Example 25 2-(3,5-dichloro-4-((1-oxo-2-(pyridazin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 25 [ka] Step 1: 6-(2,6-Dichloro-4-nitrophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 25a

[0408] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (2.0 g, 5.7 mmol) was dissolved in tetrahydrofuran (25 mL), and sodium hydride (0.80 g, 20 mmol, 60 mass% in oil) was added at 0 °C. After 20 min of reaction, 3-(bromomethyl)pyridazine hydrobromide (1.5 g, 8.7 mmol) and N,N-dimethylformamide (4 mL) were added, followed by 2 h of reaction at 8 °C. The reaction was quenched by adding water (150 mL), stirred for 10 min, filtered, and the filter cake was rinsed with water (20 mL × 3). The collected filter cake was dried, pulped with ethyl acetate / petroleum ether (1 / 4, 50 mL), filtered, and the filter cake was collected to give a yellow solid 25a (1.8 g, 71% yield).

[0409] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 25b

[0410] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 25a (1.0 g, 2.2 mmol) was dissolved in acetic acid (15 mL), iron powder (0.35 g, 6.3 mmol) was added, and the reaction was allowed to proceed at 60 °C for 8 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (80 mL), stirred for 10 min, filtered, and the filter cake was rinsed with water (20 mL × 2). The filter cake was collected and dried to give a gray solid 25b (0.74 g, 79% yield).

[0411] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 25c

[0412] 6-(4-Amino-2,6-dichlorophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 25b (0.74 g, 1.8 mmol) was dissolved in acetic acid (15 mL), and a solution of sodium nitrite (0.25 g, 3.6 mmol) in water (6 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.35 g, 2.2 mmol). The reaction was allowed to react for 2 h. The reaction was quenched by the addition of water (50 mL), stirred for 10 min, filtered, and the filter cake was rinsed with water (30 mL × 2). The filter cake was collected and dried to give a red solid 25c (0.96 g, 93% yield).

[0413] Step 4: 2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 25d

[0414] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 25c (0.96 g, 1.6 mmol) was dissolved in N,N-dimethylformamide (12 mL), and sodium acetate (0.15 g, 1.8 mmol) was added. The mixture was reacted at 120 °C for 6 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (100 mL). The mixture was stirred for 15 min, filtered, and the filter cake was collected, dried, and then recrystallized at 85 °C (N,N-dimethylformamide / ethanol / ethyl acetate / petroleum ether = 2 / 5 / 20 / 40, 128 mL) to give yellow solid 25d (0.51 g, 58% yield, HPLC purity: 93.11%).

[0415] MS (ESI, pos. ion) m / z: 537.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.23(s,1H),9.15(d,J=4.6Hz,1H),7.88(d,J=28.0Hz,3H),7.66(dd,J=10.8, 6.2Hz,2H),7.06-6.64(m,2H),4.97(s,2H),3.66(t,J=6.6Hz,2H),3.02(t,J=6.5Hz,2H).

[0416] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 25e

[0417] 2-(3,5-Dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 25d (0.23 g, 0.43 mmol) was dissolved in acetic acid (2.5 mL), concentrated hydrochloric acid (1.4 mL) was added, and the reaction was carried out at 120 °C for 24 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (15 mL × 2). The filter cake was collected and dried to give a yellow solid 25e (0.21 g, 88% yield).

[0418] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 25

[0419] 2-(3,5-Dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 25e (0.20 g, 0.40 mmol) was dissolved in thioglycolic acid (2.5 mL) and reacted at 120° C. for 36 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (100 mL) was added. The mixture was washed successively with water (20 mL), saturated sodium bicarbonate solution (20 mL), and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by preparative separation [35% ACN / 65% HO (1% TFA), Kromasil standard: C18 10 μm × 50 mm × 250 mm, flow rate: 100 mL / min] to give a white solid 25 (20 mg, yield 20%, HPLC purity: 82.95%).

[0420] MS (ESI, negative ion) m / z: 513.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),9.17(s,1H),7.99-7.83(m,3H),7.79-7.51 (m,3H),6.96-6.74(m,2H),4.95(d,J=17.0Hz,2H),3.67(s,2H),3.02(t,J=6.5Hz,2H).

[0421] Example 26 2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 26 [ka] Step 1: Synthesis of 6-(2,6-dimethyl-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b

[0422] 6-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one 1a (3.0 g, 18 mmol) and 2-fluoro-1,3-dimethyl-5-nitrobenzene 26a (3.5 g, 21 mmol) were dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (2.8 g, 28 mmol) was added, and the mixture was reacted at 80 °C for 12 h. The reaction mixture was cooled to room temperature, water (150 mL) was added, stirred for 10 min, filtered, and the filter cake was rinsed with water (30 mL × 2). The filter cake was collected, pulped with ethyl acetate / petroleum ether (1 / 6, 70 mL), filtered, and dried to give white solid 26b (4.2 g, 73% yield).

[0423] Step 2: Synthesis of 6-(4-amino-2,6-dimethylphenoxy)-3,4-dihydroisoquinolin-1(2H)-one 26c

[0424] 6-(2,6-Dimethyl-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 26b (3.0 g, 9.6 mmol) was dissolved in acetic acid (30 mL), iron powder (1.6 g, 29 mmol) was added, and the mixture was reacted at 55 °C for 5 h. The reaction mixture was cooled to room temperature, the iron powder was removed, ethyl acetate (200 mL) was added, and the mixture was washed successively with water (150 mL) and saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give yellow oil 26c (2.7 g, 100% yield).

[0425] Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetraisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 26d

[0426] 6-(4-Amino-2,6-methylphenoxy)-3,4-dihydroisoquinolin-1(2H)-one 26c (2.7 g, 9.6 mmol) was dissolved in acetic acid (10 mL). A solution of sodium nitrite (1.0 g, 14 mmol) in water (5 mL) was added at 0 °C. The mixture was allowed to react for 5 min, followed by the addition of N-cyanoacetylurethane (1.9 g, 12 mmol) for 1.5 h. Water (10 mL) was added to the reaction mixture at 0 °C. The mixture was stirred for 10 min, filtered, rinsed with water (5 mL), and the filter cake was collected and dried to give a yellow solid 26d (4.1 g, 95% yield).

[0427] Step 4: Synthesis of 2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 26

[0428] Ethyl (2-cyano-2-(2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetraisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 26d (4.1 g, 9.1 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium acetate (0.90 g, 10 mmol) was added. The mixture was reacted at 120°C for 7.5 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by preparative separation [42% ACN / 58% HO (0.1% TFA), Kromasil standard: C18 10 μm × 50 mm × 250 mm, flow rate: 100 mL / min] to give a white solid 26 (1.0 g, yield 27%, purity 95.48%).

[0429] MS (ESI, pos. ion) m / z: 404.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.05(s,1H),7.89-7.72(m,2H),7.32(s,2H) ,6.76-6.61(m,3H),3.27-3.33(m,2H),2.86(t,J=6.4Hz,2H),2.11(s,6H).

[0430] Example 27 2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 27 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one 27b

[0431] 6-Hydroxy-2-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one 27a (preparation method see Steps 1 and 2 of Example 23 of Chinese Patent Application No. 109988109A) (0.32 g, 1.3 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.34 g, 1.5 mmol) were dissolved in N,N-dimethylformamide (6 mL), potassium carbonate (0.35 g, 2.5 mmol) was added, and the reaction was carried out at 60 °C for 3 h. The reaction mixture was cooled to room temperature, water (8 mL) was added, stirred for 10 min, filtered, and the filter cake was rinsed with water (3 mL × 2). The filter cake was collected and dried to give a gray solid 27b (0.56 g, 99% yield).

[0432] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one 27c

[0433] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one 27b (0.56 g, 1.25 mmol) was dissolved in acetic acid (5 mL), iron powder (0.21 g, 3.75 mmol) was added, and the mixture was reacted at 60 °C for 5 h. The reaction mixture was cooled to room temperature, the iron powder was removed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give 27c (0.37 g, 72% yield) as a white solid.

[0434] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 27d

[0435] 6-(4-Amino-2,6-dichlorophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one 27c (0.37 g, 0.90 mmol) was dissolved in acetic acid (4 mL), and N-cyanoacetylurethane (0.15 g, 1.08 mmol) was added at 0 °C. After stirring for 5 min, a solution of sodium nitrite (93 mg, 1.35 mmol) in water (1 mL) was added and the mixture was allowed to react for 1 h. Water (5 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred for 10 min. The mixture was filtered, rinsed with water (3 mL), and the filter cake was collected and dried to give a yellow solid 27d (0.50 g, 96% yield).

[0436] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 27

[0437] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 27d (0.50 g, 0.86 mmol) was dissolved in N,N-dimethylformamide (6 mL), and sodium acetate (0.14 g, 1.66 mmol) was added. The mixture was reacted at 120°C for 3 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (50 mL), stirred for 10 min, filtered, and the filter cake was collected and dried. The resulting solid was purified by preparative separation [60% ACN / 40% HO (0.1% TFA), Kromasil standard: C18 10 μm × 50 mm × 250 mm, flow rate: 100 mL / min] to give a white solid 27 (0.23 g, yield: 50%, HPLC purity: 98.72%).

[0438] MS (ESI, negative ion) m / z: 534.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.31(s,1H).7.94(d,J=6.4Hz,1H),7.86(s,2H),7.24(dd, J =23.6Hz,J = 8.4Hz,4H),6.97- 6.82(m,2H),3.91(t,J=6.4Hz,2H),3.11(t,J=6.8Hz,2H),2.32(s,3H).

[0439] Example 28 2-(3,5-dichloro-4-((1-oxo-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 28 [ka] Step 1: Synthesis of 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 28b

[0440] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (1.50 g, 8.5 mmol), sodium iodide (0.32 g, 1.7 mmol), 1-fluoro-4-iodobenzene (3.76 g, 16.9 mmol), and potassium carbonate (1.17 g, 8.47 mmol) were dissolved in N,N-dimethylformamide (40 mL) and reacted at 150 °C for 16 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (100 mL). The mixture was extracted with ethyl acetate (200 mL). The combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give 28b (1.05 g, 46% yield) as a white solid.

[0441] 1 H NMR(400MHz, CDCl3)δ(ppm)8.11(d,J=8.6Hz,1H),7.36(ddt,J=6.8, 4.9, 2.8Hz,2H),7.16-7.08(m,2H),6.90(dd,J=8.7, 2.6Hz,1H), 6.74(d,J=2.5Hz,1H),3.96(t,J=6.4Hz,2H),3.89(s,3H),3.13(t,J=6.4Hz,2H).

[0442] Step 2: Synthesis of 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 28c

[0443] Boron tribromide (0.71 mL, 7.4 mmol) was added dropwise to a solution of 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 28b (1.00 g, 3.7 mmol) in dichloromethane (30 mL) at 0° C., followed by reaction at room temperature for 4 h. The reaction was quenched by pouring into ice water (30 mL), stirring for 10 min, filtering, rinsing the filter cake with water (10 mL), and drying to give 28c (0.87 g, 92% yield) as a white solid.

[0444] MS (ESI, pos. ion) m / z: 258.1 [M+H] + .

[0445] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one 28d

[0446] 2-(4-Fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 28c (0.87 g, 3.4 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.87 g, 3.8 mmol) were dissolved in N,N-dimethylformamide (15 mL), potassium carbonate (0.93 g, 6.8 mmol) was added, and the reaction was carried out at 70 °C for 17 h. The reaction mixture was cooled to room temperature, water (30 mL) was added, stirred for 10 min, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried to give 28d (1.50 g, 99% yield) as a white solid.

[0447] MS (ESI, pos. ion) m / z: 448.0 [M+H] + .

[0448] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one 28e

[0449] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one 28d (1.50 g, 3.30 mmol) was dissolved in acetic acid (20 mL), iron powder (0.37 g, 6.70 mmol) was added, and the mixture was reacted at 50 °C for 3 h. The reaction mixture was cooled to room temperature, the iron powder was removed, water (80 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 28e (1.05 g, 75% yield) as a pale yellow oil.

[0450] MS (ESI, pos. ion) m / z: 417.1 [M+H] + .

[0451] Step 5: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 28f

[0452] 6-(4-Amino-2,6-dichlorophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one 28e (1.00 g, 2.40 mmol) was dissolved in acetic acid (36 mL) and a solution of sodium nitrite (0.33 g, 4.8 mmol) in water (18 mL) was added dropwise at 0 °C. After stirring for 15 min, N-cyanoacetylurethane (0.56 g, 3.60 mmol) was added and the mixture was allowed to react for 5 h. Water (50 mL) was added to the reaction mixture, which was stirred for 10 min, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to give 28f (1.30 g, 93% yield) as a yellow solid.

[0453] MS (ESI, pos. ion) m / z: 585.1 [M+H] + .

[0454] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 28g

[0455] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 28f (1.30 g, 2.20 mmol) was dissolved in N,N-dimethylformamide (40 mL), and sodium acetate (0.40 g, 2.90 mmol) was added. The mixture was reacted at 120° C. for 15 hours. The reaction mixture was cooled to room temperature, quenched by adding water (80 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate). The resulting solid was eluted with 80 mL of ethyl acetate. o The solid was recrystallized from 100 ml of petroleum ether / ethyl acetate (petroleum ether / ethyl acetate = 1 / 2, 24 mL) to give 28 g of a yellow solid (0.71 g, yield 59%, HPLC purity: 97.86%).

[0456] MS (ESI, negative ion) m / z: 537.1 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.31(s,1H),7.95(d,J=8.6Hz,1H),7.86(s,2H),7.43(dd,J=8.8, 5.0Hz,2H), 7.25(t,J=8.8Hz,2H),6.95(d,J=2.6Hz,1H),6.88(dd,J=8.6, 2.7Hz,1H),3.93(t,J=6.4Hz,2H),3.13(t,J=6.5Hz,2H).

[0457] Step 7: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 28h

[0458] 2-(3,5-Dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 28g (0.45g, 0.84mmol) was dissolved in acetic acid (8mL), concentrated hydrochloric acid (4mL) was added, and the reaction was carried out at 100°C for 17 hours. The reaction solution was cooled to room temperature, water (20mL) was added, stirred for 10 minutes, filtered, the filter cake was rinsed with water (10mL x 2), and the filter cake was collected and dried to give a yellow solid 28h (0.35g, 75% yield).

[0459] Step 8: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 28

[0460] 2-(3,5-Dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 28h (0.35 g, 0.63 mmol) was dissolved in thioglycolic acid (2.5 mL) and reacted at 140 °C for 24 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (60 mL) was added. The mixture was washed successively with water (20 mL), saturated sodium bicarbonate solution (30 mL × 2), and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give a yellow solid 28 (0.21 g, 61% yield, HPLC purity: 96.79%).

[0461] MS (ESI, negative ion) m / z: 514.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),7.95(d,J=8.6Hz,1H),7.88(s,2H),7.73(s,1H),7.43(dd,J=8.9, 5.2Hz,2H), 7.24(t,J=8.8Hz,2H),6.93(d,J=2.6Hz,1H),6.85(dd,J=8.6, 2.6Hz,1H),3.92(t,J=6.4Hz,2H),3.13(t,J=6.4Hz,2H).

[0462] Example 29 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 29 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 29a

[0463] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.50 g, 4.2 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (0.25 mg, 6.3 mmol, 60 mass% in oil) was added at 0°C. After reacting for 30 minutes, 1-bromomethyl-4-(trifluoromethyl)benzene (2.0 g, 8.37 mmol) and N,N-dimethylformamide (6 mL) were added dropwise, followed by reacting at room temperature for 3.5 hours. The reaction was quenched by adding ice water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give pale yellow oil 29a (2.2 g, 100% yield).

[0464] MS (ESI, pos. ion) m / z: 511.0 [M+H] + .

[0465] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 29b

[0466] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 29a (2.2 g, 4.2 mmol) was dissolved in acetic acid (50 mL), iron powder (0.99 g, 17.8 mmol) was added, and the mixture was reacted at 55 °C for 10 h. The reaction mixture was cooled to room temperature and quenched by adding water (100 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give 29b (1.65 g, 77% yield) as a pale yellow oil.

[0467] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 29c

[0468] 6-(4-Amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 29b (0.60 g, 1.25 mmol) was dissolved in acetic acid (12 mL), and a solution of sodium nitrite (0.19 g, 12.78 mmol) in water (6 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.26 g, 1.67 mmol). The reaction was allowed to react for 3 h. The reaction was quenched by the addition of water (100 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (5 mL × 2). The filter cake was collected and dried to give a pale yellow solid 29c (0.76 g, 94% yield).

[0469] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 29d

[0470] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 29c (0.72 g, 1.12 mmol) was dissolved in N,N-dimethylformamide (25 mL), and sodium acetate (0.20 g, 2.45 mmol) was added. The mixture was reacted at 120 °C for 6 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), stirred for 15 min, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 2 / 1, 15 mL) to give yellow solid 29d (0.65 g, 97% yield, HPLC purity: 96.68%).

[0471] MS (ESI, negative ion) m / z: 600.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.94(d,J=8.4Hz,1H),7.84(s,2H),7. 71(d,J=8.0Hz,2H),7.54(d,J=8.0Hz,2H),6.88(d,J=2.6Hz,1H),6.85(dd,J=8.3, 2.7Hz, 1H), 4.78 (s, 2H), 3.53 (t, J=6.6Hz, 2H), 2.99 (t, J=6.6Hz, 2H).

[0472] Step 5: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 29e

[0473] 2-(3,5-Dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 29d (0.65 g, 1.01 mmol) was dissolved in acetic acid (10 mL), concentrated hydrochloric acid (5 mL) was added, and the reaction was carried out at 120 °C for 13 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 29e (0.55 g, 82% yield).

[0474] Step 6: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 29

[0475] 2-(3,5-Dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 29e (0.55 g, 0.89 mmol) was dissolved in thioglycolic acid (5 mL) and reacted at 150 °C for 24 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1). The resulting solid was recrystallized at 70 °C (ethyl acetate / methanol / petroleum ether (v / v / v) = 5 / 1 / 10, 32 mL) to give 29 (0.32 g, 62% yield, HPLC purity: 96.97%) as a white solid.

[0476] MS (ESI, negative ion) m / z: 575.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),7.94(d,J=8.4Hz,1H),7.87(s,2H),7.73(s,1H),7.70(d,J=7.9Hz,2H) ,7.54(d,J=7.9Hz,2H),6.85(s,1H),6.84-6.79(m,1H),4.78(s,2H),3.52(t,J=6.5Hz,2H),2.98(t,J=6.6Hz,2H).

[0477] Example 30 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 30 [ka] Step 1: 6-(2,6-Dichloro-4-nitrophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 30a

[0478] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.00 g, 2.83 mmol) was dissolved in tetrahydrofuran (40 mL), and sodium hydride (0.17 g, 4.25 mmol, 60 mass% in oil) was added at 0°C. After reacting for 30 minutes, 3,4-difluorobenzyl bromide (1.17 g, 5.66 mmol) and N,N-dimethylformamide (6 mL) were added dropwise, followed by reacting at room temperature for 12 hours. The reaction was quenched by adding ice water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give pale yellow oil 30a (1.10 g, 81% yield).

[0479] MS (ESI, pos. ion) m / z: 479.1 [M+H] + .

[0480] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 30b

[0481] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 30a (1.10 g, 2.29 mmol) was dissolved in acetic acid (50 mL), iron powder (0.51 g, 9.15 mmol) was added, and the mixture was reacted at 55 °C for 6 h. The reaction mixture was cooled to room temperature and quenched by adding water (80 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give 30b (0.64 g, 62% yield) as a pale yellow oil.

[0482] MS (ESI, pos. ion) m / z: 431.0 [M+H] + .

[0483] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 30c

[0484] 6-(4-Amino-2,6-dichlorophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 30b (0.65 g, 1.42 mmol) was dissolved in acetic acid (12 mL) and added with an aqueous solution (6 mL) of sodium nitrite (0.20 g, 2.90 mmol) at 0 °C, followed by N-cyanoacetylurethane (0.27 g, 1.71 mmol) for 2 h. The reaction was quenched by adding water (100 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (5 mL × 2). The filter cake was collected and dried to give a pale yellow solid 30c (0.94 g, 100% yield).

[0485] Step 4: 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 30d

[0486] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 30c (0.94 g, 1.53 mmol) was dissolved in N,N-dimethylformamide (30 mL), and sodium acetate (0.28 g, 3.36 mmol) was added. The mixture was reacted at 120 °C for 6 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 2 / 1, 15 mL) to give yellow solid 30d (0.45 g, 52% yield, HPLC purity: 94.04%).

[0487] MS (ESI, negative ion) m / z: 550.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.29(s,1H),7.93(d,J=8.3Hz,1H),7.84(s,2H),7.39(td,J=7.9, 6.1Hz,1H),7.18-7.07(m,3H),6.86(s,1H),6.84(d,J=2.7Hz,1H),4.70(s,2H),3.51(t,J=6.6Hz,2H),2.97(t,J=6.6Hz,2H).

[0488] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 30e

[0489] 2-(3,5-Dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 30d (0.45 g, 0.79 mmol) was dissolved in acetic acid (6 mL), concentrated hydrochloric acid (3 mL) was added, and the reaction was carried out at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 30e (0.41 g, 89% yield).

[0490] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 30

[0491] 2-(3,5-Dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 30e (0.41 g, 0.68 mmol) was dissolved in thioglycolic acid (3 mL) and reacted at 140° C. for 19 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1). The resulting solid was recrystallized at 70 °C (ethyl acetate / methanol / petroleum ether (v / v / v) = 5 / 1 / 10, 32 mL) to give a white solid 30 (0.25 g, yield 67%, HPLC purity: 93.81%).

[0492] MS (ESI, negative ion) m / z: 543.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),7.93(d,J=8.3Hz,1H),7.87(s,2H),7.72(s,1H),7.45-7.32(m,2H),7. 18(t,J=6.4Hz,1H),6.83(s,1H),6.81(d,J=2.6Hz,1H),4.66(s,2H),3.50(t,J=6.5Hz,2H),2.97(t,J=6.6Hz,2H).

[0493] Example 31 2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 31 [ka] Step 1: 6-(2,6-Dichloro-4-nitrophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 31a

[0494] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.00 g, 2.83 mmol) was dissolved in tetrahydrofuran (14 mL), and sodium hydride (0.17 g, 7.08 mmol, 60 mass% in oil) was added at 0°C. After reacting for 30 minutes, 1-bromomethyl-3-fluorobenzene (1.07 g, 5.66 mmol) and N,N-dimethylformamide (6 mL) were added dropwise, followed by reacting at room temperature for 3 hours. The reaction was quenched by adding ice water (10 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give pale yellow oil 31a (1.30 g, yield 99%).

[0495] MS (ESI, pos. ion) m / z: 461.1 [M+H] + .

[0496] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 31b

[0497] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 31a (1.80 g, 3.90 mmol) was dissolved in acetic acid (50 mL), iron powder (0.87 g, 15.2 mmol) was added, and the mixture was reacted at 55 °C for 7 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (80 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give 31b (1.29 g, 77% yield) as a white solid.

[0498] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 31c

[0499] 6-(4-Amino-2,6-dichlorophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 31b (0.60 g, 1.39 mmol) was dissolved in acetic acid (12 mL), and a solution of sodium nitrite (0.19 g, 2.78 mmol) in water (5 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.26 g, 1.67 mmol). The reaction was allowed to react for 2 h. The reaction was quenched by adding water (100 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (5 mL × 2). The filter cake was collected and dried to give a pale yellow solid 31c (0.92 g, 100% yield).

[0500] Step 4: 2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 31d

[0501] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 31c (0.92 g, 1.54 mmol) was dissolved in N,N-dimethylformamide (30 mL), and sodium acetate (0.28 g, 3.39 mmol) was added. The mixture was reacted at 120 °C for 6 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 2 / 1, 15 mL) to give yellow solid 31d (0.75 g, 99% yield).

[0502] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 31e

[0503] 2-(3,5-Dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 31d (0.39 g, 0.71 mmol) was dissolved in acetic acid (10 mL), concentrated hydrochloric acid (3 mL) was added, and the reaction was carried out at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 31e (0.40 g, 98% yield).

[0504] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 31

[0505] 2-(3,5-Dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 31e (0.40 g, 0.70 mmol) was dissolved in thioglycolic acid (3 mL) and reacted at 140° C. for 19 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1). The resulting solid was recrystallized at 70 °C (ethyl acetate / methanol / petroleum ether (v / v / v) = 5 / 1 / 10, 32 mL) to give a white solid 31 (0.20 g, 54% yield, HPLC purity: 93.81%).

[0506] MS (ESI, negative ion) m / z: 525.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),7.93(d,J=8.3Hz,1H),7.86(s,2H),7.73(s,1H),7.38(td,J=7.9, 6.0Hz,1H),7.18- 7.06(m,3H),6.86-6.77(m,2H),4.69(s,2H),3.50(t,J=6.5Hz,2H),2.96(t,J=6.6Hz,2H).

[0507] Example 32 2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 32 [ka] Step 1: 2-(3,5-Difluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 32a

[0508] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.0 g, 2.83 mmol) was dissolved in tetrahydrofuran (14 mL), and sodium hydride (0.17 g, 4.25 mmol, 60 mass% in oil) was added at 0°C. After reacting for 20 minutes, 3,5-difluorobenzyl bromide (1.17 g, 5.66 mmol) and N,N-dimethylformamide (10 mL) were added dropwise, followed by reaction at room temperature for 6 hours. The reaction was quenched by adding ice water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give pale yellow oil 32a (1.26 g, yield 93%).

[0509] MS (ESI, pos. ion) m / z: 480.1 [M+H] + .

[0510] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3,5-difluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 32b

[0511] 2-(3,5-Difluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 32a (0.99 g, 2.1 mmol) was dissolved in acetic acid (20 mL), iron powder (0.24 g, 4.3 mmol) was added, and the mixture was reacted at 50 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (30 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give 32b (0.68 g, 58% yield) as a pale yellow oil.

[0512] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 32c

[0513] 6-(4-Amino-2,6-dichlorophenoxy)-2-(3,5-difluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 32b (0.68 g, 1.5 mmol) was dissolved in acetic acid (20 mL), and a solution of sodium nitrite (0.21 g, 3.0 mmol) in water (9 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.35 g, 2.3 mmol). The reaction was allowed to react for 3 h. The reaction was quenched by the addition of water (60 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (10 mL). The filter cake was collected and dried to give a pale yellow solid 32c (0.93 g, 100% yield).

[0514] MS (ESI, negative ion) m / z: 615.2 [MH] - .

[0515] Step 4: 2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 32d

[0516] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 32c (0.93 g, 1.5 mmol) was dissolved in N,N-dimethylformamide (16 mL), and sodium acetate trihydrate (0.27 g, 2.0 mmol) was added. The mixture was reacted at 120 °C for 8 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (50 mL), stirred for 15 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 2 / 1, 30 mL) to give yellow solid 32d (0.63 g, 73% yield, 95.85% HPLC purity).

[0517] MS (ESI, negative ion) m / z: 571.3 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.27(s,1H),7.92(d,J=8.4Hz,1H),7.84(s,2H),7.12(td,J=9.4, 4.8Hz,1H),7.03(d,J=7.3Hz,2H),6.91-6.76(m,2H),4.69(s,2H),3.53(t,J=6.6Hz,2H),2.99(t,J=6.6Hz,2H).

[0518] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 32e

[0519] 2-(3,5-Dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 32d (0.55 g, 0.96 mmol) was dissolved in acetic acid (10 mL), concentrated hydrochloric acid (5 mL) was added, and the reaction was carried out at 100° C. for 8 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 32e (0.48 g, 84% yield).

[0520] MS (ESI, pos. ion) m / z: 590.0 [M+H] + .

[0521] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 32

[0522] 2-(3,5-Dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 32e (0.48 g, 0.81 mmol) was dissolved in thioglycolic acid (5 mL) and reacted at 140° C. for 16 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (60 mL) was added. The mixture was washed successively with 50% sodium bicarbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 2). The resulting solid was recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 1 / 2, 30 mL) to give a pale yellow solid 32 (0.20 g, yield: 45%, HPLC purity: 99.48%).

[0523] MS (ESI, negative ion) m / z: 544.2 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.51(s,1H),7.92(d,J=8.4Hz,1H),7.86(s,2H),7.72(s,1H),7.12(tt,J=9.4, 2.5Hz,1H),7.06-6.96(m,2H),6.87-6.78(m,2H),4.69(s,2H),3.53(t,J=6.6Hz,2H),2.98(t,J=6.6Hz,2H).

[0524] Example 33 2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 33 [ka] Step 1: 2-(2-Fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 33a

[0525] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.0 g, 2.8 mmol) was dissolved in tetrahydrofuran (40 mL), and sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) was added at 0°C. After reacting for 20 minutes, 2-fluorobenzyl bromide (1.1 g, 5.7 mmol) and N,N-dimethylformamide (10 mL) were added dropwise, followed by reaction at room temperature for 6 hours. The reaction was quenched by adding ice water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow solid 33a (0.99 g, yield 76%).

[0526] MS (ESI, pos. ion) m / z: 461.1 [M+H] + .

[0527] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 33b

[0528] 2-(2-Fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 33a (0.99 g, 2.1 mmol) was dissolved in acetic acid (20 mL), iron powder (0.24 g, 4.3 mmol) was added, and the mixture was reacted at 50 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (30 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give 33b (0.62 g, 67% yield) as a pale yellow oil.

[0529] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 33c

[0530] 6-(4-Amino-2,6-dichlorophenoxy)-2-(2-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 33b (0.62 g, 1.4 mmol) was dissolved in acetic acid (18 mL), and a solution of sodium nitrite (0.20 g, 2.9 mmol) in water (9 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.34 g, 2.2 mmol). The reaction was allowed to react for 3 h. The reaction was quenched by the addition of water (50 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (10 mL). The filter cake was collected and dried to give a pale yellow solid 33c (0.86 g, 100% yield).

[0531] MS (ESI, negative ion) m / z: 599.2 [MH] - .

[0532] Step 4: 2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 33d

[0533] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 33c (0.86 g, 1.4 mmol) was dissolved in N,N-dimethylformamide (16 mL), and sodium acetate trihydrate (0.26 g, 1.9 mmol) was added. The mixture was reacted at 120 °C for 6 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (50 mL), stirred for 15 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 2 / 1, 30 mL) to give yellow solid 33d (0.49 g, 63% yield, HPLC purity: 96.04%).

[0534] MS (ESI, pos. ion) m / z: 553.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.29(s,1H),7.91(d,J=8.3Hz,1H),7.83(s,2H),7.34(qd,J=6.8, 5.8, 3.3Hz,2H),7.26-7.10(m,2H),6.92-6.80(m,2H),4.73(s,2H),3.52(t,J=6.6Hz,2H),2.98(t,J=6.5Hz,2H).

[0535] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 33e

[0536] 2-(3,5-Dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 33d (0.43 g, 0.78 mmol) was dissolved in acetic acid (10 mL), concentrated hydrochloric acid (5 mL) was added, and the reaction was carried out at 100° C. for 8 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 33e (0.38 g, 85% yield).

[0537] MS (ESI, pos. ion) m / z: 572.0 [M+H] + .

[0538] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 33

[0539] 2-(3,5-Dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 33e (0.38 g, 0.66 mmol) was dissolved in thioglycolic acid (5 mL) and reacted at 140° C. for 16 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (60 mL) was added. The mixture was washed successively with 50% sodium bicarbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 2). The resulting solid was recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 1 / 2, 30 mL) to give a pale yellow solid 33 (0.29 g, yield: 83%, HPLC purity: 99.47%).

[0540] MS (ESI, pos. ion) m / z: 527.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.51(s,1H),7.91(d,J=8.4Hz,1H),7.86(s,2H),7.72(s,1H),7.33(q,J=7. 8Hz,2H),7.24-7.12(m,2H),6.87-6.78(m,2H),4.73(s,2H),3.52(t,J=6.6Hz,2H),2.97(t,J=6.5Hz,2H).

[0541] Example 34 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 34 [ka] Step 1: 2-(3-(trifluoromethyl)benzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 34a

[0542] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.0 g, 2.8 mmol) was dissolved in tetrahydrofuran (40 mL), and sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) was added at 0°C. After reacting for 20 minutes, 3-trifluoromethylbromobenzyl (1.4 g, 5.7 mmol) and N,N-dimethylformamide (10 mL) were added dropwise, followed by reaction at room temperature for 6 hours. The reaction was quenched by adding ice water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give pale yellow oil 34a (0.86 g, yield 59%).

[0543] MS (ESI, negative ion) m / z: 647.1 [MH] - .

[0544] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 34b

[0545] 2-(3-(Trifluoromethyl)benzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 34a (0.86 g, 1.7 mmol) was dissolved in acetic acid (20 mL), iron powder (0.24 g, 4.3 mmol) was added, and the mixture was reacted at 50 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (30 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to give 34b (0.63 g, 78% yield) as a pale yellow oil.

[0546] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 34c

[0547] 6-(4-Amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 34b (0.63 g, 1.3 mmol) was dissolved in acetic acid (18 mL), and a solution of sodium nitrite (0.18 g, 2.6 mmol) in water (9 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.31 g, 2.0 mmol). The reaction was allowed to react for 3 h. The reaction was quenched by the addition of water (50 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (10 mL). The filter cake was collected and dried to give a pale yellow solid 34c (0.85 g, 100% yield).

[0548] MS (ESI, negative ion) m / z: 647.1 [MH] - .

[0549] Step 4: 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 34d

[0550] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 34c (0.85 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (16 mL), and sodium acetate trihydrate (0.23 g, 1.7 mmol) was added. The mixture was reacted at 120 °C for 6 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (50 mL). The mixture was stirred for 15 min, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 1 / 2, 30 mL) to give yellow solid 34d (0.55 g, 70% yield, HPLC purity: 97.82%).

[0551] MS (ESI, negative ion) m / z: 601.3 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.29(s,1H),7.93(d,J=8.3Hz,1H),7.84(s,2H),7.72-7.5 5(m,4H),6.85(d,J=8.8Hz,2H),4.77(s,2H),3.52(t,J=6.6Hz,2H),2.97(t,J=6.6Hz,2H).

[0552] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 34e

[0553] 2-(3,5-Dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 34d (0.47 g, 0.80 mmol) was dissolved in acetic acid (10 mL), concentrated hydrochloric acid (5 mL) was added, and the reaction was carried out at 100° C. for 8 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 34e (0.43 g, 89% yield).

[0554] MS (ESI, negative ion) m / z: 622.0 [MH] - .

[0555] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 34

[0556] 2-(3,5-Dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 34e (0.43 g, 0.71 mmol) was dissolved in thioglycolic acid (5 mL) and reacted at 140° C. for 15 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (60 mL) was added. The mixture was washed successively with 50% sodium bicarbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 2). The resulting solid was recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 1 / 2, 30 mL) to give a pale yellow solid 34 (0.24 g, yield 60%, HPLC purity: 99.41%).

[0557] MS (ESI, negative ion) m / z: 576.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.51(s,1H),7.93(d,J=8.4Hz,1H),7.86(s,2H),7.72(s,1H),7 .69-7.54(m,4H),6.88-6.77(m,2H),4.77(s,2H),3.52(t,J=6.6Hz,2H),2.96(t,J=6.5Hz,2H).

[0558] Example 35 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 35 [ka] Step 1: 2-(3-chloro-4-fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 35a

[0559] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.0 g, 2.8 mmol) was dissolved in tetrahydrofuran (40 mL), and sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) was added at 0°C. After reacting for 20 minutes, 3-chloro-4-fluorobenzyl bromide (1.3 g, 5.7 mmol) and N,N-dimethylformamide (10 mL) were added dropwise, followed by reaction at room temperature for 6 hours. The reaction was quenched by adding ice water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow solid 35a (1.0 g, yield 71%).

[0560] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3-chloro-4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 35b

[0561] 2-(3-Chloro-4-fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 35a (0.99 g, 2.0 mmol) was dissolved in acetic acid (20 mL), iron powder (0.22 g, 4.0 mmol) was added, and the mixture was reacted at 50 °C for 2.5 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (30 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to give 35b (0.61 g, 66% yield) as a pale yellow oil.

[0562] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 35c

[0563] 6-(4-Amino-2,6-dichlorophenoxy)-2-(3-chloro-4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 35b (0.61 g, 1.3 mmol) was dissolved in acetic acid (18 mL), and a solution of sodium nitrite (0.18 g, 2.6 mmol) in water (9 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.31 g, 2.0 mmol). The reaction was allowed to react for 3 h. The reaction was quenched by the addition of water (50 mL), stirred for 20 min, filtered, and the filter cake was rinsed with water (10 mL). The filter cake was collected and dried to give a pale yellow solid 35c (0.83 g, 100% yield).

[0564] MS (ESI, negative ion) m / z: 631.1 [MH] - .

[0565] Step 4: 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 35d

[0566] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 35c (0.83 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (16 mL), and sodium acetate trihydrate (0.23 g, 1.7 mmol) was added. The mixture was reacted at 120 °C for 6 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (50 mL). The mixture was stirred for 15 min, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 1 / 2, 30 mL) to give yellow solid 35d (0.57 g, 74% yield, HPLC purity: 93.07%).

[0567] MS (ESI, negative ion) m / z: 585.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)13.28(s,1H),7.92(d,J=8.3Hz,1H),7.83(s,2H),7.53(dd,J=7.3, 2.1Hz,1H),7.41-7.30(m,2H),6.84(d,J=8.5Hz,2H),4.66(s,2H),3.51(t,J=6.6Hz,2H),2.96(t,J=6.6Hz,2H).

[0568] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 35e

[0569] 2-(3,5-Dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 35d (0.47 g, 0.80 mmol) was dissolved in acetic acid (10 mL), concentrated hydrochloric acid (5 mL) was added, and the reaction was carried out at 100° C. for 8 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a pale yellow solid 35e (0.43 g, 89% yield).

[0570] MS (ESI, pos. ion) m / z: 606.9 [M+H] + .

[0571] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 35

[0572] 2-(3,5-Dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 35e (0.43 g, 0.71 mmol) was dissolved in thioglycolic acid (5 mL) and reacted at 140° C. for 15 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (60 mL) was added. The mixture was washed successively with 50% sodium bicarbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 2). The resulting solid was recrystallized at 80 °C (ethyl acetate / petroleum ether (v / v) = 1 / 2, 30 mL) to give a pale yellow solid 35 (0.26 g, yield: 65%, HPLC purity: 98.66%).

[0573] MS (ESI, negative ion) m / z: 561.1 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.51(s,1H),7.92(d,J=8.3Hz,1H),7.86(s,2H),7.72(s,1H),7.52(dd,J=7.2, 2.0Hz,1H),7.41-7.30(m,2H),6.81(d,J=8.8Hz,2H),4.66(s,2H),3.50(t,J=6.6Hz,2H),2.96(t,J=6.6Hz,2H).

[0574] Example 36 2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 36 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one 36a

[0575] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.8 g, 5.1 mmol) was dissolved in tetrahydrofuran (35 mL) and added with sodium hydride (0.18 g, 7.6 mmol, 60 mass% in oil) at 0 °C. After 5 min, 1-bromomethyl-3-methoxybenzene (1.0 g, 5.0 mmol) was added dropwise and the mixture was allowed to react at room temperature for 8 h. The reaction was quenched with ice water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 36a (1.9 g, 79% yield) as a white solid.

[0576] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one 36b

[0577] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one 36a (1.9 g, 4.0 mmol) was dissolved in acetic acid (7 mL), iron powder (0.67 g, 12 mmol) was added, and the reaction was carried out at 60 °C for 4 h. The reaction mixture was cooled to room temperature, and water (5 mL) was added to quench the reaction. The excess iron powder was filtered off, and water (10 mL) was added to the filtrate. The mixture was stirred for 10 min, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to give 36b (1.7 g, 93% yield) as a brown solid.

[0578] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 36c

[0579] 6-(4-Amino-2,6-dichlorophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one 36b (1.65 g, 3.72 mmol) was dissolved in acetic acid (6 mL), and a solution of sodium nitrite (0.39 g, 5.58 mmol) in water (3 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.86 g, 4.65 mmol). The reaction was allowed to react for 1 h. The reaction was quenched by the addition of water (20 mL), stirred for 10 min, filtered, and the filter cake was rinsed with water (5 mL × 2). The filter cake was collected and dried to give a yellow solid 36c (2.1 g, 92% yield).

[0580] Step 4: Synthesis of 2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 36d

[0581] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 36c (2.10 g, 3.40 mmol) was dissolved in N,N-dimethylformamide (8 mL), and sodium acetate (0.34 g, 3.39 mmol) was added. The mixture was reacted at 120 °C for 12 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), stirred for 15 min, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether = 2 / 1, 15 mL) to give yellow solid 36d (0.75 g, 99% yield).

[0582] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 36e

[0583] 2-(3,5-Dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 36d (0.45 g, 0.80 mmol) was dissolved in acetic acid (6 mL), concentrated hydrochloric acid (3 mL) was added, and the reaction was carried out at 120 °C for 16 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (5 mL × 2). The filter cake was collected and dried to give a yellow solid 36e (0.40 g, 86% yield).

[0584] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 36

[0585] 2-(3,5-Dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 36e (0.40 g, 0.69 mmol) was dissolved in thioglycolic acid (4 mL) and reacted at 160 °C for 12 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 36 (39 mg, 11% yield, HPLC purity: 94.35%) as a white solid.

[0586] MS (ESI, negative ion) m / z: 537.1 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),8.00-7.82(m,3H),7.73(s,1H),7.25(t,J=7.6Hz, 1H),6.97-6.77(m,5H),4.66(s,2H),3.73(s,3H),3.46(t,J=6.4Hz,2H),2.94(t,J=6.4Hz,2H).

[0587] Example 37 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 37 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 37a

[0588] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (3.0 g, 8.5 mmol) was dissolved in tetrahydrofuran (35 mL) and added with sodium hydride (0.31 g, 13.0 mmol, 60 mass% in oil) at 0 °C. After 5 min of reaction, 1-chloromethyl-4-chlorobenzene (2.7 g, 17.0 mmol) was added dropwise and the mixture was allowed to react at room temperature for 8 h. The reaction was quenched by the addition of ice water (20 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 37a (1.75 g, 43% yield) as a white solid.

[0589] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 37b

[0590] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 37a (1.75 g, 3.66 mmol) was dissolved in acetic acid (7 mL), iron powder (0.61 g, 11.0 mmol) was added, and the reaction was allowed to proceed at 60° C. for 4.5 h. The reaction mixture was cooled to room temperature, and water (5 mL) was added to quench the reaction. The excess iron powder was filtered off, and water (10 mL) was added to the filtrate. The mixture was stirred for 10 min, filtered, and rinsed with water (10 mL). The filter cake was collected and dried to give 37b (1.55 g, 95% yield) as a brown solid.

[0591] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 37c

[0592] 6-(4-Amino-2,6-dichlorophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one 37b (1.55 g, 3.46 mmol) was dissolved in acetic acid (6 mL), and a solution of sodium nitrite (0.36 g, 5.25 mmol) in water (3 mL) was added at 0 °C, followed by N-cyanoacetylurethane (0.81 g, 4.37 mmol). The reaction was allowed to react for 1 h. The reaction was quenched by the addition of water (20 mL), stirred for 10 min, filtered, and the filter cake was rinsed with water (5 mL). The filter cake was collected and dried to give a yellow solid 37c (1.90 g, 89% yield).

[0593] Step 4: Synthesis of 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 37d

[0594] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 37c (1.9 g, 3.1 mmol) was dissolved in N,N-dimethylformamide (8 mL), and sodium acetate (0.30 g, 3.7 mmol) was added. The mixture was reacted at 120 °C for 12 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethyl acetate / petroleum ether = 2 / 1, 15 mL) to give yellow solid 37d (0.50 g, 28% yield, HPLC purity: 95.83%).

[0595] MS (ESI, negative ion) m / z: 566.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.32(s,1H),8.03-7.76(m,3H),7.49-7.25(m,4H ),6.94-6.76(m,2H),4.68(s,2H),3.48(t,J=6.4Hz,2H),2.96(t,J=6.4Hz,2H).

[0596] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 37e

[0597] 2-(3,5-Dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 37d (0.40 g, 0.70 mmol) was dissolved in acetic acid (6 mL), concentrated hydrochloric acid (3 mL) was added, and the reaction was carried out at 120 °C for 17 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (5 mL × 2). The filter cake was collected and dried to give a yellow solid 37e (0.40 g, 97% yield).

[0598] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 37

[0599] 2-(3,5-Dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 37e (0.15 g, 0.26 mmol) was dissolved in thioglycolic acid (3 mL) and reacted at 160 °C for 12 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 37 (0.14 g, 38% yield, 97.64% HPLC purity) as a white solid.

[0600] MS (ESI, negative ion) m / z: 541.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),8.01-7.80(m,3H),7.73(s,1H),7.46-7.2 6(m,4H),6.90-6.74(m,2H),4.68(s,2H),3.48(t,J=6.8Hz,2H),2.95(t,J=6.8Hz,2H).

[0601] Example 38 2-(3,5-dichloro-4-((2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 38 [ka] Step 1: Synthesis of 6-methoxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38a

[0602] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (2.5 g, 14.1 mmol) was dissolved in tetrahydrofuran (30 mL) and N,N-dimethylformamide (30 mL). Sodium hydride (1.41 g, 35.3 mmol, 60% in oil) was added in portions at 0°C, followed by dropwise addition of chloromethylcyclopropane (2.60 mL, 28.0 mmol), followed by addition of N,N-dimethylformamide (30 mL). After the dropwise addition was completed, the mixture was allowed to react at room temperature for 24 hours. The reaction was quenched by adding water (40 mL) and extracted with ethyl acetate (45 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (40 mL × 3), dried over anhydrous sodium sulfate, suction filtered and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give pale yellow oil 38a (2.56 g, yield 78%).

[0603] MS (ESI, pos. ion) m / z: 232.2 [M+H] + .

[0604] Step 2: Synthesis of 6-hydroxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38b

[0605] 6-Methoxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38a (2.40 g, 10.4 mmol) was dissolved in dichloromethane (35 mL) and boron tribromide (2.02 mL, 20.8 mmol) was added dropwise at 0 °C. The mixture was allowed to react for 1.5 h at 0 °C. The reaction was quenched by the addition of methanol (5 mL) at 0 °C, concentrated, and water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 38b (1.01 g, 45% yield) as a pale yellow solid.

[0606] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38c

[0607] 6-Hydroxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38b (1.01 g, 4.65 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1,2,3-trichloro-5-nitrobenzene (1.11 g, 4.90 mmol) and potassium carbonate (1.56 g, 11.2 mmol) were added. The mixture was then heated at 80 °C for 6 h. The reaction mixture was cooled to room temperature, and water (15 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 38c (0.96 g, 51% yield) as a yellow solid.

[0608] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38d

[0609] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38c (0.91 g, 2.23 mmol) was dissolved in acetic acid (15 mL), iron powder (0.51 g, 8.93 mmol) was added, and the reaction was carried out at 60 °C for 6.5 h. The reaction was cooled to room temperature, the iron powder was removed, water (25 mL) was added, stirred for 10 min, filtered, rinsed with water (10 × 2), and the filter cake was collected and dried to give a pale yellow solid 38d (0.72 g, 86% yield).

[0610] MS (ESI, pos. ion) m / z: 477.1 [M+H] + .

[0611] Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazino)acetyl)carbamate 38e

[0612] 6-(4-Amino-2,6-dichlorophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38d (0.72 g, 1.91 mmol) was dissolved in acetic acid (10 mL) and a solution of sodium nitrite (0.20 g, 2.87 mmol) in water (0.5 mL) was added dropwise at 0 °C for 20 min. After the addition of N-cyanoacetylurethane (0.34 g, 2.10 mmol), the mixture was allowed to react for 4.5 h. Water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give yellow solid 38e (0.97 g, 93% yield).

[0613] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 38

[0614] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazino)acetyl)carbamate 38e (0.97 g, 1.78 mmol) was dissolved in N,N-dimethylformamide (12 mL), and sodium acetate (0.44 g, 5.33 mmol) was added. The mixture was reacted at 120°C for 12 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1). The resulting solid was recrystallized (petroleum ether / ethyl acetate = 3 / 1, 20 mL) to give a white solid 38 (0.13 g, yield: 14%, HPLC purity: 96.32%).

[0615] MS (ESI, negative ion) m / z: 496.1 [MH] - . 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.92-7.80(m,3H),6.88-6.79(m,2H),3.61(t,J=6.5Hz,2H),3.45(dt,J=13.9, 7.1Hz,1H), 3.35(d,J=6.8Hz,2H),2.97(t,J=6.4Hz,2H),0.45(q,J=5.2Hz,2H),0.26(q,J=4.7Hz,2H).

[0616] Example 39 2-(3,5-dichloro-4-((2-(hydroxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 39 [ka] 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.20 g, 0.45 mmol) was dissolved in N-methylpyrrolidone (2 mL), and 37% formaldehyde (0.67 mL, 9.1 mmol) and ethyl phosphate were added. The mixture was reacted at 100°C for 24 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give a white solid 39 (0.12 g, yield 56%, HPLC purity: 98.48%).

[0617] MS (ESI, negative ion) m / z: 472.1 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.90(d,J=8.5Hz,1H),7.84(s,2H),6.91 -6.79(m,2H),5.87(s,1H),4.87(s,2H),3.57(t,J=6.1Hz,2H),2.96(t,J=5.9Hz,2H).

[0618] Example 40 2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 40 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 40a

[0619] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (2.0 g, 5.7 mmol) was dissolved in tetrahydrofuran (20 mL) and added with sodium hydride (0.60 g, 15.0 mmol, 60 mass% in oil) at 0 °C. After 10 min, 2-bromomethyl-4-fluoro-1-methylbenzene (1.0 mL, 7.2 mmol) and N,N-dimethylformamide (2 mL) were added dropwise and the mixture was allowed to react at room temperature for 3 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (120 mL). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 40a (2.1 g, 77% yield) as a white solid.

[0620] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 40b

[0621] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 40a (2.0 g, 4.2 mmol) was dissolved in acetic acid (25 mL), iron powder (0.60 g, 10.0 mmol) was added, and the mixture was reacted at 60 °C for 6 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (100 mL), stirred for 10 min, filtered, rinsed with water (50 mL), and the filter cake was collected and dried. The resulting solid was pulped with petroleum ether / ethyl acetate (6 / 1, 20 mL) to give white solid 40b (1.1 g, 59% yield).

[0622] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 40c

[0623] 6-(4-Amino-2,6-dichlorophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 40b (1.0 g, 2.2 mmol) was dissolved in acetic acid (12 mL) and added with an aqueous solution (5 mL) of sodium nitrite (0.31 g, 4.5 mmol) at 0 °C, followed by N-cyanoacetylurethane (0.50 g, 3.0 mmol) for 2 h. The reaction was quenched by adding water (30 mL), stirred for 10 min, filtered, rinsed with water (5 mL × 2), collected and dried, and the resulting solid was pulped with petroleum ether / ethyl acetate (5 / 2, 35 mL) to give yellow solid 40c (1.1 g, 80% yield).

[0624] Step 4: Synthesis of 2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 40d

[0625] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 40c (1.1 g, 1.8 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium acetate (0.20 g, 2.4 mmol) was added. The mixture was reacted at 120 °C for 6 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (25 mL), stirred for 10 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethanol / ethyl acetate / petroleum ether = 5 / 14 / 20, 39 mL) to give white solid 40d (0.66 g, 65% yield, HPLC purity: 97.55%).

[0626] MS (ESI, negative ion) m / z: 564.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)13.34(s,1H),7.93(d,J=8.2Hz,1H),7.85(s,2H),7.30-7.15(m,1H),6.98(dd,J=17.3, 5.6Hz, 2H), 6.86 (d, J=9.5Hz, 2H), 4.67 (s, 2H), 3.50-3.44 (m, 2H), 2.99 (s, 2H), 2.25 (s, 3H).

[0627] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 40e

[0628] 2-(3,5-Dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 40d (0.60 g, 1.1 mmol) was dissolved in acetic acid (10 mL), concentrated hydrochloric acid (3 mL) was added, and the reaction was carried out at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 40e (0.40 g, 60% yield).

[0629] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 40

[0630] 2-(3,5-Dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 40e (0.40 g, 0.68 mmol) was dissolved in thioglycolic acid (3 mL) and reacted at 150° C. for 12 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (50 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). The resulting solid was recrystallized at 80 °C (ethyl acetate / petroleum ether = 1 / 2, 24 mL) to give a white solid 40 (0.29 g, yield 78%, HPLC purity: 99.21%).

[0631] MS (ESI, negative ion) m / z: 539.2 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),7.93(d,J=8.4Hz,1H),7.87(s,2H),7.73(s,1H),7.23(dd,J=8.3, 6.0Hz,1H),7.03-6.93(m,2H),6.86-6.80(m,2H),4.67(s,2H),3.49(t,J=6.6Hz,2H),2.99(t,J=6.6Hz,2H),2.25(s,3H).

[0632] Example 41 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 41 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 41a

[0633] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (1.50 g, 4.20 mmol) was dissolved in a mixture of N,N-dimethylformamide (6 mL) and tetrahydrofuran (20 mL). Sodium hydride (0.25 g, 6.25 mmol, 60 mass% in oil) was added at 0 °C. After 30 min, 4-trifluoromethoxybromobenzyl ether (2.27 g, 8.90 mmol) was added dropwise and the mixture was allowed to react at room temperature for 3 h. The reaction was quenched by the addition of ice water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 41a (2.07 g, 93% yield) as a yellow oil.

[0634] MS(ESI,pos.ion)m / z:527.00[M+H] + .

[0635] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 41b

[0636] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 41a (2.07 g, 3.93 mmol) was dissolved in acetic acid (50 mL), iron powder (0.88 g, 15.7 mmol) was added, and the mixture was reacted at 55 °C for 5 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 41b (1.59 g, 81% yield) as a white solid.

[0637] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 41c

[0638] 6-(4-Amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 41b (0.60 g, 1.21 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution (6 mL) of sodium nitrite (0.17 g, 2.48 mmol) was added at 0 °C, followed by N-cyanoacetylurethane (0.23 g, 1.49 mmol). The reaction was allowed to react for 4 h. The reaction was quenched by adding water (100 mL), stirred for 30 min, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 41c (0.87 g, 100% yield).

[0639] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 41d

[0640] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 41c (0.87 g, 1.21 mmol) was dissolved in N,N-dimethylformamide (18 mL), and sodium acetate (0.22 g, 2.65 mmol) was added. The mixture was reacted at 120 °C for 6 hours. The reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 80 °C (ethanol / ethyl acetate / petroleum ether = 1 / 1 / 4, 30 mL) to give pale red solid 41d (0.65 g, 88% yield, HPLC purity: 98.61%).

[0641] MS (ESI, negative ion) m / z: 616.0 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)13.30(s,1H),7.93(d,J=8.4Hz,1H),7.84(s,2H),7.44(d,J=8.2Hz,2H),7 .33(d,J=8.2Hz,2H),6.85(d,J=10.7Hz,2H),4.72(s,2H),3.51(t,J=6.3Hz,2H),2.98(t,J=6.1Hz,2H).

[0642] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(1-oxo-4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 41e

[0643] 2-(3,5-Dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 41d (0.32 g, 0.52 mmol) was dissolved in acetic acid (10 mL), concentrated hydrochloric acid (5 mL) was added, and the reaction was carried out at 100° C. for 11 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (5 mL × 2). The filter cake was collected and dried to give a yellow solid 41e (0.35 g, 100% yield).

[0644] Step 6: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 41

[0645] 2-(3,5-Dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 41e (0.35 g, 0.53 mmol) was dissolved in thioglycolic acid (3 mL) and reacted at 140° C. for 14 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1). The resulting solid was recrystallized at 85 °C (ethyl acetate / petroleum ether = 1 / 1, 20 mL) to give a white solid 41 (0.22 g, yield 71%, HPLC purity: 99.21%).

[0646] MS (ESI, negative ion) m / z: 591.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.52(s,1H),7.93(d,J=8.4Hz,1H),7.87(s,2H),7.73(s,1H),7.44(d,J=8.3 Hz,2H),7.33(d,J=8.2Hz,2H),6.87-6.78(m,2H),4.72(s,2H),3.51(t,J=6.6Hz,2H),2.97(t,J=6.6Hz,2H).

[0647] Example 42 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 42 [ka] Step 1: Synthesis of 2-(3-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 42a

[0648] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (1.50 g, 8.5 mmol), cuprous iodide (0.32 g, 1.7 mmol), fluoroiodobenzene (3.76 g, 16.9 mmol), and potassium carbonate (1.17 g, 8.47 mmol) were dissolved in N,N-dimethylformamide (40 mL) and reacted at 150 °C for 19 h. The reaction mixture was cooled to room temperature and quenched by the addition of water (40 mL). The mixture was extracted with ethyl acetate (60 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give yellow solid 42a (2.22 g, 96% yield).

[0649] MS (ESI, pos. ion) m / z: 272.2 [M+H] + .

[0650] Step 2: Synthesis of 2-(3-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 42b

[0651] Boron tribromide (2.4 mL, 25.0 mmol) was added dropwise to a solution of 2-(3-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 42a (2.22 g, 8.17 mmol) in dichloromethane (30 mL) at 0 °C, followed by reaction at room temperature for 4 h. The reaction mixture was poured into ice water (30 mL) to quench the reaction, stirred for 10 min, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried, and the resulting solid was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give white solid 42b (0.13 g, 4.5% yield).

[0652] MS (ESI, pos. ion) m / z: 258.1 [M+H] + .

[0653] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one 42c

[0654] 2-(3-Fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 42b (0.13 g, 0.51 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.13 g, 0.57 mmol) were dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (0.14 g, 1.01 mmol) was added, and the reaction was carried out at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, stirred for 10 minutes, filtered, and the filter cake was washed with water (5 mL). The filter cake was collected and dried to give 42c (0.22 g, 97% yield) as a white solid.

[0655] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one 42d

[0656] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one 42c (0.22 g, 0.49 mmol) was dissolved in acetic acid (6 mL), iron powder (0.11 g, 1.95 mmol) was added, and the mixture was reacted at 55° C. for 6 hours. The reaction mixture was cooled to room temperature, the iron powder was removed, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated to give 42d (0.18 g, 85% yield) as a white solid.

[0657] Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 42e

[0658] 6-(4-Amino-2,6-dichlorophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one 42d (0.18 g, 0.42 mmol) was dissolved in acetic acid (10 mL), and a solution of sodium nitrite (58 mg, 0.84 mmol) in water (5 mL) was added dropwise at 0 °C. After stirring for 15 min, N-cyanoacetylurethane (79 mg, 0.51 mmol) was added and the mixture was allowed to react for 3.5 h. Water (20 mL) was added to the reaction mixture, which was stirred for 10 min, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to give yellow solid 42e (0.19 g, 73% yield).

[0659] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 42f

[0660] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 42e (0.35 g, 0.60 mmol) was dissolved in N,N-dimethylformamide (40 mL), sodium acetate (0.12 g, 1.40 mmol) was added, and the reaction was carried out at 120 °C for 8 hours. The reaction solution was cooled to room temperature, water (80 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate). The resulting solid was eluted with 80 mL of ethyl acetate. o C (petroleum ether / ethyl acetate = 1 / 2, 24 mL) to give a yellow solid 42f (0.25 g, yield 76%, HPLC purity: 99.44%).

[0661] MS (ESI, negative ion) m / z: 536.1 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)13.31(s,1H),7.96(d,J=8.7Hz,1H),7.86(s,2H),7.45(q,J=7.8Hz,1H),7.34-7.23(m,2H),7.09(td,J=8.6, 2.6Hz,1H),6.95(d,J=2.6Hz,1H),6.89(dd,J=8.7, 2.6Hz,1H),3.97(t,J=6.4Hz,2H),3.13(t,J=6.4Hz,2H).

[0662] Step 7: Synthesis of 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid 42g

[0663] 2-(3,5-Dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile 42f (0.26 g, 0.49 mmol) was dissolved in acetic acid (5 mL), concentrated hydrochloric acid (2.5 mL) was added, and the reaction was carried out at 100° C. for 7 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 42g (0.22 g, 78% yield).

[0664] Step 8: Synthesis of 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 42

[0665] 42 g (0.22 g, 0.40 mmol) of 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formic acid was dissolved in thioglycolic acid (2 mL) and reacted at 140° C. for 14 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1). The resulting solid was 85% s, 10% chloroform ... o C (petroleum ether / ethyl acetate = 1 / 1, 20 mL) to give a white solid 42 (88 mg, yield 43%, HPLC purity: 98.94%).

[0666] MS (ESI, negative ion) m / z: 511.1 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ(ppm)12.53(s,1H),7.96(s,1H),7.88(s,2H),7.74(s,1H),7.45(s,1H),7.28(dd,J=21.9, 9.6Hz, 2H), 7.10 (s, 1H), 6.93 (s, 1H), 6.86 (s, 1H), 3.97 (s, 2H), 3.13 (s, 2H).

[0667] Example 43 2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 43 [ka] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 43a

[0668] 6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 1b (2.5 g, 7.1 mmol) was dissolved in tetrahydrofuran (25 mL). Sodium hydride (0.60 g, 20 mmol, 60 mass% in oil) was added at 0 °C. 3-Trifluoromethoxybromobenzyl (1.4 g, 8.6 mmol) and N,N-dimethylformamide (2 mL) were added dropwise, and the mixture was allowed to react for 5 h at 0 °C. The reaction was quenched by the addition of water (100 mL). The mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with saturated sodium chloride (30 mL × 3), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give yellow oil 43a (2.6 g, 70% yield).

[0669] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 43b

[0670] 6-(2,6-Dichloro-4-nitrophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 43a (2.5 g, 4.7 mmol) was dissolved in acetic acid (30 mL), iron powder (0.55 g, 9.8 mmol) was added, and the mixture was reacted at 60 °C for 6 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (60 mL), extracted with ethyl acetate (150 mL), and the organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, suction filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 43b (1.5 g, 64% yield) as a yellow oil.

[0671] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate ethyl 43c

[0672] 6-(4-Amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-1(2H)-one 43b (1.5 g, 3.0 mmol) was dissolved in acetic acid (20 mL), and an aqueous solution (6 mL) of sodium nitrite (0.42 g, 6.1 mmol) was added at 0 °C, followed by N-cyanoacetylurethane (0.61 g, 3.9 mmol). The reaction was allowed to react for 2 h. The reaction was quenched by adding water (30 mL), stirred for 10 min, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 43c (1.6 g, 80% yield).

[0673] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 43d

[0674] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 43c (1.5 g, 3.7 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium acetate (0.30 g, 3.7 mmol) was added. The mixt...

Claims

1. A compound which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, solvate of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, Y is —O—; R3a and R ３ｄ are each independently H, deuterium, F, Cl, Br, I, —CN, or —NO ２ , -COOH, -OH, -NH ２ , -SH,C １－６ Alkyl group or C １－６ is a halogenated alkyl group, R 3b and R 3c are independently H or deuterium; R １ represents H, deuterium, F, Cl, Br, I, -CN, and -NO ２ , -COOH, -OH, -NH ２ , -SH,C １－６ Alkyl group, —C(═O)—C １－６ Alkoxy group or -C(=O)-C １－６ is an alkyl group, R ２ is H, deuterium or C １－６ is an alkyl group, Ring A is 【Chemistry 2】 and wherein ring A is one, two or three R ｙ may be substituted with E1 is independently -(CR ４ａ R ４ｂ ) ｑ - and E2 is independently -CR ４ｃ R ４ｄ - and E ３ and E6 are each independently —NR ｃ - and E ４ Ha-CR ４ｇ = and E ５ Ha-CR ４ｈ = and q is 1, 2 or 3; Each R c is independently H, deuterium, or C. １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Halogenated alkyl group, C ３－６ Cycloalkyl group, 5- to 6-membered heterocyclic group, C ６－１０ an aryl group or a 5- to 6-membered heteroaryl group, and each R c is independently 1, 2, or 3 R ｙ１ may be substituted with R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ４ｇ and R ４ｈ are each independently H, deuterium, F, Cl, Br, I, —CN, or —NO ２ , -COOH, -OH, -NH ２ , -SH,C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Alkylamino group, C １－６ Halogenated alkyl group or C １－６ is a halogenated alkoxy group, and the R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ４ｇ and R ４ｈ independently represent one, two or three R ｙ２ may be substituted with Each R ｙ are independently deuterium, F, Cl, Br, I, —CN, —OH, or —NH ２ , C １－６ Alkyl group or C １－６ is a halogenated alkyl group, Each R ｙ１ are independently deuterium, F, Cl, Br, I, —CN, —OH, or —NH ２ , -SH, oxo, -OC(=O)-C １－６ Alkyl group, —C(═O)—C １－６ Alkoxy group, —C(═O)—C １－６ Alkyl group, —C(═O)—C １－６ Alkylamino group, —C(═O)NH ２ , C １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Halogenated alkoxy group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ Cycloalkyl group, 5- to 6-membered heterocyclic group, C ６－１０ an aryl group or a 5- to 6-membered heteroaryl group, ｙ１ independently represent one, two or three R ｚ may be substituted with R ｚ and Ry2 are each independently deuterium, F, Cl, Br, I, —CN, —OH, or —NH ２ , -COOH, C １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Halogenated alkoxy group or C １－６ is an alkoxy group.)

2. The R3a and R ３ｄ are each independently H, deuterium, F, Cl, Br, I, —CN, or —NO ２ , -COOH, -OH, -NH ２ , —SH, methyl group, ethyl group, n-propyl group, isopropyl group, —CF ３ , -CHF ２ , -CH ２ F, -CH ２ CF ３ or -CH ２ The compound of claim 1 which is CHF2.

3. The R １ is H, deuterium, F, Cl, Br, I, -CN, -NO ２ , -COOH, -OH, -NH ２ , —SH, methyl group, ethyl group, n-propyl group, isopropyl group, —C(═O)—OCH ３ , -C(=O)-OCH ２ CH ３ , -C(=O)-OCH(CH ３ ) ２ , -C(=O)-OCH ２ CH ２ CH ３ , -C(=O)-O(CH ２ ) ３ CH ３ , -C(=O)-OCH ２ CH (CH ３ ) ２ , -C(=O)-CH ３ or -C(=O)-CH ２ 3. The compound of claim 1 or 2, wherein the compound is CH3.

4. The R c s each independently represent H, deuterium, or C. １－４ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－４ Halogenated alkyl group, C ３－６ Cycloalkyl group, 5- to 6-membered heterocyclic group, C ６－１０ an aryl group or a 5- to 6-membered heteroaryl group, and each R c is independently 1, 2, or 3 R ｙ１ The compound according to any one of claims 1 to 3, optionally substituted with

5. The R c s each independently represent H, deuterium, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, or —CH═CH ２ , -CH ２ CH=CH ２ , -CH=CHCH ３ , -C≡CH, -CF ３ , -CHF ２ , -CH ２ F, -CH ２ CF ３ , -CH ２ CHF ２ , cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, pyrrolidinyl group, pyrazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyranyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, phenyl group, furanyl group, thienyl group, imidazolyl group, pyrimidinyl group, pyridyl group, pyrrolyl group, pyrazinyl group, thiazolyl group or oxazolyl group, and said R c is independently 1, 2 or 3 R ｙ１ The compound according to any one of claims 1 to 4, optionally substituted with

6. Each of the R ｙ１ are independently deuterium, F, Cl, Br, I, —CN, —OH, or —NH ２ , -SH, oxo, -OC(=O)-C １－４ Alkyl group, —C(═O)—C １－４ Alkoxy group, —C(═O)—C １－４ Alkyl group, —C(═O)—C １－４ Alkylamino group, —C(═O)NH ２ , C １－４ Alkyl group, C １－４ Halogenated alkyl group, C １－４ Halogenated alkoxy group, C １－４ Alkoxy group, C １－４ Alkylthio group, C １－４ Alkylamino group, C ３－６ Cycloalkyl group, 5- to 6-membered heterocyclic group, C ６－１０ an aryl group or a 5- to 6-membered heteroaryl group, ｙ１ independently represent one, two or three R ｚ The compound according to any one of claims 1 to 5, optionally substituted with

7. Each of the R ｙ１ are independently deuterium, F, Cl, Br, I, —CN, —OH, or —NH ２ , -SH, oxo, -OC(=O)-methyl group, -OC(=O)-ethyl group, -OC(=O)-n-propyl group, -OC(=O)-isopropyl group, -OC(=O)-n-butyl group, -OC(=O)-tert-butyl group, -OC(=O)-isobutyl group, -C(=O)O-methyl group, -C(=O)O-ethyl group, -C(=O)O-n-propyl group, -C(=O)O-isopropyl group, -C(=O) O-n-butyl group, —C(═O)O-tert-butyl group, —C(═O)O-isobutyl group, —C(═O)-methyl group, —C(═O)-ethyl group, —C(═O)-n-propyl group, —C(═O)-isopropyl group, —C(═O)-n-butyl group, —C(═O)-tert-butyl group, —C(═O)-isobutyl group, —C(═O)-methylamino group, —C(═O)-ethylamino group, —C(═O)NH ２ , methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group, —CF ３ , -CHF ２ , -CH ２ F, -CH ２ CF ３ , -CH ２ CHF ２ , -OCF ３ , -OCHF ２ , -OCH ２ F, -OCH ２ CF ３ , -OCH ２ CHF ２ , -OCHFCH ３ , a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a methylthio group, an ethylthio group, a methylamino group, an ethylamino group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyrrolidinyl group, a pyrazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a piperazinyl group, a phenyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrimidinyl group, a pyridyl group, a pyrrolyl group, a pyridazinyl group, a pyrazinyl group, a thiazolyl group, or an oxazolyl group, ｙ１ independently represent one, two or three R ｚ The compound according to any one of claims 1 to 6, optionally substituted with

8. The R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ４ｇ and R ４ｈ are each independently H, deuterium, F, Cl, Br, I, —CN, or —NO ２ , -COOH, -OH, -NH ２ , —SH, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, —CH═CH ２ , -CH ２ CH=CH ２ , -CH=CHCH ３ , —C≡CH, methoxy group, ethoxy group, methylamino group, ethylamino group, —CF ３ , -CHF ２ , -CH ２ F, -CH ２ CF ３ , -CH ２ CHF ２ , -OCF ３ , -OCHF ２ or -OCH ２ F, and said R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ４ｇ and R ４ｈ independently represent one, two or three R ｙ２ The compound according to any one of claims 1 to 7, optionally substituted with

9. The R ｚ and Ry2 are each independently deuterium, F, Cl, Br, I, —CN, —OH, or —NH ２ , —COOH, methyl group, ethyl group, n-propyl group, isopropyl group, —CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ The compound according to any one of claims 1 to 8, wherein F is a methoxy group or an ethoxy group.

10. The following structure: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 or a stereoisomer, geometric isomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

11. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, and optionally further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or any combination thereof.

12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 in the manufacture of a medicament which agonizes thyroid hormone receptors or which prevents, treats or alleviates diseases modulated by thyroid hormone receptors.

13. The use according to claim 12, wherein the thyroid hormone receptor is a thyroid hormone beta receptor.

14. 13. The use according to claim 12, wherein the disease modulated by the thyroid hormone receptor is a neurodegenerative disease, non-alcoholic fatty liver disease, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type I, hypothyroidism or thyroid cancer.

15. 12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 in the manufacture of a medicament for the prevention, treatment or amelioration of neurodegenerative diseases, non-alcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, dyslipidemia, glycogen storage disease type 1, hypothyroidism or thyroid cancer.

16. The non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated idiopathic cirrhosis or primary liver cancer; 16. The use according to claim 14 or 15, wherein the neurodegenerative disease is demyelination, chronic demyelination, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy, amyotrophic lateral sclerosis or Alzheimer's disease.

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