A compound as a thyroid hormone beta receptor agonist and its use

Abstract

The present invention relates to a compound as a thyroid hormone beta receptor agonist and its use, and further relates to a pharmaceutical composition comprising the compound. The compound or pharmaceutical composition of the present invention can be used to prepare a drug for preventing, treating or alleviating a disease regulated by a thyroid hormone beta receptor, especially for preparing a drug for treating non-alcoholic fatty liver disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a compound as a thyroid hormone β-receptor agonist and its use, and further relating to pharmaceutical compositions comprising said compound. This invention further relates to the use of said compound and pharmaceutical compositions in the preparation of medicaments for the prevention, treatment, or relief of diseases regulated by thyroid hormone β-receptors, particularly in the preparation of medicaments for the treatment of non-alcoholic fatty liver disease. Background Technology

[0002] Thyroid hormones (TH) play a crucial role in growth, differentiation, development, and maintaining metabolic homeostasis. TH is synthesized by the thyroid gland and secreted into the circulatory system primarily in two forms: triiodothyronine (T3) and tetraiodothyronine (T4). Although T4 is the predominant form secreted by the thyroid, T3 is the physiologically more active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues, but are primarily found in the liver and kidneys.

[0003] The physiological functions of thyroid hormone (TH) are primarily mediated through the thyroid hormone receptor (TR). TR belongs to the nuclear receptor superfamily and is a T3-induced transcription factor, playing a central role in mediating T3's action. TR is mainly located in the cell nucleus, forming heterodimers with the retinoid X receptor (RXR) and other nuclear receptors to bind to the thyroid hormone response element (TRE) in the promoter region of target genes, thereby regulating gene transcription. There are two subtypes of TR: TRα and TRβ. TRα can be further divided into TRα1 and TRα2, and TRβ into TRβ1 and TRβ2. Only TRα1, TRβ1, and TRβ2 can bind to the T3 ligand. TRα mainly regulates heart rate, while TRβ plays a crucial role in controlling hepatic cholesterol metabolism and inhibiting 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, then thrombocytopenia (TH) has certain therapeutic benefits (Paul M. Yenet. al. Physiological Reviews, Vol. 81(3):pp. 1097-1126 (2001); Paul Webbet. al. Expert Opin. Investig. Drugs, Vol. 13(5):pp. 489-500 (2004)). For example, TH can increase metabolic rate, oxygen consumption, and heat production, thereby reducing body weight. Weight loss will improve obesity-related comorbidities and has beneficial effects on obese patients, and may also have beneficial effects on glycemic control in obese patients with type 2 diabetes.

[0005] Th can also lower serum low-density lipoprotein (LDL) (Eugene Morkin et al. Journal of Molecular and Cellular Cardiology, Vol. 37: pp. 1137-1146 (2004)). Hyperthyroidism has been found to be associated with low total serum cholesterol, which is attributed to TH increasing hepatic LDL receptor expression and stimulating cholesterol metabolism to bile acids (JJ. Abrams et al. J. Lipid Res., Vol. 22: pp. 323-38 (1981)). Hypothyroidism is associated with hypercholesterolemia, and there are reports of TH replacement therapy lowering total cholesterol (M. Aviramet. 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 in increasing HDL cholesterol and improving the conversion rate of LDL to HDL by increasing the expression of apo A-1 (one of the major apoproteins of 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 through its regulatory effects on LDL and HDL, TH may also reduce the risk of atherosclerosis and other cardiovascular diseases. In addition, there is evidence that TH lowers 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 a key signaling agent for oligodendrocyte differentiation and myelination during development, and it stimulates myelin regeneration in an adult model of multiple sclerosis (MS) (Calza et al., Brain Res Revs 48:339-346, 2005). However, due to the limited therapeutic window for achieving myelin regeneration while avoiding cardiotoxicity and bone demineralization associated with chronic hyperthyroidism, thrombolysis cannot be used for long-term treatment. Some thrombolysis analogs can activate thrombolysis-responsive genes while avoiding the associated drawbacks of thrombolysis by utilizing the molecular and physiological characteristics of the thrombolysis receptor (Malm et al. Mini Rev Med Chem 7:79-86, 2007).

[0007] In addition, non-alcoholic fatty liver disease (NAFLD) is also closely related to thrombocytopenic purpura (TH). On the one hand, NAFLD affects the conversion and inactivation of TH, leading to a decrease in serum TH levels; on the other hand, the decrease in TH levels further causes lipid metabolism disorders and glucose metabolism disorders, participating in the occurrence of NAFLD. Studies have shown that fatty liver formation in rats induced by a choline-methionine-deficient diet can be reversed after feeding them T3 (Perra A, et al. Faseb, 2008, 22(8):2981).

[0008] However, endogenous thyroxine (TH) is non-selective and has side effects, such as hyperthyroidism, particularly cardiovascular toxicity. Therefore, the development of TH analogs (e.g., thyroid hormone beta-agonists) that avoid the adverse effects of hyperthyroidism while maintaining the beneficial effects of TH will open new avenues for treating patients with conditions such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic fatty liver disease, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disorders, and related conditions and diseases. Summary of the Invention

[0009] This invention provides a class of compounds with good agonistic activity against thyroid hormone β receptors. These compounds and their pharmaceutical compositions can be used to prepare drugs for the prevention, treatment, or relief of patients with non-alcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism, or thyroid cancer.

[0010] On one hand, the present invention relates to a compound, which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0011]

[0012] in,

[0013] Y is -O-, -S-, -NR 0 -、-C(=O)-、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -NR 0 C(=O)-or-C(=O)NR 0 -; wherein Y is optionally divided by 1, 2 or 3 R x Replaced;

[0014] R 0 H, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl or cyano C 1-6 alkyl;

[0015] R 3a R 3b R 3c and R 3d Each of the following can be independently represented as H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl or cyano C 1-6 alkyl;

[0016] R 1 For H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, -C(=O)-C 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6Alkylamino, -C(=O)NH2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylamino, -S(=O)2NH2, C 1-6 Alkylamino, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or cyano C 1-6 alkyl;

[0017] R 2 H, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 Aryl or heteroaryl groups composed of 5-6 atoms;

[0018] Ring A is Among them, ring A is arbitrarily divided by 1, 2 or 3 R. y Replaced;

[0019] E1, U1, and Z1 are each independently -(CR 4a R 4b ) q -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR a -;

[0020] E2, U2, and Z2 are each independently -CR 4c R 4d -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR b -;

[0021] E3, E6, U3, and Z3 are each independently -CR 4e R 4f -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR c -;

[0022] E4 is -CR 4g = or -N=; E5 is -CR 4h = or -N=;

[0023] q can be 0, 1, 2, or 3;

[0024] R a Rb R c and R 5 Each is independently H, deuterium, and C. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 aryl or heteroaryl groups consisting of 5-6 atoms, wherein R a R b R c and R 5 Independently and arbitrarily controlled by 1, 2 or 3 R y1 Replaced;

[0025] R 4a R 4b R 4c R 4d R 4e R 4f R 4g and R 4h Each of the following can be independently represented as H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 5-6 atoms, (heterocyclic group consisting of 5-6 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl group consisting of 5-6 atoms, or (heteroaryl group consisting of 5-6 atoms)-C 1-4 alkylene, wherein R 4a R 4b R 4c R 4d R 4e R 4f R 4g and R 4h Independently and arbitrarily controlled by 1, 2 or 3 R y2 Replaced;

[0026] Or R 4a R 4bTogether with the carbon atoms attached to them, they form C 3-8 Carbon rings or heterocycles consisting of 5-6 atoms, or R 4c R 4d Together with the carbon atoms attached to them, they form C 3-8 Carbon rings or heterocycles consisting of 5-6 atoms, or R 4e R 4f Together with the carbon atoms attached to them, they form C 3-8 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-8 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y3 Replaced;

[0027] Each R x Independently, it can be deuterium, F, Cl, Br, I, -CN, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy or C 1-6 Alkylamino;

[0028] Each R y Independently, it can be deuterium, F, Cl, Br, I, -CN, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy or C 1-6 Alkylamino; or two R atoms linked to adjacent atoms y Together with the atoms bonded to them, they form C 3-8 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-8 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y4 Replaced;

[0029] Each R y1 Independently, it can be deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkylamino, -C(=O)NH2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylamino, -S(=O)2NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Halogenated alkoxy, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 aryl or heteroaryl groups consisting of 5-6 atoms, wherein R y1 Optionally by 1, 2 or 3 R z Replaced;

[0030] R z R y2 R y3 and R y4 Each of the following can be independently represented as deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino.

[0031] In some embodiments, R 3a R 3b R 3c and R 3d Each of these can be independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl, or cyanomethyl.

[0032] In some embodiments, R 1The following are the possible values ​​for H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, -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, and -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, ethylamino, methoxy, ethoxy, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.

[0033] In some embodiments, R a R b R c and R 5 Each is independently H, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 aryl or heteroaryl groups consisting of 5-6 atoms, wherein R a R b R c and R 5 Optionally not replaced or replaced by 1, 2 or 3 Rs y1 Replaced; where R y1 It has the meaning described in this invention.

[0034] In some embodiments, R a R b R c and R 5Each of the following is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, thiophenyl, imidazolyl, pyrimidinyl, pyridinyl, pyrroloyl, pyrazinyl, thiazolyl, or oxazolyl, wherein R a R b R c and R 5 Independently and arbitrarily controlled by 1, 2 or 3 R y1 Replaced; where R y1 It has the meaning described in this invention.

[0035] In some embodiments, each R y1 Independently, it can be deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkoxy group, -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkylamino, -C(=O)NH2, -S(=O)2-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkylamino, -S(=O)2NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 aryl or heteroaryl groups consisting of 5-6 atoms, wherein each R y1 Independently and arbitrarily controlled by 1, 2 or 3 R z Replaced; where R z It has the meaning described in this invention.

[0036] In some embodiments, each R y1Independently, it can be 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, -C(=O)O-n-butyl, -C(=O)O-tert-butyl, -C(=O)O-isobutyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-isopropyl, -C(=O)-n-butyl, -C(=O)-tert-butyl, -C(=O)-isobutyl, -C(=O)-methylamino, -C(=O)-ethylamino, -C(=O)NH2, -S(=O)2-C 1-3 Alkyl group, -S(=O)2-C 1-3 Alkylamino, -S(=O)2NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCHFCH3, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, ethylthio, methylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenylfuranyl, thiophenyl, imidazoleyl, pyrimidinyl, pyridinyl, pyrroloyl, pyrazinyl, thiazolyl, or oxazolyl, wherein each of the R... y1 Independently and arbitrarily controlled by 1, 2 or 3 R z Replaced; where R z It has the meaning described in this invention.

[0037] In some embodiments, R 4a R 4b R 4c R 4d R 4e R 4f R 4g and R 4hEach of these can be independently represented as H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, methoxy, ethoxy, methylamino, ethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, pyrrolidinyl, pyrazole Alkyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, pyrrolyl-CH2-, pyrazolyl-CH2-, tetrahydrofuranyl-CH2-, tetrahydrothiophenyl-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, thiomorpholinyl-CH2-, piperazine-CH2-, phenyl, phenyl-CH2-, phenyl-CH2CH2-, furanyl, thiophenyl, imidazolyl, pyrimidinyl, pyridinyl, pyrroloyl, pyridazinyl, pyrazine, thiazolyl, oxazolyl, furanyl-CH2-, thiophenyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, pyridinyl-CH2-, or pyrroloyl-CH2-, wherein R 4a R 4b R 4c R 4d R 4e R 4f R 4g and R 4h Independently and arbitrarily controlled by 1, 2 or 3 R y2 Replaced;

[0038] Or R 4a R 4b Together with the carbon atoms attached to them, they form C 3-6 Carbon rings or heterocycles consisting of 5-6 atoms, or R 4c R 4d Together with the carbon atoms attached to them, they form C 3-6 Carbon rings or heterocycles consisting of 5-6 atoms, or R 4e R 4f Together with the carbon atoms attached to them, they form C 3-6 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-6 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y3 Replaced; where R y2 and R y3 It has the meaning described in this invention.

[0039] In some embodiments, R z R y2 R y3 and R y4 Each can be independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -COOH, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, methoxy, ethoxy, or methylamino.

[0040] On the other hand, the present invention relates to a pharmaceutical composition comprising the compound described herein, optionally further comprising any one or any combination thereof of a pharmaceutically acceptable carrier, excipient, adjuvant, or mediator.

[0041] On one hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to stimulate thyroid hormone receptors; or to prevent, treat or alleviate diseases regulated by thyroid hormone receptors.

[0042] In some embodiments, the thyroid hormone receptor described in this invention is a thyroid hormone β receptor.

[0043] In some embodiments, the diseases regulated by thyroid hormone receptors as described in this invention are neurodegenerative diseases, non-alcoholic fatty liver disease, idiopathic pulmonary fibrosis (IPF), atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism, or thyroid cancer.

[0044] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate the following diseases: 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, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer.

[0045] In some embodiments, the non-alcoholic fatty liver disease described in this invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis, or primary liver cancer.

[0046] In some embodiments, the neurodegenerative diseases described in this invention are demyelinating diseases, chronic demyelinating diseases, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenocortical dystrophy (ALD), amyotrophic lateral sclerosis (ALS), or Alzheimer's disease.

[0047] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below. Detailed Implementation

[0048] This invention provides a class of compounds with good agonistic activity against thyroid hormone β receptors, their preparation methods, pharmaceutical compositions, and uses. Those skilled in the art can refer to the content herein and appropriately modify the process parameters to achieve the desired results. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

[0049] Definitions and General Terms

[0050] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to encompass all alternatives, modifications, and equivalents, all of which are included within its scope. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the invention. The invention is by no means limited to the methods and materials described herein, and in the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0051] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0052] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0053] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0054] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0055] Unless otherwise stated, the terms used in the specification and claims of this invention have the following definitions.

[0056] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0057] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "unsubstituted or substituted with...". The terms "optionally," "optionally," or "optionally" mean that the event or condition described below may, but is not necessarily, occur, and the description includes both cases where such an event or condition occurs and cases where it does not occur. Generally, unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the same or different positions. The substituents mentioned therein can be, but are not limited to, H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cyanoalkyl, carboxylalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkylene, heterocyclic-alkylene, carbocyclic, heterocyclic, aryl, aryl-alkylene, heteroaryl, heteroaryl-alkylene, etc.

[0058] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each…independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0059] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "alkyl" specifically refers to independently disclosed C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl; "C 3-8 "Cycloalkyl" specifically refers to independently disclosed C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, and C8 cycloalkyl; "heterocyclic group consisting of 3-6 atoms" refers to heterocyclic groups consisting of 3 atoms, 4 atoms, 5 atoms, and 6 ring atoms.

[0060] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0061] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In some embodiments, alkylene groups contain 1-6 carbon atoms, i.e., C64-C ... 1-6 Alkylene; in some embodiments, the alkylene group contains 1-4 carbon atoms, i.e., C64-C ... 1-4 Alkylenes; examples of such alkylenes include, but are not limited to, methylene (-CH2-), ethylene (including -CH2CH2- or -CH(CH3)-), isopropylene (including -CH(CH3)CH2- or -C(CH3)2-), n-propylene (including -CH2CH2CH2-, -CH(CH2CH3)- or -CH2CH(CH3)-), and so on. The alkylene group may optionally be substituted with one or more substituents described in this invention.

[0062] The term "alkyl" or "alkyl group" refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents as described in this invention. In some embodiments, the alkyl group contains 1 to 10 carbon atoms; in some embodiments, the alkyl group contains 1 to 8 carbon atoms, i.e., C646. 1-8 Alkyl group; in some embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C64-C ... 1-6 Alkyl group; in some embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C64. 1-4 alkyl.

[0063] Examples of alkyl groups include, but are not limited to, 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), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-heptyl, n-octyl, etc.

[0064] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein at least one unsaturated site is a carbon-carbon sp group. 2 The double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "trans", or the orientation of "E" and "Z". In some embodiments, the alkenyl group comprises 2-8 carbon atoms; in some embodiments, the alkenyl group comprises 2-6 carbon atoms, i.e., C 2-6 Alkenyl group; in some embodiments, the alkenyl group contains 2-4 carbon atoms, i.e., C64-C74-C6 ... 2-4 Alkenyl group.

[0065] Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), propenyl (-CH=CHCH3), butenyl (-CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=C(CH3)2, -CH=C(CH3)2, -CH2C(CH3)=CH2), pentenyl (-CH2CH2CH2CH=CH2, -CH2CH2CH=CHCH3, -CH2CH2CH=CHCH3, -CH2CH=CHCH2CH3, -CH=CHCH2CH2CH3, -CH2CH2C(CH3)=CH2, -CH2CH=C(CH3)2, -CH=CHCH(CH3)2, -C(CH2CH3)=CHCH3, -CH(CH2CH3)CH=CH2), and so on.

[0066] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein at least one unsaturated site is a carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkynyl group comprises 2-8 carbon atoms; in some embodiments, the alkynyl group comprises 2-6 carbon atoms, i.e., C0... 2-6 Alkynyl group; in some embodiments, the alkynyl group contains 2-4 carbon atoms, i.e., C64-C ... 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡CH-CH3), propynyl (-CH2C≡CH), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptyynyl, 1-octyynyl, etc.

[0067] The term "alkoxy group" refers to an alkyl group attached to the remainder of a molecule via an oxygen atom, i.e., -O-alkyl, wherein the alkyl group has the meaning as described in this invention, and wherein the alkoxy group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkoxy group contains 1-20 carbon atoms; in some embodiments, the alkoxy group contains 1-10 carbon atoms; in some embodiments, the alkoxy group contains 1-8 carbon atoms; in some embodiments, the alkoxy group contains 1-6 carbon atoms, i.e., C 1-6 Alkoxy group; in some embodiments, the alkoxy group contains 1-4 carbon atoms, i.e., C64-C44. 1-4 Alkoxy.

[0068] Examples of alkoxy groups include, but are not limited to, methoxy (MeO,-OCH3), ethoxy (EtO,-OCH2CH3), n-propyloxy (n-PrO,n-propoxy,-OCH2CH2CH3), isopropyloxy (i-PrO,i-propoxy,-OCH(CH3)2), 1-butoxy (n-BuO,n-butoxy,-OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO,i-butoxy,-OCH2CH(CH3)2), 2-butoxy (s-BuO,s-butoxy,-OCH(CH3)CH2CH3), 2-methyl-isopropyloxy (t-BuO,t-butoxy,-OC(CH3)3), etc.

[0069] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino," indicating that the amino group is independently substituted by one or two alkyl groups, which have the definition described in this invention. The alkylamino group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkylamino group is one or two C14 groups. 1-6 An alkyl group is attached to an alkylamino group on a nitrogen atom, i.e., C 1-6 Alkylamino; in some embodiments, the alkylamino group is one or two C14 groups. 1-4 An alkyl group is attached to an alkylamino group on a nitrogen atom, i.e., C 1-4 Alkylamino. 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 (N-n-propylamino), isopropylamino (N-isopropylamino), etc.

[0070] The term "alkathioyl" refers to an alkyl group attached to the remainder of the molecule via a sulfur atom, i.e., -S-alkyl, wherein the alkyl group has the meaning as described in this invention, and wherein the alkathioyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkathioyl group contains 1-10 carbon atoms; in some embodiments, the alkathioyl group contains 1-8 carbon atoms; in some embodiments, the alkathioyl group contains 1-6 carbon atoms, i.e., C 1-6 Alkylthio group; in some embodiments, the alkylthio group contains 1-4 carbon atoms, i.e., C64. 1-4 Alkylthio group; in some embodiments, the alkylthio group contains 1-3 carbon atoms, i.e., C64-C ... 1-3 Alkylthio group. Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, etc.

[0071] The term "haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the haloalkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the haloalkyl group contains 1-10 carbon atoms; in some embodiments, the haloalkyl group contains 1-8 carbon atoms; in some embodiments, the haloalkyl group contains 1-6 carbon atoms, i.e., C64-C ... 1-6 Halogenated alkyl group; in some embodiments, the halogenated alkyl group contains 1-4 carbon atoms, i.e., C64-C74-C ... 1-4 Halogenated alkyl group; in some embodiments, the halogenated alkyl group contains 1-3 carbon atoms, i.e., C64-C ... 1-3Alkyl halogens. Examples of alkyl halogens include, but are not limited to, fluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), fluoroethyl (-CHFCH3,-CH2CH2F), difluoroethyl (-CF2CH3,-CFHCFH2,-CH2CHF2), perfluoroethyl, fluoropropyl (-CHFCH2CH3,-CH2CHFCH3,-CH2CH2CH2F), and so on.

[0072] The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogen substituents, wherein the haloalkoxy group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the haloalkoxy group contains 1-10 carbon atoms; in some embodiments, the haloalkoxy group contains 1-8 carbon atoms; in some embodiments, the haloalkoxy group contains 1-6 carbon atoms, i.e., C64-C ... 1-6 Haloalkoxy group; in some embodiments, the haloalkoxy group contains 1-4 carbon atoms, i.e., C64-C74-C ... 1-4 Haloalkoxy group; in some embodiments, the haloalkoxy group contains 1-3 carbon atoms, i.e., C64-C74-C ... 1-3 Haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2, -OCH2F, etc.

[0073] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl (-OH) groups, which has the meaning described in this invention, wherein the hydroxyalkyl group may optionally be substituted with one or more substituents described in this invention. In some embodiments, the hydroxyalkyl group described in this invention refers to a C group substituted with one or more hydroxyl (-OH) groups. 1-6 Alkyl, i.e., hydroxyl C 1-6 Alkyl; in some embodiments, a hydroxyalkyl group refers to a C group substituted with one or more hydroxyl groups (-OH). 1-4 Alkyl, i.e., hydroxyl C 1-4 Alkyl groups. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl (e.g., -CH2OH), hydroxyethyl (e.g., 2-hydroxyethyl), and so on.

[0074] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups (-NH2), which has the meaning described in this invention, wherein the aminoalkyl group may optionally be substituted with one or more substituents described in this invention. In some embodiments, the aminoalkyl group described in this invention refers to a C group substituted with one or more amino groups (-NH2). 1-6 Alkyl, i.e., amino C 1-6Alkyl; in some embodiments, an aminoalkyl group refers to a C group substituted with one or more amino groups (-NH2). 1-4 Alkyl, i.e., amino C 1-4 Alkyl, i.e., amino C 1-2 Alkyl groups. Examples of aminoalkyl groups include, but are not limited to, aminomethyl (-CH2NH2), diaminomethyl (-CH(NH2)2), aminoethyl (e.g., 2-aminoethyl), etc.

[0075] The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups (-CN), which has the meaning described in this invention, wherein the cyanoalkyl group may optionally be substituted with one or more substituents described in this invention. In some embodiments, the cyanoalkyl group described in this invention refers to a C group substituted with one or more cyano groups (-CN). 1-6 Alkyl, i.e., cyano C 1-6 Alkyl; in some embodiments, the cyanoalkyl group refers to a C group substituted with one or more cyano groups (-CN). 1-4 Alkyl, i.e., cyano C 1-4 Alkyl groups. Examples of cyanoalkyl groups include, but are not limited to, cyanomethyl (e.g., -CH2CN), cyanoethyl (e.g., 2-cyanoethyl), and so on.

[0076] The term "carboxyalkyl" refers to an alkyl group substituted with one or more carboxyl groups (-COOH), which has the meaning described in this invention, wherein the carboxyalkyl group may optionally be substituted with one or more substituents described in this invention. In some embodiments, the carboxyalkyl group described in this invention refers to a C group substituted with one or more carboxyl groups (-COOH). 1-6 Alkyl group, i.e., carboxyl group C 1-6 Alkyl; in some embodiments, a carboxyl alkyl group refers to a C group substituted with one or more carboxyl groups (-COOH). 1-4 Alkyl group, i.e., carboxyl group C 1-4 Alkyl groups. Examples of carboxyl alkyl groups include, but are not limited to, carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl), etc.

[0077] The term "cycloalkyl" or "carbocyclic" refers to a monocyclic, bicyclic, or tricyclic system containing 3-14 ring carbon atoms, saturated or partially unsaturated, with one or more linkages to the remainder of the molecule, wherein the cycloalkyl group is optionally substituted with the substituents described in this invention. In some embodiments, the cycloalkyl is a cyclic system containing 3-10 ring carbon atoms, i.e., C1... 3-10 Cycloalkyl; in some embodiments, the cycloalkyl group is a cyclic system containing 3-8 ring carbon atoms, i.e., C64-C84-C6 ... 3-8Cycloalkyl; in some embodiments, the cycloalkyl group is a cyclic system containing 3-6 ring carbon atoms, i.e., C64-C ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, etc.

[0078] The term "heterocyclic group" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic system comprising 3-12 atoms, wherein at least one ring atom is selected from heteroatoms such as nitrogen, sulfur, oxygen, and phosphorus, wherein the heterocyclic group is non-aromatic and contains no aromatic rings, and this ring system has one or more connection points attached to the remainder of the molecule. The heterocyclic group may optionally be substituted by one or more substituents described in this invention. The term "heterocyclic group" includes monocyclic, bicyclic, or polycyclic fused, spirocyclic, or bridged heterocyclic ring systems. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spirobicyclic heterocyclic groups. The terms "heterocyclic group" and "heterocyclic" are used interchangeably herein. Unless otherwise stated, the heterocyclic group may be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. The phosphorus atom of the ring can optionally be oxidized to a p-oxygen compound. In some embodiments, the heterocyclic group is a ring system consisting of 3-10 atoms; in some embodiments, the heterocyclic group is a ring system consisting of 5-10 atoms; in some embodiments, the heterocyclic group is a ring system consisting of 5-8 atoms; in some embodiments, the heterocyclic group is a ring system consisting of 6-8 atoms; in some embodiments, the heterocyclic group is a ring system consisting of 5-6 atoms, i.e., a heterocyclic group consisting of 5-6 atoms; in some embodiments, the heterocyclic group is a ring system consisting of 3-6 atoms, i.e., a heterocyclic group consisting of 3-6 atoms; in some embodiments, the heterocyclic group is a system consisting of 3 ring atoms; in some embodiments, the heterocyclic group is a ring system consisting of 4 atoms; in other embodiments, the heterocyclic group is a ring system consisting of 5 atoms; in other embodiments, the heterocyclic group is a ring system consisting of 6 atoms.

[0079] Examples of heterocyclic groups include, but are not limited to: ethylene oxide, azirrobutyl, oxocyclobutyl, thiocyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, thiooxane, homopiperazine, homopiperidinyl, oxoheptanyl, thioheptanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrazine, tetrahydropyridinyl, tetrahydropyridazine, indololinyl, 1,2,3,4-tetrahydroisoquinolinyl, etc. Examples of heterocyclic groups in which the -CH2- group is substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, pyrimidinide, and 3,4-dihydroisoquinoline-1(2H)-one. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholino. Bridging heterocyclic groups include, but are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, etc.

[0080] The term "composed of m atoms," where m is an integer, typically describes the number of ring-forming atoms in a molecule, where the number of ring-forming atoms in the molecule is m. For example, piperidinyl is a heterocyclic group composed of 6 atoms, while furanyl is a heteroaryl group composed of 5 atoms. Similarly, "a heterocyclic group composed of 3-6 atoms" refers to a heterocyclic group composed of 3, 4, 5, or 6 atoms.

[0081] The term "aryl" refers to an aromatic carbocyclic system containing 6-14 ring atoms, or 6-10 ring atoms, of monocyclic, bicyclic, and tricyclic forms, wherein each ring comprises 3-7 ring atoms and has one or more attachment sites connected to the remainder of the molecule. The aryl group may optionally be substituted by one or more substituents described in this invention. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic cyclic ring," and examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, and anthracene, etc.

[0082] The term "heteroaryl" refers to an aromatic system containing 5-14 ring atoms in monocyclic, bicyclic, and tricyclic forms, wherein at least one ring contains one or more heteroatoms, the entire ring system is aromatic, and the heteroaryl group has one or more attachment sites attached to the remainder of the molecule. The heteroaryl group may optionally be substituted by one or more substituents described in this invention. Unless otherwise stated, the heteroaryl group may be attached to the remainder of the molecule (e.g., the main structure in the general formula) through any reasonable site (such as C in CH or N in NH). When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be substituted by -C(=O)-. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-7 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; and in some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0083] Examples of heteroaryl groups include, but are not limited to, the following monocyclic groups: furanyl (2-furanyl, 3-furanyl), imidazolyl (N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophene (2-thiophene, 3-thiophene), pyridazinyl... Azolium (e.g., 2-pyrazolium and 3-pyrazolium), isothiazolium, 1,2,3-oxadiazolium, 1,2,5-oxadiazolium, 1,2,4-oxadiazolium, 1,3,4-oxadiazolium, 1,2,3-thiodiazolium, 1,3,4-thiodiazolium, 1,2,5-thiodiazolium, pyrazinium, 1,3,5-triazinium; also including, but not limited to, the following bicyclic or tricyclic groups: benzimidazolium, benzofuranium, benzothiophene, indolium (e.g., 2-indolium), purine, quinolinium (e.g., 2-quinolinium, 3-quinolinium, 4-quinolinium), isoquinolinium (e.g., 1-isoquinolinium, 3-isoquinolinium or 4-isoquinolinium), dibenzimidazolium, dibenzofuranium, dibenzothiophene.

[0084] The term "cycloalkyl-alkylene" means that a cycloalkyl group is attached to the remainder of the molecule via an alkylene group, wherein cycloalkyl and alkylene have the meanings described in this invention. The cycloalkyl-alkylene may optionally be substituted by one or more substituents described in this invention. The "C" mentioned in this invention... 3-6 Cycloalkyl-C 1-4 "alkylene" indicates C 3-6 cycloalkyl groups via C 1-4 The alkylene group is attached to the rest of the molecule. The "C" described in this invention... 3-6 Cycloalkyl-C 1-2 "alkylene" indicates C 3-6 cycloalkyl groups via C 1-2 The alkylene group is attached to the rest of the molecule. Examples of such groups include, but are not limited to, cyclopropyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl-CH2-, cyclobutyl-CH2CH2-, cyclopentyl-CH2-, cyclopentyl-CH2CH2-, cyclohexyl-CH2-, cyclohexyl-CH2CH2-, etc.

[0085] The term "heterocyclic-alkylene" indicates that a heterocyclic group is attached to the remainder of the molecule via an alkylene group, wherein the heterocyclic group and alkylene group have the meanings described herein. The heterocyclic-alkylene group may optionally be substituted with one or more substituents described herein. The "(5-6 atom heterocyclic group)-C" described herein... 1-4 "alkylene" indicates a heterocyclic group consisting of 5-6 atoms connected via C 1-4 The alkylene group is attached to the rest of the molecule. The "(heterocyclic group consisting of 5-6 atoms)-C" described in this invention... 1-2 "alkylene" indicates a heterocyclic group consisting of 5-6 atoms connected via C 1-2 The alkylene group is attached to the rest of the molecule. Examples of such groups include, but are not limited to, tetrahydropyranyl-CH2-, tetrahydropyranyl-CH2CH2-, tetrahydrofuranyl-CH2-, tetrahydrofuranyl-CH2CH2-, pyrrolidinyl-CH2-, piperidinyl-CH2-, piperidinyl-CH2CH2-, morpholinyl-CH2-, morpholinyl-CH2CH2-, etc.

[0086] The term "aryl-alkylene" indicates that an aryl group is attached to the remainder of the molecule via an alkylene group, wherein the aryl and alkylene groups have the meanings described herein. The aryl-alkylene group may optionally be substituted with one or more substituents described herein. For example, the "C" group described herein... 6-10 Aryl-C 1-4 "alkylene" indicates C 6-10 Aryl via C 1-4 The alkylene group is attached to the rest of the molecule. The "C" described in this invention... 6-10 Aryl-C 1-2 "alkylene" indicates C 6-10 Aryl via C 1-2 The alkylene group is attached to the rest of the molecule. Examples of such groups include, but are not limited to, phenyl-CH2-, phenyl-CH2CH2-, naphthyl-CH2-, etc.

[0087] The term "heteroaryl-alkylene" indicates that a heteroaryl group is attached to the remainder of the molecule via an alkylene group, wherein the heteroaryl and alkylene groups have the meanings described in this invention. The heteroaryl-alkylene group may optionally be substituted by one or more substituents described in this invention. The "(5-6 atoms of heteroaryl)-C" described in this invention... 1-4 "alkylene" refers to a heteroaryl group consisting of 5-6 atoms connected via C 1-4 The alkylene group is attached to the rest of the molecule. The "(5-6 atoms of heteroaryl)-C" described in this invention... 1-2 "alkylene" refers to a heteroaryl group consisting of 5-6 atoms connected via C 1-2The alkylene group is attached to the rest of the molecule. Examples of such groups include, but are not limited to, pyridyl-CH2-, pyrrolo-CH2CH2-, quinolinyl-CH2-, thiophenyl-CH2-, furanyl-CH2-, pyrimidinyl-CH2-, pyridyl-CH2-, etc.

[0088] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of S, N, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NR. T (like NR in N-substituted pyrroleyl groups) T , R T (Substituents on N).

[0089] The term "carbonyl", whether used alone or in conjunction with other terms such as "aminocarbonyl" or "acyloxy", signifies -(C=O)-.

[0090] The term "deuterium" refers to deuteration, that is... 2 H.

[0091] The term "pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated. Preferably, "pharmaceutical acceptable" as used herein means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, particularly in humans.

[0092] The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, all of which are known to those skilled in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.

[0093] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutical acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutical acceptable carriers, excipients, diluents, binders, fillers, and other excipients, as well as adjunctive 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 the administration of the compound to a living organism.

[0094] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent hydroxyl group. A complete discussion of prodrugs can be found in the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium 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.

[0095] The term "metabolite" refers to the product obtained in vivo through the metabolism of a specific compound or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0096] The term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well known in the field, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19.

[0097] The term "solvent" refers to an association formed by one or more solvent molecules with the compounds 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 formed by solvent molecules that are water.

[0098] The term "nitrogen oxide" refers to the oxidation of one or more nitrogen atoms to form N-oxides when a compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th ed., Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0099] Any asymmetric atom (e.g., carbon, etc.) in the compounds of the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R,S)- configuration. In some embodiments, each asymmetric atom has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% enantiomeric excess in the (R)- or (S)- configuration. If possible, substituents on atoms having unsaturated double bonds may be present in cis-(Z)- or trans-(E)- form.

[0100] Therefore, as described in this invention, the compounds of this invention can exist in the form of one of the possible isomers, rotational isomers, tautomers, tautomers, or mixtures thereof, for example, in the form of essentially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0101] Any mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, and racemates based on the physicochemical differences of the components, for example by chromatography and / or stepwise crystallization.

[0102] Racemates of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating their diastereomeric salts. Racemate products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ndEd. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry 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)).

[0103] This invention also includes isotopically labeled compounds of the invention that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those of naturally occurring common atoms. Exemplary isotopes that may also be introduced into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0104] Compounds of the present invention comprising other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this invention. Isotope-labeled compounds of the present invention, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this invention can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds, i.e., 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. Additionally, isotopes with higher mass numbers, such as deuterium, are used. 2 H substitution can offer therapeutic advantages such as greater metabolic stability, including increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some situations.

[0105] The stereochemical definitions and conventions used in this invention are generally in accordance with those described 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 this invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof such as racemic mixtures, are also included within the scope of this invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes d and l, or (+) and (–), are symbols used to specify the plane-polarized rotation of light caused by a compound, where (–) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are generally called mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method.

[0106] Depending on the choice of raw materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, for example, as pure optical isomers, or as mixtures of isomers, such as as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may be cis or trans (cis- or trans-) configuration.

[0107] Unless otherwise stated, the structures described in this invention also represent all isomers (e.g., enantiomers, diastereomers, atropisomers, and geometric (or conformations)) including this structure; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of this invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformations) are all within the scope of this invention.

[0108] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0109] The term "geometric isomers," also known as "cis-trans isomers," refers to isomers that cannot rotate freely due to the double bond (including the double bond, C=N double bond, and N=N double bond in alkenes) or the single bond of a cyclic carbon atom.

[0110] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also refer to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0111] The terms "recipient" and "patient" as used in this invention are used interchangeably. The terms "recipient" and "patient" refer to animals (e.g., birds such as chickens, quails, or turkeys) or mammals, particularly "mammals" including non-primates (e.g., cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more specifically, humans. In one embodiment, the recipient is a non-human animal, such as livestock (e.g., horses, cattle, pigs, or sheep) or a pet (e.g., dogs, cats, guinea pigs, or rabbits). In other embodiments, "patient" refers to a human.

[0112] In addition, unless otherwise indicated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0113] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0114] Description of the compounds of the present invention

[0115] This invention provides a class of compounds with good agonistic activity against thyroid hormone β-receptors, for use in the preparation of medicaments for treating 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, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism, or thyroid cancer. This invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods for preparing medicaments for treating the aforementioned diseases in mammals, particularly humans, using these compounds and pharmaceutical compositions. Compared with existing similar compounds, the compounds of this invention not only possess good pharmacological activity and selectivity but also excellent in vivo metabolic kinetic and pharmacodynamic properties. The preparation methods of the compounds described in this invention are simple and easy to implement, with stable processes suitable for industrial production. Therefore, the compounds provided by this invention have superior drug-like properties compared to existing similar compounds.

[0116] Specifically:

[0117] On one hand, the present invention relates to a compound, which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0118]

[0119] Among them, rings A, Y, and R 1 R 2 R 3a R 3b R 3c and R 3d It has the definition as described in this invention.

[0120] In some implementations, Y is -O-, -S-, or -NR. 0 -、-C(=O)-、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -NR 0 C(=O)-or-C(=O)NR 0 -; wherein Y can optionally be divided by 1, 2 or 3 R x Replaced; wherein, the R 0 and R x It has the definition as described in this invention.

[0121] In some embodiments, R 0 H, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl or cyano C 1-6 alkyl.

[0122] In some embodiments, R 0 H, deuterium, methyl, ethyl, n-propyl, isopropyl, C 1-4 Halogenated alkyl, hydroxymethyl, hydroxyethyl, aminomethyl or cyanomethyl.

[0123] In some embodiments, R 3a R 3b R 3c and R 3d Each of the following can be independently represented as H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl or cyano C 1-6 alkyl.

[0124] In some embodiments, R 1 For H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, -C(=O)-C 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkylamino, -C(=O)NH2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylamino, -S(=O)2NH2, C 1-6 Alkylamino, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or cyano C 1-6 alkyl.

[0125] In some embodiments, R 2 H, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0126] In some embodiments, R 2 H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 5-6 atoms, phenyl, or heteroaryl group consisting of 5-6 atoms.

[0127] In some implementations, ring A is In the middle, ring A can be optionally divided by 1, 2 or 3 R. y Replaced by; E1, E2, E3, E4, E5, E6, U1, U2, U3, Z1, Z2, Z3, R 5 and R y It has the definition described in this invention.

[0128] In some implementations, E1, U1, and Z1 are each independently -(CR 4a R 4b ) q -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR a -, the R 4a R 4b R a And q have the definitions described in this invention.

[0129] In some implementations, E2, U2, and Z2 are each independently -CR 4c R 4d -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR b -, the R 4c R 4d and R b It has the definition described in this invention.

[0130] In some implementations, E3, E6, U3, and Z3 are each independently -CR 4e R 4f -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2- or -NR c -, the R 4e R 4f and R c It has the definition described in this invention.

[0131] In some implementations, E4 is -CR 4g = or -N=; where R 4g It has the definition described in this invention.

[0132] In some implementations, E5 is -CR 4h = or -N=; where R 4h It has the definition described in this invention.

[0133] In some implementations, q is 0, 1, 2, or 3.

[0134] In some embodiments, R a R b R c and R 5 Each is independently H, deuterium, and C. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 aryl or heteroaryl groups consisting of 5-6 atoms, wherein R a R b R c and R 5 Can be independently and optionally controlled by 1, 2 or 3 R y1 The R that was replaced y1 It has the definition as described in this invention.

[0135] In some embodiments, R 4a R 4b R 4c R 4d R 4e R 4f R 4g and R 4h Each of the following can be independently represented as H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 5-6 atoms, (heterocyclic group consisting of 5-6 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl group consisting of 5-6 atoms, or (heteroaryl group consisting of 5-6 atoms)-C 1-4 alkylene, wherein R 4a R 4b R 4c R 4d R 4e R 4f R 4g and R 4h Optionally not replaced or replaced by 1, 2 or 3 Rs y2 The R that was replaced y2 It has the definition as described in this invention.

[0136] In some embodiments, R 4a R 4b Together with the carbon atoms attached to them, they form C 3-8 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C3-8 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y3 The R that was replaced y3 It has the definition described in this invention.

[0137] In some embodiments, R 4c R 4d Together with the carbon atoms attached to them, they form C 3-8 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-8 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y3 The R that was replaced y3 It has the definition described in this invention.

[0138] In some embodiments, R 4e R 4f Together with the carbon atoms attached to them, they form C 3-8 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-8 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y3 The R that was replaced y3 It has the definition described in this invention.

[0139] In some implementations, two R atoms linked on adjacent atoms y Together with the atoms bonded to them, they form C 3-8 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-8 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y4 The R that was replaced y4 It has the definition described in this invention.

[0140] In some embodiments, each R x Independently, it can be deuterium, F, Cl, Br, I, -CN, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy or C 1-6 Alkylamino.

[0141] In some embodiments, each R x It can be 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.

[0142] In some embodiments, each R y Independently, it can be deuterium, F, Cl, Br, I, -CN, -OH, -NH2, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy or C 1-6 Alkylamino.

[0143] In some embodiments, each R y It can be 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.

[0144] In some embodiments, each R y1 Independently, it can be deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkylamino, -C(=O)NH2, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkylamino, -S(=O)2NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 aryl or heteroaryl groups consisting of 5-6 atoms, wherein each R y1 Can be independently and optionally controlled by 1, 2 or 3 R z The R that was replaced z It has the definition described in this invention.

[0145] In some embodiments, R z R y2 R y3 and R y4 Each of the following can be independently represented as deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Halogenated alkoxy, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamino.

[0146] In some embodiments, R 3a R 3b R 3c and R 3d Each of these can be independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl, or cyanomethyl.

[0147] In some embodiments, R 1 The following are the possible values ​​for H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, -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, and -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, ethylamino, methoxy, ethoxy, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.

[0148] In some embodiments, R a R b R c and R 5 Each is independently H, deuterium, and C. 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 aryl or heteroaryl groups consisting of 5-6 atoms, wherein R aR b R c and R 5 Can be independently and optionally controlled by 1, 2 or 3 R y1 The R that was replaced y1 It has the definition described in this invention.

[0149] In some embodiments, R a R b R c and R 5 Each of the following is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, thiophenyl, imidazolyl, pyrimidinyl, pyridinyl, pyrroloyl, pyrazinyl, thiazolyl, or oxazolyl, wherein R a R b R c and R 5 Can be independently and optionally controlled by 1, 2 or 3 R y1 The R that was replaced y1 It has the definition described in this invention.

[0150] In some embodiments, each R y1 Independently, it can be deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -OC(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkoxy group, -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkylamino, -C(=O)NH2, -S(=O)2-C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkylamino, -S(=O)2NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C 6-10 aryl or heteroaryl groups consisting of 5-6 atoms, wherein R y1 Can be optionally bounded by 1, 2 or 3 R z The R that was replacedz It has the definition described in this invention.

[0151] In some embodiments, each R y1 Independently, it can be 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, -C(=O)O-n-butyl, -C(=O)O-tert-butyl, -C(=O)O-isobutyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-isopropyl, -C(=O)-n-butyl, -C(=O)-tert-butyl, -C(=O)-isobutyl, -C(=O)-methylamino, -C(=O)-ethylamino, -C(=O)NH2, -S(=O)2-C 1-3 Alkyl group, -S(=O)2-C 1-3 Alkylamino, -S(=O)2NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCHFCH3, methoxy, ethoxy, n-propyloxy, isopropyloxy, methylthio, ethylthio, methylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolylalkyl, pyrazolylalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, thiophenyl, imidazolyl, pyrimidinyl, pyridinyl, pyrroloyl, pyrazinyl, thiazolyl, or oxazolyl, wherein R y1 Optionally not replaced or replaced by 1, 2 or 3 Rs z The R that was replaced z It has the definition described in this invention.

[0152] In some embodiments, R 4a R 4b R 4c R 4d R 4e R 4f R 4g and R 4hEach of these can be independently represented as H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C≡CH, oxy, ethoxy, methylamino, ethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, pyrrolidinyl, pyrazole Alkyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, pyrrolyl-CH2-, pyrazolyl-CH2-, tetrahydrofuranyl-CH2-, tetrahydrothiophenyl-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, thiomorpholinyl-CH2-, piperazine-CH2-, phenyl, phenyl-CH2-, phenyl-CH2CH2-, furanyl, thiophenyl, imidazolyl, pyrimidinyl, pyridinyl, pyrroloyl, pyridazinyl, pyrazine, thiazolyl, oxazolyl, furanyl-CH2-, thiophenyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, pyridinyl-CH2-, or pyrroloyl-CH2-, wherein R 4a R 4b R 4c R 4d R 4e R 4f R 4g and R 4h Can be independently and optionally controlled by 1, 2 or 3 R y2 The R that was replaced y2 It has the definition described in this invention.

[0153] In some embodiments, R 4a R 4b Together with the carbon atoms attached to them, they form C 3-6 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-6 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y3 The R that was replaced y3 It has the definition described in this invention.

[0154] In some embodiments, R 4c R 4d Together with the carbon atoms attached to them, they form C 3-6 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-6 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms.y3 The R that was replaced y3 It has the definition described in this invention.

[0155] In some embodiments, R 4e R 4f Together with the carbon atoms attached to them, they form C 3-6 A carbon ring or a heterocycle consisting of 5-6 atoms, wherein the C 3-6 The carbon ring and the heterocycle consisting of 5-6 atoms are each independently unsubstituted or replaced by 1, 2 or 3 R atoms. y3 The R that was replaced y3 It has the definition described in this invention.

[0156] In some embodiments, R z R y2 R y3 and R y4 Each can be independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -COOH, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, methoxy, ethoxy, or methylamino.

[0157] On the other hand, the present invention relates to structures, or stereoisomers, geometric isomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, of any of the following:

[0158]

[0159]

[0160]

[0161]

[0162]

[0163] On the other hand, the present invention relates to a pharmaceutical composition comprising the compounds described herein.

[0164] In some embodiments, the pharmaceutical composition of the present invention optionally further comprises any one or any combination thereof of a pharmaceutically acceptable carrier, excipient, adjuvant, or mediator.

[0165] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to stimulate thyroid hormone receptors; or to prevent, treat or alleviate diseases regulated by thyroid hormone receptors.

[0166] On the other hand, the present invention relates to a method for stimulating thyroid hormone receptors using the compounds or pharmaceutical compositions described herein, or a method for preventing, treating, or alleviating diseases regulated by thyroid hormone receptors, wherein the method administers an effective therapeutic amount of the compound or pharmaceutical composition to an individual in need. Furthermore, the compounds or pharmaceutical compositions provided by the present invention can be administered in combination with other therapies or therapeutic agents. Administration can be simultaneous, sequential, or at time intervals.

[0167] On the other hand, the present invention relates to using the compounds or pharmaceutical compositions described herein to stimulate thyroid hormone receptors, or to prevent, treat or alleviate diseases regulated by thyroid hormone receptors.

[0168] In some embodiments, the thyroid hormone receptor described in this invention is a thyroid hormone β receptor.

[0169] In some embodiments, the diseases regulated by thyroid hormone receptors described in this invention are neurodegenerative diseases, non-alcoholic fatty liver disease, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism, or thyroid cancer.

[0170] On one hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate the following diseases: 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, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer.

[0171] On one hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein for the prevention, treatment or relief of the following diseases: 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, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer.

[0172] On one hand, the present invention relates to a method for preventing, treating, or alleviating diseases using the compounds or pharmaceutical compositions described herein: 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, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism, or thyroid cancer, wherein the method is to administer an effective therapeutic amount of the compound or pharmaceutical composition to an individual in need.

[0173] In some embodiments, the non-alcoholic fatty liver disease described in this invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis, or primary liver cancer.

[0174] In some embodiments, the neurodegenerative diseases described in this invention are demyelinating diseases, chronic demyelinating diseases, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenocortical dystrophy (ALD), amyotrophic lateral sclerosis (ALS), or Alzheimer's disease.

[0175] The dosage of the compound or pharmaceutical composition required to achieve therapeutic, preventive, or delaying effects typically depends on the specific compound being administered, the patient, the specific disease or condition and its severity, the route of administration, and the frequency, and needs to be determined by the attending physician based on the specific circumstances. For example, when administering the compound or pharmaceutical composition provided by this invention via intravenous route, it can be administered once a week or even at longer intervals.

[0176] In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals treated with it.

[0177] The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for the preparation and / or purification of the compounds of the present invention and / or for the isolation of enantiomers of the compounds of the present invention.

[0178] Furthermore, the compounds of the present invention, including their salts, can also be obtained in their hydrate form, or include other solvents used for their crystallization. The compounds of the present invention can be inherently or by design formed into solvates having pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.

[0179] Pharmaceutical compositions, formulations, and administration of the compounds of the present invention

[0180] This invention relates to a pharmaceutical composition comprising the compound described in this invention or a compound with the structure shown in the examples, or a stereoisomer, geometric isomer, tautomer, nitride, solvate, metabolite, and pharmaceutically acceptable salt or prodrug thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, mediator, or combination thereof, and optionally, other therapeutic and / or preventative components. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound described in this invention and at least one pharmaceutically acceptable carrier, excipient, adjuvant, or mediator. The amount of the compound in the pharmaceutical composition of this invention can effectively and detectably stimulate thyroid hormone β receptors in biological specimens or patients.

[0181] Pharmaceutically acceptable carriers may contain inert components that do not excessively inhibit the biological activity of the compound. Pharmaceutically acceptable carriers should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or have no other adverse reactions or side effects once administered to a patient. Standard pharmaceutical techniques can be used.

[0182] As described in this invention, the pharmaceutical compositions or pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, excipients, or mediators, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, or lubricant, etc., suitable for the specific 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 various carriers used in formulating pharmaceutically acceptable compositions and their known preparation methods. Any other conventional carrier media and their uses are also within the scope of this invention, except for those conventional carrier media incompatible with the compounds of this invention, such as those that would produce adverse biological effects or interact harmfully with any other component in the pharmaceutically acceptable composition.

[0183] Examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., Tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), mixtures of metaglycerides 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 copolymers, methylcellulose, hydroxypropyl methylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose). Ethyl cellulose and cellulose acetate), powdered tragacanth gum, malt, gel, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), ethylene glycol (e.g., propylene glycol or polyethylene glycol), esters (e.g., ethyl oleate and ethyl dodecyl oleate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffers, and other non-toxic and compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as colorants, anti-sticking agents, coating agents, sweeteners and flavorings, preservatives, and antioxidants as determined by the formulator, may also be present in the composition.

[0184] The pharmaceutical compositions of the present invention can be administered directly or in the form of a pharmaceutical composition or drug, as is well known in the art. The treatment methods of the present invention may comprise administration of an effective compound of the present invention to an individual in need. In some embodiments, the individual is a mammalian individual, and in other embodiments, the individual is a human individual.

[0185] The effective amount of the compounds, pharmaceutical compositions, or drugs described in this invention can be easily determined by conventional methods, and the most effective and convenient route of administration and the most suitable formulation can also be determined by conventional methods.

[0186] The compounds or compositions of the present invention can be administered by any suitable means, and can be given to humans or other animals orally, rectally, parenterally, intracerebrospinal, vaginally, intraperitoneally, topically (such as by powder, ointment or drops), or nasal spray, depending on the severity of the disease.

[0187] 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), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and aroma enhancers.

[0188] Injectable formulations can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oil suspensions. Sterile injectable formulations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable media and solvents, water, Ringer's solution, and isotonic sodium chloride solution are acceptable. Additionally, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any odorless non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids, such as octadecenoic acid, are used in the preparation of injectable formulations.

[0189] For example, injectable formulations can be sterilized by filtering with a bacterial retention filter or by adding a sterilizing agent, which is soluble or dispersed in sterile water or other sterile injectable media in the form of a sterile solid composition, before use.

[0190] To prolong the effect of the compounds or compositions described in this invention, it is often desirable to slow the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystals or amorphous substances. The absorption rate of the compound then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered compounds can be achieved by dissolving or suspending the compound in an oil medium. Injectable storage forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable storage formulations can also be prepared by retaining the compound in liposomes or microemulsions that are compatible with body tissues.

[0191] Compositions administered rectally or vaginally, particularly suppositories prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at ambient temperature but liquid at body temperature, and thus melt and release the active compound within the rectal or vaginal cavity.

[0192] 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 swelling agents, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gel, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glyceryl monostearate; 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. In the case of dosage forms such as capsules, tablets, and pills, the dosage form may also contain buffers.

[0193] Excipients such as lactose or toffee and high-molecular-weight polyethylene glycol can also be used as fillers in soft and hard gel capsules for similar types of solid compositions. Coatings and shells, such as enteric coatings and other coatings well-known in the pharmaceutical industry, can be used to prepare solid dosage forms of tablets, lozenges, capsules, pills, and granules. These may optionally contain emulsifiers and may also have properties such that they optionally release the active ingredient only in a delayed manner, or preferably, in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0194] The active compound may also be in a microencapsulated form having one or more of the excipients described above. 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 also contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. They may optionally contain emulsifiers and may also have compositional properties such that they optionally release only the active ingredient in a delayed manner, or preferably, release it in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0195] Topical or transdermal dosage forms of the compounds described in this invention include ointments, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any desired preservatives or, if necessary, buffers. Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of this invention. Additionally, this invention is contemplated for the use of skin patches with the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow rate of the compound through the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0196] The compositions of this invention can also be administered orally, parenterically, via inhalation spray, topically, rectally, nasally, or vaginally, or via implanted cartridges. As used herein, the term "parenterectomy" includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In particular, the compositions can be administered orally, intraperitoneally, or intravenously.

[0197] The sterile injectable form of the compositions of this invention may be an aqueous or oil suspension. These suspensions may be prepared using suitable dispersants or wetting agents and suspending agents, following techniques known in the art. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among acceptable media and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. Additionally, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any odorless non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, as with pharmaceutically acceptable natural oils, particularly in polyoxyethylene form, such as olive oil or castor oil, fatty acids such as octadecenoic acid and its glyceride derivatives are used in the preparation of injectable formulations. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0198] The pharmaceutical compositions of the present invention can be taken orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral administration, common carriers include, but are not limited to, lactose and starch. Lubricants, such as magnesium stearate, are also typically 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 a suspending agent. If desired, certain sweeteners, flavor enhancers, or colorants may also be added.

[0199] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing reagents and non-irritating excipients, including but not limited to cocoa butter, beeswax, and polyethylene glycol.

[0200] The pharmaceutical compositions described herein can be applied topically, especially when the treatment target includes locally applied drops to easily accessible areas or organs, including diseases of the eyes, skin, or lower intestine. Suitable topical formulations can be easily prepared for each of these areas or organs.

[0201] Local application to the lower intestine can be achieved using rectal suppositories (see above) or suitable enema formulations. Topical skin patches may also be used.

[0202] For topical application, the pharmaceutical composition can be formulated as a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers suitable for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing an 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 ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0203] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or particularly as a solution in isotonic pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

[0204] The pharmaceutical composition can also be administered via nasal aerosol spray or inhalation. This composition is prepared according to techniques well-known in the pharmaceutical industry and is formulated as a solution in saline using benzyl alcohol and other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0205] Uses of the compounds and pharmaceutical compositions of the present invention

[0206] The compounds or pharmaceutical compositions provided by this invention can be used to prepare drugs for stimulating thyroid hormone receptors, or for preparing drugs for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

[0207] The compounds or pharmaceutical compositions provided by this invention can be used to stimulate thyroid hormone receptors, or to prevent, treat or alleviate diseases regulated by thyroid hormone receptors.

[0208] This invention provides a method for stimulating thyroid hormone receptors, or a method for preventing, treating, or alleviating diseases regulated by thyroid hormone receptors, said method comprising administering a therapeutically effective amount of the aforementioned compound or a pharmaceutical composition thereof to a patient in need of treatment. Furthermore, the aforementioned compound or pharmaceutical composition thereof provided by this invention can be administered in combination with other therapies or therapeutic agents. Administration can be simultaneous, sequential, or at certain time intervals.

[0209] The thyroid hormone receptor described in this invention is the thyroid hormone β receptor.

[0210] The diseases described in this invention are non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism, or thyroid cancer. The non-alcoholic fatty liver disease described here includes non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis, or primary liver cancer.

[0211] The compounds or pharmaceutical compositions described in this invention can be used to treat fibrotic diseases, including but not limited to liver fibrosis and idiopathic pulmonary fibrosis.

[0212] In addition to their therapeutic benefits for humans, the compounds of this invention can also be used in veterinary treatment of pets, introduced breeds of animals, and farm animals, including mammals, rodents, etc. Other examples of animals include horses, dogs, and cats. Herein, the compounds of this invention include their pharmaceutically acceptable derivatives.

[0213] The term "effective amount," "effective therapeutic amount," or "effective dose" for the compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly wide dose range. For example, the daily dose is approximately in the range of 0.1 mg to 1000 mg per person, divided into one or more administrations. The methods, compounds, and pharmaceutical compositions according to the present invention can be used at any dosage and via any route of administration to effectively treat or reduce the severity of a disease. The exact amount required will vary depending on the patient's condition, which may depend on age, the patient's general condition, the severity of the infection, specific factors, the route of administration, etc. The compounds or pharmaceutical compositions of the present invention can be administered in combination with one or more other therapeutic agents, as discussed in this invention.

[0214] General synthesis and detection methods

[0215] Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0216] In this specification, if there are any differences between chemical names and chemical structures, the structure is preferred.

[0217] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0218] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known pharmaceutical agents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0219] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 H-NMR, 13 C-NMR or / and 19 It was determined by F-NMR. 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1H-NMR, 13 C-NMR, 19 F-NMR measurements were performed using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer. The solvents used were deuterated chloroform (CDCl3), deuterated methanol (CD3OD or MeOH-d4), or deuterated dimethyl sulfoxide (DMSO-d6). TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiple peaks are observed, the following abbreviations are used: s (single peak), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), brs (broadened singlet). The coupling constant J is expressed in Hertz (Hz).

[0220] Preparation, purification, or separation is generally performed using a Novasep Pump 250 high-performance liquid chromatograph.

[0221] The LC-MS determination was performed using an Agilen-6120 Quadrupole LC / MS mass spectrometer.

[0222] Column chromatography typically uses 300-400 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0223] The starting materials of this invention are known and commercially available, purchased from companies such as Shanghai Accela Company, Energy Company, J&K, and Alfa Company, or can be synthesized using methods known in the art.

[0224] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere;

[0225] Nitrogen atmosphere refers to a reaction vessel connected to a nitrogen balloon or steel vessel with a volume of approximately 1L.

[0226] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L or a stainless steel high-pressure reactor with a volume of approximately 1L.

[0227] Unless otherwise specified in the examples, "solution" refers to an aqueous solution;

[0228] Unless otherwise specified in the examples, the reaction temperature is room temperature;

[0229] Unless otherwise specified in the examples, the room temperature is 20℃~40℃.

[0230] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions were: dichloromethane and methanol, dichloromethane and ethyl acetate, and petroleum ether and ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0231] The eluent systems for column chromatography include: A: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, and C: dichloromethane and methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding small amounts of ammonia or acetic acid.

[0232] HPLC refers to high-performance liquid chromatography;

[0233] The HPLC determination was performed using an Agilent 1260 high-performance liquid chromatograph (column: Agilent ZORBAX EclipsePlus C18 4.6mm×150mm, 3.5μm);

[0234] HPLC test conditions: Run time: 25 min; Column temperature: 35℃; Detection wavelength: 210 nm; 245 nm.

[0235] Mobile phase: Phase A: 0.05% phosphoric acid solution; Phase B: acetonitrile; Flow rate: 1.0 ml / min;

[0236] The mobile phase gradient is shown in Table A:

[0237] Table A

[0238]

[0239]

[0240] The LC / MS / MS system used in the biological assays included an Agilent 1200 series vacuum degassing furnace, a binary syringe pump, an automated well plate sampler, a column oven, 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 shown in Table B.

[0241] Table B

[0242] Full scan 50～1400 Fragmentation voltage 230V Capillary voltage 55V Dryer temperature 350℃ atomizer 0.28MPa Dryer flow rate 10L / min

[0243] The analysis was performed using an Agilent XDB-C18 column, 2.1 × 30 mm, 3.5 μm, with 5 μL of sample injected. Analytical conditions: the mobile phase consisted of 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate was 0.4 mL / min. The mobile phase gradient is shown in Table C.

[0244] Table C

[0245] time gradient of mobile phase B 0.5min 5％ 1.0min 95％ 2.2min 95％ 2.3min 5％ 5.0min termination

[0246] The test conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1×30mm, 3.5μm, 6min, flow rate: 0.6mL / min, mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), detection at 210nm / 254nm using UV, and electrospray ionization mode (ESI).

[0247] The following abbreviations are used throughout this invention:

[0248] DMSO-d6: Deuterated dimethyl sulfoxide; DMSO: Dimethyl sulfoxide;

[0249] TFA: Trifluoroacetic acid; mL, ml: milliliters;

[0250] μL, μl: microliters; mol / L, mol / l: moles per liter;

[0251] mol: mole; mmol / L, mmol / L, mM: millimoles per liter;

[0252] μmol / L, μmol / L, μM: micromoles per liter; nmol / L, nmol / L, nM: nanomoles per liter;

[0253] g: gram; h: hour;

[0254] mg: milligram; μg: microgram;

[0255] ng: nanograms; %wt,mass%: weight percentage;

[0256] μm: micrometer; MPa: megapascal;

[0257] min: minutes; ACN: acetonitrile;

[0258] Me: Methyl; Et: Ethyl;

[0259] General synthesis methods

[0260] The typical synthetic steps for preparing the compounds disclosed in this invention are shown in the following synthetic scheme. Unless otherwise stated, rings A, R... 1 R 3a R 3b R 3c and R 3d As defined in this invention, X is a halogen.

[0261] Synthesis Scheme 1:

[0262]

[0263] Compounds having the structure shown in general formula (IA) can be prepared by the general synthetic method described in Synthetic Scheme 1, with specific steps as shown in the examples. First, compound (Ia) reacts with compound (Ib) in the presence of a base (such as potassium carbonate) to give compound (Ic); compound (Ic) is reduced by a nitro group to give compound (Id); compound (Id) is diazotized with an amino group and reacted with compound (Ie) to give compound (If); compound (If) is cyclized in the presence of a base (such as sodium acetate) to give the target compound shown in general formula (IA).

[0264] Synthesis Scheme 2:

[0265]

[0266] Compounds having the structure shown in general formula (IB) can be prepared by the general synthetic method described in synthetic scheme 2, with specific steps as shown in the examples. First, compound (II-a) is hydrolyzed under acidic conditions (e.g., concentrated hydrochloric acid) to give compound (II-b); compound (II-b) is decarboxylated to give the target compound shown in general formula (IB).

[0267] Preparation Examples

[0268] Example 1 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0269]

[0270] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b

[0271] 6-Hydroxy-3,4-dihydroisoquinoline-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), and potassium carbonate (2.14 g, 15.3 mmol) was added. The mixture was reacted at 120 °C for 16 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filter cake was collected. The mixture was recrystallized from 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).

[0272] MS(ESI,pos.ion)m / z:353.1[M+H] + .

[0273] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1c

[0274] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.4 g, 4.0 mmol) was dissolved in acetic acid (8 mL), and iron powder (0.22 g, 3.9 mmol) was added. The mixture was reacted at 70 °C for 2 hours. The reaction solution 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, washed with water (10 mL), and the filter cake was collected and dried to give a yellow solid 1c (1.0 g, 78% yield).

[0275] MS(ESI,pos.ion)m / z:323.2[M+H] + .

[0276] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetraisoquinoline-6-yl)oxy ethyl carbamate (1d)

[0277] 6-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1c (0.20 g, 0.62 mmol) and N-cyanoaceturane (0.11 g, 0.69 mmol) were dissolved in acetic acid (4 mL). A solution of sodium nitrite (65 mg, 0.93 mmol) in water (2 mL) was added at 0 °C, and the reaction was allowed to proceed for 4.5 hours. At 0 °C, water (10 mL) was added to the reaction solution, 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).

[0278] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)- 3,5-Dioxo-2,3,4,5-Tetrahydro-1,2,4-Triazine-6-formonitrile

[0279] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetraisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 5 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. A solid precipitated out. After stirring for 10 minutes, the mixture was filtered, washed with water (5 mL), and the filter cake was collected and dried. The resulting reddish-brown solid was recrystallized (acetonitrile / ethanol / N,N-dimethylformamide / water = 10 / 5 / 2 / 20, 37 mL), filtered, washed with water (2 mL), and the filter cake was collected and dried to obtain orange solid 1 (0.13 g, yield 48%, purity 91.86%).

[0280] MS(ESI,neg.ion)m / z:442.0[MH] - .

[0281] 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).

[0282] Example 2 2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0283]

[0284] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one 2a

[0285] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.0 g, 2.8 mmol) was dissolved in tetrahydrofuran (15 mL), and sodium hydride (0.23 g, 5.8 mmol, 60% in oil) and methyl iodoform (0.26 mL, 4.2 mmol) were added. The reaction was allowed to proceed at room temperature for 2.5 hours. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, 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).

[0286] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one 2b

[0287] 6-(2,6-dichloro-4-nitrophenoxy)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one 2a (1.0 g, 2.7 mmol) was dissolved in acetic acid (8 mL), and iron powder (0.30 g, 5.4 mmol) was added. The reaction mixture was reacted at 70 °C. After cooling the reaction solution to room temperature and removing the iron powder, water (30 mL) was added and stirred for 10 minutes. The mixture was filtered, washed with water (10 mL), and the filter cake was collected and dried. 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, yield 44%).

[0288] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline)) 2c (Phyllium-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0289] 6-(4-amino-2,6-dichlorophenoxy)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one 2b (0.40 g, 1.2 mmol) and N-cyanoaceturane (0.21 g, 1.3 mmol) were dissolved in acetic acid (8 mL). A solution of sodium nitrite (0.17 g, 2.4 mmol) in water (4 mL) was added at 0 °C, and the reaction was allowed to proceed for 4 hours. At 0 °C, water (10 mL) was added to the reaction solution, 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 a red solid 2c (0.62 g, 99% yield).

[0290] Step 4: 2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)benzene 2-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formonitrile

[0291] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 solution 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, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3). The solid was recrystallized (acetonitrile / ethyl acetate / ethanol / petroleum ether = 3 / 10 / 15 / 30, 58 mL) to give a light red solid 2 (0.21 g, yield 38%, purity: 97.61%).

[0292] MS(ESI,neg.ion)m / z:456.0[MH] - ;

[0293] 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).

[0294] Example 3 2-(3,5-dichloro-4-((2-(methoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0295]

[0296] 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 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 mixture was sealed in a tube at 100 °C and reacted for 16 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). The solid was recrystallized (methanol / ethyl acetate / petroleum ether = 1 / 6 / 12, 9.5 mL) to give a white solid 3 (50 mg, yield 45%, HPLC purity: 97.51%).

[0297] MS(ESI,neg.ion)m / z:486.0[MH] - ;

[0298] 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).

[0299] Example 4 2-(3,5-dichloro-4-((2-(ethoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0300]

[0301] 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 1 (0.40 g, 0.90 mmol) was dissolved in ethanol (10 mL), and 37% formaldehyde (2.0 mL, 27 mmol) was added. The reaction mixture was sealed at 100 °C for 48 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). The solid was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 5 / 3, 18 mL) to give a white solid 4 (0.28 g, yield 62%, HPLC purity: 96.19%). MS (ESI, neg.ion) m / z: 500.0 [MH] - ;

[0302] 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).

[0303] Example 5 2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0304]

[0305] Step 1: Synthesis of 2-ethyl-6-methoxy-3,4-dihydroisoquinoline-1(2H)-one 5b

[0306] 6-Methoxy-3,4-dihydroisoquinoline-1(2H)-one 5a (2.05 g, 11.6 mmol) was dissolved in a mixed solution of tetrahydrofuran (40 mL) and N,N-dimethylacetamide (15 mL). Sodium hydride (0.58 g, 14.5 mmol, 60% in oil) was added in portions at 0 °C, followed by dropwise addition of iodoethane (1.13 mL, 13.8 mmol). The reaction was carried out at 50 °C for 24 hours. The reaction solution was cooled to room temperature and quenched with ice water (40 mL). The tetrahydrofuran was removed by concentration under reduced pressure. The remaining solution was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (45 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a pale yellow oil 5b (2.30 g, 97% yield).

[0307] MS(ESI,pos.ion)m / z:206.2[M+H] + .

[0308] Step 2: Synthesis of 2-ethyl-6-hydroxy-3,4-dihydroisoquinoline-1(2H)-one 5c

[0309] 2-Ethyl-6-methoxy-3,4-dihydroisoquinoline-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 slowly added dropwise at 0 °C, with stirring continued for 3.5 hours. The reaction was quenched by slow addition of methanol (10 mL) at 0 °C, the mixture was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brownish-yellow solid 5c (2.01 g, 90% yield).

[0310] MS(ESI,neg.ion)m / z:190.1[MH] - .

[0311] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-ethyl-3,4-dihydroisoquinoline-1(2H)-one 5d

[0312] 2-Ethyl-6-hydroxy-3,4-dihydroisoquinoline-1(2H)-one 5c (2.00 g, 10.5 mmol) was dissolved in N,N-dimethylacetamide (25 mL), followed by the addition of 1,2,3-trichloro-5-nitrobenzene (2.37 g, 10.5 mmol) and potassium carbonate (5.61 g, 40.2 mmol). The reaction mixture was reacted at 80 °C for 7 hours. The reaction solution was cooled to room temperature and poured into water (50 mL). The mixture was stirred for 20 minutes, and then hydrochloric acid (3N, 15 mL) was added dropwise. The mixture was filtered, and the solid was collected, dried, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a white solid 5d (3.42 g, 86% yield).

[0313] MS(ESI,pos.ion)m / z:381.0[M+H] + .

[0314] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-ethyl-3,4-dihydroisoquinoline-1(2H)-one 5e

[0315] 6-(2,6-dichloro-4-nitrophenoxy)-2-ethyl-3,4-dihydroisoquinoline-1(2H)-one 5d (2.05 g, 5.38 mmol) was dissolved in acetic acid (25 mL), and iron powder (1.23 g, 21.6 mmol) was added. The mixture was reacted at 60 °C for 4 hours. The reaction solution was cooled to room temperature, the iron powder was removed, water (50 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (10 mL), and the filter cake was collected and dried to give a white solid 5e (1.80 g, 95% yield).

[0316] MS(ESI,pos.ion)m / z:351.1[M+H] + .

[0317] Step 5: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinone)) 5f lin-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0318] 6-(4-amino-2,6-dichlorophenoxy)-2-ethyl-3,4-dihydroisoquinoline-1(2H)-one 5e (0.80 g, 2.28 mmol) and N-cyanoaceturane (0.40 g, 2.50 mmol) were dissolved in acetic acid (15 mL). A solution of sodium nitrite (0.24 g, 3.42 mmol) in water (2 mL) was added at 0 °C, and the reaction was allowed to proceed for 3 hours. At 0 °C, water (35 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (10 mL), and the filter cake was collected and dried to give a yellow solid 5f (1.10 g, 93% yield).

[0319] MS(ESI,neg.ion)m / z:515.9[MH] - .

[0320] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy) (Phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile

[0321] 5f of (2-cyano-2-(2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate (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. The mixture was reacted at 120 °C for 6 hours. The reaction solution 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 prepared and purified [50% ACN / 50% H2O (0.1% TFA), Kromasil specification: C18 10μm×50mm×250mm, flow rate: 100 mL / min] to obtain white solid 5 (0.56 g, yield 54%, HPLC purity: 99.80%).

[0322] MS(ESI,neg.ion)m / z:470.0[MH] - ;

[0323] 1 H 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).

[0324] Example 6: Methyl 2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate 6

[0325]

[0326] 2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 2 (0.30 g, 0.66 mmol) was dissolved in a methanol solution of hydrogen chloride (10 mL, 40 mmol, 4.0 mol / L), and reacted at 70 °C for 48 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give a pale yellow solid 6 (35 mg, yield 11%, HPLC purity: 98.29%).

[0327] MS(ESI,pos.ion)m / z:492.00[M+H] + ;

[0328] 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).

[0329] Example 7 2-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-2H-benzo[c]azapyro-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0330]

[0331] Step 1: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azapyroxene-1- Ketone 7b

[0332] 7-hydroxy-2,3,4,5-tetrahydro-1H-benzo[c]azapyro-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), and potassium carbonate (1.2 g, 8.6 mmol) was added. The mixture was reacted at 120 °C for 16 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the collected filter cake was slurried with ethanol / ethyl acetate / petroleum ether (1 / 2 / 4, 28 mL), filtered, and the collected filter cake was dried to give a brown solid 7b (0.90 g, 72% yield).

[0333] Step 2: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azapyro-1- Ketone 7c

[0334] 7-(2,6-dichloro-4-nitrophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azapyro-1-one 7b (0.50 g, 1.4 mmol) was dissolved in acetic acid (5 mL), and iron powder (91 mg, 1.63 mmol) was added. The mixture was reacted at 70 °C for 2 hours. The reaction solution 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, washed with water (10 mL), and the solid was collected and dried to give a yellow solid 7c (0.36 g, 78% yield).

[0335] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]nitrogen) (Hydrogenol-7-yl)oxy)phenyl)hydrazine)acetyl)

[0336] ethyl carbamate 7d

[0337] 7-(4-amino-2,6-dichlorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azapyro-1-one 7c (0.26 g, 0.77 mmol) and N-cyanoaceturane (0.14 g, 0.88 mmol) were dissolved in acetic acid (8 mL). A solution of sodium nitrite (0.11 g, 1.6 mmol) in water (4 mL) was added at 0 °C, and the reaction was allowed to proceed for 2 hours. At 0 °C, water (10 mL) was added to the reaction solution, 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 a yellow solid 7d (0.39 g, 100% yield).

[0338] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-2H-benzo[c]azapyro-7-yl) (Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 7

[0339] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azapyro-7-yl)oxy)phenyl)hydrazine)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. The mixture was reacted at 120 °C for 5 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 5). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and 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%).

[0340] MS(ESI,neg.ion)m / z:456.5[MH] - ;

[0341] 1 H 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).

[0342] Example 8 2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0343]

[0344] Step 1: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroquinoline-2(1H)-one 8b

[0345] 7-Hydroxy-3,4-dihydroquinoline-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. The mixture was reacted at 80 °C for 4 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), stirred for 30 minutes, filtered, and the filter cake was collected and dried to give a pale yellow solid 8b (2.46 g, 95% yield).

[0346] MS(ESI,neg.ion)m / z:351.0[MH] - .

[0347] Step 2: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroquinoline-2(1H)-one 8c

[0348] 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroquinoline-2(1H)-one 8b (2.00 g, 5.66 mmol) was dissolved in acetic acid (40 mL), and iron powder (1.29 g, 22.6 mmol) was added. The reaction mixture was reacted at 60 °C for 4.5 h. The reaction solution was cooled to room temperature, the iron powder was removed, 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).

[0349] MS(ESI,pos.ion)m / z:323.0[M+H] + .

[0350] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)oxy 8d phenyl hydrazine acetyl urethane

[0351] 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroquinoline-2(1H)-one 8c (0.70 g, 2.17 mmol) and N-cyanoaceturane (0.38 g, 2.39 mmol) were dissolved in acetic acid (10 mL). A solution of sodium nitrite (0.23 g, 3.25 mmol) in water (3 mL) was added at 0 °C, and the reaction was allowed to proceed for 3 hours. At 0 °C, water (20 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (4 mL), and the filter cake was collected and dried to give a yellow solid 8d (0.88 g, 83% yield).

[0352] MS(ESI,neg.ion)m / z:488.1[MH] - .

[0353] 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-formonitrile

[0354] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)oxy)phenyl)hydrazine)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 reaction mixture was reacted at 120 °C for 6 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was stirred for 10 minutes. Then hydrochloric acid (2N, 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 obtain a gray solid 8 (0.56 g, yield 73%, HPLC purity: 89.58%).

[0355] MS(ESI,neg.ion)m / z:442.1[MH] - ;

[0356] 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).

[0357] Example 9 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0358]

[0359] Step 1: Synthesis of 7-hydroxy-3,4-dihydroisoquinoline-1(2H)-one 9b

[0360] At 0 °C, boron tribromide (5.5 mL, 57 mmol) was added dropwise to a solution of 7-methoxy-3,4-dihydroisoquinoline-1(2H)-one 9a (5.0 g, 28 mmol) in dichloromethane (30 mL), and the reaction was continued for 3.5 hours. The reaction solution was quenched in ice water (40 mL), stirred for 30 minutes, filtered, and the filter cake was washed with water (5 mL × 2). The solid obtained after drying was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 3 / 3, 42 mL) to give a brown solid 9b (5.0 g, 100% yield).

[0361] Step 2: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 9c

[0362] 7-hydroxy-3,4-dihydroisoquinoline-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), and potassium carbonate (2.6 g, 19 mmol) was added. The mixture was reacted at 80 °C for 4 hours. The reaction solution was cooled to room temperature, water (80 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filter cake was collected to give a yellow solid. The solid was slurried 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).

[0363] Step 3: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 9d

[0364] 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 9c (2.4 g, 6.8 mmol) was dissolved in acetic acid (15 mL), and iron powder (1.5 g, 3.9 mmol) was added. The mixture was reacted at 70 °C for 3 hours. The reaction solution 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, washed with water (10 mL), and the solid was collected and dried to give a white solid 9d (1.00 g, yield 46%).

[0365] Step 4: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)) 9e)Oxygenated phenyl hydrazine acetyl ethyl carbamate

[0366] 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 9d (0.20 g, 0.62 mmol) and N-cyanoaceturane (0.11 g, 0.69 mmol) were dissolved in acetic acid (4 mL). A solution of sodium nitrite (65 mg, 0.93 mmol) in water (2 mL) was added at 0 °C, and the reaction was allowed to proceed for 3.5 hours. At 0 °C, water (10 mL) was added to the reaction solution, 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 a yellow solid 9e (0.30 g, 99% yield).

[0367] Step 5: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)phenyl)- 3,5-Dioxo-2,3,4,5-Tetrahydro-1,2,4-Triazine-6-formonitrile 9

[0368] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)phenyl)hydrazine)acetyl)carbamate 9e (0.30 g, 0.61 mmol) was dissolved in N,N-dimethylformamide (4 mL), and sodium acetate (55 mg, 0.67 mmol) was added. The mixture was reacted at 120 °C for 5 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 7 / 11, 19 mL) to give an off-white solid 9 (0.18 g, yield 66%, HPLC purity: 98.20%).

[0369] MS(ESI,neg.ion)m / z:442.0[MH] - ;

[0370] 1H 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).

[0371] Example 10 2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0372]

[0373] Step 1: Synthesis of 6-(benzyloxy)-3,4-dihydroisoquinoline-1(2H)-one 10a

[0374] 6-Hydroxy-3,4-dihydroisoquinoline-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 reaction was carried out at room temperature for 15 minutes. Benzyl bromide (4.4 mL, 37 mmol) was added dropwise, and the reaction was carried out at room temperature for 48 hours. The reaction was quenched with water (100 mL), stirred for 20 minutes, filtered, and the solid was collected and dried to give a white solid 10a (6.2 g, 80% yield).

[0375] Step 2: Synthesis of 6-(benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1(2H)-one 10b

[0376] 6-(benzyloxy)-3,4-dihydroisoquinoline-1(2H)-one 10a (3.0 g, 12 mmol) was dissolved in tetrahydrofuran (24 mL) and N,N-dimethylformamide (6 mL), and sodium hydride (1.4 g, 35 mmol, 60% in oil) was added. The reaction was carried out at room temperature for 15 minutes, and 1-bromo-2-methoxy-ethane (1.7 mL, 18 mmol) was added dropwise. The reaction was carried out at 60 °C for 4 hours. The reaction was quenched with water (30 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil 10b (3.7 g, 100% yield).

[0377] Step 3: Synthesis of 6-hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1(2H)-one 10c

[0378] 6-(benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1(2H)-one 10b (3.7 g, 12 mmol) was dissolved in ethanol (30 mL), and 10% palladium on carbon (0.37 g) was added to replace the hydrogen gas (3 MPa). The hydrogenation reaction was carried out for 16 hours. The reaction solution was filtered, and the filtrate was collected and concentrated to give a yellow solid 10c (2.6 g, 99% yield).

[0379] Step 4: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1 (2H)-ketone 10d

[0380] 6-Hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1(2H)-one 10c (0.50 g, 2.3 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.56 g, 2.5 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (0.63 g, 4.5 mmol) was added. The mixture was reacted at 70 °C for 3 hours. The solution was cooled to room temperature, water (10 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filter cake was collected and recrystallized (ethyl acetate / petroleum ether = 3 / 5, 12 mL) to give a yellow solid 10d (0.49 g, 53% yield).

[0381] Step 5: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 10e

[0382] 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1(2H)-one 10d (0.40 g, 0.97 mmol) was dissolved in acetic acid (4 mL), and iron powder (0.14 g, 2.48 mmol) was added. The mixture was reacted at 60 °C for 5 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (12 mL). The mixture was stirred for 10 minutes, filtered, washed with water (20 mL), and the solid was collected and dried to give an off-white solid 10e (0.33 g, 89% yield).

[0383] Step 6: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)ethyl carbamate 10f

[0384] 6-(4-amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1(2H)-one 10e (0.33 g, 0.87 mmol) was dissolved in acetic acid (6.6 mL). A solution of sodium nitrite (90 mg, 1.29 mmol) in water (3.3 mL) was added at 0 °C, and the reaction was allowed to proceed for 10 minutes. Then, N-cyanoaceturane (0.17 g, 1.1 mmol) was added, and the reaction was continued at 0 °C for 1 hour. At 0 °C, water (12 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (10 mL), and the filter cake was collected and dried to give a yellow solid 10f (0.47 g, 99% yield).

[0385] Step 7: Synthesis of 2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 10

[0386] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 was carried out at 120 °C. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the solid was collected and recrystallized (ethanol / ethyl acetate / petroleum ether = 7.5 / 20 / 10, 37.5 mL). The solid was filtered again, and the filter cake was collected and dried to give an off-white solid 10 (0.23 g, yield 53%, HPLC purity: 96.55%). MS (ESI, neg.ion) m / z: 500.1 [MH] - ;

[0387] 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).

[0388] Example 11 Methyl 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate 11

[0389]

[0390] A methanol solution of hydrogen chloride (5 mL, 4.5 mol / L) was added to 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 1 (0.10 g, 0.23 mmol), and the reaction was carried out at 70 °C for 24 hours. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give a white solid 11 (45 mg, yield 42%, HPLC purity: 95.69%).

[0391] MS(ESI,pos.ion)m / z:477.0[M+H] + ;

[0392] 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, 1 H), 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).

[0393] Example 12 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 12

[0394]

[0395] Step 1: Synthesis of 6-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinoline-1(2H)- Ketone 12a

[0396] 6-Methoxy-3,4-dihydroisoquinoline-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 dropwise addition of bromomethylpyran (1.13 mL, 13.8 mmol). After the addition was complete, the reaction was continued at room temperature for 24 hours. The reaction was quenched with water (30 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a pale yellow oil 12a (4.35 g, 93% yield).

[0397] MS(ESI,pos.ion)m / z:276.2[M+H] + .

[0398] Step 2: Synthesis of 6-hydroxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinoline-1(2H)-one 12b

[0399] 6-Methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinoline-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 slowly added dropwise at 0 °C, maintaining the reaction at 0 °C for 2.5 h. The reaction was quenched by adding methanol (5 mL) at 0 °C, concentrated, and then water (50 mL) was added. The mixture was extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, 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, yield 55%).

[0400] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4- Dihydroisoquinoline-1(2H)-one 12c

[0401] 6-Hydroxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinoline-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 reacted at 80 °C for 5 hours. The reaction solution was cooled to room temperature, and water (15 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid 12c (0.31 g, yield 54%).

[0402] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4- dihydroisoquinoline-1(2H)-one 12d

[0403] 6-(2,6-dichloro-4-nitrophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinoline-1(2H)-one 12c (0.31 g, 0.69 mmol) was dissolved in acetic acid (10 mL), and iron powder (0.19 g, 3.3 mmol) was added. The reaction was carried out at 60 °C for 3.5 h. After cooling 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 phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a pale yellow solid 12d (0.18 g, yield 62%).

[0404] MS(ESI,pos.ion)m / z:421.1[M+H] + .

[0405] 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-tetrahydroisoquinoline-6-yl)oxy)

[0406] 12e-phenylhydrazine acetyl carbamate

[0407] 6-(4-amino-2,6-dichlorophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinoline-1(2H)-one 12d (0.18 g, 0.43 mmol) was dissolved in acetic acid (8 mL). A solution of sodium nitrite (46 mg, 0.65 mmol) in water (0.5 mL) was slowly added dropwise at 0 °C. After reacting for 20 minutes, N-cyano-aceturane (75 mg, 0.47 mmol) was added, and the reaction continued for 4.5 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 12e (0.25 g, 99% yield).

[0408] MS(ESI,neg.ion)m / z:586.1[MH] - .

[0409] Step 6: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4- Tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 12

[0410] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazyl)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. The mixture was reacted at 120 °C for 4 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1). The solid obtained was then recrystallized (petroleum ether / ethyl acetate = 3 / 1, 5 mL) to give a white solid 12 (0.21 g, yield 89%, HPLC purity: 97.04%).

[0411] MS(ESI,neg.ion)m / z:540.1[MH] - .

[0412] 1H 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).

[0413] Example 13 2-(3,5-dichloro-4-((2-(isopropoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0414]

[0415] 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 1 (0.30 g, 0.68 mmol) was dissolved in isopropanol (10 mL), and 37% formaldehyde (1.5 mL, 20 mmol) was added. The reaction mixture was sealed in a tube at 100 °C for 24 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1). The solid was recrystallized (ethyl acetate / petroleum ether = 1 / 2, 6 mL) to give a white solid 13 (85 mg, yield 24%, HPLC purity: 99.85%).

[0416] MS(ESI,neg.ion)m / z:514.1[MH] - ;

[0417] 1 H 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).

[0418] Example 14 2-(3,5-dichloro-4-((1-oxo-2-((2,2,2-trifluoroethoxy)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 14

[0419]

[0420] 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 1 (0.48 g, 1.08 mmol) was dissolved in trifluoroethanol (8 mL), and 37% formaldehyde (1.60 mL, 22 mmol) was added. The reaction mixture was sealed at 100 °C for 24 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2). The solid was recrystallized (ethyl acetate / petroleum ether = 1 / 2, 6 mL) to give a white solid 14 (0.23 g, yield 38%, HPLC purity: 96.05%). MS (ESI, neg.ion) m / z: 554.0 [MH] - ;

[0421] 1 H 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);

[0422] 19 F NMR(376MHz,DMSO-d6)δ(ppm)-73.04.

[0423] Example 15 2-(3,5-dichloro-4-((1-oxo-2-((2,2-difluoroethoxy)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 15

[0424]

[0425] 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 1 (0.30 g, 0.68 mmol) was dissolved in 2,2-difluoroethanol (6 mL), and 37% formaldehyde (1.0 mL, 14 mmol) was added. The reaction mixture was sealed at 100 °C for 24 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2). The solid was recrystallized (ethyl acetate / petroleum ether = 1 / 2, 6 mL) to give a white solid 15 (85 mg, yield 23%, HPLC purity: 97.53%). MS (ESI, negative) m / z: 536.1 [MH] - ;

[0426] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.31 (s, 1H), 7.89 (dd, J = 27.8, 8.3Hz, 3H), 6.95-6.78 (m, 2 H),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);

[0427] 19 F NMR(376MHz,DMSO-d6)δ(ppm)-125.56.

[0428] Example 16 2-(3,5-dichloro-4-((2-(1-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0429]

[0430] 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 1 (0.20 g, 0.45 mmol) was dissolved in ethanol (4 mL), and acetaldehyde (0.8 mL, 14 mmol) was added. The reaction mixture was sealed at 90 °C for 48 hours. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2). The solid was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 7 / 10, 18 mL) to give a yellow solid 16 (60 mg, yield 26%, HPLC purity: 87.08%).

[0431] MS(ESI,neg.ion)m / z:514.1[MH] - ;

[0432] 1 H 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).

[0433] Example 17 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0434]

[0435] Step 1: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)- 17a of 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0436] Concentrated hydrochloric acid (1.5 mL) was added to a solution of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 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 solution was cooled to room temperature, water (6 mL) was added, and the mixture was stirred for 5 minutes. The mixture was filtered, and the filter cake was collected and dried to give a yellow solid 17a (90 mg, 87% product). MS (ESI, negative ion) m / z: 463.0 [MH] - .

[0437] Step 2: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)- 1,2,4-Triazine-3,5(2H,4H)-dione 17

[0438] 17a (175 mg, 0.38 mmol) of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid) was dissolved in 2.5 mL of mercaptoacetic acid and reacted at 140 °C for 17 h. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give a light red solid 17 (63 mg, yield 40%, HPLC purity: 95.58%).

[0439] MS(ESI,neg.ion)m / z:418.0[MH] - ;

[0440] 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).

[0441] Example 18 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0442]

[0443] Step 1: Synthesis of 2-benzyl-6-methoxy-3,4-dihydroisoquinoline-1(2H)-one 18a

[0444] At 0 °C, 3.0 g (17 mmol) of 6-methoxy-3,4-dihydroisoquinoline-1(2H)-one 5a was added to a mixed solution of N,N-dimethylformamide (24 mL) and tetrahydrofuran (18 mL) in sodium hydride (0.81 g, 20 mmol, 60% in oil), and benzyl bromide (2.2 mL, 19 mmol) was added dropwise. The reaction was carried out at room temperature for 6 hours. The reaction was quenched with water (120 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a pale yellow oil 18a (4.51 g, 100% yield).

[0445] Step 2: Synthesis of 2-benzyl-6-hydroxy-3,4-dihydroisoquinoline-1(2H)-one 18b

[0446] At 0 °C, boron tribromide (3.2 mL, 34 mmol) was added dropwise to a solution of 2-benzyl-6-methoxy-3,4-dihydroisoquinoline-1(2H)-one 18a (4.5 g, 17 mmol) in dichloromethane (36 mL), and the reaction was allowed to proceed at room temperature for 5 hours. The reaction mixture was then quenched in ice water (100 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (20 mL × 2). The filter cake was collected and dried to give a white solid 18b (3.8 g, 89% yield).

[0447] Step 3: Synthesis of 2-benzyl-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 18c

[0448] 2-Benzyl-6-hydroxy-3,4-dihydroisoquinoline-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), and potassium carbonate (3.14 g, 22.5 mmol) was added. The mixture was reacted at 70 °C for 7 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was stirred for 10 minutes, 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 an off-white solid 18c (6.10 g, 92% yield).

[0449] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-benzyl-3,4-dihydroisoquinoline-1(2H)-one 18d

[0450] The synthesized 2-benzyl-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 18c (3.0 g, 6.8 mmol) was dissolved in acetic acid (18 mL), and iron powder (1.1 g, 20 mmol) was added. The reaction mixture was reacted at 60 °C for 3 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was stirred for 10 minutes. The mixture was 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 a brown solid 18d (1.1 g, 39% yield).

[0451] Step 5: Synthesis of (2-(2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5- ethyl dichlorophenyl(hydrazine)-2-cyanoacetyl)carbamate 18e

[0452] 6-(4-amino-2,6-dichlorophenoxy)-2-benzyl-3,4-dihydroisoquinoline-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). An aqueous solution of sodium nitrite (0.33 g, 4.8 mmol) (10 mL) was added at 0 °C, and the reaction was continued at 0 °C for 2 hours. Water (30 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred for 10 minutes. The mixture was 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, yield 43%).

[0453] Step 6: Synthesis of 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5-dichloro phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 18

[0454] Ethyl (2-(2-(2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5-dichlorophenyl)hydrazine)-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 reaction mixture was reacted at 120 °C for 4 hours. 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 phases were washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was recrystallized (ethanol / ethyl acetate / petroleum ether = 1 / 3 / 6, 50 mL) to give red solid 18 (0.26 g, yield 40%, HPLC purity: 98.24%).

[0455] MS(ESI,neg.ion)m / z:533.4[MH] - ;

[0456] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.94 (d, J = 8.6 Hz, 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).

[0457] Example 19 2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinoline-6-yl)oxy)-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0458]

[0459] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)isoquinoline-1(2H)-one 19b

[0460] 6-Hydroxyisoquinoline-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 reacted at 80 °C for 3 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (35 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (35 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid 19b (1.83 g, 91% yield).

[0461] MS(ESI,pos.ion)m / z:351.1[M+H] + .

[0462] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)isoquinoline-1(2H)-one 19c

[0463] 6-(2,6-dichloro-4-nitrophenoxy)isoquinoline-1(2H)-one 19b (0.45 g, 1.30 mmol) was dissolved in acetic acid (15 mL), and iron powder (0.29 g, 5.1 mmol) was added. The mixture was reacted at 60 °C for 2.5 h. The reaction solution was cooled to room temperature, the iron powder was removed, water (30 mL) was added, the mixture was stirred for 10 min, filtered, and the filter cake was collected and dried to give a pale yellow solid 19c (0.38 g, 92% yield).

[0464] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinoline-6-yl)oxy) phenyl(hydrazine)acetyl)carbamate ethyl 19d

[0465] 6-(4-amino-2,6-dichlorophenoxy)isoquinoline-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. The reaction was allowed to proceed for 20 minutes, and then N-cyanoaceturane (0.22 g, 1.40 mmol) was added, and the reaction was continued for 4 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (35 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 19d (0.60 g, 99% yield).

[0466] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinoline-6-yl)oxy)phenyl)-3,5- Dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formonitrile 19

[0467] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate 19d (0.45 g, 0.92 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium acetate (0.38 g, 4.61 mmol) was added. The reaction was carried out at 120 °C for 3 hours. The reaction was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, 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, yield 55%, HPLC purity: 96.04%).

[0468] MS(ESI,neg.ion)m / z:440[MH] - ;

[0469] 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).

[0470] Example 20 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 20

[0471]

[0472] Step 1: 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 20a

[0473] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (0.50 g, 1.4 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (85 mg, 2.1 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 20 minutes, 1-bromomethyl-4-fluorobenzene (0.55 g, 2.8 mmol) and N,N-dimethylformamide (5 mL) were added dropwise, followed by reaction at room temperature for 15 hours. The reaction was quenched with ice water (30 mL), and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a pale yellow oil 20a (0.65 g, 99% yield).

[0474] MS(ESI,pos.ion)m / z:461.2[M+H] + ;

[0475] 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), 6.7 9 (dd, J = 8.7, 2.6 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 4.76 (s, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.93 (t, J = 6.6 Hz, 2H).

[0476] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 20b

[0477] 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 20a (0.65 g, 1.4 mmol) was dissolved in acetic acid (10 mL), and iron powder (0.16 g, 2.8 mmol) was added. The reaction mixture was reacted at 50 °C for 2.5 h. The reaction solution was cooled to room temperature, and the reaction was quenched with water (30 mL). The mixture was 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a pale yellow oil 20b (0.37 g, yield 61%). MS (ESI, pos.ion) m / z: 431.0 [M+H] + .

[0478] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) 20c (P-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0479] 6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 20b (0.37 g, 0.86 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution of sodium nitrite (0.12 g, 1.7 mmol) (6 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.20 g, 1.3 mmol), and the reaction was allowed to proceed for 3 hours. The reaction was quenched with water (30 mL), stirred for 20 minutes, filtered, and the filter cake was washed with water (5 mL). The filter cake was collected and dried to give a pale yellow solid 20c (0.50 g, 97% yield).

[0480] MS(ESI,pos.ion)m / z:596.0[M+H] + .

[0481] Step 4: 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy (20d)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile.

[0482] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was 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 a yellow solid 20d (0.28 g, yield 61%, HPLC purity: 100%). MS (ESI, neg.ion) m / z: 550.0 [MH] - ;

[0483] 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);

[0484] 19 F NMR(376MHz,DMSO-d6)δ(ppm)-115.68.

[0485] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- 20e) ( ...

[0486] 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 20d (0.17 g, 0.31 mmol) was dissolved in acetic acid (4 mL), and concentrated hydrochloric acid (2 mL) was added. The mixture was reacted at 100 °C for 18 hours. The reaction solution was cooled to room temperature, and water (18 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 20e (0.15 g, yield 85%).

[0487] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (2H,4H)-1,2,4-triazine-3,5(2H,4H)-dione

[0488] 2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 20e (0.15 g, 0.26 mmol) was dissolved in mercaptoacetic 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). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a white solid 20 (90 mg, yield 65%, HPLC purity: 98.12%).

[0489] MS(ESI,neg.ion)m / z:525.0[MH] - ;

[0490] 1 H 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).

[0491] Example 21 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 21

[0492]

[0493] Step 1: 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinoline-1(2H)- Ketone 21a

[0494] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (0.50 g, 1.4 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (85 mg, 2.1 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 20 minutes, 1-bromomethyl-4-toluene (0.54 g, 2.8 mmol) and N,N-dimethylformamide (5 mL) were added dropwise, followed by reaction at room temperature for 14 hours. The reaction was quenched with ice water (30 mL), and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a pale yellow oil 21a (0.63 g, 98% yield).

[0495] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinoline-1(2H)-one 21b

[0496] 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinoline-1(2H)-one 21a (0.63 g, 1.4 mmol) was dissolved in acetic acid (10 mL), and iron powder (0.16 g, 2.8 mmol) was added. The reaction mixture was reacted at 50 °C for 2.5 h. The reaction solution was cooled to room temperature, and the reaction was quenched with water (30 mL). The mixture was 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a pale yellow oil 21b (0.46 g, 78% yield). MS (ESI, pos.ion) m / z: 428.1 [M+H] + .

[0497] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisocyano) Quinoline-6-yl)oxy)phenyl)hydrazine)acetyl)

[0498] 21c of urethane

[0499] 6-(4-amino-2,6-dichlorophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinoline-1(2H)-one 21b (0.46 g, 1.1 mmol) was dissolved in acetic acid (16 mL), and an aqueous solution of sodium nitrite (0.15 g, 2.1 mmol) (8 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.25 g, 1.6 mmol). The reaction was allowed to proceed for 2.5 h. The reaction was quenched with water (30 mL), stirred for 20 min, filtered, and the filter cake was washed with water (5 mL). The filter cake was collected and dried to give a pale yellow solid 21c (0.48 g, 75% yield).

[0500] MS(ESI,pos.ion)m / z:595.0[M+H] + .

[0501] Step 4: 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl) (Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 21d.

[0502] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 8 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was 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 a yellow solid 21d (0.41 g, yield 93%, HPLC purity: 98.71%).

[0503] MS(ESI,neg.ion)m / z:547.0[MH] - ;

[0504] 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).

[0505] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- 21e) 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0506] 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 21d (0.21 g, 0.37 mmol) was dissolved in acetic acid (4 mL), and concentrated hydrochloric acid (2 mL) was added. The mixture was reacted at 100 °C for 18 hours. The reaction solution was cooled to room temperature, and water (18 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 21e (0.20 g, 93% yield).

[0507] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (2H,4H)-1,2,4-triazine-3,5(2H,4H)-dione

[0508] 2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 21e (0.20 g, 0.35 mmol) was dissolved in mercaptoacetic acid (3 mL) and reacted at 150 °C for 24 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The solution was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL). The solution was dried over anhydrous sodium sulfate, 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, yield 52%, HPLC purity: 96.18%).

[0509] MS(ESI,neg.ion)m / z:521.0[MH] - ;

[0510] 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).

[0511] Example 22 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione 22

[0512]

[0513] Step 1: Synthesis of 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5-dichloro 22a of phenyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0514] 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 18 (0.21 g, 0.37 mmol) was dissolved in acetic acid (4 mL), and concentrated hydrochloric acid (1.5 mL) was added. The mixture was reacted at 120 °C for 24 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 22a (0.20 g, 100% yield).

[0515] Step 2: Synthesis of 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5-dichloro phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 22

[0516] 2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 22a (0.20 g, 0.36 mmol) was dissolved in mercaptoacetic acid (4 mL) and reacted at 160 °C for 24 hours. The reaction solution was cooled to room temperature, water (10 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, 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, yield 68%, HPLC purity: 98.02%).

[0517] MS(ESI,neg.ion)m / z:507.5[MH] - ;

[0518] 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), 7.3 5-7.22(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).

[0519] Example 23 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 23

[0520]

[0521] Step 1: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4- Tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 23a

[0522] 12 (1.3 g, 2.4 mmol) of 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 12 was dissolved in acetic acid (20 mL), concentrated hydrochloric acid (6 mL) was added, and the reaction was carried out at 120 °C for 4.5 hours. The reaction solution was cooled to room temperature, concentrated, and 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 collected aqueous phase was adjusted to pH 2-3 with dilute hydrochloric acid (4N), and then extracted with ethyl acetate (25 mL × 3). The extracted organic phases were combined after acidification, washed with saturated sodium chloride solution (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 23a (0.87 g, yield 65%).

[0523] Step 2: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4- Tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 23

[0524] 2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 23a (0.85 g, 1.5 mmol) was dissolved in mercaptoacetic acid (4 mL) and reacted at 160 °C for 24 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution (15 mL) was slowly added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The 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%).

[0525] MS(ESI,neg.ion)m / z:515.2[MH] - ;

[0526] 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).

[0527] Example 24 2-(3,5-dichloro-4-((1-oxo-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 24

[0528]

[0529] Step 1: 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinoline-1 (2H)-Keto24a

[0530] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (2.0 g, 5.7 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (0.80 g, 20 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 20 minutes, 4-(bromomethyl)pyridine hydrobromide (1.5 g, 8.7 mmol) and N,N-dimethylformamide (3 mL) were added, followed by reaction at 5 °C for 2 hours. The reaction was quenched with water (70 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (20 mL × 3). The filter cake was collected and dried to give a yellow solid 24a (2.3 g, 91% yield).

[0531] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinoline-1 (2H)-Keto24b

[0532] 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinoline-1(2H)-one 24a (1.9 g, 4.3 mmol) was dissolved in acetic acid (25 mL), and iron powder (0.60 g, 11 mmol) was added. The reaction mixture was reacted at 55 °C for 8 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (120 mL). The mixture was extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a gray solid 24b (1.8 g, 100% yield).

[0533] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetracycline) Hydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate ethyl 24c

[0534] 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinoline-1(2H)-one 24b (1.8 g, 4.3 mmol) was dissolved in acetic acid (27 mL), and an aqueous solution of sodium nitrite (0.60 g, 8.7 mmol) (14 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.81 g, 5.3 mmol), and the reaction was allowed to proceed for 2 hours. The reaction was quenched with water (80 mL), and the mixture was extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a red, foamy solid 24c (2.5 g, 99% yield). Step 4: 2-(3,5-dichloro-4-((2- (pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5- Tetrahydro-1,2,4-triazine-6-formonitrile 24d.

[0535] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (100 mL). The mixture was stirred for 15 minutes, 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 a yellow solid 24d (0.90 g, yield 53%, HPLC purity: 82.28%).

[0536] MS(ESI,pos.ion)m / z:536.3[M+H] + ;

[0537] 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).

[0538] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinone) (24e)-P-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0539] 2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 24d (0.45 g, 0.84 mmol) was dissolved in acetic acid (8 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 °C for 24 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to obtain a pale yellow solid 24e (0.45 g, yield 97%).

[0540] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinone) (Lin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 24

[0541] 2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 24e (0.37 g, 0.67 mmol) was dissolved in mercaptoacetic 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). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give a pale yellow solid 24 (0.20 g, yield 59%, HPLC purity: 92.08%).

[0542] MS(ESI,neg.ion)m / z:511.3[M+H] + ;

[0543] 1 H 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).

[0544] Example 25 2-(3,5-dichloro-4-((1-oxo-2-(pyridazin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione 25

[0545]

[0546] Step 1: 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridazine-3-ylmethyl)-3,4-dihydroisoquinoline-1 (2H)-Keto25a

[0547] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (2.0 g, 5.7 mmol) was dissolved in tetrahydrofuran (25 mL). Sodium hydride (0.80 g, 20 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 20 minutes, 3-(bromomethyl)pyridazine hydrobromide (1.5 g, 8.7 mmol) and N,N-dimethylformamide (4 mL) were added, followed by reaction at 8 °C for 2 hours. The reaction was quenched with water (150 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (20 mL × 3). The collected filter cake was dried and slurried with ethyl acetate / petroleum ether (1 / 4, 50 mL). After filtration, the filter cake was collected to give a yellow solid 25a (1.8 g, 71% yield).

[0548] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridazine-3-ylmethyl)-3,4-dihydroisoquinoline-1 (2H)-Keto25b

[0549] 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinoline-1(2H)-one 25a (1.0 g, 2.2 mmol) was dissolved in acetic acid (15 mL), and iron powder (0.35 g, 6.3 mmol) was added. The mixture was reacted at 60 °C for 8 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (80 mL). The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (20 mL × 2). The filter cake was collected and dried to give a gray solid 25b (0.74 g, 79% yield). Step 3: (2-Cyano-2-(2-(3,5-Dichloro-4-((2-(Da)) (-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate)ethyl) Ester 25c

[0550] 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinoline-1(2H)-one 25b (0.74 g, 1.8 mmol) was dissolved in acetic acid (15 mL), and an aqueous solution of sodium nitrite (0.25 g, 3.6 mmol) (6 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.35 g, 2.2 mmol). The reaction was allowed to proceed for 2 hours. The reaction was quenched with water (50 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (30 mL × 2). The filter cake was collected and dried to give a red solid 25c (0.96 g, 93% yield).

[0551] Step 4: 2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-) (25d)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile.

[0552] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (100 mL). The mixture was stirred for 15 minutes, 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 a yellow solid 24d (0.51 g, yield 58%, HPLC purity: 93.11%).

[0553] MS(ESI,pos.ion)m / z:537.3[M+H] + ;

[0554] 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). Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(pyridazine-3-ylmethyl)-1- Oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6- Formic acid 25e

[0555] 2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxynitrile 25d (0.23 g, 0.43 mmol) was dissolved in acetic acid (2.5 mL), and concentrated hydrochloric acid (1.4 mL) was added. The reaction mixture was reacted at 120 °C for 24 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (15 mL × 2). The filter cake was collected and dried to give a yellow solid 25e (0.21 g, yield 88%).

[0556] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinone) (Lin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 25

[0557] 2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxylic acid 25e (0.20 g, 0.40 mmol) was dissolved in mercaptoacetic acid (2.5 mL) and reacted at 120 °C for 36 hours. The reaction solution was cooled to room temperature, and ethyl acetate (100 mL) was added. The solution was washed successively with water (20 mL), saturated sodium bicarbonate solution (20 mL), and saturated sodium chloride solution (20 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then purified by preparative separation [35% ACN / 65% H2O (1% TFA), Kromasil specification: C18 10 μm × 50 mm × 250 mm, flow rate: 100 mL / min] to give 25 (20 mg, yield 20%, HPLC purity: 82.95%), a white solid.

[0558] MS(ESI,neg.ion)m / z:513.3[M+H] + ;

[0559] 1 H 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).

[0560] Example 26 2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0561]

[0562] Step 1: Synthesis of 6-(2,6-dimethyl-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b

[0563] 6-Hydroxy-3,4-dihydroisoquinoline-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), and potassium carbonate (2.8 g, 28 mmol) was added. The mixture was reacted at 80 °C for 12 hours. The reaction solution was cooled to room temperature, and water (150 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (30 mL × 2). The filter cake was collected, slurried with ethyl acetate / petroleum ether (1 / 6, 70 mL), filtered, and the collected filter cake was dried to give a white solid 26b (4.2 g, 73% yield).

[0564] Step 2: Synthesis of 6-(4-amino-2,6-dimethylphenoxy)-3,4-dihydroisoquinoline-1(2H)-one 26c

[0565] 6-(2,6-dimethyl-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 26b (3.0 g, 9.6 mmol) was dissolved in acetic acid (30 mL), and iron powder (1.6 g, 29 mmol) was added. The mixture was reacted at 55 °C for 5 hours. The reaction solution was cooled to room temperature, the iron powder was removed, and ethyl acetate (200 mL) was added. The mixture was washed successively with water (150 mL) and saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give a yellow oily substance 26c (2.7 g, 100% yield).

[0566] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetraisoquinoline-6-yl)) 26d (Oxygenated) Phenyl) Hydrazine) Acetyl) Ethyl carbamate

[0567] 2.7 g (9.6 mmol) of 6-(4-amino-2,6-methylphenoxy)-3,4-dihydroisoquinoline-1(2H)-one 26c 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. After reacting for 5 minutes, N-cyanoaceturane (1.9 g, 12 mmol) was added, and the reaction was allowed to proceed for 1.5 hours. Water (10 mL) was added to the reaction solution at 0 °C, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (5 mL), and the filter cake was collected and dried to give a yellow solid 26d (4.1 g, 95% yield).

[0568] Step 4: Synthesis of 2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)benzene 26-(3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-formonitrile)

[0569] Ethyl (2-cyano-2-(2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetraisoquinoline-6-yl)oxy)phenyl)hydrazine)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 solution 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, filtered and concentrated. The residue was then purified by preparative separation [42% ACN / 58% H2O (0.1% TFA), Kromasil specification: 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%).

[0570] MS(ESI,pos.ion)m / z:404.2[M+H] + .

[0571] 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).

[0572] Example 27 2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0573]

[0574] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinoline-1 (2H)-Keto27b

[0575] 6-Hydroxy-2-(p-Tolyl)-3,4-Dihydroisoquinoline-1(2H)-one 27a (preparation method referred to steps 1 and 2 of Example 23 in patent application CN 109988109 A) (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), and potassium carbonate (0.35 g, 2.5 mmol) was added. The mixture was reacted at 60 °C for 3 hours. The reaction solution was cooled to room temperature, water (8 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (3 mL × 2). The filter cake was collected and dried to obtain gray solid 27b (0.56 g, 99% yield).

[0576] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinoline-1 (2H)-Ketone 27c

[0577] 6-(2,6-dichloro-4-nitrophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinoline-1(2H)-one 27b (0.56 g, 1.25 mmol) was dissolved in acetic acid (5 mL), and iron powder (0.21 g, 3.75 mmol) was added. The mixture was reacted at 60 °C for 5 hours. The reaction solution 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 phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid 27c (0.37 g, 72% yield).

[0578] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydro) Isoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate ethyl 27d

[0579] 6-(4-amino-2,6-dichlorophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinoline-1(2H)-one 27c (0.37 g, 0.90 mmol) was dissolved in acetic acid (4 mL). N-cyanoaceturane (0.15 g, 1.08 mmol) was added at 0 °C, and the mixture was stirred for 5 minutes. Then, a solution of sodium nitrite (93 mg, 1.35 mmol) in water (1 mL) was added, and the reaction was allowed to proceed for 1 hour. At 0 °C, water (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (3 mL), and the filter cake was collected and dried to obtain a yellow solid 27d (0.50 g, 96% yield).

[0580] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline-6- (27)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile

[0581] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 solution was cooled to room temperature, and water (50 mL) was added to quench the reaction. The mixture was stirred for 10 minutes, filtered, and the filter cake was collected and dried. The obtained solid was prepared and purified [60% ACN / 40% H2O (0.1% TFA), Kromasil specification: C18 10μm×50mm×250mm, flow rate: 100mL / min] to obtain white solid 27 (0.23 g, yield 50%, HPLC purity: 98.72%).

[0582] MS(ESI,neg.ion)m / z:534.0[MH] - ;

[0583] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.31 (s, 1H). 7.94 (d, J = 6.4 Hz, 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).

[0584] Example 28 2-(3,5-dichloro-4-((1-oxo-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0585]

[0586] Step 1: Synthesis of 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline-1(2H)-one 28b

[0587] 6-Methoxy-3,4-dihydroisoquinoline-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) solution and reacted at 150 °C for 16 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (100 mL). The mixture was extracted with ethyl acetate (200 mL), and the combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give an off-white solid 28b (1.05 g, 46% yield).

[0588] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.11 (d, J = 8.6 Hz, 1H), 7.36 (ddt, J = 6.8, 4.9, 2.8 Hz, 2H), 7.16-7.08 (m, 2H), 6. 90 (dd, J = 8.7, 2.6 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 3.13 (t, J = 6.4 Hz, 2H).

[0589] Step 2: Synthesis of 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinoline-1(2H)-one 28c

[0590] At 0 °C, boron tribromide (0.71 mL, 7.4 mmol) was added dropwise to a solution of 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline-1(2H)-one 28b (1.00 g, 3.7 mmol) in dichloromethane (30 mL), and the reaction was allowed to proceed at room temperature for 4 hours. The reaction mixture was then quenched in ice water (30 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried to give a white solid 28c (0.87 g, 92% yield). MS (ESI, pos.ion) m / z: 258.1 [M+H] + .

[0591] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinoline-1 (2H)-ketone 28d

[0592] 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinoline-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), and potassium carbonate (0.93 g, 6.8 mmol) was added. The mixture was reacted at 70 °C for 17 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried to give an off-white solid 28d (1.50 g, 99% yield).

[0593] MS(ESI,pos.ion)m / z:448.0[M+H] + .

[0594] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinoline-1 (2H)-Keto28e

[0595] 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinoline-1(2H)-one 28d (1.50 g, 3.30 mmol) was dissolved in acetic acid (20 mL), and iron powder (0.37 g, 6.70 mmol) was added. The mixture was reacted at 50 °C for 3 hours. The reaction solution 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 phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a pale yellow oil 28e (1.05 g, 75% yield). MS (ESI, pos.ion) m / z: 417.1 [M+H] + .

[0596] Step 5: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydro) Isoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate ethyl 28f

[0597] 6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinoline-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 minutes, N-cyanoaceturane (0.56 g, 3.60 mmol) was added, and the reaction was allowed to proceed for 5 hours. Water (50 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (10 mL), and the filter cake was collected and dried to give a yellow solid 28f (1.30 g, 93% yield).

[0598] MS(ESI,pos.ion)m / z:585.1[M+H] + .

[0599] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- 28g of (-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0600] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 solution was cooled to room temperature, and the reaction was quenched with water (80 mL). It was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate). The obtained solid was recrystallized at 80 °C (petroleum ether / ethyl acetate = 1 / 2, 24 mL) to give 28 g of yellow solid (0.71 g, yield 59%, HPLC purity: 97.86%).

[0601] MS(ESI,neg.ion)m / z:537.1[MH] - ;

[0602] 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).

[0603] Step 7: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (28h)

[0604] 28 g (0.45 g, 0.84 mmol) of 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile) was dissolved in acetic acid (8 mL), and concentrated hydrochloric acid (4 mL) was added. The mixture was reacted at 100 °C for 17 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid (0.35 g, 75% yield) for 28 hours.

[0605] Step 8: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (28)-1,2,4-triazine-3,5(2H,4H)-dione

[0606] 2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 28h (0.35 g, 0.63 mmol) was dissolved in mercaptoacetic acid (2.5 mL) and reacted at 140 °C for 24 h. The reaction solution was cooled to room temperature, and ethyl acetate (60 mL) was added. The solution was washed successively with water (20 mL), saturated sodium bicarbonate solution (30 mL × 2), and saturated sodium chloride solution (30 mL). The solution was dried over anhydrous sodium sulfate, 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, yield 61%, HPLC purity: 96.79%).

[0607] MS(ESI,neg.ion)m / z:514.1[M+H] + ;

[0608] 1 H 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).

[0609] Example 29 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0610]

[0611] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline 1-Lin-1(2H)-one 29a

[0612] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.50 g, 4.2 mmol) was dissolved in tetrahydrofuran (20 mL). 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 reaction at room temperature for 3.5 hours. The reaction was quenched with 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, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a pale yellow oil 29a (2.2 g, 100% yield).

[0613] MS(ESI,pos.ion)m / z:511.0[M+H] + .

[0614] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinone 1-Lin-1(2H)-one 29b

[0615] 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-1(2H)-one 29a (2.2 g, 4.2 mmol) was dissolved in acetic acid (50 mL), and iron powder (0.99 g, 17.8 mmol) was added. The reaction mixture was reacted at 55 °C for 10 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (100 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow oil 29b (1.65 g, 77% yield).

[0616] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2, 3,4-Tetrahydroisoquinoline-6-yl)oxy)phenyl)

[0617] 29c hydrazine (acetyl)carbamate

[0618] 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-1(2H)-one 29b (0.60 g, 1.25 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution of sodium nitrite (0.19 g, 12.78 mmol) (6 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.26 g, 1.67 mmol). The reaction was allowed to proceed for 3 hours. The reaction was quenched with water (100 mL), stirred for 20 minutes, filtered, and the filter cake was washed with water (5 mL × 2). The filter cake was collected and dried to give a pale yellow solid 29c (0.76 g, 94% yield).

[0619] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisocyanuric acid) Quinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 29d

[0620] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was 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 a yellow solid 29d (0.65 g, yield 97%, HPLC purity: 96.68%).

[0621] MS(ESI,neg.ion)m / z:600.0[MH] - ;

[0622] 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 = 8.0 Hz, 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).

[0623] Step 5: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisocyanuric acid) Quinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 29e

[0624] 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 29d (0.65 g, 1.01 mmol) was dissolved in acetic acid (10 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 120 °C for 13 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 29e (0.55 g, yield 82%).

[0625] Step 6: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisocyanuric acid) Quinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 29

[0626] 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 29e (0.55 g, 0.89 mmol) was dissolved in mercaptoacetic acid (5 mL) and reacted at 150 °C for 24 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The solution was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1). The solid was recrystallized at 70 °C (ethyl acetate / methanol / petroleum ether (v / v / v) = 5 / 1 / 10, 32 mL) to give a white solid 29 (0.32 g, yield 62%, HPLC purity: 96.97%).

[0627] MS(ESI,neg.ion)m / z:575.0[MH] - ;

[0628] 1 H 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).

[0629] Example 30 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 30

[0630]

[0631] Step 1: 6-(2,6-dichloro-4-nitrophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 30a

[0632] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.00 g, 2.83 mmol) was dissolved in tetrahydrofuran (40 mL). 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 reaction at room temperature for 12 hours. The reaction was quenched with 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, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give a pale yellow oil 30a (1.10 g, 81% yield).

[0633] MS(ESI,pos.ion)m / z:479.1[M+H] + .

[0634] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 30b

[0635] 6-(2,6-dichloro-4-nitrophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 30a (1.10 g, 2.29 mmol) was dissolved in acetic acid (50 mL), and iron powder (0.51 g, 9.15 mmol) was added. The reaction mixture was reacted at 55 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (80 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow oil 30b (0.64 g, yield 62%).

[0636] MS(ESI,pos.ion)m / z:431.0[M+H] + .

[0637] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydro) Isoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)

[0638] 30c of urethane

[0639] 6-(4-amino-2,6-dichlorophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 30b (0.65 g, 1.42 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution of sodium nitrite (0.20 g, 2.90 mmol) (6 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.27 g, 1.71 mmol). The reaction was allowed to proceed for 2 hours. The reaction was quenched with water (100 mL), stirred for 20 minutes, filtered, and the filter cake was washed with water (5 mL × 2). The filter cake was collected and dried to give a pale yellow solid 30c (0.94 g, 100% yield).

[0640] Step 4: 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 30d)

[0641] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was 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 a yellow solid 30d (0.45 g, yield 52%, HPLC purity: 94.04%).

[0642] MS(ESI,neg.ion)m / z:550.0[MH] - ;

[0643] 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).

[0644] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) (Lin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 30e

[0645] 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 30d (0.45 g, 0.79 mmol) was dissolved in acetic acid (6 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 30e (0.41 g, yield 89%).

[0646] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 30

[0647] 30e of 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 30e (0.41 g, 0.68 mmol) was dissolved in mercaptoacetic acid (3 mL) and reacted at 140 °C for 19 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The solution was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1). The 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%).

[0648] MS(ESI,neg.ion)m / z:543.0[MH] - ;

[0649] 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).

[0650] Example 31 2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 31

[0651]

[0652] Step 1: 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 31a

[0653] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.00 g, 2.83 mmol) was dissolved in tetrahydrofuran (14 mL). 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 reaction at room temperature for 3 hours. The reaction was quenched with 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, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give a pale yellow oil 31a (1.30 g, 99% yield). MS(ESI,pos.ion)m / z:461.1[M+H] + .

[0654] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 31b

[0655] 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 31a (1.80 g, 3.90 mmol) was dissolved in acetic acid (50 mL), and iron powder (0.87 g, 15.2 mmol) was added. The reaction mixture was reacted at 55 °C for 7 hours. The reaction mixture was cooled to room temperature, and the reaction was quenched with water (80 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a white solid 31b (1.29 g, 77% yield). Step 3: (2-Cyano-2-(2-(3,5-) Dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)amino Ethyl carbamate 31c

[0656] 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 31b (0.60 g, 1.39 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution of sodium nitrite (0.19 g, 2.78 mmol) (5 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.26 g, 1.67 mmol). The reaction was allowed to proceed for 2 hours. The reaction was quenched with water (100 mL), stirred for 20 minutes, filtered, and the filter cake was washed with water (5 mL × 2). The filter cake was collected and dried to give a pale yellow solid 31c (0.92 g, 100% yield).

[0657] Step 4: 2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy (3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0658] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was 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 a yellow solid 31d (0.75 g, 99% yield).

[0659] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(((3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 31e

[0660] 2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 31d (0.39 g, 0.71 mmol) was dissolved in acetic acid (10 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 31e (0.40 g, 98% yield).

[0661] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (2H,4H)-1,2,4-triazine-3,5(2H,4H)-dione

[0662] 2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 31e (0.40 g, 0.70 mmol) was dissolved in mercaptoacetic acid (3 mL) and reacted at 140 °C for 19 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The solution was washed successively with water (10 mL) and saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1). The solid was recrystallized at 70 °C (ethyl acetate / methanol / petroleum ether (v / v / v) = 5 / 1 / 10, 32 mL) to give white solid 31 (0.20 g, yield 54%, HPLC purity: 93.81%).

[0663] MS(ESI,neg.ion)m / z:525.0[MH] - ;

[0664] 1 H 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).

[0665] Example 32 2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 32

[0666]

[0667] Step 1: 2-(3,5-difluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1 (2H)-Keto 32a

[0668] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.0 g, 2.83 mmol) was dissolved in tetrahydrofuran (14 mL). 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 with 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, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow oil 32a (1.26 g, 93% yield).

[0669] MS(ESI,pos.ion)m / z:480.1[M+H] + .

[0670] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3,5-difluorobenzyl)-3,4-dihydroisoquinoline-1 (2H)-Ketone 32b

[0671] 2-(3,5-difluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 32a (0.99 g, 2.1 mmol) was dissolved in acetic acid (20 mL), and iron powder (0.24 g, 4.3 mmol) was added. The reaction mixture was reacted at 50 °C for 2.5 h. The reaction mixture was cooled to room temperature, and the reaction was quenched with water (30 mL). The mixture was 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give a pale yellow oil 32b (0.68 g, yield 58%).

[0672] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydro) Isoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)

[0673] 32c of urethane

[0674] 6-(4-amino-2,6-dichlorophenoxy)-2-(3,5-difluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 32b (0.68 g, 1.5 mmol) was dissolved in acetic acid (20 mL), and an aqueous solution of sodium nitrite (0.21 g, 3.0 mmol) (9 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.35 g, 2.3 mmol). The reaction was allowed to proceed for 3 hours. The reaction was quenched with water (60 mL), stirred for 20 minutes, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried to give a pale yellow solid 32c (0.93 g, 100% yield).

[0675] MS(ESI,neg.ion)m / z:615.2[MH] - .

[0676] Step 4: 2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (32d)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile

[0677] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 8 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (50 mL). The mixture was 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 a yellow solid 32d (0.63 g, yield 73%, HPLC purity: 95.85%).

[0678] MS(ESI,neg.ion)m / z:571.3[MH] - ;

[0679] 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).

[0680] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) (32e)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0681] 2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 32d (0.55 g, 0.96 mmol) was dissolved in acetic acid (10 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 °C for 8 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 32e (0.48 g, yield 84%).

[0682] MS(ESI,pos.ion)m / z:590.0[M+H] + .

[0683] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3,4-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 32

[0684] 0.48 g (0.81 mmol) of 2-(3,5-dichloro-4-((2-(3,5-difluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 32e was dissolved in mercaptoacetic acid (5 mL) and reacted at 140 °C for 16 hours. The reaction solution 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). The solution was dried over anhydrous sodium sulfate, 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%). MS (ESI, neg.ion) m / z: 544.2 [MH] - ;

[0685] 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).

[0686] Example 33 2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 33

[0687]

[0688] Step 1: 2-(2-fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 33a

[0689] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.0 g, 2.8 mmol) was dissolved in tetrahydrofuran (40 mL). 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 with 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, filtered and concentrated. The 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, 76% yield).

[0690] MS(ESI,pos.ion)m / z:461.1[M+H] + .

[0691] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 33b

[0692] 2-(2-fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 33a (0.99 g, 2.1 mmol) was dissolved in acetic acid (20 mL), and iron powder (0.24 g, 4.3 mmol) was added. The reaction mixture was reacted at 50 °C for 2.5 h. The reaction solution was cooled to room temperature, and the reaction was quenched with water (30 mL). The mixture was 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow oil 33b (0.62 g, yield 67%).

[0693] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) 33c (P-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0694] 6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 33b (0.62 g, 1.4 mmol) was dissolved in acetic acid (18 mL), and an aqueous solution of sodium nitrite (0.20 g, 2.9 mmol) (9 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.34 g, 2.2 mmol). The reaction was allowed to proceed for 3 hours. The reaction was quenched with water (50 mL), stirred for 20 minutes, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried to give a pale yellow solid 33c (0.86 g, 100% yield).

[0695] MS(ESI,neg.ion)m / z:599.2[MH] - .

[0696] Step 4: 2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy (3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0697] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (50 mL). The mixture was 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 a yellow solid 33d (0.49 g, yield 63%, HPLC purity: 96.04%).

[0698] MS(ESI,pos.ion)m / z:553.0[M+H] + ;

[0699] 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, 3.3 Hz,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).

[0700] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 33e

[0701] 2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 33d (0.43 g, 0.78 mmol) was dissolved in acetic acid (10 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 °C for 8 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 33e (0.38 g, yield 85%).

[0702] MS(ESI,pos.ion)m / z:572.0[M+H] + .

[0703] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (33)-1,2,4-triazine-3,5(2H,4H)-dione

[0704] 0.38 g (0.66 mmol) of 2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 33e was dissolved in mercaptoacetic acid (5 mL) and reacted at 140 °C for 16 hours. The reaction solution 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). The solution was dried over anhydrous sodium sulfate, 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 33 (0.29 g, yield 83%, HPLC purity: 99.47%). MS (ESI, pos.ion) m / z: 527.0 [M+H] + ;

[0705] 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).

[0706] Example 34 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 34

[0707]

[0708] Step 1: 2-(3-(trifluoromethyl)benzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1 (2H)-Keto 34a

[0709] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.0 g, 2.8 mmol) was dissolved in tetrahydrofuran (40 mL). Sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 20 minutes, 3-trifluoromethylbenzyl bromide (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 with 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, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a pale yellow oil 34a (0.86 g, yield 59%).

[0710] MS(ESI,neg.ion)m / z:647.1[MH] - .

[0711] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 34b

[0712] 2-(3-(trifluoromethyl)benzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 34a (0.86 g, 1.7 mmol) was dissolved in acetic acid (20 mL), and iron powder (0.24 g, 4.3 mmol) was added. The reaction mixture was reacted at 50 °C for 2.5 h. The reaction solution was cooled to room temperature, and the reaction was quenched with water (30 mL). The mixture was 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, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to give a pale yellow oil 34b (0.63 g, 78% yield).

[0713] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)

[0714] Acetyl 34c

[0715] 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-1(2H)-one 34b (0.63 g, 1.3 mmol) was dissolved in acetic acid (18 mL), and an aqueous solution of sodium nitrite (0.18 g, 2.6 mmol) (9 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.31 g, 2.0 mmol). The reaction was allowed to proceed for 3 hours. The reaction was quenched with water (50 mL), stirred for 20 minutes, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried to give a pale yellow solid 34c (0.85 g, 100% yield).

[0716] MS(ESI,neg.ion)m / z:647.1[MH] - .

[0717] Step 4: 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 34d

[0718] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (50 mL). The mixture was stirred for 15 minutes, 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 a yellow solid 34d (0.55 g, yield 70%, HPLC purity: 97.82%).

[0719] MS(ESI,neg.ion)m / z:601.3[MH] - ;

[0720] 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).

[0721] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisocyanuric acid) Quinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 34e

[0722] 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 34d (0.47 g, 0.80 mmol) was dissolved in acetic acid (10 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 °C for 8 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 34e (0.43 g, yield 89%).

[0723] MS(ESI,neg.ion)m / z:622.0[MH] - .

[0724] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisocyanuric acid) Quinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 34

[0725] 0.43 g (0.71 mmol) of 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 34e was dissolved in mercaptoacetic acid (5 mL) and reacted at 140 °C for 15 hours. The reaction solution 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). After drying with anhydrous sodium sulfate, the solution was 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 34 (0.24 g, yield 60%, HPLC purity: 99.41%). MS (ESI, neg.ion) m / z: 576.0 [MH] - ;

[0726] 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).

[0727] Example 35 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 35

[0728]

[0729] Step 1: 2-(3-chloro-4-fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1 (2H)-Keto 35a

[0730] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.0 g, 2.8 mmol) was dissolved in tetrahydrofuran (40 mL). 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 with 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, filtered and concentrated. The 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, 71% yield).

[0731] Step 2: 6-(4-amino-2,6-dichlorophenoxy)-2-(3-chloro-4-fluorobenzyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 35b

[0732] 2-(3-chloro-4-fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 35a (0.99 g, 2.0 mmol) was dissolved in acetic acid (20 mL), and iron powder (0.22 g, 4.0 mmol) was added. The reaction mixture was reacted at 50 °C for 2.5 h. The reaction solution was cooled to room temperature, and the reaction was quenched with water (30 mL). The mixture was 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to give a pale yellow oil 35b (0.61 g, yield 66%).

[0733] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrachloro) Hydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate ethyl 35c

[0734] 6-(4-amino-2,6-dichlorophenoxy)-2-(3-chloro-4-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 35b (0.61 g, 1.3 mmol) was dissolved in acetic acid (18 mL), and an aqueous solution of sodium nitrite (0.18 g, 2.6 mmol) (9 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.31 g, 2.0 mmol). The reaction was allowed to proceed for 3 hours. The reaction was quenched with water (50 mL), stirred for 20 minutes, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried to give a pale yellow solid 35c (0.83 g, 100% yield).

[0735] MS(ESI,neg.ion)m / z:631.1[MH] - .

[0736] Step 4: 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0737] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (50 mL). The mixture was stirred for 15 minutes, 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 a yellow solid 35d (0.57 g, yield 74%, HPLC purity: 93.07%).

[0738] MS(ESI,neg.ion)m / z:585.0[MH] - ;

[0739] 1 H 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).

[0740] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) (35e)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0741] 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 35d (0.47 g, 0.80 mmol) was dissolved in acetic acid (10 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 °C for 8 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to obtain a light yellow solid 35e (0.43 g, yield 89%).

[0742] MS(ESI,pos.ion)m / z:606.9[M+H] + .

[0743] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) (Lin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 35

[0744] 0.43 g (0.71 mmol) of 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 35e was dissolved in mercaptoacetic acid (5 mL), and the reaction was carried out at 140 °C for 15 hours. The reaction solution 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). The solution was dried over anhydrous sodium sulfate, 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 35 (0.26 g, yield 65%, HPLC purity: 98.66%). MS (ESI, neg.ion) m / z: 561.1 [MH] - ;

[0745] 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).

[0746] Example 36 2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 36

[0747]

[0748] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 36a

[0749] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.8 g, 5.1 mmol) was dissolved in tetrahydrofuran (35 mL). Sodium hydride (0.18 g, 7.6 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 5 minutes, 1-bromomethyl-3-methoxybenzene (1.0 g, 5.0 mmol) was added dropwise, and the reaction was continued at room temperature for 8 hours. The reaction was quenched with ice water (20 mL), and the mixture was 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a white solid 36a (1.9 g, 79% yield).

[0750] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 36b

[0751] 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinoline-1(2H)-one 36a (1.9 g, 4.0 mmol) was dissolved in acetic acid (7 mL), and iron powder (0.67 g, 12 mmol) was added. The reaction was carried out at 60 °C for 4 hours. The reaction solution was cooled to room temperature, and the reaction was quenched by adding water (5 mL). Excess iron powder was filtered off, and water (10 mL) was added to the filtrate. The mixture was stirred for 10 minutes, filtered, washed with water (10 mL), and the filter cake was collected and dried to obtain brown solid 36b (1.7 g, 93% yield).

[0752] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4- Tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)

[0753] Acetyl 36c

[0754] 6-(4-amino-2,6-dichlorophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinoline-1(2H)-one 36b (1.65 g, 3.72 mmol) was dissolved in acetic acid (6 mL), and an aqueous solution of sodium nitrite (0.39 g, 5.58 mmol) (3 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.86 g, 4.65 mmol). The reaction was allowed to proceed for 1 hour. The reaction was quenched with water (20 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (5 mL × 2). The filter cake was collected and dried to give a yellow solid 36c (2.1 g, 92% yield).

[0755] Step 4: Synthesis of 2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 36d.

[0756] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was 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 a yellow solid 36d (0.75 g, 99% yield).

[0757] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) (Lin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 36e

[0758] 2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 36d (0.45 g, 0.80 mmol) was dissolved in acetic acid (6 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 °C for 16 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (5 mL × 2). The filter cake was collected and dried to give a yellow solid 36e (0.40 g, yield 86%).

[0759] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 36

[0760] 0.40 g (0.69 mmol) of 2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 36e was dissolved in mercaptoacetic 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a white solid 36 (39 mg, yield 11%, HPLC purity: 94.35%).

[0761] MS(ESI,neg.ion)m / z:537.1[MH] - ;

[0762] 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).

[0763] Example 37 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 37

[0764]

[0765] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 37a

[0766] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (3.0 g, 8.5 mmol) was dissolved in tetrahydrofuran (35 mL). Sodium hydride (0.31 g, 13.0 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 5 minutes, 1-chloromethyl-4-chlorobenzene (2.7 g, 17.0 mmol) was added dropwise, and the reaction was continued at room temperature for 8 hours. The reaction was quenched with ice water (20 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a white solid 37a (1.75 g, 43% yield).

[0767] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 37b

[0768] 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 37a (1.75 g, 3.66 mmol) was dissolved in acetic acid (7 mL), and iron powder (0.61 g, 11.0 mmol) was added. The reaction was carried out at 60 °C for 4.5 h. The reaction solution was cooled to room temperature, and the reaction was quenched by adding water (5 mL). Excess iron powder was filtered off, and water (10 mL) was added to the filtrate. The mixture was stirred for 10 min, filtered, washed with water (10 mL), and the filter cake was collected and dried to obtain brown solid 37b (1.55 g, 95% yield).

[0769] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydro) Isoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate ethyl 37c

[0770] 6-(4-amino-2,6-dichlorophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one 37b (1.55 g, 3.46 mmol) was dissolved in acetic acid (6 mL), and an aqueous solution of sodium nitrite (0.36 g, 5.25 mmol) (3 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.81 g, 4.37 mmol). The reaction was allowed to proceed for 1 hour. The reaction was quenched with water (20 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (5 mL). The filter cake was collected and dried to give a yellow solid 37c (1.90 g, 89% yield).

[0771] Step 4: Synthesis of 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 37d.

[0772] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was 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 a yellow solid 37d (0.50 g, yield 28%, HPLC purity: 95.83%). MS (ESI, neg.ion) m / z: 566.0 [MH] - ;

[0773] 1H 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).

[0774] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- 37e)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0775] 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 37d (0.40 g, 0.70 mmol) was dissolved in acetic acid (6 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 °C for 17 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (5 mL × 2). The filter cake was collected and dried to give a yellow solid 37e (0.40 g, 97% yield).

[0776] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (2H,4H)-1,2,4-triazine-3,5(2H,4H)-dione 37

[0777] 0.15 g (0.26 mmol) of 2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 37e was dissolved in mercaptoacetic acid (3 mL) and reacted at 160 °C for 12 h. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The solution was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL), and saturated sodium chloride solution (10 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a white solid 37 (0.14 g, yield 38%, HPLC purity: 97.64%).

[0778] MS(ESI,neg.ion)m / z:541.0[MH] - ;

[0779] 1H 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).

[0780] Example 38 2-(3,5-dichloro-4-((2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0781]

[0782] Step 1: Synthesis of 6-methoxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinoline-1(2H)-one 38a

[0783] 6-Methoxy-3,4-dihydroisoquinoline-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), and then N,N-dimethylformamide (30 mL). After the addition was complete, the reaction was continued at room temperature for 24 hours. The reaction was quenched with water (40 mL), and the mixture was extracted with ethyl acetate (45 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a pale yellow oil 38a (2.56 g, 78% yield).

[0784] MS(ESI,pos.ion)m / z:232.2[M+H] + .

[0785] Step 2: Synthesis of 6-hydroxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinoline-1(2H)-one 38b

[0786] 6-Methoxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinoline-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 slowly added dropwise at 0 °C, maintaining the reaction at 0 °C for 1.5 h. The reaction was quenched by adding methanol (5 mL) at 0 °C, concentrated, and then water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a pale yellow solid 38b (1.01 g, 45% yield).

[0787] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 38c

[0788] 6-Hydroxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinoline-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 reacted at 80 °C for 6 hours. The reaction solution was cooled to room temperature, and water (15 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid 38c (0.96 g, yield 51%).

[0789] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinoline-1 (2H)-ketone 38d

[0790] 6-(2,6-dichloro-4-nitrophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinoline-1(2H)-one 38c (0.91 g, 2.23 mmol) was dissolved in acetic acid (15 mL), and iron powder (0.51 g, 8.93 mmol) was added. The reaction was carried out at 60 °C for 6.5 h. After cooling to room temperature, the iron powder was removed, water (25 mL) was added, and the mixture was stirred for 10 min. The mixture was filtered, washed with water (10 × 2), and the filter cake was collected and dried to give a pale yellow solid 38d (0.72 g, 86% yield). MS (ESI, pos.ion) m / z: 477.1 [M+H] + .

[0791] Step 5: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrachloro) Hydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate ethyl 38e

[0792] 6-(4-amino-2,6-dichlorophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinoline-1(2H)-one 38d (0.72 g, 1.91 mmol) was dissolved in acetic acid (10 mL). A solution of sodium nitrite (0.20 g, 2.87 mmol) in water (0.5 mL) was slowly added dropwise at 0 °C. After reacting for 20 minutes, N-cyanoaceturane (0.34 g, 2.10 mmol) was added, and the reaction continued for 4.5 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 38e (0.97 g, 93% yield).

[0793] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0794] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazyl)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 solution was cooled to room temperature, water (20 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 × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1). The solid obtained was then recrystallized (petroleum ether / ethyl acetate = 3 / 1, 20 mL) to give a white solid 38 (0.13 g, yield 14%, HPLC purity: 96.32%).

[0795] MS(ESI,neg.ion)m / z:496.1[MH] - .

[0796] 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 (d t,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).

[0797] Example 39 2-(3,5-dichloro-4-((2-(hydroxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0798]

[0799] 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 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 solution was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The 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%).

[0800] MS(ESI,neg.ion)m / z:472.1[MH] - ;

[0801] 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).

[0802] Example 40 2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 40

[0803]

[0804] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinoline 1-Lin-1(2H)-one 40a

[0805] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (2.0 g, 5.7 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium hydride (0.60 g, 15.0 mmol, 60 mass% in oil) was added at 0 °C. After reacting for 10 minutes, 2-bromomethyl-4-fluoro-1-methylbenzene (1.0 mL, 7.2 mmol) and N,N-dimethylformamide (2 mL) were added dropwise, followed by reaction at room temperature for 3 hours. The reaction was quenched with water (100 mL), extracted with ethyl acetate (120 mL), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a white solid 40a (2.1 g, 77% yield).

[0806] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinone 1-Lin-1(2H)-one 40b

[0807] 6-(2,6-dichloro-4-nitrophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinoline-1(2H)-one 40a (2.0 g, 4.2 mmol) was dissolved in acetic acid (25 mL), and iron powder (0.60 g, 10.0 mmol) was added. The reaction was carried out at 60 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched by adding water (100 mL). The mixture was stirred for 10 minutes, filtered, washed with water (50 mL), and the filter cake was collected and dried. The resulting solid was slurried with petroleum ether / ethyl acetate (6 / 1, 20 mL) to give a white solid 40b (1.1 g, 59% yield).

[0808] Step 3: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2, 3,4-Tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)

[0809] Acetyl 40c

[0810] 6-(4-amino-2,6-dichlorophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinoline-1(2H)-one 40b (1.0 g, 2.2 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution of sodium nitrite (0.31 g, 4.5 mmol) (5 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.50 g, 3.0 mmol), and the reaction was allowed to proceed for 2 hours. The reaction was quenched with water (30 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (5 mL × 2). The filter cake was collected, dried, and the resulting solid was slurried with petroleum ether / ethyl acetate (5 / 2, 35 mL) to give a yellow solid 40c (1.1 g, 80% yield).

[0811] Step 4: Synthesis of 2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) lin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 40d.

[0812] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched by adding water (25 mL). The mixture was 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 a white solid 40d (0.66 g, yield 65%, HPLC purity: 97.55%).

[0813] MS(ESI,neg.ion)m / z:564.0[MH] - ;

[0814] 1 H 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).

[0815] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisocyanuric acid) Quinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 40e

[0816] 2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 40d (0.60 g, 1.1 mmol) was dissolved in acetic acid (10 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 40e (0.40 g, 60% yield).

[0817] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline) (Lin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 40

[0818] 0.40 g (0.68 mmol) of 2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 40e was dissolved in mercaptoacetic 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, filtered, and concentrated. The 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%).

[0819] MS(ESI,neg.ion)m / z:539.2[MH] - ;

[0820] 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).

[0821] Example 41 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 41

[0822]

[0823] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisocyanate Quinoline-1(2H)-one 41a

[0824] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (1.50 g, 4.20 mmol) was dissolved in a mixed solution 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 reacting for 30 minutes, 4-trifluoromethoxybenzyl bromide (2.27 g, 8.90 mmol) was added dropwise, followed by reaction at room temperature for 3 hours. The reaction was quenched with ice water (20 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a yellow oil 41a (2.07 g, 93% yield).

[0825] MS(ESI,pos.ion)m / z:527.00[M+H] + .

[0826] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisocyanate Quinoline-1(2H)-one 41b

[0827] 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinoline-1(2H)-one 41a (2.07 g, 3.93 mmol) was dissolved in acetic acid (50 mL), and iron powder (0.88 g, 15.7 mmol) was added. The reaction mixture was reacted at 55 °C for 5 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (50 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a white solid 41b (1.59 g, 81% yield). Step 3: Synthesis of (2-cyano-2- (2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy) (phenyl)

[0828] 41c hydrazine (acetyl)carbamate

[0829] 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinoline-1(2H)-one 41b (0.60 g, 1.21 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution of sodium nitrite (0.17 g, 2.48 mmol) (6 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.23 g, 1.49 mmol). The reaction was allowed to proceed for 4 hours. The reaction was quenched with water (100 mL), stirred for 30 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 41c (0.87 g, 100% yield).

[0830] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydro Isoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 41d.

[0831] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was 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 a light red solid 41d (0.65 g, yield 88%, HPLC purity: 98.61%).

[0832] MS(ESI,neg.ion)m / z:616.0[MH] - ;

[0833] 1 H 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).

[0834] Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(1-oxo-4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydro Isoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 41e

[0835] 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 41d (0.32 g, 0.52 mmol) was dissolved in acetic acid (10 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 °C for 11 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (5 mL × 2). The filter cake was collected and dried to give a yellow solid 41e (0.35 g, 100% yield).

[0836] Step 6: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydro Isoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 41

[0837] 0.35 g (0.53 mmol) of 2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 41e was dissolved in mercaptoacetic 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, filtered, and concentrated. The 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%).

[0838] MS(ESI,neg.ion)m / z:591.0[MH] - ;

[0839] 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).

[0840] Example 42 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile)

[0841]

[0842] Step 1: Synthesis of 2-(3-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline-1(2H)-one 42a

[0843] 6-Methoxy-3,4-dihydroisoquinoline-1(2H)-one 5a (1.50 g, 8.5 mmol), iodide ionone (0.32 g, 1.7 mmol), m-fluoroiodobenzene (3.76 g, 16.9 mmol), and potassium carbonate (1.17 g, 8.47 mmol) were dissolved in N,N-dimethylformamide (40 mL) solution and reacted at 150 °C for 19 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (40 mL). The mixture was extracted with ethyl acetate (60 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 42a (2.22 g, 96% yield).

[0844] MS(ESI,pos.ion)m / z:272.2[M+H] + .

[0845] Step 2: Synthesis of 2-(3-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinoline-1(2H)-one 42b

[0846] At 0 °C, boron tribromide (2.4 mL, 25.0 mmol) was added dropwise to a solution of 2-(3-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline-1(2H)-one 42a (2.22 g, 8.17 mmol) in dichloromethane (30 mL), and the reaction was allowed to proceed at room temperature for 4 hours. The reaction mixture was then quenched in ice water (30 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL). The filter cake was collected, dried, and the resulting solid was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a white solid 42b (0.13 g, yield 4.5%).

[0847] MS(ESI,pos.ion)m / z:258.1[M+H] + .

[0848] Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinoline-1 (2H)-Ketone 42c

[0849] 2-(3-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinoline-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), and potassium carbonate (0.14 g, 1.01 mmol) was added. The mixture was reacted at 70 °C for 2 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (5 mL). The filter cake was collected and dried to give an off-white solid 42c (0.22 g, 97% yield).

[0850] Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinoline-1 (2H)-ketone 42d

[0851] 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinoline-1(2H)-one 42c (0.22 g, 0.49 mmol) was dissolved in acetic acid (6 mL), and iron powder (0.11 g, 1.95 mmol) was added. The mixture was reacted at 55 °C for 6 hours. The reaction solution 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 phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid 42d (0.18 g, 85% yield).

[0852] Step 5: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydro) Isoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate 42e

[0853] 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinoline-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 minutes, N-cyanoaceturane (79 mg, 0.51 mmol) was added, and the reaction was allowed to proceed for 3.5 hours. Water (20 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with water (10 mL), and the filter cake was collected and dried to give a yellow solid 42e (0.19 g, 73% yield).

[0854] Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (42f)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile

[0855] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)acetyl)carbamate 42e (0.35 g, 0.60 mmol) was dissolved in N,N-dimethylformamide (40 mL), and sodium acetate (0.12 g, 1.40 mmol) was added. The mixture was reacted at 120 °C for 8 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (80 mL). It was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate). The solid obtained was recrystallized at 80 °C (petroleum ether / ethyl acetate = 1 / 2, 24 mL) to give a yellow solid 42f (0.25 g, yield 76%, HPLC purity: 99.44%).

[0856] MS(ESI,neg.ion)m / z:536.1[MH] - ;

[0857] 1H 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).

[0858] Step 7: Synthesis of 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- 42g of (hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0859] 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 42f (0.26 g, 0.49 mmol) was dissolved in acetic acid (5 mL), and concentrated hydrochloric acid (2.5 mL) was added. The mixture was reacted at 100 °C for 7 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give 42 g (0.22 g, 78% yield) of a yellow solid.

[0860] Step 8: Synthesis of 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- (2H,4H)-1,2,4-triazine-3,5(2H,4H)-dione 42

[0861] 42 g (0.22 g, 0.40 mmol) of 2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was dissolved in 2 mL of mercaptoacetic acid and reacted at 140 °C for 14 hours. The reaction mixture was cooled to room temperature, and 30 mL of ethyl acetate was added. The mixture was washed successively with 10 mL of water and 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1). The resulting solid was recrystallized at 85 °C (petroleum ether / ethyl acetate = 1 / 1, 20 mL) to give 42 g (88 mg, yield 43%, HPLC purity: 98.94%) of a white solid.

[0862] MS(ESI,neg.ion)m / z:511.1[MH] - ;

[0863] 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).

[0864] Example 43 2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 43

[0865]

[0866] Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisocyanate Quinoline-1(2H)-one 43a

[0867] 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2H)-one 1b (2.5 g, 7.1 mmol) was dissolved in tetrahydrofuran (25 mL), and sodium hydride (0.60 g, 20 mmol, 60 mass% in oil) was added at 0 °C. 3-trifluoromethoxybenzyl bromide (1.4 g, 8.6 mmol) and N,N-dimethylformamide (2 mL) were then added dropwise, and the reaction was maintained at 0 °C for 5 hours. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was washed with saturated sodium chloride (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a yellow oil 43a (2.6 g, 70% yield).

[0868] Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisocyanate Quinoline-1(2H)-one 43b

[0869] 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinoline-1(2H)-one 43a (2.5 g, 4.7 mmol) was dissolved in acetic acid (30 mL), and iron powder (0.55 g, 9.8 mmol) was added. The reaction mixture was reacted at 60 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (60 mL). The mixture was 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, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a yellow oil 43b (1.5 g, 64% yield).

[0870] Step 3: Synthesize (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1, 2,3,4-Tetrahydroisoquinoline-6-yl)oxy)phenyl)

[0871] 43c hydrazine (acetyl)carbamate

[0872] 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinoline-1(2H)-one 43b (1.5 g, 3.0 mmol) was dissolved in acetic acid (20 mL), and an aqueous solution of sodium nitrite (0.42 g, 6.1 mmol) (6 mL) was added at 0 °C, followed by the addition of N-cyanoaceturane (0.61 g, 3.9 mmol). The reaction was allowed to proceed for 2 hours. The reaction was quenched with water (30 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried to give a yellow solid 43c (1.6 g, 80% yield).

[0873] Step 4: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydro Isoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile 43d.

[0874] Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)hydrazine)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 reaction was carried out at 120 °C for 6 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with water (35 mL). The mixture was stirred for 10 minutes, filtered, and the filter cake was collected, dried, and then recrystallized at 85 °C (ethanol / ethyl acetate / petroleum ether = 5 / 20 / 18, 43 mL) to give a white solid 43d (0.80 g, yield 57%, HPLC purity: 98.83%).

[0875] MS(ESI,neg.ion)m / z:616.0[MH] - ;

[0876] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.33 (s, 1H), 7.93 (d, J = 8.3Hz, 1H), 7.84 (s, 2H), 7.48 (t, J = 7.8Hz, 1H), 7.36 (d, J =7.7Hz,1H),7.33-7.13(m,2H),6.85(d,J=9.3Hz,2H),4.74(s,2H),3.52(t,J=6.4Hz,2H),2.97(t,J=6.2Hz,2H).

[0877] Step 5: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydro Isoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 43e

[0878] 2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 43d (0.80 g, 1.3 mmol) was dissolved in acetic acid (12 mL), ...

Claims

1. A compound, which is a compound represented by formula (I) or a pharmaceutically acceptable salt of a compound represented by formula (I), in, Y is -O-; R 3a , R 3b , R 3c and R 3d are independently H, deuterium, F, Cl, Br, I, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1 H, deuterium, F, Cl, Br, I, -CN, C 1-6 Alkyl or -C(=O)-C 1-6 Alkoxy; R 2 H, deuterium or C 1-6 alkyl; Ring A is wherein ring A is optionally substituted by 1, 2 or 3 R y replaced by; E1 is -(CR 4a R 4b ) q -; E2 is -CR 4c R 4d -; E3 and E6 are each independently -NR c -; E4-CR 4g =; E5 is -CR 4h =; q is 1 or 2; R c H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5-6 atoms, wherein R c 1, 2 or 3 R y1 replaced by; R 4a , R 4b , R 4c , R 4d , R 4g and R 4h are independently H, deuterium, F, Cl, Br, I, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 A haloalkoxy group, wherein R 4a , R 4b , R 4c , R 4d , R 4g and R 4h 1, 2 or 3 R y2 replaced by; Each R y Deuterium, F, Cl, Br, I, C 1-6 Alkyl or C 1-6 Haloalkyl; Each R y1 are independently deuterium, F, Cl, Br, I, -OH, oxo, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 Aryl or heteroaryl composed of 5-6 atoms, wherein each R y1 1, 2 or 3 R z replaced by; R z and R y2 each independently deuterium, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy or C 1-6 Alkoxy; The heterocyclic group consisting of 5 to 6 atoms refers to a saturated or partially unsaturated, non-aromatic monocyclic ring system containing 5 to 6 atoms.

2. The compound according to claim 1, wherein R 3a , R 3b , R 3c and R 3d Each is independently H, deuterium, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3 or -CH2CHF2.

3. The compound according to claim 1 or 2, wherein R 1 It is H, deuterium, F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, -C(=O)-OCH3, -C(=O)-OCH2CH3, -C(=O)-OCH(CH3)2, -C(=O)-OCH2CH2CH3, -C(=O)-O(CH2)3CH3 or -C(=O)-OCH2CH(CH3)2.

4. The compound according to claim 1, wherein R c H, deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5-6 atoms, wherein R c 1, 2 or 3 R y1 replaced.

5. The compound according to claim 1 or 4, wherein R c is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, thienyl, imidazolyl, pyrimidinyl, pyridinyl, pyrrolyl, pyrazinyl, thiazolyl or oxazolyl, wherein R c 1, 2 or 3 R y1 replaced.

6. The compound according to claim 1, wherein each R y1 are independently deuterium, F, Cl, Br, I, -OH, oxo, -C(=O)-C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Alkoxy, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 Aryl or heteroaryl composed of 5-6 atoms, wherein each R y1 1, 2 or 3 R z replaced.

7. The compound according to claim 1 or 6, wherein each R y1 are independently deuterium, F, Cl, Br, I, -OH, oxo, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-n-propyl, -C(=O)-isopropyl, -C(=O)-n-butyl, -C(=O)-tert-butyl, -C(=O)-isobutyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCHFCH3, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, thienyl, imidazolyl, pyrimidinyl, pyridinyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl or oxazolyl, wherein each R y1 1, 2 or 3 R z replaced.

8. The compound according to claim 1, wherein R 4a , R 4b , R 4c , R 4d , R 4g and R 4h are each independently H, deuterium, F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2 or -OCH2F, wherein R 4a , R 4b , R 4c , R 4d , R 4g and R 4h 1, 2 or 3 R y2 replaced.

9. The compound according to claim 1, wherein R z and R y2 Each is independently deuterium, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, methoxy or ethoxy.

10. A compound having one of the following structures: or a pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, further comprising a pharmaceutically acceptable excipient.

12. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 in the preparation of a drug, wherein: The drug is used to prevent, treat or alleviate the following diseases: neurodegenerative diseases, non-alcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, obesity, diabetes, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer.

13. The use according to claim 12, wherein The non-alcoholic fatty liver disease is non-alcoholic simple fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer; The neurodegenerative disease is a demyelinating disease, leukodystrophy, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenocortical dystrophy, amyotrophic lateral sclerosis or Alzheimer's disease.

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