TW202325701A - A COMPOUND AS A THYROID HORMONE β RECEPTOR AGONIST AND USE THEREOF - Google Patents

Abstract

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

Description

A compound as thyroid hormone beta receptor agonist and its use

The invention belongs to the field of medicines, and specifically relates to a compound as a thyroid hormone beta receptor agonist and its use, and further relates to a pharmaceutical composition containing the compound. The present invention further relates to the use of said compounds and pharmaceutical compositions in the preparation of medicines for preventing, treating or alleviating diseases regulated by thyroid hormone beta receptors, especially the preparation of medicines for treating non-alcoholic fatty liver disease use in .

Thyroid hormone (TH) plays an extremely important role in growth, differentiation, development and maintenance of metabolic balance. TH is synthesized by the thyroid gland and secreted into the circulation in two major forms, triiodothyronine (T3) and tetraiodothyronine (T4). Although T4 is the predominant form secreted by the thyroid, T3 is the more physiologically active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues but mainly in the liver and kidney.

The physiological role of TH is mainly carried out through the thyroid hormone receptor (thyroid hormone receptor, TR). TR is a member of the nuclear receptor superfamily, is a transcription factor induced by ligand T3, and plays a central role in mediating the action of ligand T3. TR is mainly located in the nucleus, forms a heterodimer with retinoid X receptor (RXR) and other nuclear receptors, and binds to the thyroid hormone response element (TRE) in the promoter region of the target gene , thereby regulating gene transcription. There are two subtypes of TR: TRα and TRβ. TRα can be divided into TRα1 and TRα2, and TRβ can be further divided into TRβ1 and TRβ2. Among them, only TRα1, TRβ1 and TRβ2 can bind the ligand T3. TRα mainly regulates heart rate, and TRβ plays a key 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.

If the side effects can be minimized or eliminated, then TH has certain therapeutic benefits (Paul M. Yen et. al. Physiological Reviews, Vol. 81(3): pp. 1097-1126 (2001); Paul Webb et. al. Expert Opin. Investig. Drugs, Vol. 13(5): pp. 489-500 (2004)). For example, TH increases metabolic rate, oxygen consumption, and heat production, thereby reducing body weight. Reducing body weight will have a beneficial effect on obese patients by improving obesity-related co-morbidities and may also have a beneficial effect on glycemic control in obese patients with type 2 diabetes.

TH also lowers 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 due to TH increasing hepatic LDL receptor expression and stimulating the metabolism of cholesterol to bile acids (JJ. Abrams et. al. J. Lipid Res., Vol. 22 : pp. 323-38 (1981)). Hypothyroidism is associated with hypercholesterolemia, and TH replacement therapy has been reported to reduce total cholesterol (M. Aviram et. al. Clin. Biochem., Vol. 15: pp. 62-66 (1982); JJ . Abrams et. al. J. Lipid Res., Vol. 22: pp. 323-38 (1981)). In animal models, TH has been shown to have beneficial effects in increasing HDL cholesterol and increasing the conversion rate of LDL to HDL by increasing the expression of apo A-1 (one of the major apolipoproteins of HDL) (Gene C. Ness et al. . 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 the level of LDL cholesterol. Through the regulation of LDL and HDL, TH may also reduce the risk of atherosclerosis and other cardiovascular diseases. In addition, there is evidence that TH reduces lipoprotein(a), an important risk factor, which 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)).

TH is also a key signal for oligodendrocyte differentiation and myelination during development and stimulates remyelination in adult models of multiple sclerosis (MS) (Calza et al., Brain Res Revs 48:339-346, 2005 ). However, due to the limited therapeutic window to achieve remyelination while avoiding the cardiotoxicity and bone demineralization associated with chronic hyperthyroidism, TH cannot be used in a long-term course. Some TH analogs can turn on TH-responsive genes while avoiding TH-related disadvantages by exploiting the molecular and physiological features of TH receptors (Malm et. al. Mini Rev Med Chem 7:79-86, 2007).

In addition, non-alcoholic fatty liver disease (NAFLD) is also closely related to TH. On the one hand, NAFLD affects the transformation and inactivation of TH, which can lead to a decrease in serum TH level; on the other hand, the decrease in TH level further causes lipid metabolism disorder and glucose metabolism disorder, and participates in the occurrence of NAFLD. Studies have shown that fatty liver formation in rats was induced by a choline-methionine-deficient diet, and the reversal of fatty liver can be observed after feeding T3 (Perra A, et al. Faseb, 2008, 22 (8): 2981).

However, endogenous TH is non-selective and has side effects, such as hyperthyroidism, especially related to cardiovascular toxicity. Therefore, the development of TH analogues (such as thyroid hormone β receptor agonists) that avoid the adverse effects of hyperthyroidism while maintaining the beneficial effects of TH will open new avenues for the treatment of patients with diseases such as obesity, hyperlipidemia , hypercholesterolemia, diabetes mellitus, hepatic steatosis, nonalcoholic fatty liver disease, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, and related conditions and diseases.

The present invention provides a class of compounds with good agonistic activity on thyroid hormone β receptors. Such compounds and their pharmaceutical compositions can be prepared for preventing, treating or alleviating non-alcoholic fatty liver disease, liver fibrosis, special Oncogenic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, 1A Glycogen storage disease, hypothyroidism, or thyroid cancer.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite products, pharmaceutically acceptable salts or their prodrugs, (I),

in,

Y is -O-, -S-, -NR ⁰ -, -C(=O)-, C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, -NR ⁰ C(=O)- or -C(=O)NR ⁰ -; wherein said Y is optionally substituted by 1, 2 or 3 R ^x ;

R ⁰ is H, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , hydroxy C _1-6 alkyl, amino C _1-6 alkyl or cyano C _1-6 alkyl;

R ^3a , R ^3b , R ^3c and R ^3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, C _{1- 6} alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkyl, C _{1-6 haloalkoxy} , hydroxy C _1-6 alkane Base, amino C _1-6 alkyl or cyano C _1-6 alkyl;

R ¹ is H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C(=O)-C _1-6 alkoxy, -C(=O)-C _1-6 alkyl, -C(=O)-C _1-6 alkylamino, - C(=O)NH ₂ , -S(=O) ₂ -C _1-6 alkyl, -S(=O) ₂ -C _1-6 alkylamino, -S(=O) ₂ NH ₂ , C _{1 -6} alkylamino, C _1-6 alkoxy, C _1-6 haloalkyl, C _{1-6 haloalkoxy} , hydroxy C _1-6 alkyl, amino C _1-6 alkyl, carboxy C _{1- 6} alkyl or cyano C _1-6 alkyl;

R ² is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclic group consisting of 5-6 atoms, C _{6- 10} aryl groups or heteroaryl groups consisting of 5-6 atoms;

Ring A is , , or ; wherein Ring A is optionally substituted by 1, 2 or 3 ^Ry ;

E ₁ , U ₁ and Z ₁ are each independently -(CR ^4a R ^4b ) _q -, -C(=O)-, -O-, -S-, -S(=O)-, -S(= O) ₂ -or -NR ^a -;

E ₂ , U ₂ and Z ₂ are each independently -CR ^4c R ^4d -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O) ₂ -or-NR ^b- ;

E ₃ , E ₆ , U ₃ and Z ₃ are each independently -CR ^4e R ^4f -, -C(=O)-, -O-, -S-, -S(=O)-, -S(= O) ₂ - or -NR ^c -;

E ₄ is -CR ^4g = or -N=; E ₅ is -CR ^4h = or -N=;

q is 0, 1, 2 or 3;

R ^a , R ^b , R ^c and R ⁵ are each independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl groups, heterocyclic groups consisting of 5-6 atoms, C _6-10 aryl groups or heteroaryl groups consisting of 5-6 atoms, wherein R ^a , R ^b , R ^c and R ⁵ independently optionally substituted by 1, 2 or 3 ^Ry1 ;

R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^4g and R ^4h are each independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, - OH, -NH ₂ , -SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _{1-6 halogen Substituted} alkyl, C _{1-6 haloalkoxy} , C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, heterocyclic group consisting of 5-6 atoms, (5- Heterocyclyl consisting of 6 atoms)-C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, heteroaryl consisting of 5-6 atoms or (heteroaryl consisting of 5-6 atoms)-C _1-4 alkylene, wherein, the R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^4g and R ^4h are independently optionally substituted by 1, 2 or 3 ^Ry2 ;

Or R ^4a , R ^4b and the carbon atoms connected to them together form a C _3-8 carbon ring or a heterocyclic ring composed of 5-6 atoms, or R ^4c , R ^4d and the carbon atoms connected to them form a C _{3- 8} carbon rings or heterocyclic rings consisting of 5-6 atoms, or R ^4e , R ^4f and the carbon atoms connected to them together form a C _3-8 carbon ring or a heterocyclic ring consisting of 5-6 atoms, wherein the C _3-8 carbon rings and heterocycles consisting of 5-6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 ^Ry3 ;

Each R ^x is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _{1-6 haloalkoxy} , C _1-6 alkoxy or C _1-6 alkylamino;

Each R ^y is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _{1-6 haloalkoxy} , C _1-6 alkoxy or C _1-6 alkylamino; or two R ^y connected to adjacent atoms and the atoms connected to them together form a C _3-8 carbon ring or a heterocyclic ring composed of 5-6 atoms Ring, wherein the C _3-8 carbocycle and the heterocycle composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y4 ;

Each R ^y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -SH, oxo, -OC(=O)-C _1-6 alkyl, -C(= O)-C _1-6 alkoxy, -C(=O)-C _1-6 alkyl, -C(=O)-C _1-6 alkylamino, -C(=O)NH ₂ , -S (=O) ₂ -C _1-6 alkyl, -S(=O) ₂ -C _1-6 alkylamino, -S(=O) ₂ NH ₂ , C _1-6 alkyl, C _{1-6 halogen Substituted} alkyl, C _{1-6 haloalkoxy} , C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-6 cycloalkyl, 5-6 atoms Heterocyclyl, C _6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein the R ^y1 is optionally substituted by 1, 2 or 3 R ^z ;

R ^z , R ^y2 , R ^y3 and R ^y4 are each independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -COOH, C _1-6 alkyl, C _{1-6 halogen Substituted} alkyl, C _{1-6 haloalkoxy} , C _1-6 alkoxy, C _1-6 alkylthio or C _1-6 alkylamino.

In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , _-CH2CHF2 , _-OCF3 , _-OCHF2 , _-OCH2F , hydroxymethyl, _aminomethyl or cyanomethyl.

In some embodiments, ^R1 is H, deuterium, F, Cl, Br, I, -CN, _-NO2 , -COOH, -OH, _-NH2 , -SH, methyl, ethyl, n-propyl , Isopropyl, -CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, -C(=O)-OCH ₃ , -C(=O)-OCH ₂ CH _3. -C(=O)-OCH(CH ₃ ) ₂ , -C(=O)-OCH ₂ CH ₂ CH ₃ , -C(=O)-O(CH ₂ ) ₃ CH ₃ , -C(= O)-OCH ₂ CH(CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-NHCH ₃ , -C(=O) -N(CH ₃ ) ₂ , -C(=O)NH ₂ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -CH ₂ CH ₃ , -S(=O) ₂ -NHCH _3. -S(=O) ₂ NH ₂ , methylamino, ethylamino, methoxy, ethoxy, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.

In some embodiments, R ^a , R ^b , R ^c and R ⁵ are each independently H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{1-4 Haloalkyl} , C _3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, C _6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein R ^a , R ^b , R ^c and R ⁵ can be optionally unsubstituted or substituted by 1, 2 or 3 R ^y1 ; wherein R ^y1 has the meaning described in the present invention.

In some embodiments, R ^a , R ^b , R ^c and R ⁵ are each independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH= CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperidine Azinyl, phenyl, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl or oxazolyl, wherein said R ^a , R ^b , R ^c and R ⁵ are independent Optionally substituted by 1, 2 or 3 R ^y1 ; wherein R ^y1 has the meaning described in the present invention.

In some embodiments, each R ^y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -SH, oxo, -OC(=O)-C _1-4 alkane Base, -C(=O)-C _1-4 alkoxy, -C(=O)-C _1-4 alkyl, -C(=O)-C _1-4 alkylamino, -C(=O )NH ₂ , -S(=O) ₂ -C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkylamino, -S(=O) ₂ NH ₂ , C _1-4 alkyl , C _{1-4 haloalkyl} , C _{1-4 haloalkoxy} , C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _3-6 cycloalkyl, 5 -Heterocyclic group consisting of 6 atoms, C _6-10 aryl group or heteroaryl group consisting of 5-6 atoms, wherein each R ^y1 is independently and optionally substituted by 1, 2 or 3 R ^z ; Wherein, R ^z has the meaning described in the present invention.

In some embodiments, each ^Ry1 is independently deuterium, F, Cl, Br, I, -CN, -OH, _-NH2 , -SH, oxo, -OC(=O)-methyl, -OC (=O)-ethyl, -OC(=O)-n-propyl, -OC(=O)-isopropyl, -OC(=O)-n-butyl, -OC(=O)-tert-butyl -OC(=O)-isobutyl, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C( =O)O-isopropyl, -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)NH ₂ , - S(=O) ₂ -C _1-3 alkyl, -S(=O) ₂ -C _1-3 alkylamino, -S(=O) ₂ NH ₂ , methyl, ethyl, n-propyl, iso Propyl, tert-butyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCHFCH ₃ , methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, ethylthio, methylamino, ethylamino, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, benzene Furanyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl or oxazolyl, wherein each R ^y1 is independently optionally replaced by 1, 2 or 3 R ^z are substituted; wherein, R ^z has the meaning described in the present invention.

In some embodiments, R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^{4g ,} and R ^4h are each independently H, deuterium, F, Cl, Br, I, -CN, -NO _2. -COOH, -OH, -NH ₂ , -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, methoxy, ethoxy, methylamino, ethylamino, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH ₂ -, cyclobutyl-CH ₂ -, cyclopentyl-CH ₂ -, cyclohexyl-CH ₂ -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl-CH ₂ -, pyrazolidinyl-CH ₂ -, tetrahydrofuranyl-CH ₂ -, tetrahydrothienyl-CH ₂ -, piperidinyl-CH ₂ -, morpholinyl-CH ₂ -, thiomorpholinyl- CH ₂ -, piperazinyl-CH ₂ -, phenyl, phenyl-CH ₂ -, phenyl-CH ₂ CH ₂ -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyridyl Azinyl, pyrazinyl, thiazolyl, oxazolyl, furyl- _CH2- , thienyl- _CH2- , imidazolyl- _CH2- , pyrimidinyl- _CH2- , pyridyl- _CH2- or pyrrole The group -CH ₂ -, wherein, the R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^4g and R ^4h are independently optionally substituted by 1, 2 or 3 R ^y2 ;

Or R ^4a , R ^4b and the carbon atoms connected to them together form a C _3-6 carbon ring or a heterocyclic ring composed of 5-6 atoms, or R ^4c , R ^4d and the carbon atoms connected to them form a C _{3- A 6-} carbon ring or a heterocyclic ring consisting of 5-6 atoms, or R ^4e , R ^4f and the carbon atoms connected to them together form a C _3-6 carbon ring or a heterocyclic ring consisting of 5-6 atoms, wherein the C _3-6 carbon rings and 5-6 atom heterocycles are independently unsubstituted or substituted by 1, 2 or 3 R ^y3 ; wherein, R ^y2 and R ^y3 have the meanings described in the present invention.

In some embodiments, ^Rz , ^Ry2 , ^Ry3 , and ^Ry4 are each 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.

In another aspect, the present invention relates to a pharmaceutical composition, which comprises the compound described in the present invention, optionally, further comprises any one of pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or their random combination.

In one aspect, the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used for stimulating thyroid hormone receptors; or for preventing, treating or alleviating the effects of Diseases of thyroid hormone receptor regulation.

In some embodiments, the thyroid hormone receptor of the present invention is thyroid hormone beta receptor.

In some embodiments, the diseases regulated by thyroid hormone receptors in the present invention are neurodegenerative diseases, nonalcoholic fatty liver disease, idiopathic pulmonary fibrosis (IPF), atherosclerosis, coronary heart disease, Hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer .

In another aspect, the present invention relates to the use of the compounds of the present invention or the pharmaceutical compositions of the present invention in the preparation of medicines, wherein the medicines are 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 mellitus, metabolic disorder, lipid disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer.

In some embodiments, the nonalcoholic fatty liver disease described in the present invention is nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, cryptogenic cirrhosis associated with nonalcoholic fatty liver disease, or primary liver cancer.

In some embodiments, the neurodegenerative disease of the invention is demyelinating disease, chronic demyelinating disease, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency X-linked adrenal dystrophy (ALD), amyotrophic lateral sclerosis (ALS), or Alzheimer's disease.

The foregoing merely outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail and more fully below.

The invention provides a class of compounds with good agonistic activity on thyroid hormone beta receptors, its preparation method, its pharmaceutical composition and its application. Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the scope of the present invention.

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention intends to cover all alternatives, modifications and equivalent technical solutions, which are all included in the scope of the present invention. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein, in the event that one or more of the incorporated literature, patents and similar materials differs from or contradicts this application (including but not limited to defined terms, terms applications, techniques described, etc.), this application controls.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry can be referred to 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 description, the entire contents of which are incorporated herein by reference.

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless otherwise stated or clearly contradicted by context. Therefore, these articles as used herein refer to articles of one or more than one (ie at least one) object. For example, "a component" refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment.

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

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "unsubstituted or substituted" are used interchangeably. The terms "optionally", "optionally" or "optionally" mean that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not or situation. In general, unless indicated otherwise, an optional substituent may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents may be substituted at each position the same or differently. The substituents mentioned therein can be, but not limited to, H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, alkyl, alkane Oxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkylene radical, heterocyclyl-alkylene, carbocyclyl, heterocyclyl, aryl, aryl-alkylene, heteroaryl, heteroaryl-alkylene, and the like.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used in the present invention are interchangeable with "...independently" and "...independently". , should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and it can also mean that in the same group, the options expressed by the same symbols The specific options do not affect each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C _1-6 alkyl" specifically refers to independently disclosed C ₁ alkyl (methyl), C ₂ alkyl (ethyl), C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl; "C _3-8 cycloalkyl" specifically refers to independently disclosed C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl and C ₈ Cycloalkyl; "Heterocyclyl consisting of 3-6 atoms" means a heterocyclyl consisting of 3 atoms, a heterocyclyl consisting of 4 atoms, a heterocyclyl consisting of 5 atoms and a heterocyclic group consisting of 6 ring atoms heterocyclyl.

In various sections of the specification linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represent the linking group. An alkylene group or an arylene group.

The term "alkylene" means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms, that is, C _1-6 alkylene; in some embodiments, the alkylene group contains 1-4 carbon atoms, that is, C _{1-6 -4} alkylene; such examples include, but are not limited to, methylene (-CH ₂ -), ethylene (including -CH ₂ CH ₂ - or -CH(CH ₃ )-), isopropylidene (including -CH(CH ₃ )CH ₂ - or -C(CH ₃ ) ₂ -), n-propylene (including -CH ₂ CH ₂ CH ₂ -, -CH(CH ₂ CH ₃ )- or -CH ₂ CH( _CH3 )-), etc. Wherein, the alkylene group may be optionally substituted by one or more substituents described in the present invention.

The term "alkyl" or "alkyl group" refers to a saturated linear or branched monovalent hydrocarbyl group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be Substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1-10 carbon atoms; in some embodiments, the alkyl group contains 1-8 carbon atoms, that is, C _1-8 alkyl; in some embodiments, Alkyl groups contain 1-6 carbon atoms, ie, C _1-6 alkyl; in some embodiments, alkyl groups contain 1-4 carbon atoms, ie, C _1-4 alkyl.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl ( n- Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl ( i -Pr, -CH(CH ₃ ) ₂ ), n-butyl ( n -Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl ( i -Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl ( s -Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl ( t -Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH _{2CH 2} CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH (CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-heptyl, n-octyl, etc. .

The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein at least one unsaturated site is a carbon-carbon sp ^double bond, wherein the alkenyl group can be any Optionally substituted with one or more substituents described herein, including the " cis " and " trans " positions, or the " E " and " Z " positions. In some embodiments, alkenyl groups contain 2-8 carbon atoms; in some embodiments, alkenyl groups contain 2-6 carbon atoms, i.e., C _2-6 alkenyl; in some embodiments, Alkenyl groups contain 2-4 carbon atoms, ie _C2-4 alkenyl.

Examples of alkenyl groups include, but are not limited to, vinyl (—CH=CH ₂ ), allyl (—CH ₂ CH=CH ₂ ), propenyl (—CH=CHCH ₃ ), butenyl ( -CH=CHCH ₂ CH ₃ , -CH ₂ CH=CHCH ₃ , -CH ₂ CH ₂ CH=CH ₂ , -CH=C(CH ₃ ) ₂ , -CH=C(CH ₃ ) ₂ , -CH ₂ C (CH ₃ )=CH ₂ ), pentenyl (-CH ₂ CH ₂ CH ₂ CH=CH ₂ , -CH ₂ CH ₂ CH=CHCH ₃ , -CH ₂ CH ₂ CH=CHCH ₃ , -CH ₂ CH= CHCH ₂ CH ₃ , -CH=CHCH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ C(CH ₃ )=CH ₂ , -CH ₂ CH=C(CH ₃ ) ₂ , -CH=CHCH(CH ₃ ) ₂ , -C(CH ₂ CH ₃ )=CHCH ₃ , -CH(CH ₂ CH ₃ )CH=CH ₂ ), and so on.

The term "alkynyl" means a linear 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 can be optionally substituted by one or more of the substituents described in the present invention. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in some embodiments, alkynyl groups contain 2-6 carbon atoms, ie, _C2-6 alkynyl; in some embodiments, An alkynyl group contains 2-4 carbon atoms, ie a C _2-4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡CH-CH ₃ ), propargyl (-CH ₂ C≡CH), 1-butanyl Alkynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, etc.

The term "alkoxy" refers to an alkyl group connected to the rest of the molecule through an oxygen atom, i.e. -O-alkyl, wherein the alkyl group has the meaning as described in the present invention, wherein the alkoxy group A group can be optionally substituted with one or more substituents described herein. In some embodiments, alkoxy groups contain 1-20 carbon atoms; in some embodiments, alkoxy groups contain 1-10 carbon atoms; in some embodiments, alkoxy groups contain 1-8 carbon atoms; In some embodiments, the alkoxy group contains 1-6 carbon atoms, i.e. C _1-6 alkoxy; In some embodiments, the alkoxy group contains 1-4 carbon atoms, that is, C _1-4 alkoxy.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), n-propyloxy ( n -PrO, n - Propoxy, -OCH ₂ CH ₂ CH ₃ ), isopropyloxy ( i -PrO, i -propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy ( n -BuO, n - Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy ( i -BuO, i -butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-Butyl Oxygen ( s -BuO, s -butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-isopropyloxy ( t -BuO, t -butoxy, -OC(CH ₃ ) ₃ ), and so on.

The term "alkylamino" includes " N -alkylamino" and " N,N -dialkylamino", which means that the amino groups are independently substituted by one or two alkyl groups having the Definitions of Invention. Wherein, the alkylamino group may be optionally substituted by one or more substituents described in the present invention. In some embodiments, an alkylamino group is an alkylamino group with one or two C1-6 alkyl groups attached to a nitrogen atom, that is, a C1-6 alkylamino group; in some embodiments, an alkylamino group is one or two C1-6 An alkylamino group in which -4 alkyl is connected to a nitrogen atom, that is, a C1-4 alkylamino group. 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) and the like.

The term "alkylthio" refers to an alkyl group connected to the rest of the molecule through a sulfur atom, i.e. -S-alkyl, wherein the alkyl group has the meaning as described in the present invention, wherein the alkylthio group A group can be optionally substituted with one or more substituents described herein. In some embodiments, an alkylthio group contains 1-10 carbon atoms; in some embodiments, an alkylthio group contains 1-8 carbon atoms; in some embodiments, an alkylthio group contains 1-6 carbon atoms, i.e. C _1-6 alkylthio; in some embodiments, the alkylthio group contains 1-4 carbon atoms, i.e. C _1-4 alkylthio; in some embodiments, Alkylthio groups contain 1-3 carbon atoms, i.e. C _1-3 alkylthio. Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, and the like.

The term "haloalkyl" refers to an alkyl group having one or more halo substituents, wherein the haloalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, haloalkyl groups contain 1-10 carbon atoms; in some embodiments, haloalkyl groups contain 1-8 carbon atoms; in some embodiments, haloalkyl groups contain 1-6 carbon atoms, that is, C _{1-6 haloalkyl} ; in some embodiments, haloalkyl groups contain 1-4 carbon atoms, that is, C _1-4 haloalkyl; in some embodiments, haloalkyl The group contains 1-3 carbon atoms, that is, C _1-3 haloalkyl. Examples of haloalkyl include, but are not limited to, fluoromethyl (-CH ₂ F), difluoromethyl (-CHF ₂ ), trifluoromethyl (-CF ₃ ), fluoroethyl (-CHFCH ₃ , - CH ₂ CH ₂ F), difluoroethyl (-CF ₂ CH ₃ , -CFHCFH ₂ , -CH ₂ CHF ₂ ), perfluoroethyl, fluoropropyl (-CHFCH ₂ CH ₃ , -CH ₂ CHFCH ₃ , _-CH2CH2CH2F ) _{and the} like.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen substituents, wherein the haloalkoxy group may optionally be substituted with one or more substituents described herein . In some embodiments, haloalkoxy groups contain 1-10 carbon atoms; in some embodiments, haloalkoxy groups contain 1-8 carbon atoms; in some embodiments, haloalkoxy groups contain 1-6 carbon atoms, i.e. C _{1-6 haloalkoxy} ; in some embodiments, the haloalkoxy group contains 1-4 carbon atoms, i.e. C _{1-4 haloalkoxy} ; in some embodiments, A haloalkoxy group contains 1-3 carbon atoms, ie a C _{1-3 haloalkoxy group} . Examples of haloalkoxy include, but are not limited to, _-OCF3 , _-OCHF2 , _-OCH2F , and the like.

The term "hydroxyalkyl" refers to an alkyl group substituted by one or more hydroxyl groups (-OH), and the alkyl group has the meaning described in the present invention, wherein the hydroxyalkyl group can be optionally replaced by one or Substituted by a plurality of substituents described herein. In some embodiments, the hydroxyalkyl group described in the present invention refers to a C _1-6 alkyl group substituted by one or more hydroxyl groups (-OH), that is, a hydroxy C _1-6 alkyl group; in some In embodiments, a hydroxyalkyl group refers to a C _1-4 alkyl group substituted with one or more hydroxyl groups (—OH), ie, a hydroxyC _1-4 alkyl group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl (eg, _-CH2OH ), hydroxyethyl (eg, 2-hydroxyethyl), and the like.

The term "aminoalkyl" refers to an alkyl group substituted by one or more amino groups (-NH ₂ ), and the alkyl group has the meaning described in the present invention, wherein the aminoalkyl group can be optionally replaced by one Or a plurality of substituents described in the present invention are substituted. In some embodiments, the aminoalkyl group described in the present invention refers to a C _1-6 alkyl group substituted by one or more amino groups (-NH ₂ ), that is, an amino C _1-6 alkyl group; in In some embodiments, an aminoalkyl group refers to a C _1-4 alkyl group substituted with one or more amino groups (-NH ₂ ), ie, aminoC _1-4 alkyl, ie, aminoC _1-2 alkyl. Examples of aminoalkyl groups include, but are not limited to, aminomethyl ( _{-CH2NH2 )} , diaminomethyl (-CH( _NH2 ) ₂ ), aminoethyl (e.g., 2-aminoethyl) etc.

The term "cyanoalkyl" refers to an alkyl group substituted by one or more cyano groups (-CN), and the alkyl group has the meaning described in the present invention, wherein the cyanoalkyl group can be optionally Substituted by one or more substituents described herein. In some embodiments, the cyanoalkyl group described in the present invention refers to C _1-6 alkyl substituted by one or more cyano groups (-CN), that is, cyano C _1-6 alkyl ; in some embodiments, a cyanoalkyl group refers to a C _1-4 alkyl group substituted with one or more cyano groups (—CN), ie, a cyano C _1-4 alkyl group. Examples of cyanoalkyl groups include, but are not limited to, cyanomethyl (eg, _-CH2CN ), cyanoethyl (eg, 2-cyanoethyl), and the like.

The term "carboxyalkyl" refers to an alkyl group substituted by one or more carboxyl groups (-COOH), and the alkyl group has the meaning described in the present invention, wherein the carboxyalkyl group can be optionally replaced by one or Substituted by a plurality of substituents described herein. In some embodiments, the carboxyalkyl group described in the present invention refers to a C _1-6 alkyl group substituted by one or more carboxyl groups (-COOH), that is, a carboxy C _1-6 alkyl group; in some In embodiments, a carboxyalkyl group refers to a C _1-4 alkyl group substituted with one or more carboxy groups (—COOH), ie, a carboxyC _1-4 alkyl group. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl, carboxyethyl (eg, 2-carboxyethyl), and the like.

The term "cycloalkyl" or "carbocyclyl" refers to a monocyclic, bicyclic or tricyclic group having from 3 to 14 ring carbon atoms, saturated or partially unsaturated, having one or more points of attachment to the rest of the molecule. Ring systems, wherein the cycloalkyl group is optionally substituted with substituents described herein. In some embodiments, cycloalkyl is a ring system containing 3-10 ring carbon atoms, i.e. C _3-10 cycloalkyl; In some embodiments, cycloalkyl is a ring system containing 3-8 ring carbon atoms Ring system, that is, C _3-8 cycloalkyl; In some embodiments, cycloalkyl is a ring system containing 3-6 ring carbon atoms, that is, C _3-6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, and the like.

The term "heterocyclyl" means a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3-12 atoms, wherein at least one ring atom is selected from nitrogen, sulfur, oxygen and phosphorus Atoms and other heteroatoms, wherein the heterocyclic group is non-aromatic and does not contain any aromatic rings, and the ring system has one or more points of attachment to the rest of the molecule. Wherein, the heterocyclic group can be optionally substituted by one or more substituents described in the present invention. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclyls include bridged bicyclic heterocyclyls, fused bicyclic heterocyclyls and spirobicyclic heterocyclyls. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. Unless otherwise stated, a heterocyclyl group may be carbonyl or nitrogenyl, and a _-CH2- group may optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S -oxides. Ring nitrogen atoms can optionally be oxidized to N -oxygen compounds. The phosphorus atom of the ring can optionally be oxidized to a P -oxygen compound. In some embodiments, the heterocyclyl is a ring system consisting of 3-10 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 5-10 atoms; in some embodiments, the heterocyclyl is A ring system consisting of 5-8 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 6-8 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 5-6 atoms, That is, a heterocyclyl group consisting of 5-6 atoms; in some embodiments, a heterocyclyl group is a ring system consisting of 3-6 atoms, that is, a heterocyclyl group consisting of 3-6 atoms; in some embodiments, The heterocyclyl is a ring system consisting of 3 ring atoms; in some embodiments, the heterocyclyl is a ring system consisting of 4 atoms; in other embodiments, the heterocyclyl is a ring system consisting of 5 atoms; in In other embodiments, heterocyclyl is a 6 atom ring system.

Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H -pyranyl, 4H -pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxane base, thiaxyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydropyrimidinyl , tetrahydropyrazinyl, tetrahydropyridazinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, etc. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl, pyrimidinedionyl, 3,4-dihydroisoquinolin-1(2 H )-one. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, cyclobutanyl and 1,1-dioxothiomorpholinyl. Bridged heterocyclyl groups include, but are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2. 1] Hinkie et al.

The term "m atoms", where m is an integer, typically describes the number of ring atoms in a molecule, the number of ring atoms in said molecule being m. For example, piperidinyl is a 6-atom heterocyclyl group and furyl is a 5-atom heteroaryl group. As another example, "heterocyclyl consisting of 3-6 atoms" refers to a heterocyclyl group consisting of 3, 4, 5 or 6 atoms.

The term "aryl" denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing 6-14 ring atoms, or 6-10 ring atoms, wherein each ring contains 3-7 ring atoms, and There are one or more attachment points to which the rest of the molecule is connected. Wherein, the aryl group can be optionally substituted by one or more substituents described in the present invention. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, anthracenyl, and the like.

The term "heteroaryl" means monocyclic, bicyclic and tricyclic aromatic systems containing 5-14 ring atoms, wherein at least one ring contains one or more heteroatoms, wherein the entire ring system is aromatic, Also, the heteroaryl has one or more points of attachment to the rest of the molecule. Wherein, the heteroaryl group may be optionally substituted by one or more substituents described in the present invention. Unless otherwise stated, said heteroaryl groups can be attached to the rest of the molecule (eg, the main structure in the general formula) through any reasonable point (could be C in CH, or N in NH). When a -CH ₂ - group is present for a heteroaryl group, said -CH ₂ - group may optionally be replaced by a -C(=O)-. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" or "heteroaromatic". In some embodiments, heteroaryl is a heteroaryl consisting of 5-8 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in some embodiments, heteroaryl The radical 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 is a heteroaryl group comprising 1, 2, 3 Or a heteroaryl group consisting of 5-6 atoms of 4 heteroatoms independently selected from O, S and N; A heteroaryl group consisting of 5 atoms of heteroatoms of S and N; in some embodiments, the heteroaryl group is a 6-atom group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N Composition of heteroaryl.

Examples of heteroaryl groups include, but are not limited to, the following monocyclic groups: furyl (2-furyl, 3-furyl), imidazolyl ( N -imidazolyl, 2-imidazolyl , 4-imidazolyl, 5-imidazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), 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 (such as 3-pyridazinyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), Thienyl (2-thienyl, 3-thienyl), pyrazolyl (such as 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2 ,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thio Diazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also include, but are by no means limited to, the following bicyclic or tricyclic groups: Benzene And imidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl base), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl.

The term "cycloalkyl-alkylene" means that a cycloalkyl group is attached to the rest of the molecule through an alkylene group, wherein cycloalkyl and alkylene have the meanings described herein. Said cycloalkyl-alkylene groups may be optionally substituted with one or more substituents described herein. The "C _3-6 cycloalkyl-C _1-4 alkylene" mentioned in the present invention means that the C _3-6 cycloalkyl is linked to the rest of the molecule through a C _1-4 alkylene group. The "C _3-6 cycloalkyl-C _1-2 alkylene" mentioned in the present invention means that the C _3-6 cycloalkyl is linked to the rest of the molecule through a C _1-2 alkylene group. Such examples include, but _are not limited to, cyclopropyl- _CH2- , cyclopropyl- _{CH2CH2- ,} cyclobutyl- _CH2- , cyclobutyl- _CH2CH2- , cyclopentyl- CH ₂ -, cyclopentyl-CH ₂ CH ₂ -, cyclohexyl-CH ₂ -, cyclohexyl-CH ₂ CH ₂ -, etc.

The term "heterocyclyl-alkylene" means that a heterocyclyl group is attached to the rest of the molecule through an alkylene group, wherein heterocyclyl and alkylene have the meanings described herein. The heterocyclyl-alkylene group can be optionally substituted with one or more substituents described herein. The "(heterocyclyl group consisting of 5-6 atoms)-C _1-4 alkylene" mentioned in the present invention means that the heterocyclyl group consisting of 5-6 atoms is connected with the molecule by the C _1-4 alkylene group The rest are connected. "(Heterocyclic group consisting of 5-6 atoms)-C _1-2 alkylene" mentioned in the present invention means that the heterocyclic group composed of 5-6 atoms is connected with the molecule through the C _1-2 alkylene group The rest are connected. Such examples include, but _are not limited _to , tetrahydropyranyl- _CH2- , tetrahydropyranyl- _CH2CH2- , tetrahydrofuranyl- _CH2- , tetrahydrofuranyl- _CH2CH2- , pyrrolidine -CH ₂ -, piperidinyl-CH ₂ -, piperidinyl-CH ₂ CH ₂ -, morpholinyl-CH 2 -, _morpholinyl -CH ₂ CH ₂ -, and the like.

The term "aryl-alkylene" means that an aryl group is attached to the rest of the molecule through an alkylene group, wherein aryl and alkylene have the meanings described herein. The aryl-alkylene group can be optionally substituted with one or more substituents described herein. For example, the "C _6-10 aryl-C _1-4 alkylene group" mentioned in the present invention means that the C _6-10 aryl group is linked to the rest of the molecule through a C _1-4 alkylene group. The "C _6-10 aryl-C _1-2 alkylene group" in the present invention means that the C _6-10 aryl group is linked to the rest of the molecule through a C _1-2 alkylene group. Such examples include, but _are not limited to, phenyl- _CH2- , phenyl- _CH2CH2- , naphthyl- _CH2- , and the like.

The term "heteroaryl-alkylene" means that a heteroaryl group is attached to the rest of the molecule through an alkylene group, wherein heteroaryl and alkylene have the meanings described herein. The heteroaryl-alkylene group may be optionally substituted with one or more substituents described herein. The "(heteroaryl group consisting of 5-6 atoms)-C _1-4 alkylene" mentioned in the present invention means that the heteroaryl group consisting of 5-6 atoms is connected with the molecule through the C _1-4 alkylene group The rest are connected. The "(heteroaryl group consisting of 5-6 atoms)-C _1-2 alkylene" mentioned in the present invention means that the heteroaryl group consisting of 5-6 atoms is connected with the molecule through the C _1-2 alkylene group The rest are connected. Such examples include, but are _not limited to, pyridyl- _CH2- , pyrrolyl- _CH2CH2- , quinolinyl- _CH2- , thienyl- _CH2- , furyl- _CH2- , pyrimidinyl -CH ₂ -, pyridyl-CH ₂ -, etc.

The term "heteroatom" refers to O, S, N, P, and Si, including forms in any oxidation state of S, N, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro- 2H -pyrrolyl), NH (like NH in pyrrolidinyl) or ^NRT (like N-substituted pyrrolidinyl In ^NRT , ^RT is a substituent on N).

The term "carbonyl", whether used alone or in combination with other terms such as "aminocarbonyl" or "acyloxy", means -(C=O)-.

The term "deuterium" means deuterated, ^ie2H .

The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith. Preferably, "pharmaceutically acceptable" in the present invention refers to those approved by federal regulatory agencies or national governments, or listed in the US Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, especially humans.

The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (such as antibacterial, antifungal), isotonic agent, salt, drug stabilizer, binder, excipient Agents, dispersants, lubricants, sweeteners, flavoring agents, coloring agents, or combinations thereof, these carriers are known to those skilled in the art (such as 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 contemplated.

The term "pharmaceutical composition" means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically/pharmaceutically acceptable Carriers, excipients, diluents, binders, fillers and other auxiliary materials, as well as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerosis agents or hypoglycemic agents Lipid reagents and other additional therapeutic agents. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

The term "prodrug" used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, Carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in: Higuchi et al., Pro-drugs as Novel Delivery Systems , Vol. 14, ACS Symposium Series; Roche et al., Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press , 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery , 2008 , 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem. , 2008 , 51 , 2328-2345.

The term "metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

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

The term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The term "nitrogen oxide" means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N -oxides. Specific examples of N -oxides are N -oxides of tertiary amines or N -oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids to form N -oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N -oxides can be prepared by the method of LWDeady (Syn.Comm.1977, 7, 509-514), wherein, for example, in an inert solvent, such as dichloromethane, the amine compound and m-chloroperbenzoic acid ( MCPBA) response.

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

Thus, as described herein, the compounds of the present invention may exist in the form of one or a mixture of possible isomers, rotamers, atropisomers, tautomers, for example as Substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

Any resulting isomeric mixture may be separated into pure or substantially pure geometric or optical isomers, diastereoisomers, racemates on the basis of physicochemical differences in the components, for example by chromatography and/or separation crystallization for separation.

The racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high pressure liquid chromatography (HPLC) using a chiral adsorbent. 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 ^nd Ed. Robert E. Gawley , Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed. , Univ. of Notre Dame Press, Notre Dame, IN 1972)).

The invention also includes isotopically labeled compounds of the invention which are identical to those described herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from that found in nature. Exemplary isotopes that may also be incorporated into 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.

Compounds of the present invention comprising the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of the present invention. Isotopically labeled compounds of the invention, for example radioactive isotopes such ^{as3H and14C} , incorporated into the compounds of the invention can be used in drug and/or substrate tissue distribution assays. Tritiated, ie, ^3H , and carbon-14, ^ie14C , isotopes are particularly preferred due to ease of preparation and detection. Furthermore, substitution with a higher mass isotope, such as deuterium, ^ie2H , may afford some therapeutic advantage of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferable in some situations.

Stereochemical definitions and conventions used in the present invention are generally in accordance with SP 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", definitions and conventions documented in John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention are contemplated, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof, such as racemic mixtures, It is also included in the scope of the present invention. Many organic compounds exist in optically active forms, ie 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 center (or centers) in the molecule. The prefixes d and l or (+) and (–) are symbols used to specify the rotation of plane polarized light due to a compound, where (–) or l indicates that the compound is left-handed. Compounds prefixed with (+) 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 referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process Spin body.

Depending on the choice of starting materials and processes, the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- Mixture of enantiomers, depending on the number of asymmetric carbon atoms. Optical ( R )- or ( S )-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be cis or trans ( cis - or trans -) structure.

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (eg, enantiomeric, diastereomeric, atropisomer, and geometric (or conformational)) forms of the structure; for example, R and S configurations, ( Z ) and ( E ) double bond isomers, and ( Z ) and ( E ) conformational isomers for each asymmetric center. Accordingly, individual stereochemical isomers as well as mixtures of enantiomers, diastereomers and geometric isomers (or conformers) of the compounds of the present invention are within the scope of the present invention.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. structured. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4( 1H )-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "geometric isomer" is also called "cis-trans isomer", because the double bond (including the double bond of olefin, C=N double bond and N=N double bond) or the single bond of ring carbon atom cannot rotate freely. induced isomers.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. The subject matter also refers to primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

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

In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

The term "treating" any disease or condition as used herein means, in some embodiments, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, "treating" refers to preventing or delaying the onset, development or worsening of a disease or condition.

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

The invention provides a class of compounds with good agonistic activity on thyroid hormone β receptors, which are used for the preparation and treatment of neurodegenerative diseases, nonalcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis Cirrhosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, thyroid function Medicines for hypothyroidism or thyroid cancer. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds and pharmaceutical compositions to prepare medicaments for treating mammals, especially human beings, for the above-mentioned diseases. Compared with the existing similar compounds, the compound of the present invention not only has good pharmacological activity and selectivity, but also has excellent in vivo metabolic kinetic properties and in vivo pharmacodynamic properties. The preparation method of the compound described in the invention is simple and easy, the process method is stable, and is suitable for industrialized production. Therefore, the compounds provided by the present invention have better druggability than the existing similar compounds.

Specifically:

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite products, pharmaceutically acceptable salts or their prodrugs, (I),

Wherein, ring A, Y, R ¹ , R ² , R ^3a , R ^3b , R ^3c and R ^3d have the definitions as described in the present invention.

In some embodiments, Y is -O-, -S-, -NR ⁰ -, -C(=O)-, C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkylene Alkynyl, -NR ⁰ C(=O)- or -C(=O)NR ⁰ -; wherein said Y may be optionally substituted by 1, 2 or 3 R ^x ; wherein said R ⁰ and ^Rx has the definition as described herein.

In some embodiments, R ^O is H, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , hydroxyC _1-6 alkyl, amino C _1-6 alkyl, or cyano C _{1- 6} alkyl.

In some embodiments, R ^is H, deuterium, methyl, ethyl, n-propyl, isopropyl, C _haloalkyl , hydroxymethyl, hydroxyethyl, aminomethyl, or cyano methyl.

In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkyl, C _{1-6 haloalkoxy} , Hydroxy C _1-6 alkyl, amino C _1-6 alkyl or cyano C _1-6 alkyl.

In some embodiments, R ¹ is H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, -C(=O)-C _1-6 alkoxy, -C(=O)-C _1-6 alkyl, -C(=O)-C _{1 -6} Alkylamino, -C(=O)NH ₂ , -S(=O) ₂ -C _1-6 Alkyl, -S(=O) ₂ -C _1-6 Alkylamino, -S(=O) ₂ NH ₂ , C _1-6 alkylamino, C 1-6 alkoxy, C _{1-6 haloalkyl} , C _{1-6 haloalkoxy} , hydroxy C _1-6 alkyl, amino C _1-6 alkane group, carboxy C _1-6 alkyl or cyano C _1-6 alkyl.

In some embodiments, R ² is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, hetero of 5-6 atoms Cyclic group, C _6-10 aryl group or heteroaryl group composed of 5-6 atoms.

In some embodiments, R ^is H, deuterium, methyl, ethyl, n-propyl, isopropyl, t-butyl, C _alkenyl , C _alkynyl , C _cyclo An alkyl group, a heterocyclic group consisting of 5-6 atoms, a phenyl group or a heteroaryl group consisting of 5-6 atoms.

In some embodiments, Ring A is , , or ; wherein, ring A may be optionally substituted by 1, 2 or 3 R ^y ; said E ₁ , E ₂ , E ₃ , E ₄ , E ₅ , E ₆ , U ₁ , U ₂ , U ₃ , Z ₁ , Z ₂ , Z ₃ , R ⁵ and R ^y have the definitions described in the present invention.

In some embodiments, E ₁ , U _{1 ,} and Z ₁ 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 the present invention.

In some embodiments, E ₂ , U _{2 ,} and Z ₂ 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 have the definitions described in the present invention.

In some embodiments, E ₃ , E ₆ , U _{3 ,} and Z ₃ 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 have the definitions described in the present invention.

In some embodiments, E ₄ is -CR ^4g = or -N=; wherein, said R ^4g has the definition described herein.

In some embodiments, E ₅ is -CR ^4h = or -N=; wherein, said R ^4h has the definition described herein.

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

In some embodiments, R ^a , R ^b , R ^c and R ⁵ are each independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1-6 Haloalkyl} , C _3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, C _6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein, the R ^a , R ^{b ,} R ^c and R ⁵ may be independently and optionally substituted by 1, 2 or 3 R ^y1s having the definition as described in the present invention.

In some embodiments, R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^{4g ,} and R ^4h are each independently H, deuterium, F, Cl, Br, I, -CN, -NO _2. -COOH, -OH, -NH ₂ , -SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino , C _{1-6 haloalkyl} , C _{1-6 haloalkoxy} , C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, hetero Cyclic group, (heterocyclic group consisting of 5-6 atoms)-C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5-6 A heteroaryl group consisting of 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 are optionally unsubstituted or substituted with 1, 2 or 3 R ^y2 having the definition as described herein.

In some embodiments, R ^4a , R ^4b and the carbon atoms connected to them together form a C _3-8 carbocycle or a heterocycle consisting of 5-6 atoms, wherein the C _3-8 carbocycle and 5- The heterocyclic rings composed of 6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y3s , and the R ^y3s have the definitions described in the present invention.

In some embodiments, R ^4c , R ^4d and the carbon atoms connected to them together form a C _3-8 carbocycle or a heterocycle consisting of 5-6 atoms, wherein the C _3-8 carbocycle and 5- The heterocyclic rings composed of 6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y3s , and the R ^y3s have the definitions described in the present invention.

In some embodiments, R ^4e , R ^4f and the carbon atoms connected to them together form a C _3-8 carbocycle or a heterocycle consisting of 5-6 atoms, wherein the C _3-8 carbocycle and 5- The heterocyclic rings composed of 6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y3s , and the R ^y3s have the definitions described in the present invention.

In some embodiments, two R ^y linked to adjacent atoms and the atoms linked to them together form a C _3-8 carbon ring or a heterocyclic ring composed of 5-6 atoms, wherein the C _3-8 The carbocyclic ring and the heterocyclic ring composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y4 , and the R ^y4 has the definition described in the present invention.

In some embodiments, each R ^x is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6 haloalkoxy} , C _1-6 alkoxy or C _1-6 alkylamino.

In some embodiments, each R ^x is 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.

In some embodiments, each R ^y is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6 haloalkoxy} , C _1-6 alkoxy or C _1-6 alkylamino.

In some embodiments, each ^Ry is 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.

In some embodiments, each R ^y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -SH, oxo, -OC(=O)-C _1-6 alkane Base, -C(=O)-C _1-6 alkoxy, -C(=O)-C _1-6 alkyl, -C(=O)-C _1-6 alkylamino, -C(=O )NH ₂ , -S(=O) ₂ -C _1-6 alkyl, -S(=O) ₂ -C _1-6 alkylamino, -S(=O) ₂ NH ₂ , C _1-6 alkyl , C _{1-6 haloalkyl} , C _{1-6 haloalkoxy} , C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-6 cycloalkyl, 5 -Heterocyclic group consisting of 6 atoms, C _6-10 aryl group or heteroaryl group consisting of 5-6 atoms, wherein each R ^y1 can be independently optionally replaced by 1, 2 or 3 R ^z Instead, said R ^z has the definition described herein.

In some embodiments, R ^z , R ^y2 , R ^y3 , and R ^y4 are each independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -COOH, C _1-6 alkyl , C _1-6 haloalkyl, C _{1-6 haloalkoxy} , C _1-6 alkoxy, C _1-6 alkylthio or C _1-6 alkylamino.

In some embodiments, R ^3a , R ^3b , R ^3c and R ^3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , _-CH2CHF2 , _-OCF3 , _-OCHF2 , _-OCH2F , hydroxymethyl, _aminomethyl or cyanomethyl.

In some embodiments, ^R1 is H, deuterium, F, Cl, Br, I, -CN, _-NO2 , -COOH, -OH, _-NH2 , -SH, methyl, ethyl, n-propyl , Isopropyl, -CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, -C(=O)-OCH ₃ , -C(=O)-OCH ₂ CH _3. -C(=O)-OCH(CH ₃ ) ₂ , -C(=O)-OCH ₂ CH ₂ CH ₃ , -C(=O)-O(CH ₂ ) ₃ CH ₃ , -C(= O)-OCH ₂ CH(CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-NHCH ₃ , -C(=O) -N(CH ₃ ) ₂ , -C(=O)NH ₂ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -CH ₂ CH ₃ , -S(=O) ₂ -NHCH _3. -S(=O) ₂ NH ₂ , methylamino, ethylamino, methoxy, ethoxy, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.

In some embodiments, R ^a , R ^b , R ^c and R ⁵ are each independently H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{1-4 Haloalkyl} , C _3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, C _6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein, the R ^a , R ^b , R ^{c and} R ⁵ may be independently and optionally substituted by 1, 2 or 3 R ^y1s having the definitions described herein.

In some embodiments, R ^a , R ^b , R ^c and R ⁵ are each independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH= CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperidine Azinyl, phenyl, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl or oxazolyl, wherein, the R ^a , R ^b , R ^c and R ⁵ independently and ^optionally substituted by 1, 2 or 3 R ^y1s having the definitions described herein.

In some embodiments, each R ^y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -SH, oxo, -OC(=O)-C _1-4 alkane Base, -C(=O)-C _1-4 alkoxy, -C(=O)-C _1-4 alkyl, -C(=O)-C _1-4 alkylamino, -C(=O )NH ₂ , -S(=O) ₂ -C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkylamino, -S(=O) ₂ NH ₂ , C _1-4 alkyl , C _{1-4 haloalkyl} , C _{1-4 haloalkoxy} , C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _3-6 cycloalkyl, 5 -Heterocyclic group consisting of 6 atoms, C _6-10 aryl group or heteroaryl group consisting of 5-6 atoms, wherein the R ^y1 can be optionally substituted by 1, 2 or 3 R ^z , Said R ^z has the definition described in the present invention.

In some embodiments, each ^Ry1 is independently deuterium, F, Cl, Br, I, -CN, -OH, _-NH2 , -SH, oxo, -OC(=O)-methyl, -OC (=O)-ethyl, -OC(=O)-n-propyl, -OC(=O)-isopropyl, -OC(=O)-n-butyl, -OC(=O)-tert-butyl -OC(=O)-isobutyl, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C( =O)O-isopropyl, -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)NH ₂ , - S(=O) ₂ -C _1-3 alkyl, -S(=O) ₂ -C _1-3 alkylamino, -S(=O) ₂ NH ₂ , methyl, ethyl, n-propyl, iso Propyl, tert-butyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCHFCH ₃ , methoxy, ethoxy, n-propyloxy, isopropyloxy, methylthio, ethylthio, methylamino, ethylamino, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , phenyl, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl or oxazolyl, wherein the R ^y1 can be optionally unsubstituted or substituted by 1, 2 or 3 ^Rz having ^the definition described herein.

In some embodiments, R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^{4g ,} and R ^4h are each independently H, deuterium, F, Cl, Br, I, -CN, -NO _2. -COOH, -OH, -NH ₂ , -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, oxy, ethoxy, methylamino, ethylamino, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH ₂ -, cyclobutyl-CH ₂ -, cyclopentyl-CH ₂ -, cyclohexyl-CH ₂ -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl-CH ₂ -, pyrazolidinyl-CH ₂ -, tetrahydrofuryl-CH ₂ -, tetrahydrothienyl-CH ₂ -, piperidinyl-CH ₂ -, morpholinyl-CH ₂ -, thiomorpholinyl-CH ₂ -, piperazinyl-CH ₂ -, phenyl, phenyl-CH ₂ -, phenyl-CH ₂ CH ₂ -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyridazine Base, pyrazinyl, thiazolyl, oxazolyl, furyl-CH ₂ -, thienyl-CH ₂ -, imidazolyl-CH ₂ -, pyrimidinyl-CH ₂ -, pyridyl-CH ₂ - or pyrrolyl -CH ₂ -, wherein, the R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^4g and R ^4h can be independently and optionally substituted by 1, 2 or 3 R ^y2 , the The above-mentioned ^Ry2 has the definition described in the present invention.

In some embodiments, R ^4a , R ^4b and the carbon atoms connected to them together form a C _3-6 carbon ring or a heterocyclic ring consisting of 5-6 atoms, wherein the C _3-6 carbon ring and 5- The heterocyclic rings composed of 6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y3s , and the R ^y3s have the definitions described in the present invention.

In some embodiments, R ^4c , R ^4d and the carbon atoms connected to them together form a C _3-6 carbon ring or a heterocyclic ring consisting of 5-6 atoms, wherein the C _3-6 carbon ring and 5- The heterocyclic rings composed of 6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y3s , and the R ^y3s have the definitions described in the present invention.

In some embodiments, R ^4e , R ^4f and the carbon atoms connected to them together form a C _3-6 carbon ring or a heterocyclic ring consisting of 5-6 atoms, wherein the C _3-6 carbon ring and 5-6 The heterocyclic rings composed of atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y3 , said R ^y3 having the definition described in the present invention.

In some embodiments, ^Rz , ^Ry2 , ^Ry3 , and ^Ry4 are each 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.

In another aspect, the present invention relates to one of the following structures, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrug, (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20d), (20), (21d), (twenty one), (twenty two), (twenty three), (24d), (twenty four), (25d), (25), (26), (27), (28g), (28), (29), (30d), (30), (31d), (31), (32d), (32), (33d), (33), (34), (35d), (35), (36), (37), (38), (39), (40d), (40), (41), (42), (43), (44), (45), (46), (47f), (47), (48), (49f), (49), (50f), (50), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (72), (73), (74), (75) or (76).

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention.

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

In another aspect, the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of medicaments, wherein the medicament is used to stimulate thyroid hormone receptors; or to prevent, treat or relieve Disorders regulated by thyroid hormone receptors.

In another aspect, the present invention relates to a method of using the compound or pharmaceutical composition described in the present invention to stimulate thyroid hormone receptors, or a method for preventing, treating or alleviating diseases regulated by thyroid hormone receptors, said method is a therapeutically effective amount of the compound or the pharmaceutical composition administered to a subject in need thereof. Moreover, the above-mentioned compounds provided by the present invention or their pharmaceutical compositions can be co-administered with other therapies or therapeutic agents. The mode of administration can be carried out simultaneously, sequentially or at certain time intervals.

In another aspect, the present invention relates to the use of the compounds or pharmaceutical compositions described in the present invention for stimulating thyroid hormone receptors, or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

In some embodiments, the thyroid hormone receptor of the present invention is thyroid hormone beta receptor.

In some embodiments, the diseases regulated by thyroid hormone receptors in the present invention are neurodegenerative diseases, nonalcoholic fatty liver disease, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer.

In one aspect, the present invention relates to the use of the compounds of the present invention or the pharmaceutical compositions of the present invention in the preparation of medicines, wherein the medicines are 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 mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer.

In one aspect, the present invention relates to the compounds or pharmaceutical compositions of the present invention for preventing, treating or alleviating the following diseases: neurodegenerative diseases, non-alcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, arterial Atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, type 1A glycogen storage disease, Hypothyroidism or thyroid cancer.

In one aspect, the present invention relates to a method of using the compound or pharmaceutical composition of the present invention 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 by administering to an individual in need thereof a therapeutically effective amount of the compound or the pharmaceutical composition.

In some embodiments, the nonalcoholic fatty liver disease described in the present invention is nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, cryptogenic cirrhosis associated with nonalcoholic fatty liver disease, or primary liver cancer .

In some embodiments, the neurodegenerative disease described herein is demyelinating disease, chronic demyelinating disease, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 Deficiency, X-linked adrenal dystrophy (ALD), amyotrophic lateral sclerosis (ALS), or Alzheimer's disease.

The dosage of the compound or pharmaceutical composition required to implement the effects of treatment, prevention or delay usually depends on the specific compound to be administered, the patient, the specific disease or condition and its severity, the route and frequency of administration, etc., and needs to be determined by the attending physician according to Determine the specific situation. For example, when the compounds or pharmaceutical compositions provided by the present invention are administered by intravenous route, the administration can be performed once a week or even at longer time intervals.

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 the other ingredients comprising the formulation and/or with the mammal being treated therewith.

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

Furthermore, the compounds of the present invention, including their salts, may also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, it is intended that the present invention embrace both solvated and unsolvated forms.

Pharmaceutical Compositions, Formulations and Administration of Compounds of the Invention

The present invention relates to a pharmaceutical composition, which includes the compound of the present invention or the compound of the structure shown in the examples, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolic Products and pharmaceutically acceptable salts or their prodrugs. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound described herein and at least one pharmaceutically acceptable carrier, excipient, adjuvant or vehicle. The amount of the compound in the pharmaceutical composition of the invention is effective to detectably agonize the thyroid hormone beta receptor in a biological specimen or patient.

Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the biological activity of the compound. A pharmaceutically acceptable carrier should be biocompatible, eg, non-toxic, non-inflammatory, non-immunogenic or otherwise free of adverse effects or side effects once administered to a patient. Standard pharmaceutical techniques may be employed.

As described in the present invention, the pharmaceutical composition or pharmaceutically acceptable composition described in the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle, as used in the present invention, including Any solvents, diluents, liquid excipients, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants suitable for the particular intended dosage form, etc. 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 Dek ker, New York Various carriers used in formulating pharmaceutically acceptable compositions and known methods for their preparation are disclosed. In addition to conventional carrier media that are incompatible with the compounds of this invention, e.g., would produce adverse biological effects or deleterious interactions with any other components of a pharmaceutically acceptable composition, any other conventional carrier media and their Use is also within the scope of the present invention.

Some 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 such as human serum albumin, buffer substances such as Tween 80 , phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts) , silicone, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (such as lactose , glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, Gels, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol or polyethylene glycol) glycols), esters (such as ethyl oleate and ethyl dodecanoate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution ( Ringer's solution), ethanol and phosphate buffered saline, and other nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and, at the discretion of the formulator, coloring agents, antiadhesive agents, coating agents, sweeteners Preservatives and flavoring agents, preservatives and antioxidants can also be present in the compositions.

The pharmaceutical composition of the present invention can be administered directly or in the form of a pharmaceutical composition or drug together with a suitable carrier or excipient, which is well known in the art. The methods of treatment of the present invention may comprise administering to a subject in need thereof an effective compound of the present invention. In some embodiments, the individual is a mammalian individual, in other embodiments, the individual is a human individual.

The effective amount of the compound, pharmaceutical composition or drug of the present invention can be easily determined by conventional methods and tests, and the most effective and convenient route of administration and the most suitable preparation can also be determined by conventional tests.

The compounds or compositions of this invention may be administered by any suitable means, depending on the severity of the disease, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powder, ointment or drops) or nasal spray etc. to administer the above-mentioned compounds and pharmaceutically acceptable compositions to humans or other animals.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, 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 Esters, 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, Fatty acid esters of polyethylene glycol and sorbitan and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as octadecenoic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial retention screening program or by the addition of sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

To prolong the action of a compound or composition described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of poorly water soluble crystalline or amorphous material. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, depends upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration, in particular suppositories, may be prepared by mixing a compound according to the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which Or the carrier is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) filler or bulking agents such as starch, lactose, sucrose, Glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerin; d) disintegrants such as Agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and 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 capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and others well known in the pharmaceutical art. They may optionally contain opacifying agents and may also be of a composition so that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

The active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. In general, such dosage forms may also contain additional substances besides inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also be of a composition so that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

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

The compositions described herein may also be administered orally, parenterally, topically, rectally, nasally, buccally, vaginally or via an implanted kit by inhalation spray. The term "parenteral" as used herein 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 are administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions may be formulated following techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation 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 the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as octadecenoic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical composition of the present invention can be orally administered 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, carriers commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also usually added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents can also be added, if desired.

Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing reagents with non-irritating excipients, such substances include but are not limited to cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention may also be administered topically, especially when the target of treatment includes topical instillation of easily accessible areas or organs, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical instillation to the lower intestinal tract can be achieved with rectal suppository formulations (see above) or with suitable enema formulations. Topical skin patches may also be used.

For topical application by instillation, the pharmaceutical composition can be formulated as a suitable ointment containing the active components suspended or dissolved in one or more carriers. Carriers suitable for topical drip application of a compound of this invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water .

For ophthalmic use, the pharmaceutical composition is formulated as a micronized suspension in, or especially as a solution in, isotonic pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment, such as petrolatum.

The pharmaceutical compositions can also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and prepared in saline using benzyl alcohol and other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents. solution.

The purposes of compound of the present invention and pharmaceutical composition

The compound or pharmaceutical composition provided by the present invention can be used for the preparation of drugs for stimulating thyroid hormone receptors, or for the preparation of drugs for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

The compound or pharmaceutical composition provided by the present invention can be used to stimulate thyroid hormone receptors, or to prevent, treat or alleviate diseases regulated by thyroid hormone receptors.

The present invention provides a method for activating thyroid hormone receptors, or a method for preventing, treating or alleviating diseases regulated by thyroid hormone receptors, the method comprising administering a therapeutically effective amount of the above compound or its pharmaceutical composition. Moreover, the above-mentioned compounds provided by the present invention or their pharmaceutical compositions can be co-administered with other therapies or therapeutic agents. The mode of administration can be carried out simultaneously, sequentially or at certain time intervals.

The thyroid hormone receptor of the present invention is thyroid hormone β receptor.

The diseases described in the present invention are non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder , lipid metabolism disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer, wherein the nonalcoholic fatty liver disease is nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, nonalcoholic Cryptogenic cirrhosis or primary liver cancer associated with fatty liver disease.

The compound or pharmaceutical composition of the present invention can be used to treat fibrotic diseases, including but not limited to liver fibrosis, idiopathic pulmonary fibrosis and the like.

In addition to their therapeutic benefits in humans, the compounds of the present invention are also useful in the veterinary treatment of pets, introduced breeds and farm animals, including mammals, rodents and the like. Examples of additional animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives.

"Effective amount", "therapeutically effective amount" or "effective dose" of a compound of the present invention or a pharmaceutically acceptable pharmaceutical composition refers to an effective amount for treating or reducing the severity of one or more of the disorders mentioned in the present invention . The compounds or pharmaceutically acceptable compositions of this invention are effective over a fairly wide dosage range. For example, the daily dose is about in the range of 0.1 mg - 1000 mg/person, divided into one or several administrations. The methods, compounds and pharmaceutical compositions according to the invention may be administered in any amount and by any route of administration effective for treating or lessening the severity of a disease. The exact amount necessary will vary from patient to patient, depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. A compound or pharmaceutical composition of the invention may be administered in combination with one or more other therapeutic agents, as discussed herein.

General Synthesis and Detection Methods

In order to describe the present invention, examples are listed below. However, it should be understood that the present invention is not limited to these examples, but only provides a method of practicing the present invention.

In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure shall prevail.

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

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known drugs in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

The structure of the compound was confirmed by nuclear magnetic resonance ( ¹ H-NMR, ¹³ C-NMR or/and ¹⁹ F-NMR). ¹ H-NMR, ¹³ C-NMR, ¹⁹ F-NMR chemical shifts (δ) are given in parts per million (ppm). ¹ H-NMR, ¹³ C-NMR, and ¹⁹ F-NMR were measured with Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, and the measuring solvents were deuterated chloroform (CDCl ₃ ), deuterated Methanol (CD ₃ OD or MeOH- d ₄ ) or deuterated dimethylsulfoxide (DMSO- d ₆ ). Use TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), ddd (doublet doublet of doublets, double doublet doublet), dt (doublet of triplets, double triplet), td ( triplet of doublets, triplet doublet), brs (broadened singlet, wide singlet). The coupling constant J is expressed in Hertz (Hz).

Generally, Novasep pump 250 high-performance liquid chromatography is used for preparative purification or preparative resolution.

Agilen-6120 Quadrupole LC/MS mass spectrometer was used for the determination of LC-MS.

Column chromatography generally uses Qingdao Ocean Chemical Co., Ltd. 300-400 mesh silica gel as the carrier.

The starting materials of the present invention are known and can be purchased on the market, purchased from Shanghai Accela Company, Energy Company, J&K, Tianjin Alpha companies such as Alfa Company, or can adopt or synthesize according to methods known in the art.

No special instructions in the embodiment, the reaction is all carried out under nitrogen atmosphere;

Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon or steel kettle with a volume of about 1L;

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L or a stainless steel autoclave with a volume of about 1L;

Unless otherwise specified in the embodiments, the solution refers to an aqueous solution;

If no special instructions in the embodiment, temperature of reaction is room temperature;

If no special instructions in the embodiment, room temperature is 20 DEG C ~ 40 DEG C.

The monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of the developing agent used in the reaction has: methylene chloride and methanol system, methylene chloride and ethyl acetate system, sherwood oil and ethyl acetate system , the volume ratio of the solvent is adjusted according to the polarity of the compound.

The eluent system of column chromatography includes: A: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, 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 a small amount of ammonia and acetic acid.

HPLC means high performance liquid chromatography;

The determination of HPLC uses Agilent 1260 high pressure liquid chromatography (column: Agilent ZORBAX Eclipse Plus C18 4.6 mm×150 mm, 3.5 μm);

HPLC test conditions: Execution time: 25 min Column temperature: 35 °C Detection wavelength: 210 nm; 245 nm;

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

The mobile phase gradient is shown in Table A: [Table A] time Gradient of mobile phase A Gradient of mobile phase B 0 minutes 90% 10% 15 minutes 10% 90% 20 minutes 10% 90% 25 minutes 90% 10%

The LC/MS/MS system used for the analysis in the biological test experiment includes Agilent 1200 series vacuum degassing oven, binary syringe pump, orifice plate autosampler, column oven, Agilent G6430 three-stage with electrospray ionization (ESI) source Quadrupole mass spectrometer. Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table B: [Table B] full scan 50~1400 Fragmentation voltage 230V capillary voltage 55V Dryer temperature 350°C atomizer 0.28 MPa Dryer flow rate 10L/min

The analysis used an Agilent XDB-C18, 2.1 × 30 mm, 3.5 μm column, injecting 5 μL of the sample. Analytical conditions: The mobile phase is 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate is 0.4 mL/min. The mobile phase gradient is shown in Table C: [Table C] time Gradient of mobile phase B 0.5 minutes 5% 1.0 min 95 % 2.2 minutes 95 % 2.3 minutes 5% 5.0 minutes termination

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

The following abbreviations are used throughout this disclosure: DMSO- _d6 : Deuterated dimethyl sulfone; DMSO: Dimethylsulfone; TFA: Trifluoroacetate; mL, ml: ml; μL , μl: Microliter; mol/L, mol/l: mole/liter; mol: Moore; mmol/L, mmol/l, mM: mmol/L; μmol/L, μmol/l, μM: μmol/L; nmol/L, nmol/l, nM: nmol/L; g: gram; h: Hour; mg: mg; µg: microgram; ng: Nanogram; %wt, mass%: % by weight; μm: Micron; MPa: MPa; min: minute; ACN: Acetonitrile; Me: methyl; Et Ethyl;

General Synthesis Method

Typical synthetic procedures for the preparation of the compounds disclosed herein are shown in the following synthetic schemes. Unless otherwise specified, each ring A, R ¹ , R ^3a , R ^3b , R ^3c and R ^3d has the definition as described in the present invention, and X is halogen.

Synthetic Scheme 1 :

The compound with the structure shown in general formula (IA) can be prepared by the general synthesis method described in Synthesis Scheme 1 , and the specific steps can be referred to the examples. First, compound (Ia) reacts with compound (Ib) under the action of alkali (such as potassium carbonate), obtains compound (Ic) ; Compound (Ic) obtains compound (Id) through nitro reduction; Compound (Id) aminodiazo and react with compound (Ie) to obtain compound (If) ; compound (If) is ring-closed under the action of a base (such as sodium acetate) to obtain the target compound shown in general formula (IA) .

Synthetic scheme 2 :

The compound with the structure shown in general formula (IB) can be prepared by the general synthesis method described in Synthesis Scheme 2 , and the specific steps can be referred to the examples. First, compound (II-a) is hydrolyzed under acidic conditions (such as concentrated hydrochloric acid) to obtain compound (II-b) ; compound (II-b) is decarboxylated to obtain the target compound shown in general formula (IB) .

Preparation Example

Example 1 2-(3,5- dichloro -4-((1- oxo- 1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5 -Dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6 - carbonitrile 1

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 1b

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

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

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 1c

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

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

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -1,2,3,4- tetraisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 1d

6-(4-Amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2 H )-one 1c (0.20 g, 0.62 mmol), N -cyanoethyl Acyl urethane (0.11 g, 0.69 mmol) was dissolved in acetic acid (4 mL), and a solution of sodium nitrite (65 mg, 0.93 mmol) in water (2 mL) was added at 0 ℃, and reacted for 4.5 hours. At 0 °C, water (10 mL) was added to the reaction solution, stirred for 10 minutes, filtered, washed with water (2 mL), and the filter cake was collected and dried to obtain an orange solid 1d (0.30 g, yield 99%).

step 4 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 1

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetraisoquinolin-6-yl)oxy)benzene 1d (0.30 g, 0.61 mmol) was dissolved in N , N -dimethylformamide (3 mL), added sodium acetate (55 mg, 0.67 mmol), 120 °C for 5 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, solids were precipitated, stirred for 10 minutes, filtered, rinsed with water (5 mL), the filter cake was collected and dried, and the obtained reddish-brown solid was recrystallized (acetonitrile/ethanol / N , N -dimethylformamide/water=10/5/2/20, 37 mL), filtered, rinsed with water (2 mL), collected the filter cake and dried to obtain an orange solid 1 (0.13 g, Yield 48%, purity 91.86%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.27 (s, 1H), 7.85 (d, J = 6.4 Hz, 4H), 6.87 (s, 1H), 6.81 (dd, J = 8.6, 2.3 Hz, 1H), 3.32 (s, 2H), 2.90 (t, J = 6.2 Hz, 2H).

Example 2 2-(3,5- dichloro -4-((2 - methyl -1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 2

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2- methyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 2a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (1.0 g, 2.8 mmol) was dissolved in THF (15 mL), sodium hydride (0.23 g, 5.8 mmol, 60% in oil) and methyl iodide (0.26 mL, 4.2 mmol) were added and reacted at room temperature for 2.5 hours. Water (10 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL × 2), the combined organic phase was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was washed with Purification by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) gave 2a as a yellow solid (1.0 g, yield 99%).

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2- methyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 2b

6-(2,6-dichloro-4-nitrophenoxy)-2-methyl-3,4-dihydroisoquinolin-1(2 H )-one 2a (1.0 g, 2.7 mmol) Dissolve in acetic acid (8 mL), add iron powder (0.30 g, 5.4 mmol), and react at 70 °C. The reaction solution was cooled to room temperature, after iron powder was removed, water (30 mL) was added and stirred for 10 minutes, filtered, rinsed with water (10 mL), the filter cake was collected and dried, and the obtained solid was subjected to silica gel column chromatography (petroleum ether/ethyl acetate Esters = 1/1) were purified to give 2b as a yellow solid (0.40 g, 44% yield).

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2- methyl -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 2c

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

step 4 : 2-(3,5- Dichloro -4-((2- methyl -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 2

(2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- yl)oxy)phenyl)hydrazinylidene)acetyl)urethane 2c (0.62 g, 1.2 mmol) was dissolved in N , N -dimethylformamide (6 mL), and sodium acetate (0.11 g , 1.3 mmol), react at 120 ℃ for 6 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (80 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration , the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/3), and the obtained solid was recrystallized (acetonitrile/ethyl acetate/ethanol/petroleum ether=3/10/15/30, 58 mL ), to obtain light red solid 2 (0.21 g, yield 38%, purity: 97.61%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.29 (s, 1H), 8.11-7.63 (m, 3H), 6.91-6.76 (m, 2H), 3.53 (t, J = 6.6 Hz, 2H), 3.00 (s, 3H), 2.97 (t, J = 6.6 Hz, 2H).

Example 3 2-(3,5- dichloro -4-((2-( methoxymethyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 3

2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-di Oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.10 g, 0.23 mmol) was dissolved in methanol (4 mL), and 37% formaldehyde (0.37 mL , 5.0 mmol), react at 100 ℃ for 16 hours. The reaction solution was cooled to room temperature, concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1), and the obtained solid was recrystallized (methanol/ethyl acetate/petroleum ether=1/6/ 12, 9.5 mL), to obtain white solid 3 (50 mg, yield 45%, HPLC purity: 97.51%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.84 (s, 2H), 6.95-6.81 (m, 2H) , 4.86 (s, 2H), 3.56 (t, J = 6.4 Hz, 2H), 3.22 (s, 3H), 2.98 (t, J = 6.2 Hz, 2H).

Example 4 2-(3,5- dichloro -4-((2-( ethoxymethyl )-1- oxo - 1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 4

2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-di Oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.40 g, 0.90 mmol) was dissolved in ethanol (10 mL), and 37% formaldehyde (2.0 mL, 27 mmol), react at 100 ℃ for 48 hours. The reaction solution was cooled to room temperature, concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1), and the obtained solid was recrystallized (ethanol/ethyl acetate/petroleum ether=1/5/ 3, 18 mL), to obtain white solid 4 (0.28 g, yield 62%, HPLC purity: 96.19%).

MS (ESI, neg. ion) m/z : 500.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) 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 = 6.1 Hz, 2H), 3.49-3.43 (m, 2H), 2.98 (t, J = 5.8 Hz, 2H), 1.11 (t, J = 6.9 Hz, 3H).

Example 5 2-(3,5- dichloro -4-((2- ethyl -1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 5

step 1 :synthesis 2- Ethyl -6- Methoxy -3,4- Dihydroisoquinoline -1(2 H )- ketone 5b

6-Methoxy-3,4-dihydroisoquinolin-1( 2H )-one 5a (2.05 g, 11.6 mmol) was dissolved in THF (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, and then iodoethane (1.13 mL, 13.8 mmol) was added dropwise, and reacted at 50 °C for 24 hours. The reaction solution was cooled to room temperature, quenched by adding ice water (40 mL) to the reaction solution, concentrated under reduced pressure to remove tetrahydrofuran, the remaining solution was extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated sodium chloride The solution (45 mL × 3) was washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain light yellow oil 5b (2.30 g , yield 97%).

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

step 2 :synthesis 2- Ethyl -6- hydroxyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 5c

Dissolve 2-ethyl-6-methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5b (2.40 g, 11.7 mmol) in dichloromethane (50 mL) at 0 °C Boron tribromide (2.28 mL, 23.4 mmol) was slowly added dropwise and stirring was continued for 3.5 hours. Slowly add methanol (10 mL) dropwise at 0 ℃ to quench the reaction, concentrate under reduced pressure, add water (50 mL), extract with ethyl acetate (40 mL × 3), and wash the combined organic phase with saturated sodium chloride solution (40 mL × 2) Wash, dry over anhydrous sodium sulfate, and concentrate by suction filtration to obtain brown-yellow solid 5c (2.01 g, yield 90%).

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

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2- Ethyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 5d

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

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

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2- Ethyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 5e

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

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

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2- Ethyl -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 5f

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

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2- Ethyl -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 5

(2-cyano-2-(2-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6- Base) oxy) phenyl) hydrazino) acetyl) ethyl carbamate 5f (1.10 g, 2.12 mmol) was dissolved in N , N - dimethylformamide (25 mL), adding sodium acetate (0.88 g , 12.9 mmol), reacted at 120 ℃ for 6 hours. The reaction solution was cooled to room temperature, poured the reaction solution into water (100 mL), stirred for 30 minutes, filtered, collected the filter cake and dried, and the obtained pale yellow solid was separated and purified by preparation [50%ACN/50%H ₂ O (0.1%TFA), Kromasil specification: C18 10 μm×50 mm×250 mm, flow rate: 100 mL/min] to obtain white solid 5 (0.56 g, yield 54%, HPLC purity: 99.80%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.29 (s, 1H), 7.92-7.81 (m, 3H), 6.82 (dd, J = 13.1, 4.5 Hz, 2H), 3.55-3.50 ( m, 2H), 3.50-3.45 (m, 2H), 2.95 (t, J = 6.4 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H).

Example 6 2-(3,5- dichloro -4-((2 - methyl -1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carboxylic acid methyl ester 6

2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)- 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2 (0.30 g, 0.66 mmol) dissolved in methanolic hydrogen chloride (10 mL, 40 mmol, 4.0 mol/L ), react at 70 ℃ for 48 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/4) to obtain light yellow solid 6 (35 mg, yield 11%, HPLC purity: 98.29%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.87 (d, J = 8.7 Hz, 3H), 6.87-6.76 (m, 2H), 4.13 (d, J = 5.0 Hz, 1H), 3.85 (s, 3H), 3.52 (t, J = 6.6 Hz, 2H), 3.17 (d, J = 4.1 Hz, 3H), 2.97 (t, J = 6.7 Hz, 2H).

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

step 1 :synthesis 7-(2,6- Dichloro -4- Nitrophenoxy base )-2,3,4,5- Tetrahydro -1 H - Benzo [ c ] Azapine -1- ketone 7b

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

step 2 :synthesis 7-(4- Amino -2,6- Dichlorophenoxy )-2,3,4,5- Tetrahydro -1 H - Benzo [ c ] Azapine -1- ketone 7c

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

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2,3,4,5- Tetrahydro -1 H - Benzo [ c ] Azapine -7- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 7d

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

step 4 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2,3,4,5- Tetrahydro -2H- Benzo [ c ] Azapine -7- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 7

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.99 (t, J = 5.7 Hz, 1H), 7.84 (s, 2H), 7.51 (d, J = 8.5 Hz, 1H), 6.87 (d , J = 2.4 Hz, 1H), 6.76 (dd, J = 8.5, 2.5 Hz, 1H), 2.97-2.89 (m, 2H), 2.74 (t, J = 6.9 Hz, 2H), 1.93-1.81 (m, 2H).

Example 8 2-(3,5- dichloro -4-((2- oxo- 1,2,3,4- tetrahydroquinolin -7- yl ) oxy ) phenyl )-3,5- Dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 8

step 1 :synthesis 7-(2,6- Dichloro -4- Nitrophenoxy base )-3,4- Dihydroquinoline -2(1 H )- ketone 8b

Dissolve 7-hydroxy-3,4-dihydroquinolin-2( 1H )-one 8a (1.20 g, 7.35 mmol) in N , N -dimethylformamide (15 mL), add 1,2 , 3-trichloro-5-nitrobenzene (1.67 g, 7.38 mmol), potassium carbonate (2.46 g, 17.6 mmol), 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 obtain light yellow solid 8b (2.46 g, yield 95%).

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

step 2 :synthesis 7-(4- Amino -2,6- Dichlorophenoxy )-3,4- Dihydroquinoline -2(1 H )- ketone 8c

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

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

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2- Oxo -1,2,3,4- Tetrahydroquinoline -7- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 8d

7-(4-Amino-2,6-dichlorophenoxy)-3,4-dihydroquinolin-2(1 H )-one 8c (0.70 g, 2.17 mmol) and N -cyanoacetyl Urethane (0.38 g, 2.39 mmol) was dissolved in acetic acid (10 mL), and a solution of sodium nitrite (0.23 g, 3.25 mmol) in water (3 mL) was added at 0 °C, and reacted for 3 hours. At 0 °C, water (20 mL) was added to the reaction solution, stirred for 10 minutes, filtered, rinsed with water (4 mL), and the filter cake was collected and dried to obtain a yellow solid 8d (0.88 g, yield 83%).

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

step 4 :synthesis 2-(3,5- Dichloro -4-((2- Oxo -1,2,3,4- Tetrahydroquinoline -7- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 8

(2-cyano-2-(2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)benzene yl) hydrazino) acetyl) ethyl carbamate 8d (0.85 g, 1.73 mmol) was dissolved in N , N - dimethylformamide (10 mL), added sodium acetate (0.72 g, 8.65 mmol), 120 °C for 6 hours. The reaction solution was cooled to room temperature, added water (40 mL) and stirred for 10 minutes, then added hydrochloric acid (2 N, 3 mL) and stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain gray solid 8 (0.56 g, yield 73%, HPLC purity: 89.58%).

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

¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 13.29 (s, 1H), 9.98 (s, 1H), 7.82 (s, 2H), 7.14 (d, J = 8.3 Hz, 1H), 6.44 (dd, J = 8.2, 2.6 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H).

Example 9 2-(3,5- dichloro -4-((1- oxo- 1,2,3,4- tetrahydroisoquinolin -7- yl ) oxy ) phenyl )-3,5 -Dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6 - carbonitrile 9

step 1 :synthesis 7- hydroxyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 9b

At 0 ^o C, boron tribromide (5.5 mL, 57 mmol) was added dropwise to 7-methoxy-3,4-dihydroisoquinolin-1(2 H )-one 9a (5.0 g, 28 mmol) In dichloromethane (30 mL) solution, the reaction was continued for 3.5 hours. Pour the reaction solution into ice water (40 mL) to quench the reaction, stir for 30 minutes, filter, wash the filter cake with water (5 mL × 2), and recrystallize the obtained solid after drying (ethanol/ethyl acetate/petroleum ether= 1/3/3, 42 mL), to obtain brown solid 9b (5.0 g, yield 100%).

step 2 :synthesis 7-(2,6- Dichloro -4- Nitrophenoxy base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 9c

7-Hydroxy-3,4-dihydroisoquinolin-1(2 H )-one 9b (1.5 g, 9.2 mmol), 1,2,3-trichloro-5-nitro-benzene (2.3 g, 10 mmol) was dissolved in N , N -dimethylformamide (40 mL), and potassium carbonate (2.6 g, 19 mmol) was added to react at 80°C for 4 hours. The reaction solution was cooled to room temperature, added water (80 mL), stirred for 15 minutes, filtered, and the filter cake was collected to obtain a yellow solid, which was slurried with ethanol/ethyl acetate/petroleum ether (1/3/6, 50 mL), After filtration, the filter cake was collected and dried to obtain gray solid 9c (2.4 g, yield 74%).

step 3 :synthesis 7-(4- Amino -2,6- Dichlorophenoxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 9d

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

step 4 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -1,2,3,4- Tetrahydroisoquinoline -7- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 9e

7-(4-Amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2 H )-one 9d (0.20 g, 0.62 mmol), N -cyanoethyl Acyl urethane (0.11 g, 0.69 mmol) was dissolved in acetic acid (4 mL), and a solution of sodium nitrite (65 mg, 0.93 mmol) in water (2 mL) was added at 0 ℃, and reacted for 3.5 hours. At 0 °C, water (10 mL) was added to the reaction solution, stirred for 10 minutes, filtered, washed with water (2 mL), and the filter cake was collected and dried to obtain a yellow solid 9e (0.30 g, yield 99%).

step 5 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -1,2,3,4- Tetrahydroisoquinoline -7- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 9

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

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

¹ H NMR (600 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 8.06 (s, 1H), 7.85 (s, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 8.3, 2.8 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 3.36 (d, J = 2.3 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H).

Example 10 2-(3,5- dichloro -4-((2-(2- methoxyethyl )-1- oxo -1,2,3,4- tetrahydroisoquinoline -6- Base ) oxy ) phenyl ) -3,5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 10

step 1 :synthesis 6-( Benzyloxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 10a

Dissolve 6-hydroxy-3,4-dihydroisoquinolin-1( 2H )-one 1a (5.0 g, 31 mmol) in N , N -dimethylformamide (50 mL), add potassium carbonate (6.4 g, 46 mmol), react at room temperature for 15 minutes, add benzyl bromide (4.4 mL, 37 mmol) dropwise, and react at room temperature for 48 hours. Water (100 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the solid was collected and dried to obtain white solid 10a (6.2 g, yield 80%).

step 2 :synthesis 6-( Benzyloxy )-2-(2- Methoxyethyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 10b

6-(Benzyloxy)-3,4-dihydroisoquinolin-1( 2H )-one 10a (3.0 g, 12 mmol) was dissolved in THF (24 mL) and N , N -dimethylformaldehyde Amide (6 mL), add sodium hydride (1.4 g, 35 mmol, 60% in oil), react at room temperature for 15 minutes, add dropwise 1-bromo-2-methoxy-ethane (1.7 mL, 18 mmol) , react at 60°C for 4 hours. The reaction was quenched by adding water (30 mL), extracted with ethyl acetate (50 mL × 2), the combined organic phase was washed with saturated sodium chloride (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to obtain a yellow Oil 10b (3.7 g, 100% yield).

step 3 :synthesis 6- hydroxyl -2-(2- Methoxyethyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 10c

6-(Benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1( 2H )-one 10b (3.7 g, 12 mmol) was dissolved in ethanol ( 30 mL), add 10% palladium carbon (0.37 g), replace the hydrogen (3 MPa), hydrogenation reaction for 16 hours. The reaction solution was filtered, and the filtrate was collected and concentrated to obtain a yellow solid 10c (2.6 g, yield 99%).

step 4 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )- 2-(2- Methoxyethyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 10d

6-Hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2 H )-one 10c (0.50 g, 2.3 mmol), 1,2,3-tri Chloro-5-nitro-benzene (0.56 g, 2.5 mmol) was dissolved in N , N -dimethylformamide (5 mL), potassium carbonate (0.63 g, 4.5 mmol) was added, and reacted at 70°C for 3 hours. The solution was cooled to room temperature, added water (10 mL), stirred for 15 minutes, filtered, and the filter cake was collected for recrystallization (ethyl acetate/petroleum ether=3/5, 12 mL) to obtain a yellow solid 10d (0.49 g, produced rate 53%).

step 5 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(2- Methoxyethyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 10e

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

step 6 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-(2- Methoxyethyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 10f

6-(4-amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1( 2H )-one 10e ( 0.33 g, 0.87 mmol) was dissolved in acetic acid (6.6 mL), and a solution of sodium nitrite (90 mg, 1.29 mmol) in water (3.3 mL) was added at 0 °C for 10 minutes, and N -cyanoacetylurethane ( 0.17 g, 1.1 mmol), continue to react at 0 ℃ for 1 hour. At 0 °C, water (12 mL) was added to the reaction solution, stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to obtain a yellow solid 10f (0.47 g, yield 99%).

step 7 :synthesis 2-(3,5- Dichloro -4-((2-(2- Methoxyethyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 10

(2-cyano-2-(2-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetra Hydroisoquinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)ethyl carbamate 10f (0.47 g, 0.86 mmol) was dissolved in N , N -dimethylformamide (3 mL), Add sodium acetate (0.77 g, 0.94 mmol) and react at 120 °C. The reaction solution was cooled to room temperature, added water (10 mL), stirred for 10 minutes, filtered, collected solid recrystallization (ethanol/ethyl acetate/petroleum ether=7.5/20/10, 37.5 mL), filtered, collected filter cake and dried Drying gave an off-white solid 10 (0.23 g, 53% yield, HPLC purity: 96.55%).

MS (ESI, neg. ion) m/z : 500.1 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.28 (s, 1H), 7.86 (d, J = 12.5 Hz, 3H), 6.82 (d, J = 10.8 Hz, 2H), 3.61 (d , J = 5.3 Hz, 2H), 3.59-3.54 (m, 2H), 3.52-3.49 (m, 2H), 3.26 (s, 3H), 2.93 (t, J = 5.7 Hz, 2H).

Example 11 2-(3,5- dichloro -4-((1- oxo- 1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5 -Dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carboxylic acid methyl ester 11

Hydrogen chloride in methanol (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-carbonitrile 1 (0.10 g, 0.23 mmol) , 70°C for 24 hours. The reaction solution was cooled to room temperature and concentrated, and the obtained residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a white solid 11 (45 mg, yield 42%, HPLC purity: 95.69%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.79 (s, 1H), 7.86 (s, 3H), 7.84 (s, 1H), 6.87 (d, J = 2.2 Hz, 1H), 6.81 (dd, J = 8.6, 2.5 Hz, 1H), 3.85 (s, 3H), 3.45 (d, J = 9.4 Hz, 2H), 2.90 (t, J = 6.4 Hz, 2H).

Example 12 2-(3,5- dichloro -4-((1- oxo -2-(( tetrahydro -2H- pyran -4- yl ) methyl )-1,2,3,4- Tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 12

step 1 :synthesis 6- Methoxy -2-(( Tetrahydro -2H- pyran -4- base ) methyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 12a

6-Methoxy-3,4-dihydroisoquinolin-1( 2H )-one 5a (3.0 g, 16.9 mmol) was dissolved in THF (30 mL) and N , N -dimethylformamide (30 mL), add sodium hydride (0.85 g, 21.2 mmol, 60% in oil) in batches at 0 °C, then add bromomethylpyran (1.13 mL, 13.8 mmol) dropwise, and continue the reaction at room temperature after the addition is complete 24 hours. Water (30 mL) was added to quench the reaction, 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, and concentrated by suction to obtain The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain light yellow oil 12a (4.35 g, yield 93%).

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

step 2 :synthesis 6- hydroxyl -2-(( Tetrahydro -2H- pyran -4- base ) methyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 12b

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

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(( Tetrahydro -2H- pyran -4- base ) methyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 12c

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

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(( Tetrahydro -2H- pyran -4- base ) methyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 12d

6-(2,6-dichloro-4-nitrophenoxy)-2-((tetrahydro-2 H -pyran-4-yl)methyl)-3,4-dihydroisoquinoline -1(2 H )-one 12c (0.31 g, 0.69 mmol) was dissolved in acetic acid (10 mL), iron powder (0.19 g, 3.3 mmol) was added, and reacted at 60 ℃ for 3.5 hours. The reaction was cooled to room temperature, iron powder was removed, water (10 mL) was added, extracted with ethyl acetate (15 mL × 3), the combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), anhydrous sodium sulfate It was dried, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain a light yellow solid 12d (0.18 g, yield 62%).

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

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-(( Tetrahydro -2H- pyran -4- base ) methyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 12e

6-(4-amino-2,6-dichlorophenoxy)-2-((tetrahydro-2 H -pyran-4-yl)methyl)-3,4-dihydroisoquinoline- 1(2 H )-ketone 12d (0.18 g, 0.43 mmol) was dissolved in acetic acid (8 mL), and a solution of sodium nitrite (46 mg, 0.65 mmol) in water (0.5 mL) was slowly added dropwise at 0 °C to react 20 Minutes later, N -cyano-acetylurethane (75 mg, 0.47 mmol) was added and the reaction was continued for 4.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (15 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration, 12e was obtained as a yellow solid (0.25 g, 99% yield).

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

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(( Tetrahydro -2H- pyran -4- base ) methyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 12

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) 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 = 6.4 Hz, 2H), 3.35 (s, 2H), 3.25 (t, J = 11.2 Hz, 2H), 2.95 (t, J = 6.3 Hz, 2H), 1.95-1.85 (m, 1H ), 1.53 (d, J = 11.6 Hz, 2H), 1.21 (ddd, J = 16.5, 12.4, 5.4 Hz, 2H).

Example 13 2-(3,5- dichloro -4-((2-( isopropoxymethyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 13

2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-di Oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.30 g, 0.68 mmol) was dissolved in isopropanol (10 mL) and 37% formaldehyde was added (1.5 mL, 20 mmol), locked tube at 100 ℃ for 24 hours. The reaction solution was cooled to room temperature, concentrated, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1), and the obtained solid was recrystallized (ethyl acetate/petroleum ether=1/2, 6 mL ) to give white solid 13 (85 mg, yield 24%, HPLC purity: 99.85%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.97-7.79 (m, 3H), 6.87 (dd, J = 17.0, 4.9 Hz, 2H), 4.92 (s, 2H), 3.67 (dt, J = 12.2, 6.1 Hz, 1H), 3.56 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 6.3 Hz, 2H), 1.10 (d, J = 6.1 Hz, 6H).

Example 14 2-(3,5- dichloro -4-((1- oxo -2-((2,2,2- trifluoroethoxy ) methyl )-1,2,3,4- Tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 14

2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-di Oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.48 g, 1.08 mmol) was dissolved in trifluoroethanol (8 mL), and 37% formaldehyde was added (1.60 mL, 22 mmol), locked tube at 100 ℃ for 24 hours. The reaction solution was cooled to room temperature, concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2), and the obtained solid was recrystallized (ethyl acetate/petroleum ether=1/2, 6 mL ), to obtain white solid 14 (0.23 g, yield 38%, HPLC purity: 96.05%).

MS (ESI, neg. ion) m/z : 554.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.90-7.79 (m, 2H), 6.93-6.83 (m, 2H), 5.07 (s, 2H), 4.12 (q, J = 9.4 Hz, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 6.4 Hz, 2H);

¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ (ppm) -73.04.

Example 15 2-(3,5- dichloro -4-((1- oxo -2-((2,2 -difluoroethoxy ) methyl )-1,2,3,4- tetrahydro Isoquinolin -6- yl ) oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 15

2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-di Oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.30 g, 0.68 mmol) was dissolved in 2,2-difluoroethanol (6 mL) solution, Add 37% formaldehyde (1.0 mL, 14 mmol), and lock the tube at 100 ℃ for 24 hours. The reaction solution was cooled to room temperature, concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2), and the obtained solid was recrystallized (ethyl acetate/petroleum ether=1/2, 6 mL ) to give white solid 15 (85 mg, yield 23%, HPLC purity: 97.53%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.31 (s, 1H), 7.89 (dd, J = 27.8, 8.3 Hz, 3H), 6.95-6.78 (m, 2H), 6.14 (t, J = 55.1 Hz, 1H), 5.01 (s, 2H), 3.74 (t, J = 14.8 Hz, 2H), 3.61 (s, 2H), 3.00 (s, 2H);

¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ (ppm) -125.56.

Example 16 2-(3,5- dichloro -4-((2-(1- ethoxyethyl )-1- oxo -1,2,3,4- tetrahydroisoquinoline -6- Base ) oxy ) phenyl )-3,5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 16

2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-di Oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.20 g, 0.45 mmol) was dissolved in ethanol (4 mL), and acetaldehyde (0.8 mL , 14 mmol), react at 90 ℃ for 48 hours. The reaction solution was cooled to room temperature, concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2), and the obtained solid was recrystallized (ethanol/ethyl acetate/petroleum ether=1/7/ 10, 18 mL), to obtain yellow solid 16 (60 mg, yield 26%, HPLC purity: 87.08%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.85 (s, 2H), 6.93-6.78 (m, 2H) , 5.89 (q, J = 6.0 Hz, 1H), 3.41 (s, 2H), 3.39 (d, J = 7.0 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H), 1.26 (d, J = 6.1 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H).

Example 17 2-(3,5- dichloro -4-((1- oxo- 1,2,3,4 -tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-1,2 ,4- Triazine -3,5(2 H , 4 H ) -dione 17

step 1 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 17a

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

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

step 2 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H , 4 H )- diketone 17

2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-3,5-di Oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 17a (175 mg, 0.38 mmol) was dissolved in thioglycolic acid (2.5 mL), and reacted at 140 ℃ for 17 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), 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, It was concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a light red solid 17 (63 mg, yield 40%, HPLC purity: 95.58%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 7.85 (d, J = 10.5 Hz, 4H), 7.73 (s, 1H), 6.85 (d, J = 2.6 Hz , 1H), 6.78 (dd, J = 8.6, 2.6 Hz, 1H), 3.57- 3.38 (m, 2H), 2.89 (t, J = 6.6 Hz, 2H).

Example 18 2-(4-((2- Benzyl -1- oxo - 1,2,3,4- tetrahydroisoquinolin- 6- yl ) oxy )-3,5- dichlorophenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 18

step 1 :synthesis 2- Benzyl -6- Methoxy -3,4- Dihydroisoquinoline -1(2 H )- ketone 18a

At 0 °C, 6-methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5a (3.0 g, 17 mmol) was added to sodium hydride (0.81 g, 20 mmol, 60% in oil) in N , N -dimethylformamide (24 mL) and tetrahydrofuran (18 mL), dropwise added benzyl bromide (2.2 mL, 19 mmol), and reacted at room temperature for 6 hours. Water (120 mL) was added to quench the reaction, extracted with ethyl acetate (200 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated by suction to obtain Pale yellow oil 18a (4.51 g, 100% yield).

step 2 :synthesis 2- Benzyl -6- hydroxyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 18b

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

step 3 :synthesis 2- Benzyl -6-(2,6- Dichloro -4- Nitrophenoxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 18c

2-Benzyl-6-hydroxy-3,4-dihydroisoquinolin-1(2 H )-one 18b (3.80 g, 15.0 mmol), 1,2,3-trichloro-5-nitrobenzene (3.74 g, 16.5 mmol) was dissolved in N , N -dimethylformamide (23 mL), added potassium carbonate (3.14 g, 22.5 mmol), and reacted at 70 ℃ for 7 hours. The reaction solution was cooled to room temperature, added water (50 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (20 mL × 2), and the filter cake was collected for recrystallization (ethyl acetate/petroleum ether = 1/2, 30 mL ), affording 18c (6.10 g, 92% yield) as an off-white solid.

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2- Benzyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 18d

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

step 5 :synthesis (2-(2-(4-((2- Benzyl -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen )-3,5- Dichlorophenyl ) Hydrazine )-2- Cyanoacetyl ) Urethane 18e

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

step 6 :synthesis 2-(4-((2- Benzyl -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen )-3,5- Dichlorophenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 18

(2-(2-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichloro Phenyl)hydrazinide)-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), react at 120 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate/petroleum ether (2/1, 30 mL × 3), and the combined organic phase was washed with saturated sodium chloride solution (10 mL × 3) Washed, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was recrystallized (ethanol/ethyl acetate/petroleum ether = 1/3/6, 50 mL) to obtain a red solid 18 (0.26 g, yield 40%, HPLC Purity: 98.24%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 7.94 (d, J = 8.6 Hz, 1H), 7.84 (s, 2H), 7.32 (dq, J = 19.3, 11.0, 9.3 Hz, 5H) , 6.85 (d, J = 6.9 Hz, 2H), 4.70 (s, 2H), 3.47 (s, 3H), 2.95 (s, 2H).

Example 19 2-(3,5- dichloro -4-((1- oxo-- 1,2- dihydroisoquinolin -6- yl ) oxy ) -phenyl )-3,5- di Oxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 19

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base ) Isoquinoline -1(2 H )- ketone 19b

6-Hydroxyisoquinolin-1( 2H )-one 19a (0.92 g, 5.7 mmol) was dissolved in N , N -dimethylformamide (20 mL), and 1,2,3-trichloro- 5-Nitrobenzene (1.40 g, 6.18 mmol) and potassium carbonate (1.90 g, 13.6 mmol) were reacted at 80°C for 3 hours. The reaction solution was cooled to room temperature, water (50 mL) was added, 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain yellow solid 19b (1.83 g, yield 91%).

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

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy ) Isoquinoline -1(2 H )- ketone 19c

6-(2,6-Dichloro-4-nitrophenoxy)isoquinolin-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), reacted at 60 ℃ for 2.5 hours. The reaction solution was cooled to room temperature, iron powder was removed, water (30 mL) was added, stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain light yellow solid 19c (0.38 g, yield 92%).

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -1,2- Dihydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 19d

Dissolve 6-(4-amino-2,6-dichlorophenoxy)isoquinolin-1(2 H )-one 19c (0.40 g, 1.20 mmol) in acetic acid (12 mL), add dropwise at 0 °C Sodium nitrite (0.13 g, 1.8 mmol) in water (1.5 mL) was reacted for 20 minutes, N -cyanoacetylurethane (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, extracted with ethyl acetate (15 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (35 mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration, 19d was obtained as a yellow solid (0.60 g, 99% yield).

step 4 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -1,2- Dihydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 19

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-1,2-dihydroisoquinolin-6-yl)oxy)phenyl)hydrazine (ylidene)acetyl)urethane 19d (0.45 g, 0.92 mmol) was dissolved in N , N -dimethylformamide (15 mL), added sodium acetate (0.38 g, 4.61 mmol), and reacted at 120 ℃ for 3 Hour. The reaction was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (30 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, and extracted Concentrated by filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2) to obtain white solid 19 (0.23 g, yield 55%, HPLC purity: 96.04%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.32 (s, 1H), 11.20 (d, J = 3.8 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.86 (s , 2H), 7.24-7.10 (m, 2H), 7.02 (s, 1H), 6.52 (d, J = 7.1 Hz, 1H).

Example 20 2-(3,5- dichloro -4-((2-(4- fluorobenzyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 20

step 1 : 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(4- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 20a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (0.50 g, 1.4 mmol) was dissolved in THF (20 mL) solution, sodium hydride (85 mg, 2.1 mmol, 60 mass% in oil) was added at 0 °C, and after 20 minutes of reaction, 1-bromomethyl-4-fluorobenzene (0.55 g, 2.8 mmol) and N were added dropwise, N -dimethylformamide (5 mL), followed by reaction at room temperature for 15 hours. The reaction was quenched by adding ice water (30 mL), 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, concentrated by suction filtration, and the obtained residue The product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain light yellow oil 20a (0.65 g, yield 99%).

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

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.35 (s, 2H), 8.14 (d, J = 8.6 Hz, 1H), 7.37-7.30 (m, 2H), 7.07-7.00 (m, 2H) , 6.79 (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).

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-(4- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 20b

6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 20a (0.65 g, 1.4 mmol) was dissolved in acetic acid (10 mL), added iron powder (0.16 g, 2.8 mmol), and reacted at 50 ℃ for 2.5 hours. The reaction solution was cooled to room temperature, quenched by adding water (30 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain light yellow oil 20b (0.37 g, yield 61%).

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

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-(4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 20c

6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 20b (0.37 g , 0.86 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution (6 mL) of sodium nitrite (0.12 g, 1.7 mmol) was added at 0°C, followed by N -cyanoacetylurethane (0.20 g, 1.3 mmol) , reacted for 3 hours. Water (30 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (5 mL), collected and dried to obtain a light yellow solid 20c (0.50 g, yield 97%).

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

step 4 : 2-(3,5- Dichloro -4-((2-(4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 20d .

(2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 20c (0.50 g, 0.84 mmol) was dissolved in N , N -dimethylformamide (10 mL), added Sodium acetate (0.15 g, 1.1 mmol), react at 120°C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 60 °C (ethyl acetate/petroleum ether = 2/1, 15 mL), A yellow solid 20d was obtained (0.28 g, 61% yield, HPLC purity: 100%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.94 (dd, J = 9.0, 6.2 Hz, 1H), 7.84 (s, 2H), 7.36 (dd, J = 8.4, 5.5 Hz, 2H), 7.16 (t, J = 8.7 Hz, 2H), 6.85 (d, J = 6.7 Hz, 2H), 4.67 (s, 2H), 3.47 (t, J = 6.6 Hz, 2H) , 2.95 (t, J = 6.6 Hz, 2H);

¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ (ppm) -115.68.

step 5 :synthesis 2-(3,5- Dichloro -4-((2-(4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 20e

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 20

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 1H), 7.36 (dd, J = 8.5, 5.6 Hz, 2H), 7.16 (dd, J = 10.1, 7.6 Hz, 2H), 6.83 (s, 1H), 6.81 (d, J = 2.6 Hz, 1H), 4.67 (s, 2H), 3.47 (t, J = 6.6 Hz, 2H), 2.95 (t, J = 6.6 Hz, 2H).

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

step 1 : 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(4- Methylbenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 21a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (0.50 g, 1.4 mmol) was dissolved in THF (20 mL) solution, sodium hydride (85 mg, 2.1 mmol, 60 mass% in oil) was added at 0 °C, and after 20 minutes of reaction, 1-bromomethyl-4-toluene (0.54 g, 2.8 mmol) and N , N -Dimethylformamide (5 mL), followed by reaction at room temperature for 14 hours. The reaction was quenched by adding ice water (30 mL), 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, concentrated by suction filtration, and the obtained residue The product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain light yellow oil 21a (0.63 g, yield 98%).

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-(4- Methylbenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 21b

6-(2,6-dichloro-4-nitrophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one 21a (0.63 g , 1.4 mmol) was dissolved in acetic acid (10 mL), iron powder (0.16 g, 2.8 mmol) was added, and reacted at 50 ℃ for 2.5 hours. The reaction solution was cooled to room temperature, quenched by adding water (30 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain light yellow oil 21b (0.46 g, yield 78%).

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

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-(4- Methylbenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 21c

6-(4-amino-2,6-dichlorophenoxy)-2-(4-methylbenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 21b (0.46 g, 1.1 mmol) was dissolved in acetic acid (16 mL), and an aqueous solution (8 mL) of sodium nitrite (0.15 g, 2.1 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.25 g, 1.6 mmol ), reacted for 2.5 hours. Water (30 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (5 mL), collected and dried to obtain light yellow solid 21c (0.48 g, yield 75%).

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

step 4 : 2-(3,5- Dichloro -4-((2-(4- Methylbenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 21d .

(2-cyano-2-(2-(3,5-dichloro-4-((2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydro Isoquinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl)carbamate 21c (0.48 g, 0.81 mmol) was dissolved in N , N -dimethylformamide (10 mL), Add sodium acetate (0.14 g, 1.0 mmol) and react at 120°C for 8 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 60 °C (ethyl acetate/petroleum ether = 2/1, 15 mL), A yellow solid 21d was obtained (0.41 g, 93% yield, HPLC purity: 98.71%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.33 (s, 1H), 7.97-7.89 (m, 1H), 7.84 (s, 2H), 7.20 (d, J = 7.7 Hz, 2H) , 7.14 (d, J = 7.8 Hz, 2H), 6.85 (dd, J = 5.8, 2.9 Hz, 2H), 4.64 (s, 2H), 3.44 (t, J = 6.5 Hz, 2H), 2.93 (t, J = 6.6 Hz, 2H), 2.28 (s, 3H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-(4- Methylbenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 21e

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(4- Methylbenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone twenty one

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.53 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 7.23 –7.11 (m, 4H), 6.82 (s, 1H), 6.80 (d, J = 2.6 Hz, 1H), 4.64 (s, 2H), 3.44 (d, J = 6.5 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H), 2.27 (s, 3H).

Example 22 2-(4-((2- Benzyl -1- oxo - 1,2,3,4 -tetrahydroisoquinolin- 6- yl ) oxy )-3,5- dichlorophenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 22

step 1 :synthesis 2-(4-((2- Benzyl -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen )-3,5- Dichlorophenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 22a

2-(4-((2-Benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)- 3,5-Dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 18 (0.21 g, 0.37 mmol) was dissolved in acetic acid (4 mL), added to concentrated Hydrochloric acid (1.5 mL), react at 120°C for 24 hours. Cool the reaction solution to room temperature, add water (20 mL), stir for 10 minutes, filter, rinse the filter cake with water (10 mL × 2), collect the filter cake and dry to obtain a yellow solid 22a (0.20 g, yield 100 %).

step 2 :synthesis 2-(4-((2- Benzyl -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen )-3,5- Dichlorophenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone twenty two

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.51 (s, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.85 (s, 2H), 7.72 (s, 1H), 7.35 - 7.22 (m, 5H), 6.81 (d, J = 7.6 Hz, 2H), 4.68 (s, 2H), 3.45 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.2 Hz, 2H) .

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

step 1 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(( Tetrahydro -2H- pyran -4- base ) methyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 23a

2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2 H -pyran-4-yl)methyl)-1,2,3,4-tetra Hydroisoquinolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 12 ( 1.3 g, 2.4 mmol) was dissolved in acetic acid (20 mL), added concentrated hydrochloric acid (6 mL), and reacted at 120 °C for 4.5 hours. Cool the reaction solution to room temperature, concentrate, add water (25 mL), saturated sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL), separate the layers, extract the organic phase with water (25 mL × 2), collect The aqueous phase was adjusted to pH 2-3 with dilute hydrochloric acid (4 N), then extracted with ethyl acetate (25 mL × 3), the organic phases extracted after acidification were combined, and saturated sodium chloride solution (25 mL × 3) Washed, dried over anhydrous sodium sulfate, concentrated by suction filtration to obtain a yellow solid 23a (0.87 g, yield 65%).

step 2 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(( Tetrahydro -2H- pyran -4- base ) methyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone twenty three

2-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2 H -pyran-4-yl)methyl)-1,2,3,4-tetra Hydroisoquinolin-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 thioglycolic acid (4 mL), and reacted at 160 °C for 24 hours. The reaction solution was cooled to room temperature, slowly added saturated sodium bicarbonate solution (15 mL), extracted with ethyl acetate (15 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), and anhydrous It was dried over sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2) to obtain a light yellow solid 23 (0.42 g, yield 54%, HPLC purity: 96.10%) .

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

¹ H NMR (400 MHz, DMSO- d ₆ ) 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 = 8.9 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.35 (s, 2H), 3.25 (t, J = 11.1 Hz, 2H), 2.94 (t, J = 6.2 Hz, 2H), 1.96-1.85 (m, 1H), 1.53 (d, J = 11.9 Hz, 2H), 1.24 (dd, J = 11.7, 4.0 Hz, 2H).

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

step 1 : 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( pyridine -4- methyl group )-3,4- Dihydroisoquinoline -1(2 H )- ketone 24a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (2.0 g, 5.7 mmol) was dissolved in THF (20 mL) solution, add sodium hydride (0.80 g, 20 mmol, 60 mass% in oil) at 0 ℃, add 4-(bromomethyl)pyridine hydrobromide (1.5 g, 8.7 mmol) and N , N -dimethylformamide (3 mL), followed by reaction at 5 °C for 2 hours. Water (70 mL) was added to quench the reaction, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (20 mL × 3), collected and dried to obtain a yellow solid 24a (2.3 g, yield 91%).

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-( pyridine -4- methyl group )-3,4- Dihydroisoquinoline -1(2 H )- ketone 24b

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

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-( pyridine -4- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 24c

6-(4-Amino-2,6-dichlorophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1( 2H )-one 24b ( 1.8 g, 4.3 mmol) was dissolved in acetic acid (27 mL), and an aqueous solution (14 mL) of sodium nitrite (0.60 g, 8.7 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.81 g, 5.3 mmol), reacted for 2 hours. Water (80 mL) was added to quench the reaction, 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, and concentrated by suction to obtain Red foamy solid 24c (2.5 g, 99% yield).

step 4 : 2-(3,5- Dichloro -4-((2-( pyridine -4- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 24d .

(2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetra Hydroisoquinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)ethyl carbamate 24c (1.8 g, 3.1 mmol) was dissolved in N , N -dimethylformamide (20 mL) , add sodium acetate (0.28 g, 3.4 mmol), and react at 120°C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (100 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 85 °C ( N , N -dimethylformamide/ethanol/ethyl acetate Ester/petroleum ether = 4/25/15/20, 128 mL) to give 24d as a yellow solid (0.90 g, 53% yield, HPLC purity: 82.28%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.56 (s, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.84 (s, 2H), 7.33 (s, 2H), 6.86 (d, J = 13.0 Hz, 2H), 4.71 (s, 2H), 3.54 (s, 2H), 3.01 (s, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-( pyridine -4- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 24e

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-( pyridine -4- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone twenty four

2-(3,5-dichloro-4-((2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 24e (0.37 g, 0.67 mmol) dissolved in thioglycolic acid (5 mL), react at 120°C for 36 hours. The reaction solution was cooled to room temperature, ethyl acetate (80 mL) was added, washed with water (40 mL), saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL) successively, dried over anhydrous sodium sulfate, and pumped Concentrated by filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2) to obtain light yellow solid 24 (0.20 g, yield 59%, HPLC purity: 92.08%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.53 (s, 1H), 8.77 (s, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 1H), 7.65 (s, 2H), 6.87 (s, 1H), 6.83 (d, J = 7.6 Hz, 1H), 4.82 (s, 2H), 3.59 (d, J = 6.2 Hz, 2H) , 3.03 (d, J = 6.5 Hz, 2H).

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- triazine - 3,5(2 H ,4 H ) -dione 25

step 1 : 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( Pyridazine -3- methyl group )-3,4- Dihydroisoquinoline -1(2 H )- ketone 25a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (2.0 g, 5.7 mmol) was dissolved in THF (25 mL) solution, add sodium hydride (0.80 g, 20 mmol, 60 mass% in oil) at 0 ℃, add 3-(bromomethyl) pyridazine hydrobromide (1.5 g, 8.7 mmol) and N , N -dimethylformamide (4 mL), followed by reaction at 8°C for 2 hours. Add water (150 mL) to quench the reaction, stir for 10 minutes, filter, rinse the filter cake with water (20 mL × 3), and dry the collected filter cake with ethyl acetate/petroleum ether (1/4, 50 mL) Beat the slurry, filter, and collect the filter cake to obtain a yellow solid 25a (1.8 g, yield 71%).

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-( Pyridazine -3- methyl group )-3,4- Dihydroisoquinoline -1(2 H )- ketone 25b

6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2 H )-one 25a (1.0 g, 2.2 mmol) was dissolved in acetic acid (15 mL), iron powder (0.35 g, 6.3 mmol) was added, and reacted at 60 °C for 8 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), stirred for 10 minutes, filtered, and the filter cake was rinsed with water (20 mL × 2), collected and dried to obtain a gray solid 25b (0.74 g, rate of 79%).

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-( Pyridazine -3- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 25c

6-(4-Amino-2,6-dichlorophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2 H )-one 25b (0.74 g, 1.8 mmol) was dissolved in acetic acid (15 mL), and an aqueous solution (6 mL) of sodium nitrite (0.25 g, 3.6 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.35 g, 2.2 mmol), reacted for 2 hours. Water (50 mL) was added to quench the reaction, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (30 mL × 2), collected and dried to obtain a red solid 25c (0.96 g, yield 93%).

step 4 : 2-(3,5- Dichloro -4-((2-( Pyridazine -3- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 25d .

(2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4- Tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)ethyl)carbamate 25c (0.96 g, 1.6 mmol) was dissolved in N , N -dimethylformamide (12 mL ), added sodium acetate (0.15 g, 1.8 mmol), and reacted at 120 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (100 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 85°C ( N , N -dimethylformamide/ethanol/ethyl acetate Ester/petroleum ether = 2/5/20/40, 128 mL) to give 24d as a yellow solid (0.51 g, 58% yield, HPLC purity: 93.11%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.23 (s, 1H), 9.15 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 28.0 Hz, 3H), 7.66 (dd , J = 10.8, 6.2 Hz, 2H), 7.06-6.64 (m, 2H), 4.97 (s, 2H), 3.66 (t, J = 6.6 Hz, 2H), 3.02 (t, J = 6.5 Hz, 2H) .

step 5 :synthesis 2-(3,5- Dichloro -4-((2-( Pyridazine -3- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 25e

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-( Pyridazine -3- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 25

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) 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 = 17.0 Hz, 2H), 3.67 (s, 2H), 3.02 (t, J = 6.5 Hz, 2H).

Example 26 2-(3,5- dimethyl- 4-((1- oxo- 1,2,3,4 -tetrahydroisoquinolin- 6- yl ) oxy ) phenyl )-3, 5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 26

step 1 :synthesis 6-(2,6- Dimethyl -4- Nitrophenoxy base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 1b

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

step 2 :synthesis 6-(4- Amino -2,6- Dimethylphenoxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 26c

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

step 3 :synthesis (2- cyano -2-(2-(3,5- Dimethyl -4-((1- Oxo -1,2,3,4- tetraisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 26d

6-(4-Amino-2,6-methylphenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 26c (2.7 g, 9.6 mmol) was dissolved in acetic acid (10 mL ), add a solution of sodium nitrite (1.0 g, 14 mmol) in water (5 mL) at 0 °C, react for 5 minutes, add N -cyanoacetylurethane (1.9 g, 12 mmol), and react for 1.5 hours. At 0 °C, water (10 mL) was added to the reaction solution, stirred for 10 minutes, filtered, rinsed with water (5 mL), and the filter cake was collected and dried to obtain a yellow solid 26d (4.1 g, yield 95%).

step 4 :synthesis 2-(3,5- Dimethyl -4-((1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 26

(2-cyano-2-(2-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetraisoquinolin-6-yl)oxy) Phenyl) hydrazino) acetyl) ethyl carbamate 26d (4.1 g, 9.1 mmol) was dissolved in N , N - dimethylformamide (20 mL), sodium acetate (0.90 g, 10 mmol) was added, React at 120°C for 7.5 hours. The reaction solution was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (20 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and suction filtered Concentration, the obtained residue was separated and purified by preparation [42%ACN/58%H ₂ O (0.1%TFA), Kromasil specification: C18 10μm×50mm×250mm, flow rate: 100 mL/min] to obtain a white solid 26 (1.0 g , yield 27%, purity 95.48%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) 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 = 6.4 Hz, 2H), 2.11 (s, 6H).

Example 27 2-(3,5- dichloro -4-((1- oxo -2-( p-tolyl )-1,2,3,4- tetrahydroisoquinolin -6- yl ) oxyl group ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 27

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( p-tolyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 27b

6-Hydroxy-2-(p-tolyl)-3,4-dihydroisoquinolin-1(2 H )-one 27a (refer to Steps 1 and 2 of Example 23 of Patent Application CN 109988109 A for the preparation method) ( 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), reacted at 60°C for 3 hours. The reaction solution was cooled to room temperature, added water (8 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (3 mL × 2), collected the filter cake and dried to obtain gray solid 27b (0.56 g, yield 99 %).

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( p-tolyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 27c

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

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-( p-tolyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 27d

6-(4-Amino-2,6-dichlorophenoxy)-2-(p-tolyl)-3,4-dihydroisoquinolin-1(2 H )-one 27c (0.37 g, 0.90 mmol) was dissolved in acetic acid (4 mL), N -cyanoacetylurethane (0.15 g, 1.08 mmol) was added at 0 °C, and after stirring for 5 minutes, sodium nitrite (93 mg, 1.35 mmol) was added in water (1 mL ) solution, reacted for 1 hour. At 0 °C, water (5 mL) was added to the reaction solution, stirred for 10 minutes, filtered, rinsed with water (3 mL), and the filter cake was collected and dried to obtain a yellow solid 27d (0.50 g, yield 96%).

step 4 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( p-tolyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 27

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline -6-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate 27d (0.50 g, 0.86 mmol) was dissolved in N , N -dimethylformamide (6 mL), and sodium acetate was added (0.14 g, 1.66 mmol), react at 120 °C for 3 hours. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), stirred for 10 minutes, filtered, the filter cake was collected and dried, and the obtained solid was separated and purified by preparation [60%ACN/40%H ₂ O (0.1%TFA ), Kromasil specification: C18 10 μm×50 mm×250 mm, flow rate: 100 mL/min], and obtained white solid 27 (0.23 g, yield 50%, HPLC purity: 98.72%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.31 (s, 1H). 7.94 (d, J = 6.4 Hz, 1H), 7.86 (s, 2H), 7.24 (dd, J = 23.6 Hz , J = 8.4 Hz, 4H), 6.97- 6.82 (m, 2H), 3.91 (t, J = 6.4 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H).

Example 28 2-(3,5- dichloro -4-((1- oxo- 2-(4- fluorophenyl )-1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 28

step 1 :synthesis 2-(4- Fluorophenyl )-6- Methoxy -3,4- Dihydroisoquinoline -1(2 H )- ketone 28b

6-methoxy-3,4-dihydroisoquinolin-1(2 H )-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 ℃ for 16 hours. The reaction solution was cooled to room temperature, quenched by adding water (100 mL), extracted with ethyl acetate (200 mL), the combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and suction filtered After concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/2) to obtain off-white solid 28b (1.05 g, yield 46%).

¹ H NMR (400 MHz, CDCl ₃ ) 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).

step 2 :synthesis 2-(4- Fluorophenyl )-6- hydroxyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 28c

At 0°C, add boron tribromide (0.71 mL, 7.4 mmol) dropwise to 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline-1(2 H ) -ketone 28b (1.00 g, 3.7 mmol) in dichloromethane (30 mL), followed by reaction at room temperature for 4 hours. The reaction solution was quenched by pouring into ice water (30 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 28c (0.87 g, yield 92%).

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

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(4- Fluorophenyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 28d

2-(4-Fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-1(2 H )-one 28c (0.87 g, 3.4 mmol) and 1,2,3-trichloro- 5-Nitrobenzene (0.87 g, 3.8 mmol) was dissolved in N , N -dimethylformamide (15 mL), potassium carbonate (0.93 g, 6.8 mmol) was added, and reacted at 70 ℃ for 17 hours. The reaction solution was cooled to room temperature, added water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain off-white solid 28d (1.50 g, yield 99%).

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

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(4- Fluorophenyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 28e

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

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

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-(4- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 28f

6-(4-Amino-2,6-dichlorophenoxy)-2-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2 H )-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, and after stirring for 15 minutes, N -cyanoacetylurethane (0.56 g, 3.60 mmol), reacted for 5 hours. Water (50 mL) was added to the reaction solution, stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to obtain a yellow solid 28f (1.30 g, yield 93%).

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(4- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 28g

(2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 28f (1.30 g, 2.20 mmol) was dissolved in N , N -dimethylformamide (40 mL), added Sodium acetate (0.40 g, 2.90 mmol), react at 120°C for 15 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, Concentrated by suction filtration, the resulting residue was purified by silica gel column chromatography (100% ethyl acetate), and the obtained solid was recrystallized at 80 ^° C (petroleum ether/ethyl acetate = 1/2, 24 mL) to obtain 28 g of a yellow solid (0.71 g, yield 59%, HPLC purity: 97.86%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.31 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.86 (s, 2H), 7.43 (dd, J = 8.8, 5.0 Hz, 2H), 7.25 (t, J = 8.8 Hz, 2H), 6.95 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.6, 2.7 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.13 (t, J = 6.5 Hz, 2H).

step 7 :synthesis 2-(3,5- Dichloro -4-((2-(4- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 28 hours

2-(3,5-dichloro-4-((2-(4-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 28g (0.45 g, 0.84 mmol) dissolved in acetic acid (8 mL), concentrated hydrochloric acid (4 mL) was added and reacted at 100 °C for 17 hours. Cool the reaction solution to room temperature, add water (20 mL), stir for 10 minutes, filter, rinse the filter cake with water (10 mL × 2), collect the filter cake and dry to obtain a yellow solid 28h (0.35 g, yield 75 %).

step 8 :synthesis 2-(3,5- Dichloro -4-((2-(4- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 28

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.88 (s, 2H), 7.73 (s, 1H), 7.43 (dd, J = 8.9, 5.2 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 6.93 (d, J = 2.6 Hz, 1H), 6.85 (dd, J = 8.6, 2.6 Hz, 1H) , 3.92 (t, J = 6.4 Hz, 2H), 3.13 (t, J = 6.4 Hz, 2H).

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(2 H ,4 H ) -dione 29

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(4-( Trifluoromethyl ) Benzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 29a

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

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

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(4-( Trifluoromethyl ) Benzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 29b

6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-1(2 H ) -Kone 29a (2.2 g, 4.2 mmol) was dissolved in acetic acid (50 mL), iron powder (0.99 g, 17.8 mmol) was added, and reacted at 55 ℃ for 10 hours. The reaction solution was cooled to room temperature, quenched by adding water (100 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain light yellow oil 29b (1.65 g, yield 77%).

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-(4-( Trifluoromethyl ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 29c

6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-1(2 H )- Ketone 29b (0.60 g, 1.25 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution (6 mL) of sodium nitrite (0.19 g, 12.78 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.26 g, 1.67 mmol), reacted for 3 hours. Water (100 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (5 mL × 2), collected and dried to obtain a light yellow solid 29c (0.76 g, yield 94%).

step 4 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(4-( Trifluoromethyl ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 29d

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3, 4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)ethyl carbamate 29c (0.72 g, 1.12 mmol) dissolved in N , N -dimethylformamide ( 25 mL), add sodium acetate (0.20 g, 2.45 mmol), and react at 120 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 80 °C (ethyl acetate/petroleum ether (v/v) = 2/1 , 15 mL), a yellow solid 29d was obtained (0.65 g, yield 97%, HPLC purity: 96.68%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.84 (s, 2H), 7.71 (d, J = 8.0 Hz , 2H), 7.54 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 2.6 Hz, 1H), 6.85 (dd, J = 8.3, 2.7 Hz, 1H), 4.78 (s, 2H), 3.53 (t, J = 6.6 Hz, 2H), 2.99 (t, J = 6.6 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(4-( Trifluoromethyl ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 29e

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-carbonitrile 29d (0.65 g, 1.01 mmol) Concentrated hydrochloric acid (5 mL) was added to acetic acid (10 mL), and reacted at 120°C for 13 hours. The reaction solution was cooled to room temperature, added water (20 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 2), collected the filter cake and dried to obtain a yellow solid 29e (0.55 g, yield 82 %).

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(4-( Trifluoromethyl ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 29

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) React in thioglycolic acid (5 mL) at 150°C for 24 hours. The reaction solution was cooled to room temperature, added ethyl acetate (30 mL), washed with water (10 mL), saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, and pumped Concentrated by filtration, the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1), and the obtained solid was recrystallized at 70 °C (ethyl acetate/methanol/petroleum ether (v/v /v) = 5/1/10, 32 mL), a white solid 29 was obtained (0.32 g, 62% yield, HPLC purity: 96.97%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 6.85 (s, 1H), 6.84-6.79 (m, 1H), 4.78 (s, 2H), 3.52 (t, J = 6.5 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H).

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(2 H ,4 H ) -dione 30

step 1 : 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(3,4- Difluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 30a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (1.00 g, 2.83 mmol) was dissolved in THF (40 mL) solution, add sodium hydride (0.17 g, 4.25 mmol, 60 mass% in oil) at 0 ℃, react for 30 minutes, add dropwise 3,4-difluorobenzyl bromide (1.17 g, 5.66 mmol) and N , N - Dimethylformamide (6 mL), followed by reaction at room temperature for 12 hours. The reaction was quenched by adding ice water (30 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue The product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain light yellow oil 30a (1.10 g, yield 81%).

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

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-(3,4- Difluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 30b

6-(2,6-dichloro-4-nitrophenoxy)-2-(3,4-difluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 30a (1.10 g, 2.29 mmol) was dissolved in acetic acid (50 mL), iron powder (0.51 g, 9.15 mmol) was added, and reacted at 55 ℃ for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain light yellow oil 30b (0.64 g, yield 62%).

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

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-(3,4- Difluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 30c

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

step 4 : 2-(3,5- Dichloro -4-((2-(3,4- Difluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 30d

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.29 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.84 (s, 2H), 7.39 (td, J = 7.9, 6.1 Hz, 1H), 7.18-7.07 (m, 3H), 6.86 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 4.70 (s, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-((3,4- Difluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 30e

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(3,4- Difluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 30

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.87 (s, 2H), 7.72 (s, 1H), 7.45 -7.32 (m, 2H), 7.18 (t, J = 6.4 Hz, 1H), 6.83 (s, 1H), 6.81 (d, J = 2.6 Hz, 1H), 4.66 (s, 2H), 3.50 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H).

Example 31 2-(3,5- dichloro -4-((2-(3- fluorobenzyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 31

step 1 : 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(3- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 31a

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

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

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-(3- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 31b

6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 31a (1.80 g, 3.90 mmol) was dissolved in acetic acid (50 mL), iron powder (0.87 g, 15.2 mmol) was added, and reacted at 55 °C for 7 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain white solid 31b (1.29 g, yield 77%).

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-(3- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 31c

6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 31b (0.60 g , 1.39 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution (5 mL) of sodium nitrite (0.19 g, 2.78 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.26 g, 1.67 mmol) , reacted for 2 hours. Water (100 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (5 mL × 2), collected and dried to obtain a light yellow solid 31c (0.92 g, yield 100%).

step 4 : 2-(3,5- Dichloro -4-((2-(3- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 31d

(2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 31c (0.92 g, 1.54 mmol) was dissolved in N , N -dimethylformamide (30 mL), added Sodium acetate (0.28 g, 3.39 mmol), react at 120°C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 80 °C (ethyl acetate/petroleum ether (v/v) = 2/1 , 15 mL), a yellow solid 31d was obtained (0.75 g, yield 99%).

step 5 :synthesis 2-(3,5- Dichloro -4-(((2-((3- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 31e

2-(3,5-dichloro-4-((2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 31d (0.39 g, 0.71 mmol) dissolved in acetic acid (10 mL ), added concentrated hydrochloric acid (3 mL), and reacted at 120 °C for 12 hours. Cool the reaction solution to room temperature, add water (20 mL), stir for 10 minutes, filter, rinse the filter cake with water (10 mL × 2), collect the filter cake and dry to obtain a yellow solid 31e (0.40 g, yield 98 %).

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(3- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 31

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm) 12.52 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.86 (s, 2H), 7.73 (s, 1H), 7.38 (td, J = 7.9, 6.0 Hz, 1H), 7.18- 7.06 (m, 3H), 6.86-6.77 (m, 2H), 4.69 (s, 2H), 3.50 (t, J = 6.5 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H).

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(2 H ,4 H ) -dione 32

step 1 : 2-(3,5- Difluorobenzyl )-6-(2,6- Dichloro -4- Nitrophenoxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 32a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (1.0 g, 2.83 mmol) was dissolved in THF (14 mL) solution, sodium hydride (0.17 g, 4.25 mmol, 60 mass% in oil) was added at 0 ℃, and 3,5-difluorobenzyl bromide (1.17 g, 5.66 mmol) and N , N - Dimethylformamide (10 mL), followed by reaction at room temperature for 6 hours. The reaction was quenched by adding ice water (30 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue The product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain light yellow oil 32a (1.26 g, yield 93%).

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

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-(3,5- Difluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 32b

2-(3,5-difluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2 H )-one 32a (0.99 g, 2.1 mmol) was dissolved in acetic acid (20 mL), iron powder (0.24 g, 4.3 mmol) was added, and reacted at 50 ℃ for 2.5 hours. The reaction solution was cooled to room temperature, quenched by adding water (30 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to obtain light yellow oil 32b (0.68 g, yield 58%).

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-(3,5- Difluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 32c

6-(4-amino-2,6-dichlorophenoxy)-2-(3,5-difluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 32b (0.68 g, 1.5 mmol) was dissolved in acetic acid (20 mL), and an aqueous solution (9 mL) of sodium nitrite (0.21 g, 3.0 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.35 g, 2.3 mmol), reacted for 3 hours. Water (60 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (10 mL), collected and dried to obtain light yellow solid 32c (0.93 g, yield 100%).

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

step 4 : 2-(3,5- Dichloro -4-((2-(3,5- Difluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 32d

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.27 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.84 (s, 2H), 7.12 (td, J = 9.4, 4.8 Hz, 1H), 7.03 (d, J = 7.3 Hz, 2H), 6.91-6.76 (m, 2H), 4.69 (s, 2H), 3.53 (t, J = 6.6 Hz, 2H), 2.99 (t, J = 6.6 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-((3,5- Difluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 32e

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

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(3,4- Difluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 32

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

MS (ESI, neg. ion) m/z : 544.2 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.51 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 7.12 (tt, J = 9.4, 2.5 Hz, 1H), 7.06-6.96 (m, 2H), 6.87-6.78 (m, 2H), 4.69 (s, 2H), 3.53 (t, J = 6.6 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H).

Example 33 2-(3,5- dichloro -4-((2-(2- fluorobenzyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 33

step 1 : 2-(2- Fluorobenzyl )-6-(2,6- Dichloro -4- Nitrophenoxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 33a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (1.0 g, 2.8 mmol) was dissolved in THF (40 mL) solution, add sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) at 0 ℃, and add 2-fluorobenzyl bromide (1.1 g, 5.7 mmol) and N , N -dimethyl Formamide (10 mL), followed by reaction at room temperature for 6 hours. The reaction was quenched by adding ice water (30 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue The product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain 33a (0.99 g, yield 76%) as a pale yellow solid.

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

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-(2- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 33b

2-(2-fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2 H )-one 33a (0.99 g, 2.1 mmol) was dissolved in acetic acid (20 mL), added iron powder (0.24 g, 4.3 mmol), and reacted at 50°C for 2.5 hours. The reaction solution was cooled to room temperature, quenched by adding water (30 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain light yellow oil 33b (0.62 g, yield 67%).

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-(2- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 33c

6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 33b (0.62 g , 1.4 mmol) was dissolved in acetic acid (18 mL), and an aqueous solution (9 mL) of sodium nitrite (0.20 g, 2.9 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.34 g, 2.2 mmol) , reacted for 3 hours. Water (50 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (10 mL), collected and dried to obtain a light yellow solid 33c (0.86 g, yield 100%).

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

step 4 : 2-(3,5- Dichloro -4-((2-(2- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 33d

(2-cyano-2-(2-(3,5-dichloro-4-((2-(2-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)ethyl carbamate 33c (0.86 g, 1.4 mmol) was dissolved in N , N -dimethylformamide (16 mL), added Sodium acetate trihydrate (0.26 g, 1.9 mmol) was reacted at 120°C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 80 °C (ethyl acetate/petroleum ether (v/v) = 2/1 , 30 mL), a yellow solid 33d was obtained (0.49 g, yield 63%, HPLC purity: 96.04%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.29 (s, 1H), 7.91 (d, J = 8.3 Hz, 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 = 6.6 Hz, 2H), 2.98 (t, J = 6.5 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-(((2-((2- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 33e

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

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(2- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 33

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

MS (ESI, pos. ion) m/z : 527.0 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.51 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 7.33 (q, J = 7.8 Hz, 2H), 7.24-7.12 (m, 2H), 6.87-6.78 (m, 2H), 4.73 (s, 2H), 3.52 (t, J = 6.6 Hz, 2H), 2.97 ( t, J = 6.5 Hz, 2H).

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(2 H ,4 H ) -dione 34

step 1 : 2-(3-( Trifluoromethyl ) Benzyl )-6-(2,6- Dichloro -4- Nitrophenoxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 34a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (1.0 g, 2.8 mmol) was dissolved in THF (40 mL) solution, add sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) at 0 ℃, react for 20 minutes, add dropwise 3-trifluoromethylbenzyl bromide (1.4 g, 5.7 mmol) and N , N - Dimethylformamide (10 mL), followed by reaction at room temperature for 6 hours. The reaction was quenched by adding ice water (30 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue The product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain light yellow oil 34a (0.86 g, yield 59%).

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

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-(3-( Trifluoromethyl ) Benzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 34b

2-(3-(trifluoromethyl)benzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2 H ) -Kone 34a (0.86 g, 1.7 mmol) was dissolved in acetic acid (20 mL), iron powder (0.24 g, 4.3 mmol) was added, and reacted at 50 ℃ for 2.5 hours. The reaction solution was cooled to room temperature, quenched by adding water (30 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/2) to obtain light yellow oil 34b (0.63 g, yield 78%).

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-(3-( Trifluoromethyl ) Benzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 34c

6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-1(2 H )- Ketone 34b (0.63 g, 1.3 mmol) was dissolved in acetic acid (18 mL), and an aqueous solution (9 mL) of sodium nitrite (0.18 g, 2.6 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.31 g, 2.0 mmol), reacted for 3 hours. Water (50 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (10 mL), collected and dried to obtain a pale yellow solid 34c (0.85 g, yield 100%).

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

step 4 : 2-(3,5- Dichloro -4-((2-(3-( Trifluoromethyl ) Benzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 34d

(2-cyano-2-(2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzyl)-1-oxo-1,2,3, 4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)ethyl carbamate 34c (0.85 g, 1.3 mmol) dissolved in N , N -dimethylformamide ( 16 mL), added sodium acetate trihydrate (0.23 g, 1.7 mmol), and reacted at 120 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 80 °C (ethyl acetate/petroleum ether (v/v) = 1/2 , 30 mL), a yellow solid 34d was obtained (0.55 g, yield 70%, HPLC purity: 97.82%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.29 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.84 (s, 2H), 7.72-7.55 (m, 4H) , 6.85 (d, J = 8.8 Hz, 2H), 4.77 (s, 2H), 3.52 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-((3-( Trifluoromethyl ) Benzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 34e

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-carbonitrile 34d (0.47 g, 0.80 mmol) Concentrated hydrochloric acid (5 mL) was added to acetic acid (10 mL), and reacted at 100°C for 8 hours. The reaction solution was cooled to room temperature, added water (30 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 2), collected the filter cake and dried to obtain a yellow solid 34e (0.43 g, yield 89 %).

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(3-( Trifluoromethyl ) Benzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 34

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 (0.43 g, 0.71 mmol) React in thioglycolic acid (5 mL) at 140°C for 15 hours. The reaction solution was cooled to room temperature, ethyl acetate (60 mL) was added, washed successively with 50% sodium bicarbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration , the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/2), and the obtained solid was recrystallized at 80°C (ethyl acetate/petroleum ether (v/v) = 1/2 2, 30 mL), to obtain light yellow solid 34 (0.24 g, yield 60%, HPLC purity: 99.41%).

MS (ESI, neg. ion) m/z : 576.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.51 (s, 1H), 7.93 (d, J = 8.4 Hz, 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 = 6.6 Hz, 2H), 2.96 (t, J = 6.5 Hz, 2H).

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(2 H ,4 H ) -dione 35

step 1 : 2-(3-Chloro-4- Fluorobenzyl )-6-(2,6- Dichloro -4- Nitrophenoxy )-3,4- Dihydroisoquinoline -1(2 H )- ketone 35a

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

step 2 : 6-(4- Amino -2,6- Dichlorophenoxy )-2-(3-chloro-4- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 35b

2-(3-chloro-4-fluorobenzyl)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinoline-1(2 H )- Ketone 35a (0.99 g, 2.0 mmol) was dissolved in acetic acid (20 mL), iron powder (0.22 g, 4.0 mmol) was added, and reacted at 50 ℃ for 2.5 hours. The reaction solution was cooled to room temperature, quenched by adding water (30 mL), 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, It was concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/2) to obtain light yellow oil 35b (0.61 g, yield 66%).

step 3 : (2- cyano -2-(2-(3,5- Dichloro -4-((2-(3-chloro-4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 35c

6-(4-amino-2,6-dichlorophenoxy)-2-(3-chloro-4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 35b (0.61 g, 1.3 mmol) was dissolved in acetic acid (18 mL), and an aqueous solution (9 mL) of sodium nitrite (0.18 g, 2.6 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.31 g , 2.0 mmol), reacted for 3 hours. Water (50 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (10 mL), collected and dried to obtain a light yellow solid 35c (0.83 g, yield 100%).

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

step 4 : 2-(3,5- Dichloro -4-((2-(3-chloro-4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 35d

(2-cyano-2-(2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzyl)-1-oxo-1,2,3,4 -Tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)carbamate 35c (0.83 g, 1.3 mmol) dissolved in N , N -dimethylformamide (16 mL), sodium acetate trihydrate (0.23 g, 1.7 mmol) was added and reacted at 120 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 80 °C (ethyl acetate/petroleum ether (v/v) = 1/2 , 30 mL), a yellow solid 35d was obtained (0.57 g, yield 74%, HPLC purity: 93.07%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.28 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.83 (s, 2H), 7.53 (dd, J = 7.3, 2.1 Hz, 1H), 7.41-7.30 (m, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.66 (s, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-((3-chloro-4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 35e

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-carbonitrile 35d (0.47 g, 0.80 mmol) dissolved in Add concentrated hydrochloric acid (5 mL) to acetic acid (10 mL), and react at 100 °C for 8 hours. The reaction solution was cooled to room temperature, added water (30 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 2), collected the filter cake and dried to obtain light yellow solid 35e (0.43 g, yield 89%).

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(3-chloro-4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 35

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 (0.43 g, 0.71 mmol) dissolved in Thioglycolic acid (5 mL) was reacted at 140°C for 15 hours. The reaction solution was cooled to room temperature, ethyl acetate (60 mL) was added, washed successively with 50% sodium bicarbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration , the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/2), and the obtained solid was recrystallized at 80°C (ethyl acetate/petroleum ether (v/v) = 1/2 2, 30 mL), to obtain light yellow solid 35 (0.26 g, yield 65%, HPLC purity: 98.66%).

MS (ESI, neg. ion) m/z : 561.1 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.51 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 7.52 (dd, J = 7.2, 2.0 Hz, 1H), 7.41-7.30 (m, 2H), 6.81 (d, J = 8.8 Hz, 2H), 4.66 (s, 2H), 3.50 (t, J = 6.6 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H).

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

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(3- Methoxybenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 36a

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

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(3- Methoxybenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 36b

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

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-(3- Methoxybenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 36c

6-(4-amino-2,6-dichlorophenoxy)-2-(3-methoxybenzyl)-3,4-dihydroisoquinolin-1( 2H )-one 36b ( 1.65 g, 3.72 mmol) was dissolved in acetic acid (6 mL), and an aqueous solution (3 mL) of sodium nitrite (0.39 g, 5.58 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.86 g, 4.65 mmol), reacted for 1 hour. Add water (20 mL) to quench the reaction, stir for 10 minutes, filter, rinse the filter cake with water (5 mL × 2), collect the filter cake and dry it to obtain a yellow solid 36c (2.1 g, yield 92%).

step 4 :synthesis 2-(3,5- Dichloro -4-((2-(3- Methoxybenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 36d .

(2-cyano-2-(2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetra Hydroisoquinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)ethyl)carbamate 36c (2.10 g, 3.40 mmol) was dissolved in N , N -dimethylformamide (8 mL) , add sodium acetate (0.34 g, 3.39 mmol), and react at 120 °C for 12 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 80 °C (ethyl acetate/petroleum ether = 2/1, 15 mL), 36d was obtained as a yellow solid (0.75 g, 99% yield).

step 5 :synthesis 2-(3,5- Dichloro -4-(((2-((3- Methoxybenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 36e

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(3- Methoxybenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 36

2-(3,5-dichloro-4-((2-(3-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 36e (0.40 g, 0.69 mmol) dissolved in thioglycolic acid (4 mL), react at 160°C for 12 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium bicarbonate solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was subjected to silica gel column layer Purification by analysis (petroleum ether/ethyl acetate=1/1) gave 36 as a white solid (39 mg, yield 11%, HPLC purity: 94.35%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 8.00-7.82 (m, 3H), 7.73 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H) , 6.97-6.77 (m, 5H), 4.66 (s, 2H), 3.73 (s, 3H), 3.46 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 6.4 Hz, 2H).

Example 37 2-(3,5- dichloro -4-((2-(4-chlorobenzyl ) -1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 37

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(4-Chlorobenzyl base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 37a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (3.0 g, 8.5 mmol) was dissolved in THF (35 mL) solution, sodium hydride (0.31 g, 13.0 mmol, 60 mass% in oil) was added at 0 °C, and 1-chloromethyl-4-chlorobenzene (2.7 g, 17.0 mmol) was added dropwise after reacting for 5 minutes, followed by room Warm reaction for 8 hours. The reaction was quenched by adding ice water (20 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/ 1) Purification gave 37a (1.75 g, 43% yield) as a white solid.

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(4-Chlorobenzyl base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 37b

6-(2,6-dichloro-4-nitrophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 37a (1.75 g, 3.66 mmol) was dissolved in acetic acid (7 mL), added iron powder (0.61 g, 11.0 mmol), and reacted at 60 ℃ for 4.5 hours. The reaction solution was cooled to room temperature, quenched by adding water (5 mL), filtered off excess iron powder, added water (10 mL) to the filtrate, stirred for 10 minutes, filtered, rinsed with water (10 mL), and collected The cake was dried to give 37b as a brown solid (1.55 g, 95% yield).

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-(4-Chlorobenzyl base )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 37c

6-(4-Amino-2,6-dichlorophenoxy)-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 37b (1.55 g , 3.46 mmol) was dissolved in acetic acid (6 mL), and an aqueous solution (3 mL) of sodium nitrite (0.36 g, 5.25 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.81 g, 4.37 mmol) , reacted for 1 hour. Water (20 mL) was added to quench the reaction, stirred for 10 minutes, filtered, and the filter cake was rinsed with water (5 mL), collected and dried to obtain a yellow solid 37c (1.90 g, yield 89%).

step 4 :synthesis 2-(3,5- Dichloro -4-((2-(4-Chlorobenzyl base )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 37d .

(2-cyano-2-(2-(3,5-dichloro-4-((2-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 37c (1.9 g, 3.1 mmol) was dissolved in N , N -dimethylformamide (8 mL), added Sodium acetate (0.30 g, 3.7 mmol), react at 120°C for 12 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 80 °C (ethyl acetate/petroleum ether = 2/1, 15 mL), A yellow solid 37d was obtained (0.50 g, 28% yield, HPLC purity: 95.83%).

MS (ESI, neg. ion) m/z : 566.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) 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 = 6.4 Hz, 2H), 2.96 (t, J = 6.4 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-(4-Chlorobenzyl base )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 37e

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

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(4-Chlorobenzyl base )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 37

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 8.01-7.80 (m, 3H), 7.73 (s, 1H), 7.46-7.26 (m, 4H), 6.90- 6.74 (m, 2H), 4.68 (s, 2H), 3.48 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H).

Example 38 2-(3,5- dichloro -4-((2-( cyclopropylmethyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin - 6 - yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 38

step 1 :synthesis 6- Methoxy -2-( Cyclopropyl methyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 38a

6-Methoxy-3,4-dihydroisoquinolin-1( 2H )-one 5a (2.5 g, 14.1 mmol) was dissolved in THF (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, then chloromethylcyclopropane (2.60 mL, 28.0 mmol) was added dropwise, followed by N , N -di Methylformamide (30 mL), after the addition was complete, the reaction was continued at room temperature for 24 hours. Water (40 mL) was added to quench the reaction, 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, and concentrated by suction to obtain The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain light yellow oil 38a (2.56 g, yield 78%).

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

step 2 :synthesis 6- hydroxyl -2-( Cyclopropyl methyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 38b

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

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( Cyclopropyl methyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 38c

6-Hydroxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1( 2H )-one 38b (1.01 g, 4.65 mmol) was dissolved in N , N -dimethylformaldehyde Amide (10 mL), added 1,2,3-trichloro-5-nitrobenzene (1.11 g, 4.90 mmol) and potassium carbonate (1.56 g, 11.2 mmol), reacted at 80 ℃ for 6 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, extracted with ethyl acetate (15 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, and extracted Concentrated by filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain a yellow solid 38c (0.96 g, yield 51%).

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( Cyclopropyl methyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 38d

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

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

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-( Cyclopropyl methyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 38e

6-(4-Amino-2,6-dichlorophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2 H )-one 38d (0.72 g , 1.91 mmol) was dissolved in acetic acid (10 mL), and a solution of sodium nitrite (0.20 g, 2.87 mmol) in water (0.5 mL) was slowly added dropwise at 0 °C. After 20 minutes of reaction, N -cyanoacetyluria was added Alkane (0.34 g, 2.10 mmol), continue to react for 4.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (15 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration, 38e was obtained as a yellow solid (0.97 g, 93% yield).

step 6 :synthesis 2-(3,5- Dichloro -4-((2-( Cyclopropyl methyl ) -1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 38

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.92-7.80 (m, 3H), 6.88-6.79 (m, 2H), 3.61 (t, J = 6.5 Hz, 2H), 3.45 (dt, J = 13.9, 7.1 Hz, 1H), 3.35 (d, J = 6.8 Hz, 2H), 2.97 (t, J = 6.4 Hz, 2H), 0.45 (q, J = 5.2 Hz, 2H), 0.26 (q, J = 4.7 Hz, 2H).

Example 39 2-(3,5- dichloro -4-((2-( hydroxymethyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 39

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.84 (s, 2H), 6.91-6.79 (m, 2H) , 5.87 (s, 1H), 4.87 (s, 2H), 3.57 (t, J = 6.1 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H).

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(2 H ,4 H ) -dione 40

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(5- fluorine -2- Methylbenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 40a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (2.0 g, 5.7 mmol) was dissolved in THF (20 mL) solution, sodium hydride (0.60 g, 15.0 mmol, 60 mass% in oil) was added at 0 ℃, and 2-bromomethyl-4-fluoro-1-methylbenzene (1.0 mL, 7.2 mmol) and N , N -dimethylformamide (2 mL), followed by reaction at room temperature for 3 hours. Add water (100 mL) to quench the reaction, extract with ethyl acetate (120 mL), wash the organic phase with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, and concentrate by suction filtration. Purification by analysis (petroleum ether/ethyl acetate=5/1) gave 40a as a white solid (2.1 g, yield 77%).

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(5- fluorine -2- Methylbenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 40b

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

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-(5- fluorine -2- Methylbenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 40c

6-(4-amino-2,6-dichlorophenoxy)-2-(5-fluoro-2-methylbenzyl)-3,4-dihydroisoquinoline-1(2 H )- Ketone 40b (1.0 g, 2.2 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution (5 mL) of sodium nitrite (0.31 g, 4.5 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.50 g, 3.0 mmol), reacted for 2 hours. Add water (30 mL) to quench the reaction, stir for 10 minutes, filter, rinse the filter cake with water (5 mL × 2), collect the filter cake and dry, and the obtained solid is washed with petroleum ether/ethyl acetate (5/2, 35 mL ) to obtain a yellow solid 40c (1.1 g, yield 80%).

step 4 :synthesis 2-(3,5- Dichloro -4-((2-(5- fluorine -2- Methylbenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 40d .

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.34 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.85 (s, 2H), 7.30-7.15 (m, 1H) , 6.98 (dd, J = 17.3, 5.6 Hz, 2H), 6.86 (d, J = 9.5 Hz, 2H), 4.67 (s, 2H), 3.50-3.44 (m, 2H), 2.99 (s, 2H), 2.25 (s, 3H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-((5- fluorine -2- Methylbenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 40e

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-carbonitrile 40d (0.60 g, 1.1 mmol) Concentrated hydrochloric acid (3 mL) was added to acetic acid (10 mL), and reacted at 120°C for 12 hours. Cool the reaction solution to room temperature, add water (30 mL), stir for 10 minutes, filter, rinse the filter cake with water (10 mL × 2), collect the filter cake and dry to obtain a yellow solid 40e (0.40 g, yield 60 %).

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(5- fluorine -2- Methylbenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 40

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 (0.40 g, 0.68 mmol) React with thioglycolic acid (3 mL) at 150°C for 12 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was filtered through a silica gel column layer. Purified by analysis (petroleum ether/ethyl acetate = 1/1), the obtained solid was recrystallized at 80°C (ethyl acetate/petroleum ether = 1/2, 24 mL) to obtain a white solid 40 (0.29 g, yield 78% , HPLC purity: 99.21%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm) 12.52 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 1H), 7.23 (dd, J = 8.3, 6.0 Hz, 1H), 7.03-6.93 (m, 2H), 6.86-6.80 (m, 2H), 4.67 (s, 2H), 3.49 (t, J = 6.6 Hz, 2H), 2.99 (t, J = 6.6 Hz, 2H), 2.25 (s, 3H).

Example 41 2-(3,5- dichloro -4-((1- oxo- 2-(4-( trifluoromethoxy ) benzyl )-1,2,3,4- tetrahydroisoquine Phenyl -6- yl ) oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 41

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(4-( Trifluoromethoxy ) Benzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 41a

Dissolve 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2 H )-one 1b (1.50 g, 4.20 mmol) in N , N - Mixed solution of dimethylformamide (6 mL) and tetrahydrofuran (20 mL), add sodium hydride (0.25 g, 6.25 mmol, 60 mass% in oil) at 0 °C, react for 30 minutes, then add 4-tris Fluoromethoxybenzyl bromide (2.27 g, 8.90 mmol), followed by reaction at room temperature for 3 hours. The reaction was quenched by adding ice water (20 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 4/ 1) Purification to obtain yellow oil 41a (2.07 g, yield 93%).

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

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(4-( Trifluoromethoxy ) Benzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 41b

6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinoline-1(2 H )-ketone 41a (2.07 g, 3.93 mmol) was dissolved in acetic acid (50 mL), iron powder (0.88 g, 15.7 mmol) was added, and reacted at 55 °C for 5 hours. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), 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, Concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain white solid 41b (1.59 g, yield 81%).

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-(4-( Trifluoromethoxy ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 41c

6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinoline-1(2 H ) -Kone 41b (0.60 g, 1.21 mmol) was dissolved in acetic acid (12 mL), and an aqueous solution (6 mL) of sodium nitrite (0.17 g, 2.48 mmol) was added at 0 °C, followed by N -cyanoacetylurethane ( 0.23 g, 1.49 mmol), reacted for 4 hours. Water (100 mL) was added to quench the reaction, stirred for 30 minutes, filtered, and the filter cake was rinsed with water (10 mL × 2), collected and dried to obtain a yellow solid 41c (0.87 g, yield 100%).

step 4 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(4-( Trifluoromethoxy ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 41d .

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(4-(trifluoromethoxy)benzyl)-1,2,3 ,4-Tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazino)acetyl)ethyl carbamate 41c (0.87 g, 1.21 mmol) dissolved in N , N -dimethylformamide (18 mL), add sodium acetate (0.22 g, 2.65 mmol), and react at 120 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 80 °C (ethanol/ethyl acetate/petroleum ether=1/1/4, 30 mL), to obtain light red solid 41d (0.65 g, yield 88%, HPLC purity: 98.61%).

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

¹ H NMR (400 MHz , DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.84 (s, 2H), 7.44 (d, J = 8.2 Hz , 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 10.7 Hz, 2H), 4.72 (s, 2H), 3.51 (t, J = 6.3 Hz, 2H), 2.98 (t , J = 6.1 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-(1- Oxo -4-( Trifluoromethoxy ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 41e

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-carbonitrile 41d (0.32 g, 0.52 mmol) Dissolve in acetic acid (10 mL), add concentrated hydrochloric acid (5 mL), and react at 100 °C for 11 hours. Cool the reaction solution to room temperature, add water (20 mL), stir for 10 minutes, filter, rinse the filter cake with water (5 mL × 2), collect the filter cake and dry to obtain a yellow solid 41e (0.35 g, yield 100 %).

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(4-( Trifluoromethoxy ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 41

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 (0.35 g, 0.53 mmol) Dissolve in thioglycolic acid (3 mL) and react at 140 °C for 14 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was passed through a silica gel column layer Purified by analysis (petroleum ether/ethyl acetate = 3/1), the resulting solid was recrystallized at 85 °C (ethyl acetate/petroleum ether = 1/1, 20 mL) to obtain a white solid 41 (0.22 g, yield 71 %, HPLC purity: 99.21%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.87-6.78 (m, 2H), 4.72 (s, 2H), 3.51 (t, J = 6.6 Hz, 2H) , 2.97 (t, J = 6.6 Hz, 2H).

Example 42 2-(3,5- Dichloro -4-((2-(3- fluorophenyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5- tetrahydro -1,2,4- triazine -6- carbonitrile 42

step 1 :synthesis 2-(3- Fluorophenyl )-6- Methoxy -3,4- Dihydroisoquinoline -1(2 H )- ketone 42a

6-Methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5a (1.50 g, 8.5 mmol), ketone iodide (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 ℃ for 19 hours. The reaction solution was cooled to room temperature, quenched by adding water (40 mL), 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, Concentrate by suction filtration to obtain yellow solid 42a (2.22 g, yield 96%).

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

step 2 :synthesis 2-(3- Fluorophenyl )-6- hydroxyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 42b

At 0 °C, add boron tribromide (2.4 mL, 25.0 mmol) dropwise to 2-(3-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline-1(2 H ) -ketone 42a (2.22 g, 8.17 mmol) in dichloromethane (30 mL), followed by reaction at room temperature for 4 hours. Pour the reaction solution into ice water (30 mL) to quench, stir for 10 minutes, filter, wash the filter cake with water (10 mL), collect the filter cake and dry, and the obtained solid is subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give 42b as a white solid (0.13 g, 4.5% yield).

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

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(3- Fluorophenyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 42c

2-(3-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-1(2 H )-one 42b (0.13 g, 0.51 mmol) and 1,2,3-trichloro- 5-Nitrobenzene (0.13 g, 0.57 mmol) was dissolved in N , N -dimethylformamide (3 mL), potassium carbonate (0.14 g, 1.01 mmol) was added, and reacted at 70 °C for 2 hours. The reaction solution was cooled to room temperature, added water (10 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (5 mL), collected and dried to obtain off-white solid 42c (0.22 g, yield 97%).

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(3- Fluorophenyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 42d

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

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-(3- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 42e

6-(4-Amino-2,6-dichlorophenoxy)-2-(3-fluorophenyl)-3,4-dihydroisoquinolin-1(2 H )-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, and after stirring for 15 minutes, N -cyanoacetylurethane (79 mg, 0.51 mmol), reacted for 3.5 hours. Water (20 mL) was added to the reaction solution, stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to obtain a yellow solid 42e (0.19 g, yield 73%).

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(3- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 42f

(2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 42e (0.35 g, 0.60 mmol) was dissolved in N , N -dimethylformamide (40 mL), added Sodium acetate (0.12 g, 1.40 mmol), react at 120°C for 8 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), extracted with ethyl acetate (100 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and extracted Concentrated by filtration, the obtained residue was purified by silica gel column chromatography (100% ethyl acetate), and the obtained solid was recrystallized at 80 ^o C (petroleum ether/ethyl acetate=1/2, 24 mL) to obtain a yellow solid 42f ( 0.25 g, yield 76%, HPLC purity: 99.44%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.31 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.86 (s, 2H), 7.45 (q, J = 7.8 Hz , 1H), 7.34-7.23 (m, 2H), 7.09 (td, J = 8.6, 2.6 Hz, 1H), 6.95 (d, J = 2.6 Hz, 1H), 6.89 (dd, J = 8.7, 2.6 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.13 (t, J = 6.4 Hz, 2H).

step 7 :synthesis 2-(3,5- Dichloro -4-((2-(3- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 42g

2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 42f (0.26 g, 0.49 mmol) dissolved in acetic acid (5 mL ), added concentrated hydrochloric acid (2.5 mL), and reacted at 100 °C for 7 hours. Cool the reaction solution to room temperature, add water (20 mL), stir for 10 minutes, filter, rinse the filter cake with water (10 mL × 2), collect the filter cake and dry to obtain a yellow solid 42 g (0.22 g, yield 78 %).

step 8 :synthesis 2-(3,5- Dichloro -4-((2-(3- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 42

2-(3,5-dichloro-4-((2-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 42g (0.22 g, 0.40 mmol) dissolved in thioglycolic acid (2 mL), react at 140°C for 14 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was passed through a silica gel column layer Analysis (petroleum ether/ethyl acetate = 3/1) and purification, the resulting solid was recrystallized at 85 ^o C (petroleum ether/ethyl acetate = 1/1, 20 mL) to give white solid 42 (88 mg, yield 43%, HPLC purity: 98.94%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) 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, 9.6 Hz, 2H), 7.10 (s, 1H), 6.93 (s, 1H), 6.86 (s, 1H), 3.97 (s, 2H), 3.13 (s, 2H).

Example 43 2-(3,5- dichloro -4-((1- oxo- 2-(3-( trifluoromethoxy ) benzyl )-1,2,3,4- tetrahydroisoquine Phenyl -6- yl ) oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 43

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(3-( Trifluoromethoxy ) Benzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 43a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (2.5 g, 7.1 mmol) was dissolved in THF (25 mL), add sodium hydride (0.60 g, 20 mmol, 60 mass% in oil) at 0 ℃, add dropwise 3-trifluoromethoxybenzyl bromide (1.4 g, 8.6 mmol) and N , N -dimethylformaldehyde Amide (2 mL) was then kept at 0 °C for 5 hours. Add water (100 mL) to quench the reaction, extract with ethyl acetate (200 mL), wash the organic phase with saturated sodium chloride (30 mL × 3), dry over anhydrous sodium sulfate, concentrate by suction filtration, and pass the residue through a silica gel column Purification by chromatography (petroleum ether/ethyl acetate = 4/1) gave yellow oil 43a (2.6 g, yield 70%).

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(3-( Trifluoromethoxy ) Benzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 43b

6-(2,6-dichloro-4-nitrophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinoline-1(2 H )-ketone 43a (2.5 g, 4.7 mmol) was dissolved in acetic acid (30 mL), iron powder (0.55 g, 9.8 mmol) was added, and reacted at 60 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (60 mL), extracted with ethyl acetate (150 mL), and the organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and suction filtered After concentration, the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain yellow oil 43b (1.5 g, yield 64%).

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-(3-( Trifluoromethoxy ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 43c

6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinoline-1(2 H ) -Kone 43b (1.5 g, 3.0 mmol) was dissolved in acetic acid (20 mL), and an aqueous solution (6 mL) of sodium nitrite (0.42 g, 6.1 mmol) was added at 0 °C, followed by N -cyanoacetylurethane ( 0.61 g, 3.9 mmol), reacted for 2 hours. Add water (30 mL) to quench the reaction, stir for 10 minutes, filter, rinse the filter cake with water (10 mL × 2), collect the filter cake and dry it to obtain a yellow solid 43c (1.6 g, yield 80%).

step 4 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(3-( Trifluoromethoxy ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 43d .

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(3-(trifluoromethoxy)benzyl)-1,2,3 ,4-Tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazino)acetyl)ethyl carbamate 43c (1.5 g, 3.7 mmol) dissolved in N , N -dimethylformamide (15 mL), add sodium acetate (0.30 g, 3.7 mmol), and react at 120 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (35 mL), stirred for 10 minutes, filtered, and the filter cake was collected and dried, followed by recrystallization at 85 °C (ethanol/ethyl acetate/petroleum ether=5/20/18, 43 mL), a white solid 43d was obtained (0.80 g, yield 57%, HPLC purity: 98.83%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.33 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.84 (s, 2H), 7.48 (t, J = 7.8 Hz , 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.33-7.13 (m, 2H), 6.85 (d, J = 9.3 Hz, 2H), 4.74 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(3-( Trifluoromethoxy ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 43e

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-carbonitrile 43d (0.80 g, 1.3 mmol) Dissolve in acetic acid (12 mL), add concentrated hydrochloric acid (4 mL), and react at 120 °C for 12 hours. Cool the reaction solution to room temperature, add water (30 mL), stir for 10 minutes, filter, rinse the filter cake with water (5 mL × 2), collect the filter cake and dry to obtain a white solid 43e (0.62 g, yield 75 %).

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-(3-( Trifluoromethoxy ) Benzyl )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 43

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-carboxylic acid 43e (0.62 g, 0.97 mmol) Dissolve in thioglycolic acid (3.5 mL) and react at 150 °C for 12 hours. The reaction mixture was cooled to room temperature, quenched by adding water (20 mL), extracted with ethyl acetate (60 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), anhydrous sodium sulfate Drying, suction filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/3), and the obtained solid was recrystallized at 85 °C (ethyl acetate/petroleum ether = 2/5, 21 mL ), to obtain white solid 43 (0.38 g, yield 66%, HPLC purity: 98.38%).

MS (ESI, neg. ion) m/z : 591.1 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 1.0 Hz, 2H), 7.73 (d , J = 1.4 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.32-7.15 (m, 2H), 6.96-6.64 (m, 2H) , 4.74 (s, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H).

Example 44 2-(3,5- dichloro -4-((2-(2- fluorophenyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 44

step 1 :synthesis 2-(2- Fluorophenyl )-6- Methoxy -3,4- Dihydroisoquinoline -1(2 H )- ketone 44a

6-Methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.32 g, 1.7 mmol), o-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 ℃ for 19 hours. The reaction solution was cooled to room temperature, quenched by adding water (40 mL), 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, Concentrated by suction filtration to obtain yellow solid 44a (1.76 g, yield 75%).

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

step 2 :synthesis 2-(2- Fluorophenyl )-6- hydroxyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 44b

Add boron tribromide (1.84 mL, 19.1 mmol) dropwise to 2-(2-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline-1(2 H ) at 0 °C -ketone 44a (1.72 g, 6.34 mmol) in dichloromethane (30 mL), followed by reaction at room temperature for 4 hours. Pour the reaction solution into ice water (30 mL) to quench, stir for 10 minutes, filter, wash the filter cake with water (10 mL), collect the filter cake and dry, and the obtained solid is subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give 44b as a white solid (1.09 g, 67% yield).

MS (ESI, pos. ion) m/z : 258.2 [M+H] ⁺ .

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-(2- Fluorophenyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 44c

2-(2-Fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-1(2 H )-one 44b (0.50 g, 1.94 mmol) and 1,2,3-trichloro- 5-Nitrobenzene (0.52 g, 2.28 mmol) was dissolved in N , N -dimethylformamide (3 mL), potassium carbonate (0.54 g, 3.89 mmol) was added, and reacted at 40°C for 4.5 hours. The reaction solution was cooled to room temperature, added water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (5 mL), collected and dried to obtain off-white solid 44c (0.92 g, yield 100%).

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-(2- Fluorophenyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 44d

6-(2,6-dichloro-4-nitrophenoxy)-2-(2-fluorophenyl)-3,4-dihydroisoquinolin-1(2 H )-one 44c (0.92 g, 2.06 mmol) was dissolved in acetic acid (10 mL), iron powder (0.46 g, 8.24 mmol) was added, and reacted at 55 ℃ for 8 hours. The reaction solution was cooled to room temperature, iron powder was removed, water (50 mL) was added, extracted with ethyl acetate (20 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate , concentrated by suction filtration to obtain white solid 44d (0.84 g, yield 98%).

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-(2- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 44e

6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluorophenyl)-3,4-dihydroisoquinolin-1(2 H )-one 44d (0.55 g , 1.32 mmol) was dissolved in acetic acid (11 mL), and a solution of sodium nitrite (0.18 g, 2.64 mmol) in water (6 mL) was added dropwise at 0 °C, and after stirring for 15 minutes, N -cyanoacetylurethane (0.25 g, 1.58 mmol), reacted for 3.5 hours. Water (20 mL) was added to the reaction solution, stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to obtain a yellow solid 44e (0.76 g, yield 99%).

step 6 :synthesis 2-(3,5- Dichloro -4-((2-(2- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 44f

(2-cyano-2-(2-(3,5-dichloro-4-((2-(2-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 44e (0.42 g, 0.72 mmol) was dissolved in N , N -dimethylformamide (10 mL), added Sodium acetate (0.13 g, 1.59 mmol), react at 120°C for 8 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), stirred for 10 minutes, filtered, rinsed with water (10 mL), collected the filter cake and dried, and the obtained solid was recrystallized at 80 ^o C (petroleum ether/ Ethyl acetate=1/2, 30 mL) to give 44f as a yellow solid (0.25 g, yield 65%, HPLC purity: 96.68%).

MS (ESI, neg. ion) m/z : 536.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.31 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.86 (s, 2H), 7.48 (t, J = 7.7 Hz , 1H), 7.42-7.35 (m, 1H), 7.33 (d, J = 10.7 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.89 (d, J = 8.7 Hz, 1H), 3.93-3.83 (m, 2H), 3.20-3.11 (m, 2H).

step 7 :synthesis 2-(3,5- Dichloro -4-((2-(2- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 44g

2-(3,5-dichloro-4-((2-(2-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 44f (0.55 g, 1.02 mmol) dissolved in acetic acid (10 mL ), added concentrated hydrochloric acid (5 mL), and reacted at 100 °C for 7 hours. The reaction solution was cooled to room temperature, added water (20 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 2), collected the filter cake and dried to obtain 44 g (0.56 g, yield 98 %).

step 8 :synthesis 2-(3,5- Dichloro -4-((2-(2- Fluorophenyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 44

2-(3,5-dichloro-4-((2-(2-fluorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 44g (0.56 g, 1.01 mmol) dissolved in thioglycolic acid (2 mL), react at 130°C for 14 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was passed through a silica gel column layer Purified by analysis (petroleum ether/ethyl acetate = 3/1), the resulting solid was recrystallized at 85 ^o C (petroleum ether/ethyl acetate = 1/1, 20 mL) to give white solid 44 (0.23 g, yield 44%, HPLC purity: 97.70%).

MS (ESI, neg. ion) m/z : 511.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.53 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.89 (s, 2H), 7.74 (s, 1H), 7.48 (td, J = 7.8, 1.8 Hz, 1H), 7.41-7.25 (m, 3H), 6.95 (d, J = 2.6 Hz, 1H), 6.86 (dd, J = 8.6, 2.6 Hz, 1H), 3.88 ( t, J = 6.4 Hz, 2H), 3.14 (t, J = 6.5 Hz, 2H).

Example 45 2-(3,5- dichloro -4-((1- oxo -2-( pyridin -3- ylmethyl )-1,2,3,4- tetrahydroisoquinoline -6- Base ) oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 45

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( pyridine -3- methyl group )-3,4- Dihydroisoquinoline -1(2 H )- ketone 45a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (2.0 g, 5.7 mmol) was dissolved in THF (20 mL) solution, add sodium hydride (0.70 g, 18 mmol, 60 mass% in oil) at 0 ℃, add 3-(bromomethyl)pyridine hydrobromide (1.9 g, 7.5 mmol) and N , N -di Methylformamide (6 mL), followed by reaction at 20°C for 4 hours. At 0 °C, add water (50 mL) to quench the reaction, stir for 10 minutes, filter, rinse the filter cake with water (20 mL × 3), collect the filter cake and dry it, wash with ethyl acetate/petroleum ether (1/2, 20 mL) was beaten, filtered, and the filter cake was collected and dried to obtain a yellow solid 45a (2.2 g, yield 87%).

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( pyridine -3- methyl group )-3,4- Dihydroisoquinoline -1(2 H )- ketone 45b

6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2 H )-one 45a (2.2 g, 5.0 mmol) was dissolved in acetic acid (25 mL), added iron powder (0.72 g, 13 mmol), and reacted at 60 ℃ for 6 hours. The reaction mixture was cooled to room temperature, quenched by adding water (100 mL), extracted with ethyl acetate (150 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (20 mL × 2), anhydrous sodium sulfate It was dried and concentrated by suction filtration to obtain yellow solid 45b (1.6 g, yield 78%).

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-( pyridine -3- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 45c

6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-3-ylmethyl)-3,4-dihydroisoquinolin-1( 2H )-one 45b ( 1.6 g, 3.9 mmol) was dissolved in acetic acid (20 mL), and an aqueous solution (5 mL) of sodium nitrite (0.35 g, 5.1 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.72 g, 4.6 mmol), reacted for 2 hours. Water (100 mL) was added to quench the reaction, stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain a yellow solid 45c (2.2 g, yield 98%).

step 4 :synthesis 2-(3,5- Dichloro -4-((2-( pyridine -3- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 45d .

(2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridin-3-ylmethyl)-1-oxo-1,2,3,4-tetra Hydroisoquinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl)carbamate 45c (2.2 g, 3.8 mmol) was dissolved in N , N -dimethylformamide (18 mL) , add sodium acetate (0.40 g, 4.9 mmol), and react at 120 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (100 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried, followed by beating with ethanol/ethyl acetate (1/3, 50 mL) at 85 °C to obtain White solid 45d (0.90 g, 40% yield, HPLC purity: 83.86%).

MS (ESI, pos. ion) m/z : 535.9 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.56 (d, J = 28.8 Hz, 2H), 8.05-7.68 (m, 4H), 7.49-7.35 (m, 1H), 6.83 (d, J = 9.2 Hz, 2H), 4.71 (s, 2H), 3.52 (d, J = 6.7 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-( pyridine -3- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 45e

2-(3,5-dichloro-4-((2-(pyridin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 45d (0.80 g, 1.5 mmol) dissolved in acetic acid ( 12 mL), added concentrated hydrochloric acid (6.0 mL), and reacted at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and the reaction solution was concentrated to obtain a yellow solid 45e (0.80 g, yield 97%).

step 6 :synthesis 2-(3,5- Dichloro -4-((2-( pyridine -3- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 45

2-(3,5-dichloro-4-((2-(pyridin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 45e (0.80 g, 1.4 mmol) dissolved in thioglycolic acid (2 mL), react at 140°C for 12 hours. The reaction solution was cooled to room temperature, and the reaction solution was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain white solid 45 (0.12 g, yield 20%, HPLC purity: 93.09%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.53 (s, 1H), 9.08-8.68 (m, 2H), 8.41 (d, J = 12.8 Hz, 1H), 8.14-7.80 (m, 4H), 7.74 (d, J = 1.8 Hz, 1H), 7.05-6.70 (m, 2H), 4.84 (d, J = 2.9 Hz, 2H), 3.62 (d, J = 6.8 Hz, 2H), 3.02 ( t, J = 6.6 Hz, 2H).

Example 46 2-(3,5- dichloro -4-((1- oxo -2-( pyridin -2- ylmethyl )-1,2,3,4- tetrahydroisoquinoline -6- base ) oxy ) phenyl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 46

step 1 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( pyridine -2- methyl group )-3,4- Dihydroisoquinoline -1(2 H )- ketone 46a

6-(2,6-Dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1( 2H )-one 1b (2.0 g, 5.7 mmol) was dissolved in THF (20 mL) solution, add sodium hydride (0.60 g, 15 mmol, 60 mass% in oil) at 0 ℃, add 3-(bromomethyl)pyridine hydrobromide (1.9 g, 7.5 mmol) and N , N -di Methylformamide (2 mL), followed by reaction at 15°C for 6 hours. At 0 °C, add water (50 mL) to quench the reaction, stir for 10 minutes, extract with ethyl acetate (120 mL), wash the organic phase with saturated sodium chloride solution (20 mL × 3), dry over anhydrous sodium sulfate, and extract Concentration by filtration afforded 46a as a yellow solid (2.3 g, 91% yield).

step 2 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( pyridine -2- methyl group )-3,4- Dihydroisoquinoline -1(2 H )- ketone 46b

6-(2,6-Dichloro-4-nitrophenoxy)-2-(pyridin-2-ylmethyl)-3,4-dihydroisoquinolin-1( 2H )-one 46a (2.3 g, 5.2 mmol) was dissolved in acetic acid (25 mL), added iron powder (0.72 g, 13 mmol), and incubated at 60 °C for 6 hours. The reaction mixture was cooled to room temperature, quenched by adding water (80 mL), extracted with ethyl acetate (150 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), anhydrous sodium sulfate Drying, suction filtration and concentration gave black oil 46b (2.1 g, yield 98%).

step 3 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((2-( pyridine -2- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 46c

6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-2-ylmethyl)-3,4-dihydroisoquinolin-1( 2H )-one 46b ( 2.1 g, 5.1 mmol) was dissolved in acetic acid (20 mL), and an aqueous solution (5 mL) of sodium nitrite (0.45 g, 6.5 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.95 g, 6.1 mmol), reacted for 2 hours. Water (50 mL) was added to quench the reaction, stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain a yellow solid 46c (2.8 g, yield 95%).

step 4 :synthesis 2-(3,5- Dichloro -4-((2-( pyridine -2- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 46d .

(2-cyano-2-(2-(3,5-dichloro-4-((2-(pyridin-2-ylmethyl)-1-oxo-1,2,3,4-tetra Hydroisoquinolin-6-yl)oxy)phenyl)hydrazinylidene)acetyl)ethyl)carbamate 46c (2.8 g, 4.8 mmol) was dissolved in N , N -dimethylformamide (30 mL) , add sodium acetate (0.43 g, 5.2 mmol), and react at 120°C for 6 hours. Cool the reaction solution to room temperature, add water (50 mL) to quench the reaction, stir for 15 minutes, filter, collect the filter cake and dry, then recrystallize with ethyl acetate/petroleum ether (2/1, 30 mL) at 85 °C , to obtain white solid 46d (1.3 g, yield 50%, HPLC purity: 91.60%).

MS (ESI, pos. ion) m/z : 535.9 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.11 (s, 1H), 8.51 (d, J = 4.8 Hz, 1H), 8.16-7.81 (m, 3H), 7.76 (t, J = 7.8 Hz, 1H), 7.51-7.11 (m, 2H), 7.05- 6.72 (m, 2H), 4.78 (s, 2H), 3.61 (t, J = 6.6 Hz, 2H), 3.01 (t, J = 6.5 Hz, 2H).

step 5 :synthesis 2-(3,5- Dichloro -4-((2-( pyridine -2- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 46e

2-(3,5-dichloro-4-((2-(pyridin-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 46d (1.2 g, 2.2 mmol) dissolved in acetic acid ( 12 mL), added concentrated hydrochloric acid (6.0 mL), and reacted at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and the reaction solution was concentrated to obtain a yellow solid 46e (1.2 g, yield 97%).

step 6 :synthesis 2-(3,5- Dichloro -4-((2-( pyridine -2- methyl group )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 46

2-(3,5-dichloro-4-((2-(pyridin-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 46e (1.0 g, 1.8 mmol) in thioglycolic acid (3 mL), react at 140 °C for 12 hours. The reaction solution was cooled to room temperature, and the reaction solution was purified by silica gel column chromatography (petroleum ether/ethyl acetate=7/3) to obtain white solid 46 (0.43 g, yield 47%, HPLC purity: 92.83%).

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.52 (s, 1H), 8.51 (d, J = 4.8 Hz, 1H), 8.02-7.83 (m, 3H), 7.83-7.63 (m, 2H), 7.38-7.23 (m, 2H), 6.93-6.76 (m, 2H), 4.78 (s, 2H), 3.61 (t, J = 6.6 Hz, 2H), 3.01 (t, J = 6.6 Hz, 2H ).

Example 47 2-(3,5- dichloro -4-((1- oxo- 2-( pyridin -2- yl )-1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -3,5(2 H ,4 H ) -dione 47

step 1 :synthesis 6- Methoxy -2-( pyridine -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 47a

6-methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.48 g, 2.5 mmol), 2-iodopyridine ( 3.5 g, 17 mmol) and potassium carbonate (2.3 g, 17 mmol) were dissolved in N , N -dimethylformamide (40 mL) solution, and reacted at 150 ℃ for 11 hours. The reaction solution was cooled to room temperature, quenched by adding water (40 mL), 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, Concentrated by suction filtration, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain a white solid 47a (1.66 g, yield 77%).

MS (ESI, pos. ion) m/z : 255.1 [M+H] ⁺ .

step 2 :synthesis 6- hydroxyl -2-( pyridine -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 47b

At 0°C, add boron tribromide (1.60 mL, 16.6 mmol) dropwise to 6-methoxy-2-(pyridin-2-yl)-3,4-dihydroisoquinoline-1(2 H ) -ketone 47a (1.67 g, 6.54 mmol) in dichloromethane (40 mL), followed by reaction at room temperature for 16 hours. The reaction solution was quenched by pouring into ice water (30 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 47b (1.06 g, yield 68%).

MS (ESI, pos. ion) m/z : 258.2 [M+H] ⁺ .

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( pyridine -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 47c

6-Hydroxy-2-(pyridin-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 47b (1.06 g, 4.41 mmol) and 1,2,3-trichloro- 5-Nitrobenzene (1.10 g, 4.86 mmol) was dissolved in N , N -dimethylformamide (6 mL), potassium carbonate (1.22 g, 8.83 mmol) was added, and reacted at 40 °C for 5.5 hours. The reaction solution was cooled to room temperature, added water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 47c (1.75 g, yield 92%).

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( pyridine -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 47d

6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 47c (1.75 g, 4.07 mmol) was dissolved in acetic acid (30 mL), added iron powder (0.91 g, 16.3 mmol), and reacted at 55°C for 8 hours. The reaction solution was cooled to room temperature, iron powder was removed, water (50 mL) was added, extracted with ethyl acetate (10 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate , concentrated by suction filtration to obtain white solid 47d (1.45 g, yield 89%).

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 47e

6-(4-Amino-2,6-dichlorophenoxy)-2-(pyridin-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 47d (0.40 g , 1.0 mmol) was dissolved in acetic acid (8 mL), and a solution of sodium nitrite (0.14 g, 2.0 mmol) in water (4 mL) was added dropwise at 0 °C, and after stirring for 15 minutes, N -cyanoacetylurethane (0.16 g, 1.0 mmol), reacted for 3 hours. Water (20 mL) was added to the reaction solution, stirred for 10 minutes, filtered, rinsed with water (10 mL × 2), and the filter cake was collected and dried to obtain a yellow solid 47e (0.53 g, yield 94%).

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 47f

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 47e (0.53 g, 0.93 mmol) was dissolved in N , N -dimethylformamide (11 mL), added Sodium acetate (0.17 g, 2.1 mmol), react at 120°C for 8 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), stirred for 10 minutes, filtered, rinsed with water (10 mL × 2), and dried to obtain a yellow solid 47f (0.38 g, yield 78 %, HPLC purity: 99.44%).

MS (ESI, neg. ion) m/z : 518.9 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.31 (s, 1H), 8.46 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.92-7.78 (m, 4H), 7.21 (t, J = 6.1 Hz, 1H), 6.97 (s, 1H), 6.91 (dd, J = 8.7, 2.5 Hz, 1H), 4.19 (t, J = 6.5 Hz, 2H) , 3.10 (t, J = 6.4 Hz, 2H).

step 7 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 47g

2-(3,5-dichloro-4-((1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 47f (0.38 g, 0.73 mmol) dissolved in acetic acid (6 mL ), added concentrated hydrochloric acid (3 mL), and reacted at 100 °C for 10 hours. The reaction solution was cooled to room temperature, added water (20 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 3), collected the filter cake and dried to obtain 47 g (0.39 g, yield 96 %).

step 8 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 47

2-(3,5-dichloro-4-((1-oxo-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 47g (0.39 g, 0.72 mmol) dissolved in thioglycolic acid (2 mL), react at 130°C for 7 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was passed through a silica gel column layer Purified by analysis (petroleum ether/ethyl acetate = 3/1), the resulting solid was recrystallized at 85 ^o C (petroleum ether/ethyl acetate = 1/1, 20 mL) to give white solid 47 (0.11 g, yield 31%, HPLC purity: 93.27%).

MS (ESI, neg. ion) m/z : 494.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.54 (s, 1H), 8.46 (dd, J = 5.0, 1.9 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.92 -7.77 (m, 4H), 7.74 (s, 1H), 7.25-7.18 (m, 1H), 6.95 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.7, 2.6 Hz, 1H), 4.19 (t, J = 6.3 Hz, 2H), 3.11 (t, J = 6.4 Hz, 2H).

Example 48 2-(3,5- Dichloro -4-((1- oxo- 2-( pyridin -4- yl )-1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -3,5(2 H ,4 H ) -dione 48

step 1 :synthesis 6- Methoxy -2-( pyridine -4- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 48a

6-methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.32 g, 1.7 mmol), 4-iodopyridine ( 3.2 g, 17 mmol) and potassium carbonate (2.3 g, 17 mmol) were dissolved in toluene (20 mL), and reacted at 120 ℃ for 99 hours. The reaction solution was cooled to room temperature, quenched by adding water (40 mL), 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, Concentrated by suction filtration, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain a white solid 48a (1.85 g, yield 86%).

step 2 :synthesis 6- hydroxyl -2-( pyridine -4- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 48b

At 0°C, add boron tribromide (1.73 mL, 18.0 mmol) dropwise to 6-methoxy-2-(pyridin-4-yl)-3,4-dihydroisoquinoline-1(2 H ) -ketone 48a (1.83 g, 7.20 mmol) in dichloromethane (30 mL), followed by reaction at room temperature for 16 hours. The reaction solution was quenched by pouring into ice water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 48b (1.80 g, yield 100%).

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( pyridine -4- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 48c

6-Hydroxy-2-(pyridin-4-yl)-3,4-dihydroisoquinolin-1(2 H )-one 48b (1.73 g, 7.20 mmol) and 1,2,3-trichloro- 5-Nitrobenzene (1.79 g, 7.90 mmol) was dissolved in N , N -dimethylformamide (20 mL), potassium carbonate (3.98 g, 28.8 mmol) was added, and reacted at 40°C for 5.5 hours. The reaction solution was cooled to room temperature, added with water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 48c (2.56 g, yield 83%).

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( pyridine -4- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 48d

6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-4-yl)-3,4-dihydroisoquinolin-1(2 H )-one 48c (2.16 g, 5.02 mmol) was dissolved in acetic acid (30 mL), iron powder (1.07 g, 19.2 mmol) was added, and reacted at 55 °C for 4 hours. The reaction solution was cooled to room temperature, iron powder was removed, water (100 mL) was added, extracted with ethyl acetate (20 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate , concentrated by suction filtration to obtain white solid 48d (1.98 g, yield 98%).

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -4- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 48e

6-(4-Amino-2,6-dichlorophenoxy)-2-(pyridin-4-yl)-3,4-dihydroisoquinolin-1(2 H )-one 48d (0.50 g , 1.25 mmol) was dissolved in acetic acid (10 mL), and a solution of sodium nitrite (0.17 g, 2.49 mmol) in water (5 mL) was added dropwise at 0 °C, and after stirring for 15 minutes, N -cyanoacetylurethane (0.23 g, 1.5 mmol), reacted for 3 hours. Water (20 mL) was added to the reaction solution, stirred for 30 minutes, filtered, rinsed with water (10 mL × 2), and the filter cake was collected and dried to obtain a yellow solid 48e (0.70 g, yield 99%).

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -4- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 48f

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 48e (0.70 g, 1.23 mmol) was dissolved in N , N -dimethylformamide (15 mL), added Sodium acetate (0.25 g, 3.07 mmol), react at 120°C for 8 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), stirred for 10 minutes, filtered, rinsed with water (10 mL × 2), and dried to obtain a yellow solid 48f (0.62 g, yield 96 %, HPLC purity: 97.11%).

MS (ESI, neg. ion) m/z : 519.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.58 (s, 2H), 8.00 (d, J = 8.6 Hz, 1H), 7.86 (s, 2H), 7.52 (s, 2H), 6.97 (d, J = 2.6 Hz, 1H), 6.91 (dd, J = 8.7, 2.7 Hz, 1H), 4.04 (t, J = 6.5 Hz, 2H), 3.14 (t, J = 6.3 Hz, 2H).

step 7 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -4- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 48g

2-(3,5-dichloro-4-((1-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 48f (0.52 g, 1.00 mmol) dissolved in acetic acid (4 mL ), added concentrated hydrochloric acid (2 mL), and reacted at 100 °C for 12 hours. The reaction solution was cooled to room temperature, added water (20 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 3), collected the filter cake and dried to obtain 48 g (0.51 g, yield 95 %).

step 8 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -4- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 48

2-(3,5-dichloro-4-((1-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 48g (0.51 g, 0.94 mmol) dissolved in thioglycolic acid (2 mL), react at 120°C for 7 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was passed through a silica gel column layer Purification by analysis (petroleum ether/ethyl acetate = 1/1), the obtained solid was recrystallized at 85°C (petroleum ether/ethyl acetate = 1/1, 50 mL), and a white solid 48 (99 mg, yield 21 %, HPLC purity: 90.75%).

MS (ESI, neg. ion) m/z : 494.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.54 (s, 1H), 8.83 (d, J = 6.5 Hz, 2H), 8.08 (d, J = 6.7 Hz, 2H), 8.06 (d , J = 8.7 Hz, 1H), 7.89 (s, 2H), 7.75 (s, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.94 (dd, J = 8.7, 2.6 Hz, 1H), 4.20 (t, J = 6.3 Hz, 2H), 3.19 (t, J = 6.3 Hz, 2H).

Example 49 2-(3,5- dichloro -4-((1- oxo- 2-( pyridin -3- yl )-1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -3,5(2 H ,4 H ) -dione 49

step 1 :synthesis 6- Methoxy -2-( pyridine -3- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 49a

6-Methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.32 g, 1.7 mmol), 3-iodopyridine ( 2.60 g, 12.7 mmol) and potassium carbonate (2.34 g, 17 mmol) were dissolved in toluene (30 mL), and reacted at 120 ℃ for 90 hours. The reaction solution was cooled to room temperature, quenched by adding water (40 mL), 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, Concentrated by suction filtration, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain a white solid 49a (2.15 g, yield 100%).

step 2 :synthesis 6- hydroxyl -2-( pyridine -3- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 49b

At 0°C, add boron tribromide (2.04 mL, 21.2 mmol) dropwise to 6-methoxy-2-(pyridin-3-yl)-3,4-dihydroisoquinoline-1(2 H ) -ketone 49a (2.15 g, 8.45 mmol) in dichloromethane (40 mL), followed by reaction at room temperature for 16 hours. The reaction solution was quenched by pouring into ice water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 49b (2.03 g, yield 100%).

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( pyridine -3- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 49c

6-Hydroxy-2-(pyridin-3-yl)-3,4-dihydroisoquinolin-1(2 H )-one 49b (2.03 g, 8.45 mmol) and 1,2,3-trichloro- 5-Nitrobenzene (2.10 g, 9.27 mmol) was dissolved in N , N -dimethylformamide (40 mL), potassium carbonate (9.34 g, 67.6 mmol) was added, and reacted at 70 °C for 5.5 hours. The reaction solution was cooled to room temperature, added water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 49c (2.34 g, yield 65%).

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( pyridine -3- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 49d

6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-3-yl)-3,4-dihydroisoquinolin-1(2 H )-one 49c (2.34 g, 5.45 mmol) was dissolved in acetic acid (30 mL), iron powder (1.22 g, 21.8 mmol) was added, and reacted at 55 °C for 5 hours. The reaction solution was cooled to room temperature, iron powder was removed, water (50 mL) was added, extracted with ethyl acetate (20 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate , concentrated by suction filtration to obtain white solid 49d (1.75 g, yield 80%).

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -3- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 49e

6-(4-Amino-2,6-dichlorophenoxy)-2-(pyridin-3-yl)-3,4-dihydroisoquinolin-1(2 H )-one 49d (0.50 g , 1.25 mmol) was dissolved in acetic acid (10 mL), and a solution of sodium nitrite (0.17 g, 2.49 mmol) in water (5 mL) was added dropwise at 0 °C, and after stirring for 15 minutes, N -cyanoacetylurethane (0.23 g, 1.5 mmol), reacted for 3 hours. Water (20 mL) was added to the reaction solution, stirred for 30 minutes, filtered, rinsed with water (10 mL × 2), and the filter cake was collected and dried to obtain a yellow solid 49e (0.71 g, yield 100%).

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -3- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 49f

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(pyridin-3-yl)-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 48e (0.71 g, 1.25 mmol) was dissolved in N , N -dimethylformamide (11 mL), added Sodium acetate (0.25 g, 3.07 mmol), react at 120°C for 8 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), stirred for 10 minutes, filtered, rinsed with water (10 mL × 2), and dried to obtain a yellow solid 49f (0.62 g, yield 96 %, HPLC purity: 97.94%).

MS (ESI, neg. ion) m/z : 518.9 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.80 (s, 1H), 8.53 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.98 (d , J = 8.6 Hz, 1H), 7.86 (s, 2H), 7.65 (dd, J = 8.3, 4.9 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 6.91 (dd, J = 8.6, 2.6 Hz, 1H), 4.04 (t, J = 6.4 Hz, 2H), 3.17 (t, J = 6.2 Hz, 2H).

step 7 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -3- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 49g

2-(3,5-dichloro-4-((1-oxo-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 49f (0.68 g, 1.30 mmol) dissolved in acetic acid (8 mL ), added concentrated hydrochloric acid (4 mL), and reacted at 100 °C for 10 hours. The reaction solution was cooled to room temperature, added water (20 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 3), collected the filter cake and dried to obtain 49 g of yellow solid (0.53 g, yield 75 %).

step 8 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyridine -3- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 49

2-(3,5-dichloro-4-((1-oxo-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 49g (0.53 g, 0.97 mmol) dissolved in thioglycolic acid (2 mL), react at 130°C for 4 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was passed through a silica gel column layer Purified by analysis (petroleum ether/ethyl acetate = 3/1), the resulting solid was recrystallized at 85 ^o C (petroleum ether/ethyl acetate = 1/1, 20 mL) to give a white solid 49 (0.26 g, yield 53%, HPLC purity: 92.52%).

MS (ESI, neg. ion) m/z : 494.0 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.54 (s, 1H), 9.01 (dt, J = 8.2, 2.5 Hz, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.47 (t, J = 9.2 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.89 (s, 2H), 7.74 (d, J = 1.5 Hz , 1H), 6.97 (d, J = 2.6 Hz, 1H), 6.91 (dd, J = 8.6, 2.7 Hz, 1H), 4.11 (t, J = 6.2 Hz, 2H), 3.18 (t, J = 6.4 Hz , 2H).

Example 50 2-(3,5- dichloro -4-((1- oxo -2-( pyrimidin -2- yl )-1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -3,5(2 H ,4 H ) -dione 50

step 1 :synthesis 6- Methoxy -2-( pyrimidine -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 50a

6-methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5a (1.50 g, 8.5 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyl Xanthene (0.49 g, 0.85 mmol), cesium carbonate (3.68 g, 17.0 mmol) and 2-iodopyrimidine (3.5 g, 17.0 mmol) were dissolved in 1,4-dioxane (20 mL), and reacted at 120 °C 17 hours. The reaction solution was cooled to room temperature, filtered with Celite, the filter cake was washed with dichloromethane (50 mL) and ethanol (10 mL), the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 1 /2) to obtain 50a as a tan solid (1.29 g, yield 90%).

step 2 :synthesis 6- hydroxyl -2-( pyrimidine -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 50b

At 0°C, add boron tribromide (0.80 mL, 8.30 mmol) dropwise to 6-methoxy-2-(pyrimidin-2-yl)-3,4-dihydroisoquinoline-1(2 H ) -Kone 50a (1.29 g, 5.05 mmol) in dichloromethane (30 mL) solution, followed by reaction at room temperature for 3 hours. The reaction solution was quenched by pouring into ice water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 50b (1.22 g, yield 100%).

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( pyrimidine -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 50c

6-Hydroxy-2-(pyrimidin-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 50b (1.22 g, 5.06 mmol) and 1,2,3-trichloro- 5-Nitrobenzene (1.26 g, 5.56 mmol) was dissolved in N , N -dimethylformamide (25 mL), and potassium carbonate (1.40 g, 10.1 mmol) was added, and reacted at 70°C for 6 hours. The reaction solution was cooled to room temperature, added water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a red solid 50c (1.85 g, yield 85%).

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( pyrimidine -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 50d

6-(2,6-dichloro-4-nitrophenoxy)-2-(pyrimidin-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 50c (1.85 g, 4.29 mmol) was dissolved in acetic acid (30 mL), added iron powder (0.96 g, 17.1 mmol), and reacted at 55 ℃ for 10 hours. The reaction solution was cooled to room temperature, iron powder was removed, water (50 mL) was added, extracted with ethyl acetate (10 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate , concentrated by suction filtration to obtain white solid 50d (1.32 g, yield 77%).

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-( pyrimidine -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 50e

6-(4-amino-2,6-dichlorophenoxy)-2-(pyrimidin-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 50d (0.50 g , 1.25 mmol) was dissolved in acetic acid (10 mL), and a solution of sodium nitrite (0.17 g, 2.49 mmol) in water (5 mL) was added dropwise at 0 °C, and after stirring for 15 minutes, N -cyanoacetylurethane (0.23 g, 1.50 mmol), reacted for 3.5 hours. Water (20 mL) was added to the reaction solution, stirred for 30 minutes, filtered, rinsed with water (10 mL × 2), and the filter cake was collected and dried to obtain a yellow solid 50e (0.70 g, yield 99%).

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyrimidine -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 50f

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(pyrimidin-2-yl)-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 50e (0.70 g, 1.23 mmol) was dissolved in N , N -dimethylformamide (15 mL), added Sodium acetate (0.25 g, 3.1 mmol), react at 120°C for 10 hours. The reaction solution was cooled to room temperature, quenched by adding water (40 mL), stirred for 10 minutes, filtered, rinsed with water (10 mL × 2), and the filter cake was collected and dried to obtain a brown solid which was recrystallized at 85 °C (ethyl acetate ester/methanol/petroleum ether=2/1/2, 50 mL), to obtain 50f as a yellow solid (0.46 g, yield 71%, HPLC purity: 97.56%).

MS (ESI, neg. ion) m/z : 520.6 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.81 (d, J = 4.8 Hz, 2H), 8.02 (d, J = 8.6 Hz, 1H), 7.87 (s, 2H), 7.35 (t , J = 4.9 Hz, 1H), 6.93 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 4.10 (t, J = 6.2 Hz, 2H), 3.12 (t, J = 6.5 Hz, 2H ).

step 7 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyrimidine -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 50g

2-(3,5-dichloro-4-((1-oxo-2-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 50f (0.30 g, 0.57 mmol) dissolved in acetic acid (4 mL ), added concentrated hydrochloric acid (2 mL), and reacted at 100 °C for 12 hours. The reaction solution was cooled to room temperature, added water (20 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 3), collected the filter cake and dried to obtain 50 g (0.30 g, yield 96 %).

step 8 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( pyrimidine -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 50

2-(3,5-dichloro-4-((1-oxo-2-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 50g (0.30 g, 0.55 mmol) dissolved in thioglycolic acid (1 mL), react at 90°C for 5 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was passed through a silica gel column layer Purified by analysis (petroleum ether/ethyl acetate = 1/2), the obtained solid was separated and purified by preparation [45%ACN / 55%H ₂ O (0.1%TFA), Phenomenes ACE specifications: C18 10μm×50mm×250mm, Flow rate: 100 mL/min], a white solid 50 was obtained (60 mg, yield 22%, HPLC purity: 99.63%).

MS (ESI, neg. ion) m/z : 495.1 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.53 (s, 1H), 8.82 (d, J = 4.9 Hz, 2H), 8.03 (d, J = 8.7 Hz, 1H), 7.88 (s , 2H), 7.74 (s, 1H), 7.36 (t, J = 4.8 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J = 8.7 Hz, 1H), 4.11 (t, J = 6.2 Hz , 2H), 3.13 (t, J = 6.2 Hz, 2H).

Example 51 2-(3,5- Dichloro -4-((2- formyl -1- oxo - 1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) benzene base )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carbonitrile 51

2-(3,5-dichloro-4-((2-(hydroxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)benzene base)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 39 (30 mg, 0.063 mmol) and pyridinium dichromate ( 60 mg, 0.16 mmol) was dissolved in dichloromethane (6 mL), and reacted at room temperature for 15 hours. Ethyl acetate (10 mL) was added to the reaction solution, ultrasonically oscillated for 10 minutes, suction filtered, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/3) to obtain a white solid 51 (21 mg, yield 70%, HPLC purity: 96.92%).

MS (ESI, neg. ion) m/z : 470.4 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.30 (s, 1H), 9.44 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.86 (s, 2H), 7.01 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.6, 2.4 Hz, 1H), 3.88 (t, J = 6.2 Hz, 2H), 3.04 (t, J = 6.1 Hz, 2H).

Example 52 2-(3,5- Dichloro -4-((1- oxo -2-( thiazol -2- yl )-1,2,3,4- tetrahydroisoquinolin -6- yl ) Oxy ) phenyl )-3,5- dioxo -2,3,4,5 - tetrahydro -1,2,4- triazine -3,5(2 H ,4 H ) -dione 52

step 1 :synthesis 6- Methoxy -2-( Thiazole -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 52a

6-Methoxy-3,4-dihydroisoquinolin-1(2 H )-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.48 g, 2.5 mmol), 2-bromothiazole ( 2.80 g, 17 mmol) and potassium carbonate (2.3 g, 17 mmol) were dissolved in N , N -dimethylformamide (15 mL), and reacted at 150 ℃ for 41 hours. The reaction solution was cooled to room temperature, quenched by adding water (40 mL), 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, Concentrated by suction filtration, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 8/1) to obtain a white solid 52a (0.86 g, yield 39%).

step 2 :synthesis 6- hydroxyl -2-( Thiazole -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 52b

At 0°C, add boron tribromide (0.80 mL, 8.30 mmol) dropwise to 6-methoxy-2-(thiazol-2-yl)-3,4-dihydroisoquinoline-1(2 H ) - Ketone 50a (0.86 g, 3.30 mmol) in dichloromethane (20 mL) solution, followed by reaction at room temperature for 10 hours. The reaction solution was quenched by pouring into ice water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 52b (0.80 g, yield 98%).

step 3 :synthesis 6-(2,6- Dichloro -4- Nitrophenoxy base )-2-( Thiazole -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 52c

6-Hydroxy-2-(thiazol-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 52b (0.80 g, 3.25 mmol) and 1,2,3-trichloro- 5-Nitrobenzene (0.81 g, 3.57 mmol) was dissolved in N , N -dimethylformamide (16 mL), potassium carbonate (0.90 g, 6.50 mmol) was added, and reacted at 40 °C for 17 hours. The reaction solution was cooled to room temperature, added with water (30 mL), stirred for 10 minutes, filtered, the filter cake was washed with water (10 mL), collected and dried to obtain a white solid 52c (1.06 g, yield 75%).

step 4 :synthesis 6-(4- Amino -2,6- Dichlorophenoxy )-2-( Thiazole -2- base )-3,4- Dihydroisoquinoline -1(2 H )- ketone 52d

6-(2,6-dichloro-4-nitrophenoxy)-2-(thiazol-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 52c (1.06 g, 2.42 mmol) was dissolved in acetic acid (20 mL), added iron powder (0.54 g, 9.69 mmol), and reacted at 55 ℃ for 8 hours. The reaction solution was cooled to room temperature, iron powder was removed, water (50 mL) was added, extracted with ethyl acetate (10 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate , concentrated by suction filtration to obtain white solid 52d (0.74 g, yield 75%).

step 5 :synthesis (2- cyano -2-(2-(3,5- Dichloro -4-((1- Oxo -2-( Thiazole -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl ) Hydrazine ) Acetyl ) Urethane 52e

6-(4-Amino-2,6-dichlorophenoxy)-2-(thiazol-2-yl)-3,4-dihydroisoquinolin-1(2 H )-one 52d (0.40 g , 1.00 mmol) was dissolved in acetic acid (8 mL), and a solution of sodium nitrite (0.14 g, 2.00 mmol) in water (4 mL) was added dropwise at 0 °C. After stirring for 15 minutes, N -cyanoacetylurethane (0.19 g, 1.19 mmol), reacted for 3 hours. Water (20 mL) was added to the reaction solution, stirred for 30 minutes, filtered, rinsed with water (10 mL × 2), and the filter cake was collected and dried to obtain a yellow solid 52e (0.56 g, yield 100%).

step 6 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( Thiazole -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 52f

(2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(thiazol-2-yl)-1,2,3,4-tetrahydroiso Quinolin-6-yl)oxy)phenyl)hydrazinoylidene)acetyl)ethyl carbamate 52e (0.56 g, 0.98 mmol) was dissolved in N , N -dimethylformamide (12 mL), added Sodium acetate (0.18 g, 2.20 mmol), react at 120°C for 10 hours. The reaction solution was cooled to room temperature, quenched by adding water (80 mL), stirred for 10 minutes, filtered, rinsed with water (10 mL × 2), and the filter cake was collected and dried to obtain a brown solid which was recrystallized at 85 °C (ethyl acetate Ester/petroleum ether = 1/1, 100 mL) to give 52f as a yellow solid (0.45 g, 87% yield, HPLC purity: 89.52%).

MS (ESI, neg. ion) m/z : 525.4 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.05 (d, J = 8.6 Hz, 1H), 7.87 (s, 2H), 7.58 (s, 1H), 7.35 (s, 1H), 7.01 (s, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.51 (t, J = 6.5 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H).

step 7 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( Thiazole -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 52g

2-(3,5-dichloro-4-((1-oxo-2-(thiazol-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 52f (0.40 g, 0.76 mmol) dissolved in acetic acid (4 mL ), added concentrated hydrochloric acid (2 mL), and reacted at 100 °C for 12 hours. Cool the reaction solution to room temperature, add water (20 mL), stir for 10 minutes, filter, rinse the filter cake with water (10 mL × 3), collect the filter cake and dry to obtain a yellow solid 52 g (0.41 g, yield 100 %).

step 8 :synthesis 2-(3,5- Dichloro -4-((1- Oxo -2-( Thiazole -2- base )-1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) Phenyl )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 52

2-(3,5-dichloro-4-((1-oxo-2-(thiazol-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy )phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 52g (0.54 g, 0.99 mmol) dissolved in thioglycolic acid (2 mL), react at 130°C for 9 hours. The reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was passed through a silica gel column layer Analysis (petroleum ether/ethyl acetate = 3/1) and purification, the resulting solid was recrystallized at 85°C (ethyl acetate/petroleum ether = 1/1, 20 mL) to give white solid 52 (0.11 g, yield 46%, HPLC purity: 98.09%).

MS (ESI, neg. ion) m/z : 500.7 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.53 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.89 (s, 2H), 7.74 (s, 1H), 7.58 (d, J = 3.5 Hz, 1H), 7.35 (d, J = 3.6 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J = 8.6 Hz, 1H), 4.51 (t, J = 6.6 Hz , 2H), 3.18 (t, J = 6.4 Hz, 2H).

Example 53 2-(5-chloro-6-((2-(4- fluorobenzyl )-1- oxo -1,2,3,4- tetrahydroisoquinolin -6- yl ) oxy ) Pyridin -3- yl )-1,2,4- triazine -3,5(2 H ,4 H ) -dione 53

step 1 :synthesis 6-( Benzyloxy )-2-(4- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 53a

6-(Benzyloxy)-3,4-dihydroisoquinolin-1( 2H )-one 10a (10.0 g, 61.3 mmol) was dissolved in N , N -dimethylformamide (80 mL) , Potassium carbonate (15.0 g, 151 mmol) was added, and 4-fluorobenzyl bromide (8.8 mL, 74.0 mmol) was added dropwise with stirring, followed by reaction at 40°C for 10 hours. The reaction solution was cooled to room temperature, quenched by adding water (250 mL), filtered, and the filter cake was collected, dried, and slurried with (ethyl acetate/petroleum ether=1/7, 80 mL) to obtain a white solid 53a (10.6 g , yield 68%).

step 2 :synthesis 2-(4- Fluorobenzyl )-6- hydroxyl -3,4- Dihydroisoquinoline -1(2 H )- ketone 53b

6-(Benzyloxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1( 2H )-one 53a (4.0 g, 11.0 mmol) was dissolved in ethanol (40 mL ), add 10% palladium carbon (0.40 g), replace the hydrogen, hydrogenation reaction (hydrogen balloon) at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was collected and concentrated to obtain a white solid 53b (2.9 g, yield 97%).

step 3 :synthesis 6-((3-chloro-5- Nitropyridine -2- base ) Oxygen )-2-(4- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 53c

2-(4-fluorobenzyl)-6-hydroxy-3,4-dihydroisoquinolin-1(2 H )-one 53b (2.9 g, 11 mmol) and 2,3-dichloro-5- Nitropyridine (2.5 g, 13 mmol) was dissolved in N , N -dimethylformamide (30 mL), potassium carbonate (1.6 g, 16 mmol) was added, and reacted at 80°C for 3 hours. The reaction solution was cooled to room temperature, quenched by adding water (60 mL), stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain gray solid 53c (4.5 g, yield 98%).

step 4 :synthesis 6-((5- Amino -3-Chloropyridine Pyridine -2- base ) Oxygen )-2-(4- Fluorobenzyl )-3,4- Dihydroisoquinoline -1(2 H )- ketone 53d

6-((3-chloro-5-nitropyridin-2-yl)oxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2 H )-one 53c (4.5 g, 11 mmol) was dissolved in acetic acid (40 mL), iron powder (1.5 g, 27 mmol) was added, and reacted at 60 °C for 5 hours. The reaction mixture was cooled to room temperature, quenched by adding water (100 mL), extracted with ethyl acetate (120 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), anhydrous sodium sulfate Drying, suction filtration and concentration gave black oil 53d (4.0 g, yield 96%).

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

step 5 :synthesis (2-(2-(5-chloro-6-((2-(4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) pyridine -3- base ) Hydrazine )-2- Cyanoacetyl ) Urethane 53e

6-((5-Amino-3-chloropyridin-2-yl)oxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1( 2H )-one 53d (1.50 g, 3.77 mmol) was dissolved in acetic acid (25 mL), and an aqueous solution (10 mL) of sodium nitrite (0.52 g, 7.54 mmol) was added at 0 °C, followed by N -cyanoacetylurethane (0.88 g, 5.66 mmol), reacted for 2 hours. Water (50 mL) was added to quench the reaction, stirred for 20 minutes, filtered, and the filter cake was rinsed with water (10 mL), collected and dried to obtain light yellow solid 53e (2.00 g, yield 96%).

step 6 :synthesis 2-(5-Chloro-6-((2-(4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) pyridine -3- base )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- Formaldehyde 53f .

(2-(2-(5-chloro-6-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy Base) pyridin-3-yl) hydrazino)-2-cyanoacetyl) ethyl carbamate 53e (2.00 g, 3.62 mmol) was dissolved in N , N -dimethylformamide (25 mL), added Sodium acetate (0.36 g, 4.36 mmol), react at 120°C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), extracted with ethyl acetate (120 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (20 mL × 3), and anhydrous sodium sulfate Drying, suction filtration and concentration, the resulting residue was recrystallized at 80 °C (ethanol/ethyl acetate/petroleum ether=1/5/8, 35 mL) to obtain a white solid 53f (0.90 g, yield 48%, HPLC purity: 98.11%).

MS (ESI, neg. ion) m/z : 517.9 [MH] ^- ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 13.29 (s, 1H), 8.25 (s, 2H), 8.00 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 5.5 Hz, 2H), 7.30-6.95 (m, 4H), 4.70 (s, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H).

step 7 :synthesis 2-(5-Chloro-6-((2-(4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) pyridine -3- base )-3,5- Dioxo -2,3,4,5- Tetrahydro -1,2,4- Triazine -6- formic acid 53g

2-(5-chloro-6-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pyridine- 3-yl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 53f (0.90 g, 1.73 mmol) dissolved in acetic acid (16 mL), concentrated hydrochloric acid (4 mL) was added, and reacted at 120 °C for 12 hours. The reaction solution was cooled to room temperature, added water (45 mL), stirred for 10 minutes, filtered, rinsed the filter cake with water (10 mL × 2), collected the filter cake and dried to obtain 53 g (0.80 g, yield 86 %).

step 8 :synthesis 2-(5-Chloro-6-((2-(4- Fluorobenzyl )-1- Oxo -1,2,3,4- Tetrahydroisoquinoline -6- base ) Oxygen ) pyridine -3- base )-1,2,4- Triazine -3,5(2 H ,4 H )- diketone 53

2-(5-chloro-6-((2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pyridine- 3-yl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 53g (0.80 g, 1.49 mmol) dissolved in acetic acid (6 mL ), added thiourea (0.57 g, 7.45 mmol), and reacted at 120 °C for 24 hours. The reaction solution was cooled to room temperature, quenched by adding water (25 mL), extracted with ethyl acetate (40 mL × 2), and the combined organic phases were successively washed with water (15 mL × 3) and saturated sodium chloride solution (20 mL × 3) Washing, drying over anhydrous sodium sulfate, suction filtration and concentration, the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain a white solid 53 (0.42 g, yield 57%, HPLC Purity: 99.39%).

MS (ESI, pos. ion) m/z : 494.0 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 12.49 (s, 1H), 8.28 (q, J = 2.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.70 (s , 1H), 7.38 (dd, J = 8.4, 5.5 Hz, 2H), 7.18 (ddd, J = 9.2, 6.8, 2.6 Hz, 4H), 4.70 (s, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H).

Example of activity test

One, the compound of the present invention is opposite to in double luciferase reporter gene experiment TRα or TRβ Agonism assay

experiment material:

HEK293 cells, purchased from ATCC, Cat No. CRL-1573;

Fugene HD transfection reaagent, purchased from Promega, Cat No. E231A;

DMEM, purchased from Gibco, Cat No. 11995;

FBS, purchased from Biosera, Cat No. FB-1280/500;

0.25% Trypsin-EDTA, purchased from Gibco, Cat No. 25200-072;

Dual-Luciferase Reporter Assay System, purchased from Promega, Cat No. E1960;

96-well plate (round bottom), available from Corning, Cat No. 3365.

experiment method:

HEK293 cells were cultured in full medium of 10% FBS+DMEM. Mix pBind-TRα or pBind-TRβ (100 ng/μl), pG5Luc (100 ng/μl), FuGENE HD and Opti-MEM thoroughly, and incubate at room temperature for 15 min, and digest HEK293 cells with 0.25% Trypsin-EDTA Afterwards, resuspend with the whole medium, calculate the cell density, adjust the cell density to 500,000 cells/ml, then add the transcription mixture and mix with the cell suspension, plate in 96-well plate (100 μL/well), 37 ^o C Cultivate for 24 h. After 24 h, the test compound was dissolved in DMSO and diluted 3-fold, a total of 10 concentrations were diluted, and then the compound was diluted with DMEM to a compound solution containing 10% DMSO, and 5 μL of the compound was placed in a 96-well plate. The final concentration of DMSO was 0.5%, and the compounds were co-cultured with the cells for 18 h. After 18 h, the dual-Luciferase Reporter Assay System was used to detect the firefly and renilla fluorescence signals. The F/R ratio was calculated by dividing the firefly fluorescence signal (F) by the Renilla fluorescence signal (R), and the Graph Pad Prism software was used to draw a curve and calculate the EC ₅₀ value.

The test results show that the compound of the present invention has obvious agonistic activity and selectivity to TRβ.

Two, the compounds of the present invention are TRα or TRβ In vitro binding activity assay

experiment material:

LanthaScreen TR-FRET Thyroid Receptor beta Coactivator Assay kit was purchased from Invitrogen, Cat. No. PV4686;

LanthaScreen TR-FRET Thyroid Receptor alfa Coactivator Assay kit was purchased from Invitrogen, Cat. No. PV4687.

experiment method:

The method was experimented with LanthaScreen TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit. The test compound was dissolved in DMSO and diluted 3 times to a total of 10 concentrations, and then diluted with TR-FRET Coregulator Buffer C in the kit to form a compound solution containing 2% DMSO. Take 10 μL of compound solution containing 2% DMSO into a 384-well plate, then add 5 μL of 4 × TR beta/alfa-LBD, 5 μL of a mixture containing 0.4 μM fluorescein-SRC2-2 and 8 nM Tb anti-GST antibody Into each well, mix well, and incubate at room temperature for 1 h in the dark. After 1 h, use BMG LABTECH's PHERAstar FSX microplate reader to read the fluorescence value (RFU) at excitation 520 nm and emission 495 nm. The TR-FRET ratio was calculated by dividing the emission signal at 520 nm by the emission signal at 495 nm. Use Graph Pad Prism 5 software to draw curves and calculate EC ₅₀ values. The in vitro binding activity test results of some of the compounds of the embodiments of the present invention are shown in Table 1 below. [Table 1] In vitro binding activity test results of some compounds of the present invention Example number _EC50 (μM) Example number _EC50 (μM) TRα TRβ TRα TRβ 1 > 100 0.26 31d >100 0.034 2 1.47 0.10 31 0.107 <0.0046 3 0.29 0.026 32d >100 0.054 4 0.21 0.018 32 0.181 0.0046 5 0.074 0.014 33d >100 0.11 7 0.95 0.092 33 0.156 0.017 8 > 100 >10 34 >100 0.021 9 > 100 >10 35d >100 0.080 10 0.206 0.049 35 0.092 <0.0046 12 0.451 0.021 36 0.079 <0.0046 13 0.073 0.013 37 >100 0.043 14 0.226 0.030 38 <0.046 <0.0046 15 0.176 0.024 39 >100 0.472 16 0.211 0.022 40d >100 0.035 17 0.311 0.034 40 0.179 <0.0046 18 >100 0.192 42 >100 0.016 19 >100 0.501 43 >100 0.031 20d >100 0.534 44 >100 0.0097 20 >100 0.012 45 >100 0.061 21d >100 0.368 46 >100 0.035 twenty one >100 0.019 47f >100 0.214 twenty two 0.156 0.011 47 0.161 0.039 twenty three 0.386 0.013 48 0.558 0.065 twenty four >100 0.075 49f >100 0.769 25 >100 0.241 49 >100 0.107 26 7.037 0.476 50f 2.620 0.213 27 >100 0.14 50 0.274 0.12 28g >100 0.128 51 >100 0.904 28 >100 0.017 52 0.23 0.016 29 >100 0.091 30d >100 0.065 30 0.093 0.0062

The test results show that the compound of the present invention has strong binding affinity and selectivity to TRβ.

Three, the pharmacokinetic determination of compound of the present invention

Test purpose: The following method is used to determine the pharmacokinetics of the compounds of the present invention.

experiment material:

Experimental reagents and test items used: Propranolol (propranolol (internal standard)), methanol, ammonium acetate, K ₂ EDTA (potassium ethylenediaminetetraacetic acid), formic acid, acetonitrile, MTBE (methyl tert-butyl ether) , KolliphorHS15 (polyethylene glycol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available;

SD rats: male, 180-220 g, 7-8 weeks old, purchased from Hunan Slack Experimental Animal Co., Ltd.

experiment method:

1. Preparation of the test product

Prepare the test solution according to 5% DMSO + 5% KolliphorHS15 + 90% physiological saline, and adjust it according to the dissolution of each compound so that the compound can be completely dissolved.

2. Design of animal experiments Test substance Example compounds of the present invention animal grouping Intravenous injection/iv: n = 3; blood collection time (hour/h): 0.083, 0.25, 0.5, 1, 2, 5, 7, 24 Oral gavage/ig: n = 3; blood collection time (hour/h): 0.083, 0.25, 0.5, 1, 2, 5, 7, 24 Method of administration Intravenous: intravenous administration of hind limbs; Oral: intragastric administration. blood collection method Tail vein blood sampling blood volume 200 ~ 400 μL/time point anticoagulant K ₂ EDTA plasma preparation All samples were centrifuged at 10,000 rpm, 4 °C for 2 min within 60 min to separate the plasma. Samples were stored at -80 °C until assayed. Backup samples are stored for 1 month after analysis. fasting situation They were fasted for 15 h before administration and had free access to water. Eat 4 h after administration. stock solution Test substance: 20% DMSO; Internal standard: Propranolol aqueous solution (100 ng/mL) data processing Calculation of pharmacokinetic parameters by Win Nonlin 6.1 software non-compartmental model method

3. Animal dosage form group gender number of animals Dosage Dosing concentration Dosing volume Intravenous injection iv male 3 1 mg/kg 1 mg/mL 1 mL/kg gavage ig male 3 5mg/kg 1 mg/mL 5 mL/kg

4. Solution preparation

(1) Configuration of the stock solution of the test product: Accurately weigh an appropriate amount of the test product, dissolve it in DMSO, dilute it to 1 mg/mL with acetonitrile, and shake well. Store at -20 °C until use.

(2) Preparation of internal standard solution: Precisely draw a certain amount of 1 mg/mL Propranolol stock solution and dilute it to 100 ng/mL with water.

5. Sample analysis

Samples were processed by liquid-liquid extraction, chromatographically separated, quantitatively analyzed by multiple reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer, and the concentration of the results was calculated using the quantitative software of the instrument.

6. Plasma sample pretreatment

Precisely pipette 30 μL of plasma sample, add 250 μL of internal standard, and vortex to mix evenly. Extract once with 1 mL of MTBE, centrifuge at 13,000 rpm for 2 min at 4 °C, absorb 800 μL of the supernatant, evaporate to dryness in a 96-well nitrogen blower, and wash the residue with 150 μL of methanol/water (v/v = 50 /50) to reconstitute, vortex to mix, and inject the sample with an injection volume of 8 μL.

7. Preparation of standard samples

Accurately draw an appropriate amount of compound stock solution, add acetonitrile to dilute to make a standard series solution. Accurately draw 20 μL of each of the above standard series solutions, add 180 μL of blank plasma, vortex and mix well, and prepare the corresponding plasma concentrations of 3, 5, 10, 30, 100, 300, 1,000, 3,000, 5,000 and 10,000 ng/ The plasma samples in mL were operated according to the "plasma sample pretreatment", and double-sample analysis was performed for each concentration to establish a standard curve.

8. Analysis method

LC/MS/MS method was used to determine the content of the test compound in rat plasma after administration of different compounds.

9. Data processing

Using WinNonlin 6.1 software, non-compartmental model method to calculate pharmacokinetic parameters.

The pharmacokinetic test results of some of the compounds of the embodiments of the present invention are shown in Table 2 below. [Table 2] Pharmacokinetic test results of the compounds of some embodiments of the present invention Example number way Dose (mg/kg) C _max (ng/ml) AUC _last (h*ng/ml) AUC _INF (h*ng/ml) T _1/2 (h) Cl (ml/min/kg) Vss (L/kg) F (%) 20 iv 1 3990 16300 16400 3.16 1.01 0.251 —— ig 5 10400 93700 94400 3.57 —— —— 115.1 twenty one iv 1 2760 1020 1020 1.02 16.3 0.308 —— ig 5 4730 4160 4180 1.44 —— —— 81.9 twenty four iv 1 4020 3720 3790 1.16 4.39 0.337 —— ig 5 7790 21900 223000 2.65 —— —— 117.7 28 iv 1 8400 8730 9640 2.91 1.73 0.246 —— ig 5 15500 47000 47000 2.29 —— —— 97.6 29 iv 1 4270 48700 56000 8.47 0.297 0.194 —— ig 5 10300 159000 236000 14.1 —— —— 66.2 34 iv 1 3020 18800 22400 9.87 0.744 0.531 —— ig 5 8460 110000 124000 7.67 —— —— 111 37 iv 1 4200 20900 21100 3.61 0.789 0.212 —— ig 5 12300 121000 122000 3.5 —— —— 116.3 42 iv 1 4340 1860 1960 2.97 8.49 0.658 ——— ig 5 7700 12700 13200 2.53 —— —— 134.8 43 iv 1 3410 39800 47700 9.52 0.349 0.26 ——— ig 5 8120 134000 212000 15.7 —— —— 68.4 44 iv 1 5430 2110 2150 2.11 7.74 0.4 —— ig 5 9030 13900 14300 1.64 —— —— 133.3 45 iv 1 1780 2460 2510 1.15 6.65 0.57 —— ig 5 5320 20300 20600 4.14 —— —— 163.9 46 iv 1 4160 9810 10000 4.24 1.66 0.424 —— ig 5 6410 61900 633000 5.93 —— —— 126.5 49 iv 1 5300 3580 3730 1.14 4.46 0.306 —— ig 5 9680 25300 25800 3.63 —— —— 138.3

The test results show that the compounds of the embodiments of the present invention exhibit excellent pharmacokinetic properties when administered intravenously or orally orally.

Four, the pharmacodynamic evaluation of the compound of the present invention

experiment material:

Western diet: purchased from Research diet, item number: D12079B;

MCD diet: purchased from Nantong Trofe Feed Technology Co., Ltd., item number: TP3006R;

ALT, AST, ALP, TG, CHO, HDL, LDL and GLU: available from Roche, catalog numbers: 20764957322, 20764949322, 03333701190, 20767107322, 03039773190, 04399803190, 03038866322 and 04404 483190;

8-week-old male OB/OB mice: purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.;

8-week-old male db/db mice: purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

A , compound in Western diet diet-induced OB/OB mousenon-alcoholic steatohepatitis (NASH) Pharmacodynamic evaluation in models

OB/OB mice are leptin gene-deficient mice, and the NASH model of OB/OB mice induced by Western diet is a commonly used NASH in vivo drug efficacy evaluation model. Animals were acclimated to the experiment for 1 week. OB/OB mice were fed with Western diet, and the feed was changed three times a week (Monday, Wednesday, and Friday). The mice were given medicine at the fifth week after feeding, and were administered orally once a day for 6 weeks. The entire experimental period for 10 weeks. During the experiment, the basic situation of the animals was monitored every day, and the body weight of the mice was recorded once a week. After the end of the experiment, the mice were fasted overnight, and the mice were anesthetized, and the whole blood was collected from the orbit, centrifuged at 4,000 rpm for 10 min at 4°C to obtain serum, and stored at -80°C. Serum was used for detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. Mice were dissected and livers were removed and weighed. The middle lobe of the liver was stored in an EP tube at -80 °C for the determination of the contents of TG and CHO in the liver. The left lobe of the liver was fixed in 10% formalin, stained with HE, and scored with NAS.

B , compound in MCD diet-induced db /db mousenon-alcoholic steatohepatitis (NASH) Pharmacodynamic evaluation in models

db/db mice are leptin receptor gene-deficient mice, and the NASH model of db/db mice induced by MCD diet is a commonly used NASH in vivo drug efficacy evaluation model. Animals were acclimated to the experiment for 1 week. The db/db mice were fed with MCD feed, and the feed was changed three times a week (Monday, Wednesday, Friday). The mice were administered while modeling and administered orally once a day for 8 weeks. The whole experimental period is 8 weeks. During the experiment, the basic situation of the animals was monitored every day, and the body weight of the mice was recorded once a week. After the experiment, the mice were fasted overnight, the mice were anesthetized, and the whole blood was collected from the eye sockets, centrifuged at 4,000 rpm for 10 min at 4 °C to obtain serum, and stored at -80 °C. Serum was used for detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. Mice were dissected and livers were removed and weighed. The middle lobe of the liver was stored in an EP tube at -80 °C for the determination of the contents of TG and CHO in the liver. The left lobe of the liver was fixed in 10% formalin, stained with HE, and scored with NAS.

The test results show that the compound of the invention can effectively reduce fat accumulation in the liver, relieve inflammation, and improve liver fibrosis.

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", or "some examples" mean that specific features described in connection with the embodiment or example , structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

Claims (16)

A compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salts or their prodrugs, (I) Among them, Y is -O-, -S-, -NR ⁰ -, -C(=O)-, C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene Base, -NR ⁰ C(=O)- or -C(=O)NR ⁰ -; wherein said Y is optionally substituted by 1, 2 or 3 R ^x ; R ⁰ is H, deuterium, C _{1 -6} alkyl, C _{1-6 haloalkyl} , hydroxy C _1-6 alkyl, amino C _1-6 alkyl or cyano C _1-6 alkyl; R ^3a , R ^3b , R ^3c and R ^3d each independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, C _1-6 alkyl, C _1-6 alkoxy , C _1-6 alkylthio, C 1-6 alkylamino, C _{1-6 haloalkyl} , C _{1-6 haloalkoxy} , hydroxy C _1-6 alkyl, amino C _1-6 alkyl or cyano C _1-6 alkyl group; R ¹ is H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C(=O)-C _1-6 alkoxy, -C(=O)-C _1-6 alkyl, -C(=O)- C _1-6 alkylamino, -C(=O)NH ₂ , -S(=O) ₂ -C _1-6 alkyl, -S(=O) ₂ -C _1-6 alkylamino, -S(= O) ₂ NH ₂ , C _1-6 alkylamino, C _1-6 alkoxy, C _{1-6 haloalkyl} , C _{1-6 haloalkoxy} , hydroxy C _1-6 alkyl, amino C _{1- 6} alkyl, carboxyl C _1-6 alkyl or cyano C _1-6 alkyl; R ² is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, C _6-10 aryl group or heteroaryl group composed of 5-6 atoms; Ring A is , , or ; wherein Ring A is optionally substituted by 1, 2 or 3 R ^y ; E ₁ , U ₁ and Z ₁ are each independently -(CR ^4a R ^4b ) _q -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O) ₂ - or -NR ^a -; E ₂ , U ₂ and Z ₂ are each independently -CR ^4c R ^4d -, - C(=O)-, -O-, -S-, -S(=O)-, -S(=O) ₂ - or -NR ^b -; E ₃ , E ₆ , U ₃ and Z ₃ are each independently ground is -CR ^4e R ^4f -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O) ₂ - or -NR ^c -; E ₄ is -CR ^4g = or -N=; E ₅ is -CR ^4h = or -N=; q is 0, 1, 2 or 3; R ^a , R ^b , R ^c and R ⁵ are each independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1-6 haloalkyl} , C _3-6 cycloalkyl, heterocyclic group consisting of 5-6 atoms, C _6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein said R ^a , R ^b , R ^c and R ⁵ are independently and optionally substituted by 1, 2 or 3 R ^y1 ; R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^4g and R ^4h are each independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, - NH ₂ , -SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl , C _{1-6 haloalkoxy} , C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, heterocyclic group consisting of 5-6 atoms, (5-6 atoms Heterocyclyl)-C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, heteroaryl consisting of 5-6 atoms or (5 -Heteroaryl)-C _1-4 alkylene consisting of 6 atoms, wherein said R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^4g and R ^4h are independently optionally 1, 2 or 3 R ^y2 substituted; or R ^4a , R ^4b and the carbon atoms connected to them together form a C _3-8 carbon ring or a heterocyclic ring composed of 5-6 atoms, or R ^4c , R ^4d and Together with the carbon atoms connected to them, they form a C _3-8 carbon ring or a heterocyclic ring composed of 5-6 atoms, or R ^4e , R ^4f and the carbon atoms connected to them form a C _3-8 carbon ring or a 5-6 A heterocyclic ring composed of atoms, wherein the C _3-8 carbon ring and the heterocyclic ring composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y3 ; each R ^x is independently Deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _{1-6 haloalkoxy} , C _1-6 alkane Oxygen or C _1-6 alkylamino; each R ^y is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 haloalkane group, C _{1-6 haloalkoxy} , C _1-6 alkoxy or C _1-6 alkylamino; or two R ^y connected to adjacent atoms and the atoms connected to them together form C _3-8 carbon A ring or a heterocyclic ring consisting of 5-6 atoms, wherein the C _3-8 carbocyclic ring and the heterocyclic ring consisting of 5-6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 ^Ry4 ; Each R ^y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -SH, oxo, -OC(=O)-C _1-6 alkyl, -C(= O)-C _1-6 alkoxy, -C(=O)-C _1-6 alkyl, -C(=O)-C _1-6 alkylamino, -C(=O)NH ₂ , -S (=O) ₂ -C _1-6 alkyl, -S(=O) ₂ -C _1-6 alkylamino, -S(=O) ₂ NH ₂ , C _1-6 alkyl, C _{1-6 halogen Substituted} alkyl, C _{1-6 haloalkoxy} , C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _3-6 cycloalkyl, 5-6 atoms Heterocyclic group, C _6-10 aryl group or heteroaryl group consisting of 5-6 atoms, wherein each R ^y1 is independently and optionally substituted by 1, 2 or 3 R ^z ; R ^z , R ^y2 , R ^y3 and R ^y4 are each independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -COOH, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6 haloalkoxy} , C _1-6 alkoxy, C _1-6 alkylthio or C _1-6 alkylamino. The compound according to claim 1, wherein each of R ^3a , R ^3b , R ^3c and R ^3d is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF ₃ , -CHF ₂ , -CH ₂ F, _-CH2CF3 , _-CH2CHF2 , _-OCF3 , _-OCHF2 , _-OCH2F , _{hydroxymethyl} , _aminomethyl or cyanomethyl. The compound according to claim 1 or 2, wherein the R ¹ is H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, Methyl, ethyl, n-propyl, isopropyl, -CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, -C(=O)-OCH ₃ , - C(=O)-OCH ₂ CH ₃ , -C(=O)-OCH(CH ₃ ) ₂ , -C(=O)-OCH ₂ CH ₂ CH ₃ , -C(=O)-O(CH ₂ ) ₃ CH ₃ , -C(=O)-OCH ₂ CH(CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)- NHCH ₃ , -C(=O)-N(CH ₃ ) ₂ , -C(=O)NH ₂ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -CH ₂ CH ₃ , -S(=O) ₂ -NHCH ₃ , -S(=O) ₂ NH ₂ , methylamino, ethylamino, methoxy, ethoxy, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl. The compound as claimed in claim 1, wherein each of R ^a , R ^b , R ^c and R ⁵ is independently H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl, C _{1-4 haloalkyl} , C _3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C _6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein Said R ^a , R ^b , R ^c and R ⁵ are independently optionally substituted with 1, 2 or 3 R ^y1 . The compound according to claim 1 or 4, wherein each of R ^a , R ^b , R ^c and R ⁵ is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl group, t-butyl group, -CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholine Base, thiomorpholinyl, piperazinyl, phenyl, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl or oxazolyl, wherein, the R ^a , R ^b , R ^c and R ⁵ are independently optionally substituted with 1, 2 or 3 R ^y1 . The compound as claimed in claim 1, wherein each R ^y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -SH, oxo, -OC(=O )-C _1-4 alkyl, -C(=O)-C _1-4 alkoxy, -C(=O)-C _1-4 alkyl, -C(=O)-C _1-4 alkane Amino, -C(=O)NH ₂ , -S(=O) ₂ -C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkylamino, -S(=O) ₂ NH ₂ , C _1-4 alkyl, C _{1-4 haloalkyl} , C _{1-4 haloalkoxy} , C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _{3 -6} cycloalkyl, heterocyclyl consisting of 5-6 atoms, C _6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein each R ^y1 is independently and optionally replaced by 1, 2 or 3 R ^z replaced. The compound as claimed in claim 1 or 6, wherein each R ^y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -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)NH ₂ , -S(=O) ₂ -C _1-3 alkyl, -S(=O) ₂ -C _1-3 alkylamino, -S(=O) ₂ NH ₂ , methyl , ethyl, n-propyl, isopropyl, tert-butyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , - OCH ₂ F, -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCHFCH ₃ , methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, ethylthio, methylamino, ethyl Amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thio Morpholinyl, piperazinyl, phenyl, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl or oxazolyl, wherein each R ^y1 are independently optionally substituted with 1, 2 or 3 ^Rz . The compound as claimed in claim 1, wherein each of R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^4g and R ^4h is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂ , -COOH, -OH, -NH ₂ , -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH=CHCH ₃ , -C≡CH, methoxy, ethoxy, methylamino, ethylamino, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF _3. -CH ₂ CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH ₂ -, cyclobutyl-CH ₂ -, cyclopentyl-CH ₂ -, cyclohexyl-CH ₂ -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine Base, pyrrolidinyl-CH ₂ -, pyrazolidinyl-CH ₂ -, tetrahydrofuranyl-CH ₂ -, tetrahydrothiophenyl-CH ₂ -, piperidinyl-CH ₂ -, morpholinyl-CH ₂ - , thiomorpholinyl-CH ₂ -, piperazinyl-CH ₂ -, phenyl, phenyl-CH ₂ -, phenyl-CH ₂ CH ₂ -, furyl, thienyl, imidazolyl, pyrimidinyl, Pyridyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH ₂ -, thienyl-CH ₂ -, imidazolyl-CH ₂ -, pyrimidinyl-CH ₂ -, pyridine -CH ₂ - or pyrrolyl -CH ₂ -, wherein said R ^4a , R ^4b , R ^4c , R ^4d , R ^4e , R ^4f , R ^4g and R ^4h are independently optionally replaced by 1, 2 or 3 R ^y2 is substituted; or R ^4a , R ^4b and the carbon atoms connected to them form a C _3-6 carbon ring or a heterocyclic ring composed of 5-6 atoms, or R ^4c , R ^4d and the carbon atoms connected to them Together form a C _3-6 carbon ring or a heterocyclic ring composed of 5-6 atoms, or R ^4e , R ^4f and the carbon atoms connected to them form a C _3-6 carbon ring or a heterocyclic ring composed of 5-6 atoms , wherein the C _3-6 carbocycle and the heterocycle composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 R ^y3 . The compound as claimed in claim 1, wherein said R ^z , R ^y2 , R ^y3 and R ^y4 are each independently deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂ , -COOH , methyl, ethyl, n-propyl, isopropyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, methoxy, ethoxy or methyl Amino. The compound as described in claim 1, which has one of the following structures: (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20d), (20), (21d), (twenty one), (twenty two), (twenty three), (24d), (twenty four), (25d), (25), (26), (27), (28g), (28), (29d), (29), (30d), (30), (31d), (31), (32d), (32), (33d), (33), (34d), (34), (35d), (35), (36), (37d), (37), (38), (39), (40d), (40), (41d), (41), (42), (43d), (43), (44), (45), (46), (47f), (47), (48), (49f), (49), (50f), (50), (51), (52), (53) (54), (55), (56), (57), (58), (59), (60), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (72), (73), (74), (75), (76); or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. A pharmaceutical composition comprising the compound as described in any one of claims 1 to 10, optionally, further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or their any combination of . A use of the compound as described in any one of claims 1 to 10 or the pharmaceutical composition as described in claim 11 in the preparation of medicines, wherein the medicines are used to stimulate thyroid hormone receptors; or to prevent , Treat or alleviate diseases regulated by thyroid hormone receptors. The use according to claim 12, wherein the thyroid hormone receptor is thyroid hormone β receptor. The use according to claim 12, wherein the diseases regulated by thyroid hormone receptors are neurodegenerative diseases, non-alcoholic fatty liver disease, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, high Blood pressure, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer. A use of the compound as described in any one of claims 1 to 10 or the pharmaceutical composition as described in claim 11 in the preparation of medicines, wherein the medicines are used to prevent, treat or alleviate the following diseases: neurodegeneration disease, nonalcoholic fatty liver disease, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, blood lipids Abnormalities, obesity, diabetes mellitus, metabolic disorder, lipid disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer. The use according to claim 14 or 15, wherein the nonalcoholic fatty liver disease is nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease-associated cryptogenic cirrhosis or primary liver cancer; The neurodegenerative disease is demyelinating disease, chronic demyelinating disease, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenal dystrophy Alzheimer's disease, amyotrophic lateral sclerosis, or Alzheimer's disease.