WO2025162405A1 - Phenol derivative and pharmaceutical use thereof - Google Patents

Abstract

Disclosed in the present invention are a phenol derivative, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. The phenol derivative has a structure as shown in formula (I), wherein the definitions of X, R1-R5, Z, and Z1 are detailed in the description. In addition, further disclosed in the present invention are a pharmaceutical composition containing the phenol derivative, the isomer thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt thereof, and the use of the pharmaceutical composition in the preparation of a drug for treating diseases related to THR-β agonistic activity.

Description

Phenol derivatives and their medical uses Technical Field

The present invention relates to a phenol derivative, an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the phenol derivative, the isomer thereof, the deuterated product thereof or a pharmaceutically acceptable salt thereof, and use of the pharmaceutical composition in preparing a drug for treating a disease associated with THR-β agonist activity.

Background Art

Thyroid hormone (TH) is synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland. Thyroid hormone plays a very important role in regulating body growth, development, metabolism and matrix balance. There are two main types of thyroid hormones, 3,5,3'-triiodo-L-thyroxine (T3) and thyroxine (T4). The human body mainly secretes T4, and in peripheral organs, T4 is converted into more active T3 by deiodinase. T3 and T4 produced by the thyroid gland are under negative feedback control, and thyroid-stimulating hormone (TSH) is responsible for normal thyroid function and thyroid hormone secretion. TSH is synthesized in the anterior pituitary gland, and its secretion is controlled by thyroid-releasing hormone (TRH) synthesized in the hypothalamus.

Thyroid hormones exert their functions by binding to thyroid hormone receptors (THRs). THRs belong to a large family of nuclear receptors that regulate the expression of target genes. There are two distinct subtypes of thyroid hormone receptors: THRα and THRβ. THRα is primarily found in heart tissue and plays a crucial role in regulating cardiac function. The THRβ subtype is primarily expressed in the liver and pituitary gland, regulating cholesterol metabolism and thyroid-stimulating hormone secretion.

At normal levels, thyroid hormone (TH) maintains body weight, metabolic rate, body temperature, mood, and regulates serum cholesterol. Thyroid hormones have been used to regulate serum cholesterol. However, the cardiac side effects of natural thyroid hormones preclude their use for the treatment of high cholesterol and obesity. Animal studies with selective knockout of the THR gene, as well as studies of selective THR ligands, suggest that these cardiac side effects of thyroid hormones can be attributed to THRα.

The thyroid hormone receptor pathway regulates lipid metabolism, including cholesterol, triglycerides, and lipoproteins. Clinically, it has been shown that lowering low-density cholesterol will reduce the incidence of cardiovascular and cerebrovascular diseases. The therapeutic use of thyroid hormone itself is limited by adverse side effects associated with hyperthyroidism, especially cardiovascular toxicity. A thyroid hormone analogue, if it can avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormone, may be used to treat responsive diseases, such as metabolic diseases including obesity, hyperlipidemia, hypercholesterolemia, diabetes and other conditions such as liver steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, etc.

Nonalcoholic fatty liver disease (NAFLD) is also a type of metabolic disorder caused by excessive accumulation of triglycerides in the liver, which can further damage liver cells and trigger inflammation, leading to nonalcoholic fatty liver disease (NASH). NASH patients are usually also accompanied by type 2 diabetes, high cholesterol, high blood lipids and obesity. NASH patients have a higher probability of developing cirrhosis, liver failure, and eventually liver cancer. There is currently a lack of effective drugs to treat NASH. The function of thyroid hormones in regulating lipid metabolism makes the thyroid receptor pathway a potential target for the treatment of NASH and NAFLD. It has been confirmed in animals that thyroid hormone analogs can significantly reduce the level of liver fat in animals.

Selective THRβ agonists can be used to circumvent the cardiac side effects of conventional THR receptor agonists, selectively activating only THRβ, improving cellular lipid metabolism, and exerting cholesterol and blood lipid lowering functions. However, selective THRβ agonists may also inhibit the thyroid axis, leading to side effects such as depression, fatigue, and osteoporosis. Therefore, it is necessary to develop a selective THRβ agonist that activates THRβ but reduces the inhibitory effect on the thyroid axis, thereby circumventing the side effects associated with thyroid axis inhibition.

Patents such as WO03094845, WO2007009913, WO2010122980, and WO2011038207 disclose several THR receptor agonists, all of which are designed and developed based on the natural THR receptor ligand, T3. Given this background, there remains a need to develop selective THRβ receptor agonists that possess the beneficial therapeutic effects of thyroid hormones while avoiding the adverse cardiac side effects.

This invention also involves structural modification of T3, the natural ligand for the THR receptor. After prodrug modification, some of the compounds described herein are highly enriched in the liver, a target organ, further reducing their distribution in the heart, thereby potentially reducing clinical side effects. Furthermore, the inventors unexpectedly discovered that some of the modified compounds retain good THRβ receptor agonist or binding activity, and the compounds of this invention have enhanced selectivity for THRα.

Summary of the Invention

In response to the shortcomings of the prior art, the present invention provides a phenol derivative, its isomer, its deuterated form, or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising the phenol derivative, its isomer, its deuterated form, or a pharmaceutically acceptable salt thereof, and the use of the pharmaceutical composition in the treatment of diseases associated with THR-β agonist activity.

According to the first aspect of the present invention, there is provided a phenol derivative, an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, wherein the phenol derivative has a structure represented by formula (I):

in:

X is -CH ₂ -, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -O(CH ₂ ) _n -, -S(CH ₂ ) _n -, -(CH ₂ ) _n NH-, -NH(CH ₂ ) _n -;

R ¹ and R ² are each independently hydrogen, halogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₆ alkoxy, and may be arbitrarily substituted by halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, or C ₃ -C ₇ cycloalkoxy;

Z and ^Z1 are each independently -O- or -NH-;

R ³ and R ⁴ are each independently hydrogen, C ₁ -C ₈ alkyl, unsubstituted phenyl, phenyl substituted with at least one substituent selected from halogen, phenyl, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, unsubstituted naphthyl, -CH ₂ OC(O)-R ⁶ , or -C(RR ⁰ )C(O)OR ⁷ ;

R ³ , R ⁴ and the -ZP(O)-Z ¹ - connected thereto form the following six-membered ring:

Wherein: R ⁸ is a 5-10 membered aryl group, which may be substituted by at least one substituent selected from halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, and C ₁ -C ₆ alkoxy; a 5-10 membered heteroaryl group containing one or two heteroatoms selected from N, S, and O may be substituted by at least one substituent selected from halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, and C ₁ -C ₆ alkoxy;

R ⁵ is hydrogen, halogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl;

R ⁶ and R ⁷ are each independently hydrogen or C ₁ -C ₈ alkyl;

R and R ⁰ are each independently hydrogen, C ₁ -C ₈ alkyl, which may be substituted by halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, aryl, or optionally substituted aryl;

Het is selected from a 5-12 membered aromatic ring, a naphthalene ring, a thiophene ring, a pyrrole ring, a 5-12 membered aromatic heterocycle, a 5-12 membered heteroaromatic ring, and includes the following groups:

Het may be arbitrarily substituted by -C(=O)NR ¹⁶ R ¹⁷ , halogen, -CN, -NO ₂ , C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, -C ₁ -C ₈ alkyl, or C ₁ -C ₆ alkoxy;

^R9 and ^R10 are each independently hydrogen, _C1 - _C8 alkyl, _C3 - _C7 cycloalkyl, heterocycle, or aryl; ^R9 and ^R10 , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, which may be arbitrarily substituted by deuterium, halogen, _C1 - _C6 alkyl, halogenated _C1 - _C6 alkyl, _C3 - _C7 cycloalkyl, _C1 - _C6 alkoxy, heterocycle, or aryl;

R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁵ are each independently hydrogen, deuterium, -C ₁ -C ₈ alkyl, or C ₃ -C ₇ cycloalkyl;

R ¹⁶ and R ¹⁷ are each independently hydrogen, -C ₁ -C ₈ alkyl, or C ₃ -C ₇ cycloalkyl;

Z ² , Z ³ , and Z ^3′ are each independently —N— or —CH—;

n is 0, 1, 2, or 3.

According to one embodiment of the present invention, the phenol derivative includes the following structure:

(4-(3-Fluoro-4-hydroxy-5-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)phosphonic acid;

(4-(4-Hydroxy-3-isopropylbenzyl)-2,3,5-trimethylphenoxy)methyl)phosphonic acid;

(2R,4S)-4-(3-chlorophenyl)-2-((4-(4-hydroxy-3-isopropylbenzyl)-2,3,5-trimethylphenoxy)methyl)-1,3,2-dioxaphosphine-2-oxide;

(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphonic acid;

6-(2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)phenoxy)-4-isopropylpyridazin-3(2H)-one;

6-(2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)phenoxy)-4-isopropylpyridazin-3(2H)-one;

(3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphonic acid;

6-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one;

6-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one;

(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)methylphosphonic acid;

6-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-4-isopropylpyridazin-3(2H)-one;

6-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-4-isopropylpyridazin-3(2H)-one;

(4-((5-Isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dimethylphenoxy)methyl)phosphonic acid;

6-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropylpyridazin-3(2H)-one;

6-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropylpyridazin-3(2H)-one;

(4-((5-Isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dimethylphenoxy)methyl)phosphonic acid;

6-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one;

6-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one;

(4-(5-Isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenoxy)methylphosphonic acid;

6-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one;

6-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one;

(3,5-Dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid;

4-(2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)phthalazin-1(2H)-one;

4-(2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)phthalazin-1(2H)-one;

(3,5-Dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid;

4-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)phthalazin-1(2H)-one;

4-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)phthalazin-1(2H)-one;

(3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid;

4-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-2-methylphthalazin-1(2H)-one;

4-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-2-methylphthalazin-1(2H)-one;

(3,5-Dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid;

4-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-2-methylphthalazin-1(2H)-one;

4-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-2-methylphthalazin-1(2H)-one;

(3,5-Dichloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid;

4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dichlorobenzyl)phthalazin-1(2H)-one;

4-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dichlorobenzyl)phthalazin-1(2H)-one;

(3,5-Dichloro-4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid;

4-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-2-methylphthalazin-1(2H)-one;

4-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-2-methylphthalazin-1(2H)-one;

(3,5-Dimethyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid;

4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)phthalazin-1(2H)-one;

4-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)phthalazin-1(2H)-one;

(3,5-Dichloro-4-((4-methylquinolin-7-yl)oxy)phenoxy)methyl)phosphonic acid;

(2R,4S)-4-(3-chlorophenyl)-2-(3,5-dichloro-4-((4-methylquinolin-7-yl)oxy)phenoxy)methyl)-1,3,2-dioxaphosphine-2-oxide;

2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)benzamide;

2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)benzamide;

2-((4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)benzamide;

2-((4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)benzamide;

2-((4-((((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)-N-methylbenzamide;

2-((4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)-N-(methyl-d3)benzamide;

2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide;

2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide;

2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-N-methyl-5-(trifluoromethyl)benzamide;

5-cyclopropyl-2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide;

2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N,5-dimethylbenzamide;

2-((2,6-dibromo-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide;

2-((2,6-dibromo-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N,5-dimethylbenzamide;

2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-5-fluorobenzamide;

2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-5-methylbenzamide;

5-cyclohexyl-2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide;

5-cyclohexyl-2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide;

5-cyclohexyl-2-((2,6-dibromo-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide;

4-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxamide; or

4-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxamide.

According to a second aspect of the present invention, a pharmaceutical composition is provided, comprising the phenol derivative according to claim 1 or 2, its isomer, its deuterated product or a pharmaceutically acceptable salt thereof.

According to a third aspect of the present invention, there is provided a pharmaceutical composition as described above, for use in the preparation of a medicament for treating THRβ-related diseases, wherein the disease is selected from the group consisting of at least one of the following: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.

According to a fourth aspect of the present invention, a phenol derivative, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof is provided, wherein the phenol derivative has a structure represented by formula (II):

in:

Het ¹ is selected from a 5-12 membered aromatic ring, a naphthalene ring, a thiophene ring, a pyrrole ring, a 5-12 membered aromatic heterocycle, a 5-12 membered heterocyclic aromatic ring, and includes the following groups:

Het ¹ may be arbitrarily substituted by -C(=O)NR ²⁹ R ³⁰ , halogen, -CN, -NO ₂ , C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, -C ₁ -C ₈ alkyl, or C ₁ -C ₆ alkoxy;

X ¹ is -CH ₂ -, -(CH ₂ ) _m O-, -(CH ₂ ) _m S-, -O(CH ₂ ) _m -, -S(CH ₂ ) _m -, -(CH ₂ ) _m NH-, -NH(CH ₂ ) _m -;

Z ⁴ , Z ⁵ , and Z ⁶ are each independently -CH- or -N-;

R ¹⁸ and R ¹⁹ are each independently hydrogen, halogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₆ alkoxy, and may be arbitrarily substituted by halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, or C ₃ -C ₇ cycloalkoxy;

R ²⁰ and R ²¹ are each independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, heterocycle, or aryl; R ²⁰ and R ²¹ , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, which may be arbitrarily substituted by deuterium, halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, heterocycle, or aryl;

R ²² and R ²³ are each independently hydrogen, deuterium, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, heterocycle, or aryl; R ²² and R ²³ , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, and may be arbitrarily substituted with halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, heterocycle, or aryl;

R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are each independently hydrogen, deuterium, C ₁ -C ₈ alkyl, or C ₃ -C ₇ cycloalkyl;

R ²⁹ and R ³⁰ are each independently hydrogen, -C ₁ -C ₈ alkyl, or C ₃ -C ₇ cycloalkyl;

Q includes the following groups:

R ³¹ and R ³² are each independently hydrogen, halogen, -NH ₂ , cyano, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₆ alkoxy, and may be arbitrarily substituted by halogen, C ₁ -C ₆ alkyl, or C ₃ -C ₇ cycloalkyl;

Z ⁷ and Z ⁸ are each independently -CH- or -N-;

m is 0, 1, 2, or 3.

According to one embodiment of the present invention, the phenol derivative includes the following structure:

2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

N-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

N-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

N-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide;

6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((7,7-dimethyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[d]pyridazin-4-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione;

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

2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile; or

2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.

According to a fifth aspect of the present invention, a pharmaceutical composition is provided, comprising the phenol derivatives, isomers thereof, deuterated derivatives thereof or pharmaceutically acceptable salts thereof as described above.

According to the sixth aspect of the present invention, according to the pharmaceutical composition as described above, the use in the preparation of a medicament for treating THRβ-related diseases, the disease is selected from the group consisting of at least one of the following: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.

DETAILED DESCRIPTION

The feasibility of the present invention is illustrated below by using embodiments. Those skilled in the art should understand that according to the teachings of the prior art, modifications or replacements of corresponding technical features still fall within the scope of protection claimed by the present invention.

The term "alkyl" refers to groups such as, but not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

The term "aryl" refers to an aromatic system, which can be a single ring or multiple aromatic rings that are fused or linked together so that at least a portion of the fused or linked rings form a conjugated aromatic system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and tetrahydronaphthyl. Aryl groups can be optionally substituted, such as aryl or heterocycle substituted with one to four groups selected from the group consisting of halogen, -CN, -OH, _-NO₂ , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxyl, alkylamino, or arylthio.

The term "substituted" means that the referenced group may be substituted with one or more additional groups, wherein the additional groups are individually and independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, carbonyl, thiocarbonyl, nitro, haloalkyl, fluoroalkyl and amino, including mono- and di-substituted amino groups and protected derivatives thereof.

The term "halogen" means chlorine, fluorine, bromine or iodine. The term "halo" means chloro, fluoro, bromo or iodo. The term "haloalkyl" means an alkyl group as defined above which is substituted by one or more halogen atoms.

The term "pharmaceutically acceptable salt" means that the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc.; or with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-p-toluenesulfonic acid, camphoric acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid and cis-dienedioic acid, etc.; or (2) base addition salts, compounds of the present invention, if containing an acidic group, can react with an organic base or an inorganic base to prepare a corresponding base addition salt, such as an alkali metal base, an alkaline earth metal base, ammonia or an amine, including but not limited to Na ⁺ , K ⁺ , Li ⁺ , Mg+, etc. ²⁺ , Ca ²⁺ .

The present invention provides a drug comprising a derivative, isomer, deuterated product, or pharmaceutically acceptable salt thereof of the structure of formula (I) of the present invention as an active ingredient. The drug may further contain one or more carriers, including conventional diluents, binders, excipients, fillers, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, and the like, and, if necessary, flavoring agents, sweeteners, and the like. The drug of the present invention can be prepared in various forms, including tablets, powders, granules, capsules, oral solutions, and injections. Each of these dosage forms can be prepared according to conventional methods in the pharmaceutical field.

The present invention provides a drug comprising a derivative, isomer, deuterated form thereof, or pharmaceutically acceptable salt thereof of the structure represented by formula (II) as an active ingredient. The drug may further comprise one or more carriers, including conventional pharmaceutical diluents, binders, excipients, fillers, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, and the like. Flavoring agents, sweeteners, and the like may also be added, if necessary. The drug can be prepared in various forms, including tablets, powders, granules, capsules, oral solutions, and injections. Each of these dosage forms can be prepared according to conventional pharmaceutical methods.

The present invention provides a derivative of the structure of formula (I), an isomer, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, for use in preparing a medicament for treating THRβ-related diseases, wherein the disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.

The present invention provides a derivative of the structure of formula (II), an isomer, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, for use in preparing a medicament for treating THRβ-related diseases, wherein the disease is selected from the group consisting of: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.

Example 1, (4-(3-fluoro-4-hydroxy-5-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)phosphonic acid

Step 1: 4-Bromo-2-isopropyl-1-(methoxymethoxy)benzene

Dissolve 20 g of 4-bromo-2-fluoro-6-isopropylphenol in 100 mL of DMF, cool to 0-5°C, add 4.8 g of 60% NaH in portions, stir for 20 min, then add 8 g of bromomethyl methyl ether (MOMBr) dropwise. After completion, react at room temperature for 2 h. TLC monitoring indicates completion of the reaction. Quench the reaction by adding 100 mL of water, then extract with 100 mL of ethyl acetate. Reduce the organic phase to dryness under reduced pressure to obtain 20.0 g of the target compound as an oil.

Step 2: 2,6-Dimethyl-4-((triisopropylsilyl)oxy)benzaldehyde

Dissolve 50 g of 4-hydroxy-2,6-dimethylbenzaldehyde, 37.3 g of triethylamine, and 2.2 g of DMAP in 200 mL of THF. Cool to 0-10°C and add 57.0 g of triisopropylsilyl chloride (TIPSC1) dropwise. Stir at room temperature for 2 h. Monitor the reaction by TLC until complete. Add 200 mL of water and 200 mL of dichloromethane, extract, and reduce the organic phase to dryness under reduced pressure to obtain 70 g of the title compound as an oil.

Step 3: (2,6-Dimethyl-4-((triisopropylsilyl)oxy)phenyl)(3-fluoro-5-isopropyl-4-(methoxymethoxy)phenyl)methanol

Dissolve 2.7 g of the intermediate from step 1 in 46 mL of anhydrous THF, cool to below -70°C, and add n-BuLi (3.6 mL, 2.5 M solution in THF) dropwise. Incubate for 30 minutes. Add a solution of the intermediate from step 2 in tetrahydrofuran (4.6 g, 5 mL) dropwise and continue the reaction for 30 minutes. Monitor the reaction by TLC. Add 20 mL of saturated _NH₄Cl solution dropwise, extract with 30 mL of ethyl acetate, and concentrate the organic phase to dryness under reduced pressure. Purify by column chromatography to obtain 2.3 g of an oil.

Step 4: 4-((3-Fluoro-5-isopropyl-4-(methoxymethoxy)phenyl)(hydroxy)methyl)-3,5-dimethylphenol

3.0 g of the compound from step 3 was dissolved in 30 mL of ethyl acetate, and tetrabutylammonium fluoride (6 mL, 1 M solution in tetrahydrofuran) was added. The mixture was reacted at room temperature for 30 min, and 30 mL of water was added for extraction. The organic phase was decompressed to dryness to obtain 1.5 g of an oily product.

Step 5: 4-(3-Fluoro-5-isopropyl-4-(methoxymethoxy)benzyl)-3,5-dimethylphenol

1.5 g of the compound from step 4 was dissolved in dichloromethane, and trifluoroacetic acid (0.1 g) and Pd/C (10%, 0.15 g) were added. A hydrogen balloon was installed and the atmosphere was replaced with hydrogen twice. The reaction was stirred at room temperature overnight to obtain 0.8 g of the target compound.

Step 6: Diethyl (4-(3-fluoro-5-isopropyl-4-(methoxymethoxy)benzyl)-3,5-dimethylphenoxy)methyl)phosphonate

Dissolve 11 g of compound 5, 11.3 g of (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate, and 17.0 g of cesium carbonate in 50 mL of acetonitrile and heat to 65°C overnight. Monitor the reaction by TLC. Cool the reaction mixture to room temperature, filter, and decompress the filtrate to dryness. Column chromatography yields 12.0 g of the desired product.

Step 7: (4-(3-Fluoro-4-hydroxy-5-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)phosphonic acid

Dissolve 8g of the compound from step 6 in 100mL of dichloromethane, add 22.0g of trimethylsilyl bromide dropwise, and react overnight at room temperature. Monitor the reaction by thin-layer chromatography (TLC). Add 100mL of water, extract, and reduce to dryness under reduced pressure to obtain 4.3g of the title compound.

MS m/z：383[M+1] ⁺

Example 2, (2R, 4S)-4-(3-chlorophenyl)-2-(4-(3-fluoro-4-hydroxy-5-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)-1,3,2-dioxaphosphine-2-oxide

Dissolve 0.7 g of the compound from Example 1 in 10 mL of dichloromethane, add 20 mg of DMF, and dropwise add 0.80 g of thionyl chloride. Reflux overnight, and reduce the reaction mixture to dryness under reduced pressure to yield an oily phosphonochloridite. Add 14 mL of dichloromethane to dissolve the mixture and set aside. Dissolve 0.717 g of (S)-1-(3-chlorophenyl)propane-1,3-diol in 10 mL of dichloromethane, and add 0.36 g of titanium tetrachloride dropwise at 0-10°C. After complete dissolution, add 0.8 g of triethylamine dropwise at -20-10°C. Allow to react for 10 minutes. Add the resulting solution to the phosphonochloridite solution at -30°C and continue reacting at this temperature for 2 hours. TLC monitoring indicates that the reaction is no longer progressing. HPLC analysis of the reaction mixture indicates a cis/trans ratio of 6:1. The reaction mixture is quenched with 10 mL of water, and the organic phase is extracted and reduced to dryness under reduced pressure to yield 0.54 g of the title compound.

MS m/z：533[M+1] ⁺

Example 3, (4-(4-hydroxy-3-isopropylbenzyl)-2,3,5-trimethylphenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 1 for synthesis.

MS m/z：379[M+1] ⁺

Example 4, (2R, 4S)-4-(3-chlorophenyl)-2-((4-(4-hydroxy-3-isopropylbenzyl)-2,3,5-trimethylphenoxy)methyl)-1,3,2-dioxaphosphine-2-oxide

Refer to the preparation steps of Example 2 for synthesis.

MS m/z：529.1[M+1] ⁺

Example 5, (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphonic acid

Step 1: 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline

Dissolve 10.0 g of 3,6-dichloro-4-isopropylpyridazine and 99.3 g of 4-amino-2,6-dichlorophenol in 40 mL of DMSO, then add 28.6 g of potassium carbonate and 5.1 g of CuI. React at 90°C under argon for 3 hours. Cool the reaction mixture and filter. Wash the filter cake several times with ethyl acetate. Quench the filtrate with 600 mL of water and extract with 250 mL of ethyl acetate. Wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and obtain 6.9 g of the desired product by column chromatography.

Step 2: 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenol

Dissolve 6.00 g of the product from step 1 in 20 mL of 50% sulfuric acid and stir under an ice bath. Dissolve 1.52 g of sodium nitrite in 3 mL of water and add dropwise to the reaction solution at a temperature not exceeding 5°C. After the addition is complete, react for 30 minutes. Dissolve 42.4 g of copper sulfate in 70 mL of water and add dropwise to the reaction solution. Then, add 22.8 g of cuprous oxide and react at room temperature for 2 hours. The reaction solution is filtered to remove solids, the filter cake is washed with 200 mL of dichloromethane, and the filtrate is extracted with dichloromethane. The organic layers are combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a brown solid, which is then separated by column chromatography to obtain 1.7 g of a yellow solid.

Step 3: Diethyl (3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenoxy)methyl)phosphate

0.6 g of the product from step 2 and 0.4 g of sodium carbonate were dissolved in 10 mL of DMF, and 0.6 g of (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate were added. The mixture was reacted at 80° C. for 4 h. After the reaction was complete, the reaction solution was quenched with water, extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. 0.32 g of liquid was obtained by column chromatography.

Step 4: Diethyl (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphate

Dissolve 0.75 g of the product from step 3 and 0.4 g of sodium acetate in 40 mL of acetic acid, heat to 120°C, and react for 5 hours. Remove the acetic acid under reduced pressure, add 20 mL of water, and stir at room temperature to precipitate a solid. Filter the solid, wash the filter cake twice with water, and dry to obtain 0.32 g of a light yellow solid.

Step 5: (3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphoric acid

Dissolve 0.6 g of the product from step 4 in 6 mL of dichloromethane. Under an ice bath, dissolve 3 mL of trimethylsilyl bromide in 6 mL of dichloromethane and add dropwise to the system. After the addition, remove the ice bath and react at room temperature for 7 hours. Concentrate in vacuo to remove the solvent, add 2 mL of acetonitrile, and then add 4 mL of water. Solid precipitates and is filtered. Wash the filter cake twice with water and dry to obtain 0.4 g of a white solid.

¹ H NMR (600MHz, DMSO-d ₆ ) δ 12.15 (s, 1H), 7.35 (s, 1H), 7.27 (s, 2H), 4.21 (d, J = 9.6Hz, 2H), 3.01 (dd, J = 13.7, 6.9Hz, 1H), 1.17 (d, J = 6.9Hz, 6H).

MS m/z：409[M+1] ⁺

Example 6, 6-(2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)phenoxy)-4-isopropylpyridazin-3(2H)-one

Dissolve 0.35 g of the compound from Example 5 in 10 mL of dichloromethane, add 20 mg of DMF, and dropwise add 0.80 g of thionyl chloride. Reflux overnight, and reduce the reaction mixture to dryness under reduced pressure to yield an oily phosphonochloridite. Add 14 mL of dichloromethane to dissolve the mixture and set aside. Dissolve 0.44 g of (S)-1-(3-chlorophenyl)propane-1,3-diol in 10 mL of dichloromethane, then add 0.36 g of titanium tetrachloride dropwise at 0-10°C. After complete dissolution, add 0.8 g of triethylamine dropwise at -20-10°C. Allow to react for 10 minutes. Add the resulting solution to the phosphonochloridite solution at -30°C and allow to react for 2 hours. HPLC analysis of the reaction mixture revealed a cis/trans ratio of 6:1. The reaction mixture was quenched with 10 mL of water. The organic phase was extracted, reduced to dryness, and separated by column chromatography to yield 0.54 g of the title compound.

MS m/z：559[M+1] ⁺

Example 7, 6-(2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)phenoxy)-4-isopropylpyridazin-3(2H)-one

Prepared by column chromatography separation according to the preparation steps of Reference Example 6.

MS m/z：559[M+1] ⁺

Example 8, (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 5 for synthesis.

¹ H NMR (600MHz, MeOD) δ7.17(s,1H),7.08(s,2H),4.16(d,2H),3.38(s,3H),3.07(dp,1H),1.16(d,6H).

MS m/z：423[M+1] ⁺

Example 9, 6-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：573[M+1] ⁺

Example 10, 6-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：573[M+1] ⁺

Example 11, (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)methylphosphonic acid

Step 1: Ethyl 2-cyano-2-(2,6-dichloro-4-nitrophenyl)acetate

Add 30 mL of DMF and 21.6 g of cesium carbonate to 5 g of ethyl 2-cyanoacetate. Stir the mixture at room temperature for 10 minutes, then add 10.0 g of 1,2,3-trichloro-5-nitrobenzene. Continue stirring at room temperature for 5 hours, and the mixture will turn black. TLC monitors the reaction for completion. Filter under reduced pressure to collect the black filtrate. Add 300 mL of ice water to the filtrate, adjust the pH to slightly acidic with 2 mol/L hydrochloric acid under ice-cooling, and a large amount of white solid will precipitate. Filter under reduced pressure and wash the filter cake with tap water. Collect the white solid and dry it to yield 10.1 g.

Step 2: 2-(2,6-Dichloro-4-nitrophenyl)acetonitrile

Step 1 intermediate 4g was added to 80mL concentrated sulfuric acid/acetic acid/water = 1/10/10, and the system was kept at 120 ℃ of stirring. The system was initially completely soluble and clear, and a large amount of white solid was separated out in the later stage. After stirring for 8h, TLC monitoring reaction was complete. After the system naturally returned to room temperature, 200mL of ice water was added. More white solid was separated out, and the solid was collected by filtration under reduced pressure and added to 50mL1% sodium hydroxide aqueous solution. The mixture was stirred at room temperature for 30min. Filtered under reduced pressure, the filter cake was washed with 1% sodium hydroxide aqueous solution and then washed with pure water. The white solid was dried to obtain 2.6g.

Step 3: 2-(4-amino-2,6-dichlorophenyl)acetonitrile

2.5 g of the intermediate in step 2 was dissolved in 25 mL of methanol. After it was completely dissolved in methanol, 5.8 g of zinc powder was added. 3 mL of acetic acid solution was added dropwise. Gas was generated in the system and the mixture was stirred at room temperature for 1 hour. 50 mL of fresh methanol solution was added to the system and stirring was continued at room temperature for 30 minutes. The mixture was filtered under reduced pressure and concentrated under reduced pressure in a 35-40°C water bath. The residue was dissolved in 200 mL of dichloromethane and washed three times with saturated sodium chloride solution. The organic layer was collected and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to precipitate a white solid. Drying gave 1.9 g of a white solid.

Step 4: 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile

Under magnetic stirring at room temperature, add 4.2g of the intermediate from step 3 and 50mL of tetrahydrofuran. After complete dissolution in tetrahydrofuran, cool to 0°C in an ice bath. Slowly add 1.6g of solid sodium hydride, generating gas. After the addition is complete, remove the ice bath and allow the system to naturally return to room temperature for 10 minutes, gradually changing from clear and transparent to blue. Continue to add 2g of 3,6-dichloro-4-isopropylpyridazine. After the addition is complete, continue stirring at room temperature for 3 hours. Slowly add excess methanol dropwise while stirring in an ice bath to quench the system. In a 35-40°C water bath, concentrate under reduced pressure. After the system cools to room temperature, quench it in a 200mL ice-water mixture and extract it three times with dichloromethane. Combine the dichloromethane layers and dry them over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to precipitate a light brown solid. Dry to obtain 6.1g of a light brown solid.

Step 5: 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one

Add 2g of the intermediate from step 4 and 24mL of a 4/1/1 mixture of hydrochloric acid/acetic acid/water under nitrogen protection, raise the temperature to 120°C and stir for 8h. TLC monitors the reaction for completion. After the system cools to room temperature, 100mL of ice water is added with stirring. A large amount of white solid precipitates. Let it stand for 1h. After the system precipitates completely, filter under reduced pressure. Collect the solid and dry it at 40°C. Then, slurry it with 3mL of dichloromethane and filter under reduced pressure to obtain 1.3g of a white solid.

Step 6: 6-(2,6-dichloro-4-hydroxybenzyl)-4-isopropylpyridazin-3(2H)-one

Under magnetic stirring at room temperature, 10 g of the intermediate of step 5 and 200 mL of 50% aqueous sulfuric acid solution were added. After complete dissolution, the mixture was cooled to 0 ° C in an ice salt bath. 5 mL of an aqueous solution of 2.7 g of sodium nitrite was slowly added. Gas was generated and the color was light yellow. The reaction was kept in an ice salt bath for 1 h. TLC monitoring of the raw material point disappeared. 50 mL of an aqueous solution of 120 g of copper sulfate and 4.6 g of copper oxide were added. After the addition, the system naturally returned to room temperature and reacted for 30 min. 200 mL of tap water was added to dilute the system, and the mixture was extracted 3 times with dichloromethane. The dichloromethane layers were combined and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to precipitate a light brown solid. The mixture was purified by column chromatography on 200-300 mesh silica gel and concentrated under reduced pressure to obtain 1.2 g of a light yellow solid.

Step 7: Diethyl (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)methylphosphonate

Add 0.5 g of the intermediate from step 6, 2 mL of DMF, and 0.2 g of sodium carbonate. Heat to 60° C. and stir for 10 min. Then add 0.5 g of (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate. Heat the system to 80° C. and stir for 5 h. TLC monitors the reaction for completion. After cooling the system to room temperature, add 50 mL of ice water with stirring. Extract with ethyl acetate three times (100 mL x 3). Combine the ethyl acetate layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to precipitate a light brown solid. Purify on a 200-300 mesh silica gel column. The product is collected at DCM/MeOH = 60/1 and concentrated under reduced pressure to obtain 0.4 g of a white solid.

Step 8: (3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)methylphosphonic acid

Under magnetic stirring, 0.4 g of the intermediate of step 7 was added, 6 mL of dichloromethane was measured and placed in a 25 mL clean, dry three-necked flask. The system was cooled to 0 ° C in an ice-salt bath, and 2.7 g of trimethylsilyl bromide was slowly added dropwise. After the addition was complete, the ice bath was removed and the system was naturally returned to room temperature for 6 hours. TLC monitored the reaction to be complete. 0.5 mL of tap water was added dropwise and stirred at room temperature for 10 minutes to quench the system. A white solid precipitated. The dichloromethane was removed under reduced pressure. The residue was dissolved in 2 mL of acetonitrile and then 2 mL of tap water was added to precipitate a white solid. The solid was filtered under reduced pressure. The resulting solid was stirred with dichloromethane at room temperature for 30 minutes, filtered under reduced pressure, and dried to obtain 0.2 g of a white solid.

¹ H NMR (600MHz, MeOD) δ7.07(d,1H),7.03(s,2H),4.15(d,2H),4.13(s,2H),3.02-2.94(m,1H),1.07(d,6H).

MS m/z：407[M+1] ⁺

Example 12, 6-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-4-isopropylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：557[M+1] ⁺

Example 13, 6-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-4-isopropylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：557[M+1] ⁺

Example 14, (4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dimethylphenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 5 for synthesis.

MS m/z：369[M+1] ⁺

Example 15, 6-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：519[M+1] ⁺

Example 16, 6-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：519[M+1] ⁺

Example 17, (4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dimethylphenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 5 for synthesis.

¹ H NMR(600MHz,MeOD)δ8.28(dd,1H),8.20(d,1H),7.92(dd,1H),7.86(dd,1H),6.90(s,1H ),6.69(s,1H),4.20(d,1H),4.11(d,1H),3.44(s,3H),2.16–2.05(d,3H),2.04(s,3H).

MS m/z：383[M+1] ⁺

Example 18, 6-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：533[M+1] ⁺

Example 19, 6-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：533[M+1] ⁺

Example 20, (4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenoxy)methylphosphonic acid

Synthesized according to the preparation steps of Reference Example 11.

MS m/z：367[M+1] ⁺

Example 21, 6-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：531[M+1] ⁺

Example 22, 6-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：531[M+1] ⁺

Example 23, (3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 5 for synthesis.

¹ H NMR (600MHz, MeOD) δ8.41 (dd, J = 8.0, 1H), 8.30 (d, 1H), 8.08 (m, 1H), 8.03-7.98 (m, 1H), 7.24 (s, 2H), 4.31 (d, 2H).

MS m/z：417[M+1] ⁺

Example 24, 4-(2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)phthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：567[M+1] ⁺

Example 25, 4-(2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)phthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：567[M+1] ⁺

Example 26, (3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 5 for synthesis.

MS m/z：377[M+1] ⁺

Example 27, 4-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)phthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：527[M+1] ⁺

Example 28, 4-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)phthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：527[M+1] ⁺

Example 29, (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 5 for synthesis.

¹ H NMR (600MHz, MeOD) δ8.29(d,1H),8.16(d,1H),7.93(m,1H),7.90-7.86(m,1H),7.13(d,2H),4.20(d,2H),3.45(s,3H).

MS m/z：430[M+1] ⁺

Example 30, 4-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-2-methylphthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：581[M+1] ⁺

Example 31, 4-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-2-methylphthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：581[M+1] ⁺

Example 32, (3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 5 for synthesis.

MS m/z：391[M+1] ⁺

Example 33, 4-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-2-methylphthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：541[M+1] ⁺

Example 34, 4-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-2-methylphthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：541[M+1] ⁺

Example 35, (3,5-dichloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid

Synthesized according to the preparation steps of Reference Example 11.

¹ H NMR (600MHz, MeOD) δ8.40-8.38(m,1H),8.20(d,1H),8.04-8.00(m,1H),7.93-7.89(m,1H),7.14(s,2H),4.61(s,2H),4.25(d,2H).

Example 36, 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dichlorobenzyl)phthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：565[M+1] ⁺

Example 37, 4-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dichlorobenzyl)phthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：565[M+1] ⁺

Example 38, (3,5-dichloro-4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid

Refer to the preparation steps of Example 5 for synthesis.

¹ H NMR (600MHz, MeOD) δ8.31(dd,1H),8.09(d,1H),7.91–7.88(m,1H),7.82–7.79(m,1H),7.06(d,2H),4.53(s,2H),4.18(d,2H),3.50(d,3H).

MS m/z：429[M+1] ⁺

Example 39, 4-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-2-methylphthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：579[M+1] ⁺

Example 40, 4-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-2-methylphthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：579[M+1] ⁺

Example 41, (3,5-dimethyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：375[M+1] ⁺

Example 42, 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)phthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：525[M+1] ⁺

Example 43, 4-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)phthalazin-1(2H)-one

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：525[M+1] ⁺

Example 44, (3,5-dichloro-4-((4-methylquinolin-7-yl)oxy)phenoxy)methyl)phosphonic acid

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：414[M+1] ⁺

Example 45, (2R,4S)-4-(3-chlorophenyl)-2-(3,5-dichloro-4-((4-methylquinolin-7-yl)oxy)phenoxy)methyl)-1,3,2-dioxaphosphine-2-oxide

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：564[M+1] ⁺

Example 46, 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)benzamide

Step 1: Diethyl (3,5-dichloro-4-(chloromethyl)phenoxy)methyl)phosphonate

Dissolve 6.0 g of diethyl (3,5-dichloro-4-(hydroxymethyl)phenoxy)methyl)phosphate in 80 mL of dichloromethane and stir under ice for 15 minutes. Add 8.6 g of thionyl chloride to the mixture, remove the ice bath, and allow to react at room temperature for 2 hours. Neutralize the reaction mixture with sodium carbonate solution under ice, quench with 100 mL of water, extract with dichloromethane, wash with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to yield 4.8 g of a yellow oil.

Step 2: Diethyl (4-((2-carbamoylphenoxy)methyl)-3,5-dichlorophenoxy)methyl)phosphonate

4 g of the product from step 1 and 2.22 g of potassium carbonate were added to 15 mL of DMF, and 1.6 g of 2-hydroxybenzamide was added to the system. The mixture was reacted at room temperature for 7 h. 50 mL of water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by column chromatography to obtain 3.9 g of a white solid.

Step 3: (4-((2-Carbamoylphenoxy)methyl)-3,5-dichlorophenoxy)methyl ester)phosphoric acid

3.0 g of the product from step 2 was dissolved in 20 mL of dichloromethane and stirred under ice bath for 40 minutes. 4 g of trimethylsilyl bromide was added dropwise to the system. The ice bath was removed and the mixture was reacted at room temperature for 3 hours. The solvent was removed by vacuum concentration. 6 mL of acetonitrile and 1 mL of water were added. Solid precipitated and filtered. The filter cake was washed twice with water and dried to obtain 1.6 g of a white solid.

¹ H NMR(600MHz,MeOD)δ8.00(dd,J＝7.8,1.8Hz,1H),7.57(ddd,J＝8.4,7.4,1.8Hz,1H),7.3 7(d,J＝8.0Hz,1H),7.22(s,2H),7.15-7.08(m,1H),5.43(s,2H),4.29(d,J＝10.4Hz,2H).

Step 4: 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)benzamide

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：556[M+1] ⁺

Example 47, 2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)benzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：556[M+1] ⁺

Example 48, 2-((4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)benzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：516[M+1] ⁺

Example 49, 2-((4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)benzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：516[M+1] ⁺

Example 50, 2-((4-((((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)-N-methylbenzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：530[M+1] ⁺

Example 51, 2-((4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)-N-(methyl-d3)benzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：533[M+1] ⁺

Example 52, 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide

Step 1: (3,5-Dichloro-4-((2-(methylcarbamoyl)phenoxy)methyl)phenoxy)methyl)phosphonic acid

Refer to the method of Step 3 of Example 46, substituting diethyl (4-((2-methylcarbamoylphenoxy)methyl)-3,5-dichlorophenoxy)methyl)phosphonate for diethyl (4-((2-carbamoylphenoxy)methyl)-3,5-dichlorophenoxy)methyl)phosphonate.

¹ H NMR(600MHz,MeOD)δ7.92(dd,J＝7.8,1.8Hz,1H),7.59-7.49(m,1H),7.39(d,J＝8.2Hz,1H) ,7.24(s,2H),7.19-7.10(m,1H),5.51(s,2H),4.30(dd,J＝19.2,10.4Hz,2H),2.83(s,3H).

Step 2: 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide

Refer to the preparation steps of Example 6 for synthesis.

MS m/z：570[M+1] ⁺

Example 53, 2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide

Synthesized according to the preparation steps of Reference Example 52.

MS m/z：570[M+1] ⁺

Example 54, 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-N-methyl-5-(trifluoromethyl)benzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：638[M+1] ⁺

Example 55, 5-cyclopropyl-2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：610[M+1] ⁺

Example 56, 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N,5-dimethylbenzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：584[M+1] ⁺

Example 57, 2-((2,6-dibromo-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：658[M+1] ⁺

Example 58, 2-((2,6-dibromo-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N,5-dimethylbenzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：672[M+1] ⁺

Example 59, 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-5-fluorobenzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：574[M+1] ⁺

Example 60, 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-5-methylbenzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：570[M+1] ⁺

Example 61, 5-cyclohexyl-2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：638[M+1] ⁺

Example 62, 5-cyclohexyl-2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：638[M+1] ⁺

Example 63, 5-cyclohexyl-2-((2,6-dibromo-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：726[M+1] ⁺

Example 64, 4-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：636[M+1] ⁺

Example 65, 4-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxamide

Synthesized according to the preparation steps of Reference Example 46.

MS m/z：636[M+1] ⁺

Example 66, 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Step 1: Ethyl (Z)-(2-cyano-2-(2-(3,5-dimethyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)hydrazono)acetyl)carbamate

In an ice-salt bath, 2.1g of the raw material 4-(4-amino-2,6-dimethylphenoxy)phthalazin-1(2H)-one was added to 10.0mL of acetic acid and 20.0mL of concentrated hydrochloric acid. 0.47g of sodium nitrite was dissolved in 15mL of water and slowly added dropwise to the reaction system. After addition was complete, the reaction was continued in an ice-salt bath for 1 hour until the system became clear, yielding a light yellow solution. In an ice-salt bath, 1.1g of ethyl (2-cyanoacetyl)carbamate was added directly to the diazonium chloride solution. After stirring in an ice bath for 1 hour, sodium acetate solution was slowly added dropwise to the system. After stirring for 4 hours, the reaction was complete, and a large amount of yellow solid precipitated. Filter under reduced pressure, wash the filter cake with water and petroleum ether, and dry to yield 1.2g of the desired product.

Step 2: 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Add 0.8 g of the product from step 1 to 10.0 mL of glacial acetic acid, and then add 0.75 g of sodium acetate. After the addition is complete, raise the temperature of the reaction system to 120°C. After reacting for 4 hours, the reaction is complete. Stop heating, cool to room temperature, and dilute with water. A large amount of solid precipitates. Filter under reduced pressure to obtain a solid, wash with water, and dry to obtain 0.55 g of the target product.

MS m/z：401[M+1] ⁺

Example 67, N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

0.5 g of 4-(4-amino-2,6-dichlorobenzyl)-2-methylphthalazin-1(2H)-one was added to dry tetrahydrofuran, followed by 0.2 mL of triethylamine. The mixture was cooled to below 5°C in an ice bath, and 0.25 g of 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride was added. The mixture was stirred for 2 hours, then warmed to room temperature and reacted for 2 hours. Water was added to quench the reaction, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 0.36 g of the target product.

MS m/z：446[M+1] ⁺

Example 68, N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

Refer to Example 67 for preparation steps for synthesis.

MS m/z：448[M+1] ⁺

Example 69, N-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

4-(4-amino-2,6-dimethylphenoxy)-2-methylphthalazin-1(2H)-one was substituted for 4-(4-amino-2,6-dichlorobenzyl)-2-methylphthalazin-1(2H)-one and synthesized according to the preparation steps of Example 67.

MS m/z：408[M+1] ⁺

Example 70, N-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

4-(4-amino-2,6-dimethylbenzyl)-2-methylphthalazin-1(2H)-one was substituted for 4-(4-amino-2,6-dichlorobenzyl)-2-methylphthalazin-1(2H)-one and synthesized according to the preparation steps of Example 67.

MS m/z：406[M+1] ⁺

Example 71, N-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

4-(4-amino-2,6-dimethylbenzyl)-phthalazin-1(2H)-one was substituted for 4-(4-amino-2,6-dichlorobenzyl)-2-methylphthalazin-1(2H)-one and synthesized according to the preparation steps of Example 67.

MS m/z：392[M+1] ⁺

Example 72, 6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Step 1: 3,5-dichloro-4-(4-chlorophthalazin-1-yl)oxy)aniline

Dissolve 8.8 g of the raw material 4-amino-2,6-dichlorophenol in 80.0 mL of DMSO, then add 27.6 g of potassium carbonate, 10 g of 1,4-dichlorophthalazine, and 5.2 g of cuprous iodide. After the addition is complete, the reaction is heated to 80°C for 1 hour. When the reaction is complete, stop heating, cool to room temperature, filter, and wash the filter cake with ethyl acetate. The organic phase is washed with saturated brine (2 × 150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain a tan solid.

Step 2, N-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)acetamide

Add 8.0 g of the intermediate from step 2 to a reaction flask containing 40.0 mL of acetic acid, followed by 2 g of sodium acetate. After addition, raise the reaction temperature to 100°C for 2 h, discontinue heating, and cool to room temperature. Dilute with water to yield a large amount of solid, which is filtered under reduced pressure. The filter cake is washed with water and petroleum ether, and dried to yield 6.3 g of the desired product.

Step 3: 4-(4-amino-2,6-dichlorophenoxy)phthalazin-1(2H)-one

Dissolve 6.0 g of the product from Step 2 in 80.0 mL of ethanol and 40.0 mL of water. Then, add 20 g of sodium hydroxide to the system in an ice-salt bath. After addition, heat the system to 105°C and reflux for 2 h. End the reaction, stop heating, cool the system to room temperature, and add 4 M hydrochloric acid in an ice-salt bath to adjust the pH to 8-9. A large amount of solid precipitates. Filter under reduced pressure to obtain a filter cake, which is washed with water and n-hexane and dried to yield 4.3 g of the desired product.

Step 4: (Z)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)hydrazone)acetyl)carbamate

Under ice-salt bath conditions, 2.0g of step 3 raw materials are added to 10.0mL of acetic acid and 20.0mL of saturated hydrochloric acid. 0.48g of sodium nitrite is weighed and dissolved in 20.0mL of water and slowly added dropwise to the reaction system. After the addition is complete, the ice-salt bath reaction is continued for 1h until the system is clear to obtain a light yellow solution. Under ice-salt bath, 1.1g of (2-cyanoacetyl) ethyl carbamate is directly added to the diazonium chloride solution. After stirring in an ice bath for 1h, sodium acetate solution is slowly added dropwise to the system. After the system is stirred for 4h, the reaction is complete, and a large amount of yellow solid is precipitated. The filter cake is washed with water and petroleum ether under reduced pressure and dried to obtain 1.1g of the target product.

Step 5: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

1.0 g of the product from step 4 was added to 10.0 mL of glacial acetic acid, and then 0.75 g of sodium acetate was added. After the addition was completed, the temperature of the reaction system was raised to 120°C. After the reaction was completed for 4 hours, the heating was stopped, and the mixture was cooled to room temperature and diluted with water. A large amount of solid precipitated, and the solid was filtered under reduced pressure to obtain 0.64 g of solid. The solid was washed with water and dried.

Step 6: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

In a 25mL round-bottom flask, 10.0mL of acetic acid, 0.6g of the product from step 5, and 5mL of concentrated hydrochloric acid were added in sequence. After the addition of the raw materials, the temperature of the system was raised to 120°C for reflux reaction, and the reaction progress was monitored by TLC. After a period of reaction, the solid dissolved, and after a period of reaction, a white solid precipitated. After 5.0h of reaction, the reaction was stopped. The system was cooled to room temperature, a large amount of water was added, and then filtered, washed with water, and then the filter cake was washed with petroleum ether. The filter cake was collected and dried to obtain 0.36g of a white solid.

Step 7: 6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

To a 50 mL round-bottom flask, add 2.0 mL of N,N-dimethylformamide, 0.3 g of the product from Step 6, 0.30 g of DPPA, and 0.14 g of triethylamine. After the addition of the starting materials, raise the system temperature to 90°C and reflux for 6 h. Stop the reaction, filter under reduced pressure, wash the filter cake with water, and dry to yield 0.21 g of a solid.

¹ H NMR (600MHz, DMSO-d ₆ )δ12.28(s,1H),12.00(s,1H),8.31(dd,J＝7.9,1.3Hz,1H),8.28-8.24(m,1H),8. 09(td,J＝7.7,1.4Hz,1H),8.02(td,J＝7.6,1.3Hz,1H),7.89(s,2H),6.54(s,2H).

MS m/z：433[M+1] ⁺

Example 73, 6-amino-2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Synthesized according to the preparation steps of Reference Example 72.

¹ H NMR (600MHz, DMSO-d ₆ )δ12.12(s,1H),11.81(s,1H),8.29(t,J＝7.8Hz,2H),8.10–8.04(m,1H),8.00(t,J＝7.6Hz,1H),7.30(s,2H),6.34(s,2H),2.14(s,6H).

MS m/z：393[M+1] ⁺

Example 74, 6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Step 1: Ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)hydrazono)acetyl)carbamate

In an ice-salt bath, 5.0 g of the raw material 4-(4-amino-2,6-dichlorobenzyl)phthalazin-1(2H)-one was added to 80 mL of acetic acid and 12 mL of saturated hydrochloric acid. 1.3 g of sodium nitrite was dissolved in 50 mL of water and slowly added dropwise to the reaction system. After addition was complete, the reaction was continued in an ice-salt bath for 0.5 h until the system became clear, yielding a light yellow solution. This step was not treated and was directly used in the next step. In an ice-salt bath, 2.67 g of ethyl (2-cyanoacetyl)carbamate was added directly to the 3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)benzenediazonium chloride solution. After stirring in an ice-salt bath for 1 h, sodium acetate solution was slowly added dropwise to the system. After stirring for 4 h, TLC confirmed the reaction was complete, with the precipitation of a large amount of yellow solid. Filter under reduced pressure, wash the filter cake with water and petroleum ether, and dry to yield 4.3 g of the desired product.

Step 2: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4-5-tetrahydro-1,2,4-triazine-6-carbonitrile

Add 3.94 g of the intermediate of step 1 to 100 mL of glacial acetic acid, and then add 5.3 g of sodium acetate. After the addition is complete, the temperature of the reaction system is raised to 110°C. After the reaction is completed for 4 hours, the heating is stopped and the mixture is cooled to room temperature. Clean water is added to precipitate a large amount of solid. Filter under reduced pressure to obtain a solid. Wash the filter cake with water and dry it to obtain 2.8 g of the target product.

Step 3: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4-5-tetrahydro-1,2,4-triazine-6-carboxylic acid

At room temperature, 10 mL of acetic acid, 1.0 g of the intermediate in step 2, and 2 mL of concentrated hydrochloric acid were added to a 50 mL round-bottom flask in sequence. After the addition of the raw materials was completed, the temperature of the system was raised to 120 ° C for reflux reaction, and the reaction progress was monitored by TLC. After a period of reaction, the solid dissolved, and after another period of reaction, a white solid precipitated. After 5.0 h of reaction, the reaction was stopped. The system was cooled to room temperature, a large amount of clean water was added, and then filtered, washed with water, and then the filter cake was washed with n-hexane. The filter cake was collected and dried to obtain 0.6 g of a white solid.

Step 4: 6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

To a 50 mL round-bottom flask at room temperature, add 3.0 mL of DMF, 0.3 g of the intermediate from Step 3 (the system is clear), 0.29 g of DPPA, and 0.136 g of triethylamine. After the addition of the starting materials is complete, raise the system temperature to 90°C and reflux. Monitor the reaction progress by TLC. After 6.0 h of reaction, stop the reaction and filter under reduced pressure. Wash the filter cake with water and dry it to yield 0.18 g of a solid.

MS m/z：431[M+1] ⁺

Example 75, 6-amino-2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Synthesized according to the preparation steps of Reference Example 72.

MS m/z：391[M+1] ⁺

Example 76, 6-amino-2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Step 1: N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)acetamide

Dissolve 6.0 g of N-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)acetamide in 10.0 mL of DMF. Add 3.6 g of potassium carbonate and allow to react for 30 minutes. Then, add 2.4 g of iodomethane and continue the reaction at room temperature. TLC is used to monitor the reaction progress. Upon completion of the reaction, water is added, resulting in the precipitation of a large amount of solid. This solid is filtered, washed with water, then with petroleum ether, and dried to yield 4.5 g.

Step 2: 4-(4-amino-2,6-dichlorophenoxy)-2-methylphthalazin-1(2H)-one

Dissolve 4.0 g of the product from Step 1 in 40.0 mL of ethanol and 20.0 mL of water. Then, add 12.7 g of sodium hydroxide to the system in an ice-salt bath. After addition, heat to 105°C and reflux for 2 h. The reaction is complete, heating is stopped, and the system is cooled to room temperature. Saturated hydrochloric acid is added in an ice-salt bath to adjust the pH to 8. A large amount of solid precipitates, which is filtered to obtain a filter cake. This cake is washed with water and dried to yield 2.8 g of the desired product.

Step 3: Ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)hydrazone)acetyl)carbamate

In an ice-salt bath, 2.0 g of the raw material, 4-(4-amino-2,6-dichlorophenoxy)-2-methylphthalazin-1(2H)-one, was added to 10.0 mL of acetic acid and 5.0 mL of saturated hydrochloric acid. 0.48 g of sodium nitrite was dissolved in 15.0 mL of water and slowly added dropwise to the reaction system. After the addition was complete, the reaction was continued in an ice-salt bath for 0.5 h to obtain a light yellow solution. In an ice-salt bath, 1.1 g of ethyl (2-cyanoacetyl)urethane was added directly to the diazonium chloride solution. After stirring in an ice bath for 1 h, sodium acetate solution was slowly added dropwise to the system. After stirring for 4 h, the reaction was complete. A large amount of yellow solid was observed to precipitate. The filter cake was filtered under reduced pressure, washed with water and petroleum ether, and dried to obtain 1.6 g of the desired product.

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

1.4 g of the compound from step 3 was added to 25.0 mL of glacial acetic acid, followed by 1.2 g of sodium acetate. After the addition was complete, the temperature of the reaction system was raised to 120°C. After 4 h of reaction, the reaction was complete. Heating was stopped and the mixture was cooled to room temperature. Water was added to precipitate a large amount of solid. The solid was filtered under reduced pressure to obtain a solid. The filter cake was washed with water and petroleum ether and dried to obtain 0.8 g of the target product.

Step 5: 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

At room temperature, 10.0 mL of acetic acid, 0.5 g of the product from Step 4, and 2.50 mL of concentrated hydrochloric acid were added to a 50 mL round-bottom flask. After the addition of the raw materials, the system temperature was raised to 120°C and refluxed for 3 h. A white solid precipitated, and the reaction was stopped. The system was cooled to room temperature, and a large amount of water was added. The mixture was then filtered and washed with water. The filter cake was then washed with petroleum ether, collected, and dried. 0.26 g of a white solid was obtained.

Step 6: 6-amino-2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

To a 50 mL round-bottom flask, add 2.0 mL of DMF, 0.25 g of the product from Step 5, 0.28 g of DPPA, and 0.2 g of TEA. After addition of the starting materials, raise the system temperature to 90°C and reflux for 6 h. Stop the reaction and filter under reduced pressure. Wash the filter cake with water and dry it to yield 0.16 g of a solid.

¹ H NMR (600MHz, DMSO-d ₆ )δ12.29(s,1H),8.35-8.32(m,1H),8.27-8.24(m,1H),8.08(td,J＝7.6,1.4 Hz,1H),8.03(td,J=7.5,1.3Hz,1H),7.92(s,2H),6.55(s,2H),3.47(s,3H).

MS m/z：447[M+1] ⁺

Example 77, 6-amino-2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Synthesized according to the preparation steps of Reference Example 76.

¹ H NMR (600MHz, DMSO-d ₆ +D ₂ O) δ8.28 (dd, J = 11.2, 8.0 Hz, 2H), 8.04 (t, J = 7.6 Hz, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.24 (s, 2H), 3.42 (s, 3H), 2.10 (s, 6H).

MS m/z：407[M+1] ⁺

Example 78, 6-amino-2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Synthesized according to the preparation steps of Reference Example 76.

MS m/z：445[M+1] ⁺

Example 79, 6-amino-2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Synthesized according to the preparation steps of Reference Example 76.

MS m/z：405[M+1] ⁺

Example 80, 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

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

0.8 g of 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was dissolved in 15 mL of methanol, and 2.5 mL of thionyl chloride was slowly added dropwise under an ice bath. The reaction was allowed to proceed at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the solid was washed with water, filtered, and dried to obtain 0.65 g of the target solid.

Step 2: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

0.6 g of the product from step 1 was dissolved in 10 mL of tetrahydrofuran, and then 0.2 g of sodium borohydride was added. The temperature was raised to 60°, and methanol was slowly added dropwise until no gas was generated. The reaction was heated for 4 h. After the reaction was complete, 20 mL of water was added and the pH was adjusted to 6 with dilute hydrochloric acid. The organic layers were extracted with ethyl acetate, combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.41 g of the target compound.

Step 3: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Dissolve 300 mg of the product from step 2 in 10 mL of dichloromethane. Add 0.5 mL of DAST under ice-cooling and allow to react for 30 minutes. After completion, add the reaction solution dropwise to ice-cold water and extract with dichloromethane. Combine the organic layers, wash with saturated sodium chloride solution, dry over anhydrous sulfuric acid, filter, concentrate under reduced pressure, and purify by column chromatography to obtain 0.21 g of the desired product.

MS m/z：450[M+1] ⁺

Example 81, 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was used instead of the starting material 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid in step 1 of Example 80, and was synthesized by referring to the preparation steps of Example 80.

MS m/z：448[M+1] ⁺

Example 82, 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was used instead of the starting material 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid in step 1 of Example 80, and was synthesized by referring to the preparation steps of Example 80.

MS m/z：410[M+1] ⁺

Example 83, 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4-5-tetrahydro-1,2,4-triazine-6-carboxylic acid was used instead of the starting material 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid in step 1 of Example 80, and was synthesized by referring to the preparation steps of Example 80.

MS m/z：408[M+1] ⁺

Example 84, 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was used as the starting material and synthesized according to the preparation steps of Example 80.

¹ H NMR (400MHz, DMSO-d ₆ )δ12.72(s,1H),8.35-8.33(m,1H),8.27-8.25(m,1H),8.08-8.03(m,2H),7.88(s,2H),5.33(d,J＝47.76,2H),3.48(s,3H).

MS m/z：464[M+1] ⁺

Example 85, 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was used as the starting material and synthesized according to the preparation steps of Example 80.

MS m/z：462[M+1] ⁺

Example 86, 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was used as the starting material and synthesized according to the preparation steps of Example 80.

MS m/z：424[M+1] ⁺

Example 87, 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid was used instead of the starting material 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid in step 1 of Example 80, and was synthesized by referring to the preparation steps of Example 80.

MS m/z：422[M+1] ⁺

Example 88, 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Step 1: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbaldehyde

0.2 g of the hydroxymethylated product 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione was dissolved in 20 mL of dichloromethane, and 0.25 g of diiodoacylbenzoic acid was added at room temperature. The reaction solution was heated to 50°C and reacted for 30 minutes. After the reaction was completed, the reaction solution was added to 20 mL of ice water, extracted with ethyl acetate, and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated. It was purified by preparative chromatography to obtain 0.15 g of the target product.

Step 2: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Dissolve 0.12 g of the product from step 1 in 20 mL of dichloromethane, add 1 mL of DAST under ice bath, warm the reaction solution to room temperature, and react for 10 minutes. After the reaction is completed, add the counter-liquid into 20 mL of ice water, extract with dichloromethane, combine the organic layers, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate. The residue is purified by silica gel column chromatography to obtain 0.096 g of the target product.

MS m/z：468[M+1] ⁺

Example 89, 2-(3,5-dichloro-4-((5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：485[M+1] ⁺

Example 90, 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：466[M+1] ⁺

Example 91, 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：428[M+1] ⁺

Example 92, 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：426[M+1] ⁺

Example 93, 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：482[M+1] ⁺

Example 94, 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：442[M+1] ⁺

Example 95, 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：480[M+1] ⁺

Example 96, 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：440[M+1] ⁺

Example 97, 2-(3,5-dichloro-4-((7,7-dimethyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopentadienyl[d]pyridazin-4-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

Refer to Example 88 for preparation steps for synthesis.

MS m/z：486[M+1] ⁺

Example 98, 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

0.5 g of 4-(4-bromo-2,6-dichlorophenoxy)phthalazin-1(2H)-one and 0.24 g of 6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione were added, 0.25 g of cuprous iodide, 0.28 g of potassium phosphate, and 100 mg of N,N'-dimethylethylenediamine were dissolved in 5 mL of N,N'-dimethylformamide. The mixture was reacted at 110°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water, and extracted with dichloromethane. The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 0.14 g of the target product.

MS m/z：486[M+1] ⁺

Example 99, 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

4-(4-Bromo-2,6-dichlorophenoxy)phthalazin-1(2H)-one was substituted for 4-(4-bromo-2,6-dichlorophenoxy)phthalazin-1(2H)-one and synthesized according to the preparation steps of Example 98.

MS m/z：500[M+1] ⁺

Example 100, 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Refer to steps 1-4 of Example 74 for synthesis.

¹ H NMR (400MHz, DMSO-d ₆ ) δ13.31(brs,1H),8.35-8.33(m,1H),8.27-8.25(m,1H),8.11-8.04(m,2H),7.84(s,2H),3.47(s,3H).

MS m/z：457[M+1] ⁺

Example 101, 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Refer to Example 74 Steps 1-4 for synthesis.

MS m/z：455[M+1] ⁺

Example 102, 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Refer to Example 74 Steps 1-4 for synthesis.

MS m/z：417[M+1] ⁺

Example 103, 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Refer to Example 74 Steps 1-4 for synthesis.

MS m/z：415[M+1] ⁺

Example 104, THRβ/THRα binding experiment

(1) THRβ binding assay

Experimental Methods: Compounds' agonistic effects on THRβ were analyzed in vitro using a time-resolved fluorescence resonance energy transfer (TRFE) coactivator recruitment assay. This assay employed Eu-anti-GST antibody, biotin-SRC2-2 coactivator peptide, streptavidin-d2, RXRa, and GST-tagged THRβ-LBD. Eu-anti-GST antibody indirectly labels THRβ-LBD by binding to the GST tag.

Streptavidin-d2 indirectly labels the SRC2-2 coactivator peptide by binding to the biotin tag. In the presence of RXRa, the THRβ-LBD can form a heterodimer, THRβ-LBD/RXRa. Agonist binding to the THRβ-LBD/RXRα causes conformational changes in the THRβ-LBD, thereby increasing the heterodimer's ability to recruit the SRC2-2 coactivator peptide. Simultaneously, this decreases the distance between the d2-labeled SRC2-2 coactivator peptide and the Eu-anti-GST antibody, increasing the THR-FRET signal. The effects of different compound concentrations on THRβ activity can be used to assess the compound's agonistic ability.

The detailed procedures are as follows:

a. Prepare 100X reference compound or compound in DMSO and dilute 1:3 in equal proportions.

b. Dilute the 100X serial dilution of the reference compound or compound to 4X with 1X reaction buffer and add to the experimental plate.

c. Prepare a mixed solution of 4X THRβ-LBD and 4X RXRα using 1X reaction buffer and add it to the experimental plate.

d. Prepare a mixed solution of 2Xbiotin-SRC2-2, 2XEu-anti-GST, and 2Xstreptavidin-d2 using 1X reaction buffer and add it to the experimental plate.

e. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 4 hours in the dark.

f. Read the fluorescence signal values at 665 nm and 615 nm on an EnVision 2104 plate reader and calculate the Ratio 665 nm / 615 nm. The relationship between activity (%) and compound logarithmic concentration was fitted by nonlinear regression using Graphpad 5.0 to calculate EC ₅₀ .

(2) THRα binding assay

Experimental Methods: The in vitro analysis of the agonist effect of compounds on THRα is performed using a THRβ binding assay or a similar method for agonist effect, except that THRα is used instead of THRβ.

Experimental results: see Table 1

2. Test results

This application uses MGL-3196, ALG-055009 and T-501 as control compounds to illustrate the biological activities of the compounds of the present invention. The experimental results are shown in Table 1.

Table 1. Results of the thyroid hormone receptor THRβ/THRα binding assay



Note: A: 0.01μM≦IC ₅₀ <0.1μM, B: 0.1μM≦IC ₅₀ <0.3μM, C: 0.3μM≦IC ₅₀ ≦
0.6μM, D: 0.6μM＜IC ₅₀ ≦1.0μM, E: 1.0μM≦10μM;
*: 2≦THRα/β＜5, **: 5≦THRα/β＜10, ***: 10≦THRα/β≦20, ****: 20＜THRα/β
≦30, *****: 30＜THRα/β≦50, ******: 50＜THRα/β≦100;
MGL-3196: Compound 31 of Example 8 of WO2007009913; T-501: Compound 9 of Example 9 of WO2020123827
Compound 9; ALG-055009: WO2020227549 Example 10 Compound 10.

Conclusion: The compounds of Example 66 to Example 103 of the present invention have better binding to THRβ than the reference compounds MGL-3196, ALG-055009, and T-501. The compounds of the present invention 1-44 have better selectivity for THRα/β than the reference compound VK-2809.

Example 105: Drug metabolism experiment of prodrug in SD rats

Two groups of 12 SD male rats of similar weight were used for the experiment. Compound 23 and Compound 24, and the control drug VK-2809 (a prodrug of MB07444, structure shown below) were orally administered at a dose of 2 mg/kg, respectively. Blood and liver samples were collected at different time points.

Test sample preparation

Solutions of compound 23, compound 24, and VK2809 were prepared at a final concentration of 0.6 mg/mL, respectively, using a solvent of PEG400:pure water = 50:50 (v/v).

Groups and doses

No randomization was performed. Animal body weight was measured before administration, and healthy animals of similar body weight were selected for inclusion in the experiment. The oral dose was 3 mg/kg.

Sample collection

At least 0.2 mL of blood was collected from the tail vein or jugular vein, and the anticoagulant was sodium heparin.

Collection time

15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h after administration.

Sample processing

After blood sample collection, place it in a labeled ice-water bath centrifuge tube and quickly centrifuge to separate the plasma. The centrifugation conditions are: 3500 rpm, 10 minutes, 4°C. The plasma is stored below -40°C until testing.

After the liver sample is collected, the surface is washed with physiological saline, wiped dry with medical gauze, placed in a labeled small ziplock bag, and stored below -40°C until testing.

Results and Conclusions: After oral administration to rats, the prodrug compound 24 and the control drug VK2809 were rapidly converted into the active parent drug compound 23. At the same time, the plasma concentrations of both were not high.

Claims (8)

A phenol derivative, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, characterized in that the phenol derivative has a structure represented by formula (I):
in: X is -CH ₂ -, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -O(CH ₂ ) _n -, -S(CH ₂ ) _n -, -(CH ₂ ) _n NH-, -NH(CH ₂ ) _n -; R ¹ and R ² are each independently hydrogen, halogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₆ alkoxy, and may be arbitrarily substituted by halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, or C ₃ -C ₇ cycloalkoxy; Z and ^Z1 are each independently -O- or -NH-; R ³ and R ⁴ are each independently hydrogen, C ₁ -C ₈ alkyl, unsubstituted phenyl, phenyl substituted with at least one substituent selected from halogen, phenyl, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, unsubstituted naphthyl, -CH ₂ OC(O)-R ⁶ , or -C(RR ⁰ )C(O)OR ⁷ ; R ³ , R ⁴ and the -ZP(O)-Z ¹ - connected thereto form the following six-membered ring:
Wherein: R ⁸ is a 5-10 membered aryl group, which may be substituted by at least one substituent selected from halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, and C ₁ -C ₆ alkoxy; a 5-10 membered heteroaryl group containing one or two heteroatoms selected from N, S, and O may be substituted by at least one substituent selected from halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, and C ₁ -C ₆ alkoxy; R ⁵ is hydrogen, halogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl; R ⁶ and R ⁷ are each independently hydrogen or C ₁ -C ₈ alkyl; R and R ⁰ are each independently hydrogen, C ₁ -C ₈ alkyl, which may be substituted by halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, aryl, or optionally substituted aryl; Het is selected from a 5-12 membered aromatic ring, a naphthalene ring, a thiophene ring, a pyrrole ring, a 5-12 membered aromatic heterocycle, a 5-12 membered heteroaromatic ring, and includes the following groups:
Het may be arbitrarily substituted by -C(=O)NR ¹⁶ R ¹⁷ , halogen, -CN, -NO ₂ , C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, -C ₁ -C ₈ alkyl, or C ₁ -C ₆ alkoxy; ^R9 and ^R10 are each independently hydrogen, _C1 - _C8 alkyl, _C3 - _C7 cycloalkyl, heterocycle, or aryl; ^R9 and ^R10 , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, which may be arbitrarily substituted by deuterium, halogen, _C1 - _C6 alkyl, halogenated _C1 - _C6 alkyl, _C3 - _C7 cycloalkyl, _C1 - _C6 alkoxy, heterocycle, or aryl; R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁵ are each independently hydrogen, deuterium, -C ₁ -C ₈ alkyl, or C ₃ -C ₇ cycloalkyl; R ¹⁶ and R ¹⁷ are each independently hydrogen, -C ₁ -C ₈ alkyl, or C ₃ -C ₇ cycloalkyl; Z ² , Z ³ , and Z ^3′ are each independently —N— or —CH—; n is 0, 1, 2, or 3. The phenol derivative, its isomer, its deuterated product or its pharmaceutically acceptable salt according to claim 1, characterized in that the phenol derivative comprises the following structure: (4-(3-Fluoro-4-hydroxy-5-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)phosphonic acid; (4-(4-Hydroxy-3-isopropylbenzyl)-2,3,5-trimethylphenoxy)methyl)phosphonic acid; (2R,4S)-4-(3-chlorophenyl)-2-((4-(4-hydroxy-3-isopropylbenzyl)-2,3,5-trimethylphenoxy)methyl)-1,3,2-dioxaphosphine-2-oxide; (3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphonic acid; 6-(2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)phenoxy)-4-isopropylpyridazin-3(2H)-one; 6-(2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)phenoxy)-4-isopropylpyridazin-3(2H)-one; (3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphonic acid; 6-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one; 6-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one; (3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)methylphosphonic acid; 6-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-4-isopropylpyridazin-3(2H)-one; 6-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-4-isopropylpyridazin-3(2H)-one; (4-((5-Isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dimethylphenoxy)methyl)phosphonic acid; 6-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropylpyridazin-3(2H)-one; 6-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropylpyridazin-3(2H)-one; (4-((5-Isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dimethylphenoxy)methyl)phosphonic acid; 6-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one; 6-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one; (4-(5-Isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenoxy)methylphosphonic acid; 6-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one; 6-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one; (3,5-Dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid; 4-(2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)phthalazin-1(2H)-one; 4-(2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)phthalazin-1(2H)-one; (3,5-Dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid; 4-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)phthalazin-1(2H)-one; 4-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)phthalazin-1(2H)-one; (3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid; 4-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-2-methylphthalazin-1(2H)-one; 4-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)phenoxy)-2-methylphthalazin-1(2H)-one; (3,5-Dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenoxy)methyl)phosphonic acid; 4-(4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-2-methylphthalazin-1(2H)-one; 4-(4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)-2,6-dimethylphenoxy)-2-methylphthalazin-1(2H)-one; (3,5-Dichloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid; 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dichlorobenzyl)phthalazin-1(2H)-one; 4-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dichlorobenzyl)phthalazin-1(2H)-one; (3,5-Dichloro-4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid; 4-(2,6-dichloro-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-2-methylphthalazin-1(2H)-one; 4-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-2-methylphthalazin-1(2H)-one; (3,5-Dimethyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenoxy)methylphosphonic acid; 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)phthalazin-1(2H)-one; 4-(4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)phthalazin-1(2H)-one; (3,5-Dichloro-4-((4-methylquinolin-7-yl)oxy)phenoxy)methyl)phosphonic acid; (2R,4S)-4-(3-chlorophenyl)-2-(3,5-dichloro-4-((4-methylquinolin-7-yl)oxy)phenoxy)methyl)-1,3,2-dioxaphosphine-2-oxide; 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)benzamide; 2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)benzamide; 2-((4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)benzamide; 2-((4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)benzamide; 2-((4-((((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)-N-methylbenzamide; 2-((4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dimethylbenzyl)oxy)-N-(methyl-d3)benzamide; 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide; 2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide; 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-N-methyl-5-(trifluoromethyl)benzamide; 5-cyclopropyl-2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide; 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N,5-dimethylbenzamide; 2-((2,6-dibromo-4-((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide; 2-((2,6-dibromo-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N,5-dimethylbenzamide; 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-5-fluorobenzamide; 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-5-methylbenzamide; 5-cyclohexyl-2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide; 5-cyclohexyl-2-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide; 5-cyclohexyl-2-((2,6-dibromo-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)benzamide; 4-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxamide; or 4-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxamide. A pharmaceutical composition comprising the phenol derivative according to claim 1 or 2, its isomer, its deuterated product or its pharmaceutically acceptable salt. The use of the pharmaceutical composition according to claim 3 in the preparation of a medicament for treating THRβ-related diseases, characterized in that the disease is selected from the group consisting of at least one of the following: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism. A phenol derivative, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, characterized in that the phenol derivative has a structure represented by formula (II):
in: Het ¹ is selected from a 5-12 membered aromatic ring, a naphthalene ring, a thiophene ring, a pyrrole ring, a 5-12 membered aromatic heterocycle, a 5-12 membered heterocyclic aromatic ring, and includes the following groups:
Het ¹ may be arbitrarily substituted by -C(=O)NR ²⁹ R ³⁰ , halogen, -CN, -NO ₂ , C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, -C ₁ -C ₈ alkyl, or C ₁ -C ₆ alkoxy; X ¹ is -CH ₂ -, -(CH ₂ ) _m O-, -(CH ₂ ) _m S-, -O(CH ₂ ) _m -, -S(CH ₂ ) _m -, -(CH ₂ ) _m NH-, -NH(CH ₂ ) _m -; Z ⁴ , Z ⁵ , and Z ⁶ are each independently -CH- or -N-; R ¹⁸ and R ¹⁹ are each independently hydrogen, halogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₆ alkoxy, and may be arbitrarily substituted by halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, or C ₃ -C ₇ cycloalkoxy; R ²⁰ and R ²¹ are each independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, heterocycle, or aryl; R ²⁰ and R ²¹ , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, which may be arbitrarily substituted with halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, heterocycle, or aryl; R ²² and R ²³ are each independently hydrogen, deuterium, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, heterocycle, or aryl; R ²² and R ²³ , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, and may be arbitrarily substituted with halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, heterocycle, or aryl; R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are each independently hydrogen, deuterium, C ₁ -C ₈ alkyl, or C ₃ -C ₇ cycloalkyl; R ²⁹ and R ³⁰ are each independently hydrogen, -C ₁ -C ₈ alkyl, or C ₃ -C ₇ cycloalkyl; Q includes the following groups:
R ³¹ and R ³² are each independently hydrogen, halogen, -NH ₂ , cyano, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₆ alkoxy, and may be arbitrarily substituted by halogen, C ₁ -C ₆ alkyl, or C ₃ -C ₇ cycloalkyl; Z ⁷ and Z ⁸ are each independently -CH- or -N-; m is 0, 1, 2, or 3. The phenol derivative, its isomer, its deuterated product or its pharmaceutically acceptable salt according to claim 5, characterized in that the phenol derivative comprises the following structure: 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile; N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; N-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide; 6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-amino-2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-amino-2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-amino-2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-amino-2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-amino-2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione; 6-amino-2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((7,7-dimethyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopentadien[d]pyridazin-4-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione; 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile; 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile; 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile; or 2-(3,5-dimethyl-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. A pharmaceutical composition comprising the phenol derivative according to claim 5 or 6, its isomer, its deuterated product or a pharmaceutically acceptable salt thereof. The use of the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating THRβ-related diseases, characterized in that the disease is selected from the group consisting of at least one of the following: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.