CN112442013A

CN112442013A - Compound as thyroid hormone beta receptor agonist and application thereof

Info

Publication number: CN112442013A
Application number: CN202010912749.9A
Authority: CN
Inventors: 顾峥; 黎健豪; 李峥; 邓新山; 陈道乾; 邓建超
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2019-09-04
Filing date: 2020-09-03
Publication date: 2021-03-05
Anticipated expiration: 2040-09-03
Also published as: WO2021043185A1; CN112442013B

Abstract

The invention relates to a compound serving as a thyroid hormone beta receptor agonist and application thereof, and further relates to a pharmaceutical composition containing the compound. The compound or the pharmaceutical composition can be used for preparing medicaments for preventing, treating or relieving diseases modulated by thyroid hormone beta receptors, and particularly can be used for preparing medicaments for treating non-alcoholic fatty liver diseases.

Description

Compound as thyroid hormone beta receptor agonist and application thereof

Technical Field

The invention belongs to the field of medicines, particularly relates to a compound serving as a thyroid hormone beta receptor agonist and application thereof, and further relates to a pharmaceutical composition containing the compound. The invention further relates to application of the compound and the pharmaceutical composition in preparing medicines for preventing, treating or alleviating diseases modulated by thyroid hormone beta receptors, in particular to application in preparing medicines for treating non-alcoholic fatty liver diseases.

Background

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

The physiological effects of TH are mainly performed by thyroid hormone receptors (TR). TR, a member of the nuclear receptor superfamily, is a transcription factor induced by ligand T3 and is central in mediating the action of ligand T3. TR is mainly located in the nucleus, forms a heterodimer with retinoic acid X receptor (RXR) and other nuclear receptors, binds to a thyroid hormone response element (TRE) in the promoter region of a target gene, and thus regulates gene transcription. There are two subtypes of TR: TR α and TR β. TR α is further divided into TR α 1 and TR α 2, and TR β is further divided into TR β 1 and TR β 2. Of these, only TR α 1, TR β 1 and TR β 2 are capable of binding ligand T3. TR α primarily regulates heart rate, and TR β plays a key role in controlling hepatic cholesterol metabolism and inhibiting Thyroid Stimulating Hormone (TSH) release, which may be associated with high expression of TR β in the liver and pituitary.

Thyroid hormones have certain therapeutic benefits if side effects can be minimized or eliminated (Paul M. Yen et al. physiological Reviews, Vol.81(3): pp.1097-1126 (2001); Paul Webb et al. expert Opin. investig. drugs, Vol.13(5): pp.489-500 (2004)). For example, thyroid hormones can increase metabolic rate, oxygen consumption, and heat production, thereby reducing body weight. Reducing body weight will improve the co-morbidities associated with obesity with beneficial effects on obese patients, and may also have beneficial effects on glycemic control in obese patients with type 2 diabetes.

Thyroid hormones also lower serum Low Density Lipoprotein (LDL) (Eugene Morkin et al. journal of Molecular and Cellular diagnostics, Vol.37: pp.1137-1146 (2004)). Hyperthyroidism has been found to be associated with low total serum cholesterol, due to thyroid hormones increasing hepatic LDL receptor expression and stimulating cholesterol metabolism to bile acids (jj. abrams et al. j. lipid res., vol.22: pp.323-38 (1981)). Hypothyroidism is in turn associated with hypercholesterolemia and reduction of total cholesterol by thyroid hormone replacement therapy has been reported (M.Aviram et al. Clin. biochem., Vol.15: pp.62-66 (1982); JJ.Abrams et al. J.lipid Res., Vol.22: pp.323-38 (1981)). In animal models, thyroid hormones have been shown to have beneficial effects of increasing HDL cholesterol and increasing the conversion rate of LDL to HDL by increasing the expression of apo A-1, one of the major apoproteins of HDL (Gene C.Ness et al. biochemical Pharmacology, Vol.56: pp.121-129 (1998); GJ.Grover et al. Endocrinology, Vol.145: pp.1656-1661 (2004); GJ.Grover et al. Proc.Natl.Acad.Sci.USA, Vol.100: pp.10067-10072 (2003)). The incidence of atherosclerotic vascular disease is directly related to LDL cholesterol levels, and by modulating LDL and HDL, thyroid hormones may also reduce the risk of atherosclerosis and other cardiovascular diseases. In addition, there is evidence that the thyroid hormone reduces lipoprotein (a), an important risk factor, which is elevated in patients with atherosclerosis (Paul Webb et al. expert Opin. investig. drugs, Vol.13(5): pp.489-500 (2004); de Bruin et al. J. Clin. endo. Metab. Vol.76: pp.121-126 (1993)).

In addition, nonalcoholic fatty liver disease (NAFLD) is also closely related to thyroid hormone. On one hand, patients with NAFLD have influence on the functions of thyroid hormone such as transformation, inactivation and the like, and can cause the reduction of serum thyroid hormone level; on the other hand, the decrease of thyroid hormone level further causes lipid metabolism disorder and carbohydrate metabolism disorder, and is involved in the occurrence of NAFLD. It has been shown that the induction of fatty liver formation in rats by a choline-methionine deficient diet, followed by feeding T3, is observed in the reversal of fatty liver (Perra A, et al. Faseeb, 2008,22(8): 2981).

However, endogenous thyroid hormones are non-selective and present side effects, such as hyperthyroidism, in particular side effects associated with cardiovascular toxicity. Thus, the development of thyroid hormone analogs (e.g., thyroid hormone beta receptor agonists) that avoid the adverse effects of hyperthyroidism while maintaining the beneficial effects of thyroid hormone will open new avenues for treating patients with the following disorders: such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic fatty liver disease, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, thyroid diseases, and related conditions and diseases.

Disclosure of Invention

The invention provides a compound with better agonistic activity to a thyroid hormone beta receptor, and the compound and a composition thereof can be used for preparing medicaments for preventing, treating or relieving non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, 1A type glycogen storage disease, hypothyroidism or thyroid cancer of patients.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I), or prodrug thereof,

wherein,

y is-O-, -NH-, -CH₂-、-CH＝CH-、-C(＝O)-、-CH(OH)-、-CH(CH₃)-、-C(CH₃)₂-or-S-;

R^3a、R^3b、R^3cand R^3dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, hydroxy C_1-6Alkyl, amino C_1-6Alkyl or cyano C_1-6An alkyl group;

R¹is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (═ O) -C_1-6Alkoxy radical、-C(＝O)-C_1-6Alkyl, -C (═ O) -C_1-6Alkylamino, -C (═ O) NH₂、-S(＝O)₂-C_1-6Alkyl, -S (═ O)₂-C_1-6Alkylamino, -S (═ O)₂NH₂、C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl or cyano C_1-6An alkyl group;

R²is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, heterocyclic radical of 5-6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms;

ring A is

X is N or CH;

E₁is- (CR)^aR^b)_q-、-C(＝O)-、-O-、-C(＝CR^jR^k)-、-S-、-S(＝O)-、-S(＝O)₂-or-NR^g-; q is 0,1, 2 or 3;

E₂is-CR^cR^d-、-C(＝O)-、-C(＝CR^hRⁱ)-、-O-、-S-、-S(＝O)-、-S(＝O)₂-or-NR^g-；

E₃is-CR^eR^f-、-C(＝O)-、-C(＝CR^mRⁿ)-、-O-、-S-、-S(＝O)-、-S(＝O)₂-or-NR^g-；

Each R^a、R^b、R^c、R^d、R^e、R^f、R^h、Rⁱ、R^j、R^k、R^mAnd RⁿIndependently H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted;

or R^a、R^bTogether with the carbon atom to which they are attached form C_3-8Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R^c、R^dTogether with the carbon atom to which they are attached form C_3-8Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R^e、R^fTogether with the carbon atom to which they are attached form C_3-8A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-8The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted;

each R⁴And R^gIndependently of one another H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted;

or R^a、R^cAnd together with the carbon atom to which they are each attached form-C ═ C-;

or R^c、R^eAnd together with the carbon atom to which they are each attached form-C ═ C-;

or R⁴、R^eAnd together with the atom to which they are each attached form-N ═ C-;

each R^yIndependently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_1-6Alkoxy or C_1-6An alkylamino group;

each R^y1Independently deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_1-6Alkoxy or C_1-6An alkylamino group.

In some embodiments, R^3a、R^3b、R^3cAnd R^3dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂-SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF₃、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl or cyanomethyl.

In some embodiments, R¹Is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂-SH, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-C(＝O)-OCH₃、-C(＝O)-OCH₂CH₃、-C(＝O)-OCH(CH₃)₂、-C(＝O)-OCH₂CH₂CH₃、-C(＝O)-O(CH₂)₃CH₃、-C(＝O)-OCH₂CH(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-CH₂CH₃、-C(＝O)-NHCH₃、-C(＝O)-N(CH₃)₂、-C(＝O)NH₂、-S(＝O)₂-CH₃、-S(＝O)₂-CH₂CH₃、-S(＝O)₂-NHCH₃、-S(＝O)₂NH₂Methylamino, ethylamino, methoxy, ethoxy, -CF₃、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.

In some embodiments, R²Is H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃C ≡ CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl with 5-6 atoms, phenyl, naphthyl or heteroaryl with 5-6 atoms.

In some embodiments, each R is^a、R^b、R^c、R^d、R^e、R^f、R^h、Rⁱ、R^j、R^k、R^mAnd RⁿIndependently H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted;

or R^a、R^bTogether with the carbon atom to which they are attached form C_3-8Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R^c、R^dTogether with the carbon atom to which they are attached form C_3-8Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R^e、R^fTogether with the carbon atom to which they are attached form C_3-8A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-8The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1And (4) substituting.

In some embodiments, each R is^a、R^b、R^c、R^d、R^e、R^f、R^h、Rⁱ、R^j、R^k、R^mAnd RⁿIndependently H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂-SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃-C.ident.CH, methoxy, ethoxy, methylamino, -CF₃、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH₂-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-CH₂-, phenyl-CH₂CH₂-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH₂-, thienyl-CH₂-, imidazolyl-CH₂-, pyrimidinyl-CH₂-, pyridinyl-CH₂-or pyrrolyl-CH₂-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃-C.ident.CH, methoxy, ethoxy, methylamino, -CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH₂-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-CH₂-, phenyl-CH₂CH₂-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH₂-, thienyl-CH₂-, imidazolyl-CH₂-, pyrimidinyl-CH₂-, pyridinyl-CH₂-and pyrrolyl-CH₂Each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted;

or R^a、R^bTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a heterocyclic ring of 5 to 6 atoms, or R^c、R^dTogether with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylRadicals, cycloheptyl or heterocyclic rings of 5 to 6 atoms, or R^e、R^fTogether with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a 5-6 atom heterocycle wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R^y1And (4) substituting.

In some embodiments, each R is⁴And R^gEach independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-CF₃、-CHF₂、-CH₂F、-CH₂CHF₂、-CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein the methyl, ethyl, n-propyl, isopropyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-CHF₂、-CH₂F、-CH₂CHF₂、-CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1And (4) substituting.

In some embodiments, each R is^yIndependently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CHF₂Trifluoromethoxy, difluoromethoxy, methoxy, ethoxy or methylamino.

In some embodiments, each R is^y1Independently deuterium, F, Cl, Br, I, -CN, -OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CHF₂Trifluoromethoxy, difluoromethoxy, methoxy, ethoxy or methylamino. In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, optionally further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or any combination thereof.

In another aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for agonizing a thyroid hormone receptor; or for the prevention, treatment or alleviation of diseases modulated by thyroid hormone receptors.

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

In some embodiments, the disease modulated by a thyroid hormone receptor of the present invention is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, a metabolic disorder, a lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer.

In some embodiments, the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated cryptogenic cirrhosis, or primary liver cancer.

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

Detailed Description

The invention provides a compound with better agonistic activity to a thyroid hormone beta receptor, a preparation method thereof, a pharmaceutical composition thereof and application thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein, and in cases where one or more of the incorporated documents, patents, and similar materials is different from or contradictory to the present application (including but not limited to defined terms, application of terms, described techniques, and the like), the present application shall control.

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

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

Unless otherwise indicated, the terms used in the specification and claims have the following definitions.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" is used interchangeably with the term "unsubstituted or … … substituted". The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. Generally, an optional substituent group may be substituted at each substitutable position of the group, unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂SH, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkenyl, alkynyl, cycloalkyl-alkylene, heterocyclyl-alkylene, carbocyclyl, heterocyclyl, aryl-alkylene, heteroarylAlkyl-alkylene, and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… … independently" and "… … independently" and "… … independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "in particular denotes independently disclosed C₁Alkyl (methyl), C₂Alkyl (ethyl), C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group; "C_3-8Cycloalkyl "especially refers to independently disclosed C₃Cycloalkyl radical, C₄Cycloalkyl radical, C₅Cycloalkyl radical, C₆Cycloalkyl radical, C₇Cycloalkyl and C₈A cycloalkyl group; "heterocyclic group consisting of 3 to 6 atoms" means a heterocyclic group consisting of 3 atoms, a heterocyclic group consisting of 4 atoms, a heterocyclic group consisting of 5 atoms and a heterocyclic group consisting of 6 ring atoms.

In the various parts of this specification, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1 to 8A carbon atom; in other embodiments, the alkylene group contains 1 to 6 carbon atoms, i.e., C_1-6An alkylene group; in some embodiments, the alkylene group contains 1 to 4 carbon atoms, i.e., C_1-4An alkylene group; in some embodiments, the alkylene group contains 1 to 3 carbon atoms, i.e., C_1-3An alkylene group; in some embodiments, the alkylene group contains 1-2 carbon atoms, i.e., C_1-2An alkylene group. Examples include, but are not limited to, methylene (-CH)₂-, ethylene (including-CH)₂CH₂-or-CH (CH)₃) -, isopropylidene (including-CH (CH)₃)CH₂-or-C (CH)₃)₂-), n-propylidene (including-CH)₂CH₂CH₂-、-CH(CH₂CH₃) -or-CH₂CH(CH₃) -) n-butylene (including-CH)₂(CH₂)₂CH₂-、-CH(CH₂CH₂CH₃)-、-CH₂CH(CH₂CH₃)-、-CH₂CH₂CH(CH₃) -or-CH (CH)₃)CH(CH₃) -), tert-butylidene (including-CH (CH)₃)₂)-、-CH₂CH(CH₃)CH₂-or-CH₂C(CH₃)₂-), pentylene (e.g., -CH)₂(CH₂)₃CH₂-), hexylene (e.g. -CH₂(CH₂)₄CH₂-) and the like. Wherein said alkylene may be optionally substituted with one or more substituents as described herein.

The term "alkyl" or "alkyl group" refers to a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms; in some embodiments, the alkyl group contains 1-8 carbon atoms, i.e., C_1-8An alkyl group; in some embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C_1-6An alkyl group; in some embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C_1-4An alkyl group; in some embodiments, the alkyl group contains 1-2 carbon atoms, i.e., C_1-2An alkyl group.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂)2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-heptylOctyl, and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation is a carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In some embodiments, alkenyl groups contain 2 to 8 carbon atoms; in some embodiments, the alkenyl group contains 2 to 6 carbon atoms, i.e., C_2-6An alkenyl group; in some embodiments, the alkenyl group contains 2 to 4 carbon atoms, i.e., C_2-4An alkenyl group.

Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) Propenyl (-CH ═ CHCH)₃) Butenyl (-CH ═ CHCH)₂CH₃、-CH₂CH＝CHCH₃、-CH₂CH₂CH＝CH₂、-CH＝C(CH₃)₂、-CH＝C(CH₃)₂、-CH₂C(CH₃)＝CH₂) Pentenyl (-CH)₂CH₂CH₂CH＝CH₂、-CH₂CH₂CH＝CHCH₃、-CH₂CH₂CH＝CHCH₃、-CH₂CH＝CHCH₂CH₃、-CH＝CHCH₂CH₂CH₃、-CH₂CH₂C(CH₃)＝CH₂、-CH₂CH＝C(CH₃)₂、-CH＝CHCH(CH₃)₂、-C(CH₂CH₃)＝CHCH₃、-CH(CH₂CH₃)CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms wherein at least one site of unsaturation is a carbon-carbon sp triple bond, wherein the alkynyl radical may be optionally substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in some embodiments, alkynyl groups contain 2-6Carbon atoms, i.e. C_2-6An alkynyl group; in some embodiments, alkynyl groups contain 2-4 carbon atoms, i.e., C_2-4Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.CH-CH)₃) Propargyl (-CH)₂C.ident.CH), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, i.e., -O-alkyl, wherein the alkyl group has the meaning as described herein, wherein the alkoxy group may be optionally substituted with one or more substituents as described herein. In some embodiments, alkoxy groups contain 1 to 20 carbon atoms; in some embodiments, alkoxy groups contain 1 to 10 carbon atoms; in some embodiments, alkoxy groups contain 1 to 8 carbon atoms; in some embodiments, the alkoxy group contains 1 to 6 carbon atoms, i.e., C_1-6An alkoxy group; in some embodiments, the alkoxy group contains 1 to 4 carbon atoms, i.e., C_1-4An alkoxy group; in some embodiments, the alkoxy group contains 1-3 carbon atoms, i.e., C_1-3An alkoxy group.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) N-propyloxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) i-Propyloxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-isopropyloxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino", meaning that the amino groups are each independently substituted with one or two alkyl groups having the definitions described herein. Wherein the alkylamino group may be optionally substituted with one or more substituents described herein. In some embodiments, alkylamino is one or two C_1-6Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C_1-6An alkylamino group; in some embodiments, alkylamino is one or two C_1-4Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C_1-4An alkylamino group; in some embodiments, alkylamino is one or two C_1-2Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C_1-2An alkylamino group. Examples of alkylamino groups include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), dimethylamino (N, N-dimethylamino), diethylamino (N, N-diethylamino), N-propylamino (N-N-propylamino), isopropylamino (N-isopropylamino), tert-butylamino (N-tert-butylamino), and the like.

The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, i.e., -S-alkyl, wherein the alkyl group has the meaning as described herein, wherein the alkylthio group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkylthio group contains 1 to 20 carbon atoms; in some embodiments, the alkylthio group contains 1 to 10 carbon atoms; in some embodiments, the alkylthio group contains 1 to 8 carbon atoms; in some embodiments, the alkylthio group contains 1-6 carbon atoms, i.e., C_1-6An alkylthio group; in some embodiments of the present invention, the substrate is,the alkylthio radical having 1 to 4 carbon atoms, i.e. C_1-4An alkylthio group; in some embodiments, the alkylthio group contains 1-3 carbon atoms, i.e., C_1-3An alkylthio group. Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, and the like.

The term "haloalkyl" refers to an alkyl group having one or more halo substituents, wherein the haloalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, haloalkyl groups contain 1 to 10 carbon atoms; in some embodiments, haloalkyl groups contain 1 to 8 carbon atoms; in some embodiments, the haloalkyl group contains 1 to 6 carbon atoms, i.e., C_1-6A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 4 carbon atoms, i.e., C_1-4A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 3 carbon atoms, i.e., C_1-3A haloalkyl group; in some embodiments, the haloalkyl group contains 1-2 carbon atoms, i.e., C_1-2A haloalkyl group. Examples of haloalkyl groups include, but are not limited to, fluoromethyl (-CH)₂F) Difluoromethyl (-CHF)₂) Trifluoromethyl (-CF)₃) Fluoroethyl (-CHFCH)₃,-CH₂CH₂F) Difluoroethyl (-CF)₂CH₃,-CFHCFH₂,-CH₂CHF₂) Perfluoroethyl, fluoropropyl (-CHFCH)₂CH₃,-CH₂CHFCH₃,-CH₂CH₂CH₂F) Difluoropropyl (-CF)₂CH₂CH₃,-CFHCFHCH₃,-CH₂CH₂CHF₂,-CH₂CF₂CH₃,-CH₂CHFCH₂F) Trifluoropropyl, 1-dichloroethyl, 1, 2-dichloropropyl, and the like.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen substituents, wherein the haloalkoxy group may be optionally substituted with one or more substituents described herein. In some embodiments, haloalkoxy groups contain 1 to 10 carbon atoms; in some implementationsIn this embodiment, the haloalkoxy group contains 1 to 8 carbon atoms; in some embodiments, the haloalkoxy group contains 1-6 carbon atoms, i.e., C_1-6A haloalkoxy group; in some embodiments, the haloalkoxy group contains 1-4 carbon atoms, i.e., C_1-4A haloalkoxy group; in some embodiments, the haloalkoxy group contains 1-3 carbon atoms, i.e., C_1-3A haloalkoxy group; in some embodiments, the haloalkyl group contains 1-2 carbon atoms, i.e., C_1-2A haloalkoxy group. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups (-OH), the alkyl group having the meaning described herein, wherein the hydroxyalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, a hydroxyalkyl group as described herein refers to C substituted with one or more hydroxyl (-OH) groups_1-6Alkyl, i.e. hydroxy C_1-6An alkyl group; in some embodiments, a hydroxyalkyl group refers to C substituted with one or more hydroxyl (-OH) groups_1-4Alkyl, i.e. hydroxy C_1-4An alkyl group; in some embodiments, a hydroxyalkyl group refers to C substituted with one or more hydroxyl (-OH) groups_1-2Alkyl, i.e. hydroxy C_1-2An alkyl group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl (e.g., -CH)₂OH), hydroxyethyl (e.g., 2-hydroxyethyl), hydroxy-n-propyl (e.g., -CH)₂CH₂CH₂OH), and the like.

The term "aminoalkyl" refers to a substituted amino group (-NH)₂) Substituted alkyl having the meaning described herein, wherein the aminoalkyl may be optionally substituted with one or more substituents described herein. In some embodiments, an aminoalkyl group, as described herein, is defined as being substituted with one or more amino (-NH) groups₂) Substituted C_1-6Alkyl radicals, i.e. amino radicals C_1-6An alkyl group; in some embodiments, an aminoalkyl group is referred to as being mono-substitutedOne or more amino groups (-NH)₂) Substituted C_1-4Alkyl radicals, i.e. amino radicals C_1-4An alkyl group; in some embodiments, an aminoalkyl group is defined as being substituted with one or more amino (-NH) groups₂) Substituted C_1-2Alkyl radicals, i.e. amino radicals C_1-2An alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl (-CH)₂NH₂) Diamino methyl (-CH (NH)₂)₂) Aminoethyl (e.g., -2-aminoethyl), amino-n-propyl (e.g., -CH)₂CH₂CH₂NH₂) And so on.

The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups (-CN), the alkyl group having the meaning described herein, wherein the cyanoalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, a cyanoalkyl group as described herein refers to C substituted with one or more cyano (-CN) groups_1-6Alkyl, i.e. cyano C_1-6An alkyl group; in some embodiments, cyanoalkyl refers to C substituted with one or more cyano (-CN) groups_1-4Alkyl, i.e. cyano C_1-4An alkyl group; in some embodiments, cyanoalkyl refers to C substituted with one or more cyano (-CN) groups_1-2Alkyl, i.e. cyano C_1-2An alkyl group. Examples of cyanoalkyl groups include, but are not limited to, cyanomethyl (e.g., -CH)₂CN), cyanoethyl (e.g., 2-cyanoethyl), and the like.

The term "carboxyalkyl" refers to an alkyl group substituted with one or more carboxy groups (-COOH), said alkyl group having the meaning described herein, wherein said carboxyalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, a carboxyalkyl group as described herein refers to C substituted with one or more carboxyl groups (-COOH)_1-6Alkyl, i.e. carboxyl C_1-6An alkyl group; in some embodiments, a carboxyalkyl group refers to C substituted with one or more carboxyl groups (-COOH)_1-4Alkyl, i.e. carboxyl C_1-4An alkyl group; in some embodimentsWherein carboxyalkyl refers to C substituted with one or more carboxyl groups (-COOH)_1-2Alkyl, i.e. carboxyl C_1-2An alkyl group. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl), and the like.

The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring carbon atoms having one or more points of attachment to the rest of the molecule, wherein the cycloalkyl group is optionally substituted with the substituents described herein. In some embodiments, cycloalkyl is a ring system containing 3 to 10 ring carbon atoms, i.e., C_3-10A cycloalkyl group; in some embodiments, cycloalkyl is a ring system containing 3 to 8 ring carbon atoms, i.e., C_3-8A cycloalkyl group; in some embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms, i.e., C_3-6A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, oxygen, and phosphorus, wherein the heterocyclyl is non-aromatic and does not contain any aromatic rings, and wherein the ring system has one or more attachment points to the rest of the molecule. Wherein said heterocyclyl group may be optionally substituted by one or more substituents as described herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂The-group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. The phosphorus atom of the ring may optionally be oxidized to a P-oxygen compound. In some embodiments, heterocyclyl is 3-10 atomsA ring system of components; in some embodiments, heterocyclyl is a ring system of 5-10 atoms; in some embodiments, heterocyclyl is a ring system of 5-8 atoms; in some embodiments, heterocyclyl is a ring system of 6-8 atoms; in some embodiments, heterocyclyl is a 5-6 atom ring system, i.e., 5-6 atom heterocyclyl; in some embodiments, heterocyclyl is a ring system of 3-6 atoms, i.e., heterocyclyl of 3-6 atoms; in some embodiments, heterocyclyl is a system of 3 ring atoms; in some embodiments, heterocyclyl is a ring system of 4 atoms; in other embodiments, heterocyclyl is a 5 atom ring system; in other embodiments, heterocyclyl is a 6 atom ring system.

Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, etc. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Bridging heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.2.1]Octyl, and the like.

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

The term "aryl" denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein each ring contains 3 to 7 ring atoms and has one or more attachment points to the rest of the molecule. Wherein said aryl group may be optionally substituted with one or more substituents as described herein. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", and examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, and anthryl, and the like.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic aromatic systems containing 5 to 10 ring atoms, wherein at least one ring contains one or more heteroatoms, wherein each ring contains 5 to 7 ring atoms, wherein at least one ring system is aromatic, and wherein the heteroaryl has one or more attachment points to the rest of the molecule. Wherein said heteroaryl group may be optionally substituted with one or more substituents as described herein. Unless otherwise indicated, the heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) via any reasonable site (which may be C in CH, or N in NH). When a heteroaryl group is present-CH₂When said radical is-CH₂-the group may optionally be replaced by-C (═ O) -. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl consisting of 5 to 8 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 5-7 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is 5-6 containing 1,2,3, or 4 heteroatoms independently selected from O, S, and NAn atomic heteroaryl group; in some embodiments, heteroaryl is a heteroaryl consisting of 5 atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 6 atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Examples of heteroaryl groups include, but are not limited to, the following monocyclic groups: furyl (2-furyl, 3-furyl), imidazolyl (N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g. 5H-tetrazolyl), 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-triazolyl), thienyl (2-thienyl, 3-thienyl), pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic or tricyclic groups are also included, but in no way limited to these groups: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), phenoxathiin, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl.

The term "carbocyclyl" refers to a non-aromatic carbocyclic ring system of 3 to 14 ring carbon atoms that is saturated or contains one or more units of unsaturation. The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein. In some embodiments, the number of carbon ring carbon atoms of the carbocyclic ring is from 3 to 12; in other embodimentsIn which the number of carbon ring carbon atoms is 3 to 10; in other embodiments, the number of carbon ring carbon atoms of the carbocyclic ring is from 3 to 8; in other embodiments, the number of carbon ring carbon atoms of the carbocyclic ring is 3 to 6, i.e., C_3-6A carbocyclic group; in other embodiments, the number of carbon ring carbon atoms of the carbocyclic ring is from 5 to 6, i.e., C_5-6A carbocyclic group; in other embodiments, the number of carbon ring carbon atoms in a carbocyclic ring is from 5 to 8. In other embodiments, the number of carbon ring carbon atoms in a carbocyclic ring is from 6 to 8. "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbocyclic rings may be fused to one or more non-aromatic carbocyclic rings or one or more aromatic rings or combinations thereof. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spirobicyclic carbocyclyl, and a "fused" bicyclic ring system comprises two rings that share 2 adjacent ring atoms. The bridged bicyclic group includes two rings that share 3 or 4 adjacent ring atoms. Spiro ring systems share 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridged carbocyclyl groups include, but are not limited to, bicyclo [2.2.2]Octyl, bicyclo [2.2.1]Heptyl, bicyclo [3.3.1]Nonyl, bicyclo [3.2.3]Nonyl, and the like.

The term "cycloalkyl-alkylene" means that the cycloalkyl group is attached to the rest of the molecule through an alkylene group, wherein cycloalkyl and alkylene have the meaning described herein. The cycloalkyl-alkylene groups may be optionally substituted with one or more substituents as described herein. The term "C" in the present invention_3-6cycloalkyl-C_1-4Alkylene "represents C_3-6Cycloalkyl radicals through C_1-4The alkylene group is attached to the rest of the molecule. The term "C" in the present invention_3-6cycloalkyl-C_1-2Alkylene "represents C_3-6Cycloalkyl radicals through C_1-2The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, cyclopropyl-CH₂-, cyclopropyl-CH₂CH₂-, cyclobutyl-CH₂-, cyclobutyl-CH₂CH₂-, cyclopentyl-CH₂-, cyclopentyl-CH₂CH₂-, cyclohexyl-CH₂-, cyclohexyl-CH₂CH₂-and the like.

The term "heterocyclyl-alkylene" means that the heterocyclyl group is attached to the rest of the molecule through an alkylene group, wherein heterocyclyl and alkylene have the meaning described herein. The heterocyclyl-alkylene group may be optionally substituted with one or more substituents as described herein. (heterocyclic group consisting of 5 to 6 atoms) -C described in the present invention_1-4Alkylene "denotes a heterocyclic radical of 5 to 6 atoms bonded via C_1-4The alkylene group is attached to the rest of the molecule. (heterocyclic group consisting of 5 to 6 atoms) -C described in the present invention_1-2Alkylene "denotes a heterocyclic radical of 5 to 6 atoms bonded via C_1-2The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, tetrahydropyranyl-CH₂-, tetrahydropyranyl-CH₂CH₂-, tetrahydrofuryl-CH₂-, tetrahydrofuryl-CH₂CH₂-, pyrrolidinyl-CH₂-, piperidinyl-CH₂-, piperidinyl-CH₂CH₂-, morpholinyl-CH₂-, morpholinyl-CH₂CH₂-and so on.

The term "aryl-alkylene" means that the aryl group is attached to the rest of the molecule through an alkylene group, wherein aryl and alkylene have the meaning described herein. The aryl-alkylene groups may be optionally substituted with one or more substituents as described herein. For example, "C" according to the invention_6-10aryl-C_1-4Alkylene "represents C_6-10Aryl radicals through C_1-4The alkylene group is attached to the rest of the molecule. "C" according to the invention_6-10aryl-C_1-2Alkylene "represents C_6-10Aryl radicals through C_1-2The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, phenyl-CH₂-, phenyl-CH₂CH₂-, naphthyl-CH₂-and the like.

The term "heteroaryl-alkylene" means that the heteroaryl group is attached to the rest of the molecule through an alkylene group, wherein heteroaryl and alkylene have the meaning described herein. The heteroaryl-alkylene group may be optionally substituted with one or more substituents described herein. (5-6-atom-constituting heteroaryl) -C as defined in the invention_1-4Alkylene "denotes a heteroaryl group of 5 to 6 atoms bonded via C_1-4The alkylene group is attached to the rest of the molecule. (5-6-atom-constituting heteroaryl) -C as defined in the invention_1-2Alkylene "denotes a heteroaryl group of 5 to 6 atoms bonded via C_1-2The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, pyridyl-CH₂-, pyrrolyl-CH₂CH₂-, quinolyl-CH₂-, thienyl-CH₂-, furyl-CH₂-, pyrimidinyl-CH₂-, pyridinyl-CH₂-and the like.

The term "heteroatom" refers to O, S, N, P and any oxidation state form of Si, including S, N, and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or hydrogen on nitrogen atoms in the heterocycle substituted, e.g. N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR^T(like NR in N-substituted pyrrolidinyl^T，R^TAs a substituent on N).

The term "halogen" refers to F, Cl, Br or I.

The term "nitro" means-NO₂。

The term "mercapto" refers to-SH.

The term "hydroxy" refers to-OH.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "carboxylic acid" or "carboxyl" refers to-C (═ O) OH or-COOH.

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

The term "deuterium" means deuterated, i.e.²H。

As described herein, the ring system formed by a ring with a substituent R bonded to the center represents that the substituent R may be substituted at any substitutable or any reasonable position on the ring to which it is attached. For example, formula a represents that substituent R may be substituted at any possible substituted position on the C ring as shown in formulas a-1 to a-4:

the term "protecting group" or "PG" refers to a substituent group that blocks or protects a particular functionality when other functional groups in a compound are reacted. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxybenzyl, silyl, and the like. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "leaving group" or "LG" refers to an atom or functional group that is removed from a larger molecule in a chemical reaction, a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms cleaved away from the substrate molecule with a pair of electrons is called the leaving group. Common leaving groups are, for example, but not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azide groups, hydroxyl groups, or the like.

The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

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

The term "pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and like excipients, and additional therapeutic agents such as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents or lipid-lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: higuchi et al, Pro-drugs as Novel Delivery Systems, vol.14, a.c.s.symposium Series; roche et al, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; rautio et al, primers: Design and Clinical Applications, Nature Reviews Discovery,2008,7, 255-.

The term "metabolite" refers to the product of the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

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

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

The term "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

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

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

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

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, e.g., High Pressure Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by Asymmetric Synthesis (e.g., Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972))。

The present invention also includes isotopically-labelled compounds of the present invention which are identical to those recited herein, except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H，³H，¹³C，¹⁴C，¹⁵N，¹⁶O，¹⁷O，³¹P，³²P，³⁶S，¹⁸F and³⁷Cl。

compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of such compounds, are included within the scope of the present invention. Isotopically-labelled compounds of the invention, e.g. radioisotopes, e.g.³H and¹⁴incorporation of C into the compounds of the invention can be used in drug and/or substrate tissue distribution assays. Tritiated, i.e.,³h, and carbon-14, i.e¹⁴C, an isotope is particularly preferred. Furthermore, with isotopes having a larger mass number, e.g. deuterium, i.e. with²H substitution may provide some of the therapeutic advantages of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.

The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; definitions and conventions described by and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", John Wiley & Sons, inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as the pure optical isomer, or as a mixture of isomers, for example as a mixture of racemic and non-corresponding isomers, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.

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

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

The term "geometric isomer," also known as "cis-trans isomer," is an isomer resulting from the inability of double bonds (including olefinic double bonds, C ═ N double bonds, and N ═ N double bonds) or single bonds of ring carbon atoms to rotate freely.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.

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

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

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

Description of the Compounds of the invention

The invention provides a compound with better agonistic activity on thyroid hormone beta receptor, which is used for preparing medicaments for treating non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, 1A type glycogen storage disease, hypothyroidism or thyroid cancer. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of using these compounds and pharmaceutical compositions in the manufacture of medicaments for the treatment of the above-mentioned diseases in mammals, especially humans. Compared with the existing similar compounds, the compound of the invention not only has good pharmacological activity and selectivity, but also has excellent in vivo metabolic kinetics property and in vivo pharmacodynamics property. The preparation method of the compound is simple and feasible, has stable process method, and is suitable for industrial production. Therefore, compared with the existing similar compounds, the compound provided by the invention has better drugability.

Specifically, the method comprises the following steps:

wherein, ring A, Y, R¹、R²、R^3a、R^3b、R^3cAnd R^3dHaving the definitions as described in the present invention.

In some embodiments, Y is-O-, -NH-, -CH₂-、-CH＝CH-、-C(＝O)-、-CH(OH)-、-CH(CH₃)-、-C(CH₃)₂-or-S-.

In some embodiments, R^3a、R^3b、R^3cAnd R^3dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, hydroxy C_1-6Alkyl, amino C_1-6Alkyl or cyano C_1-6An alkyl group.

In some embodiments, R¹Is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (═ O) -C_1-6Alkoxy, -C (═ O) -C_1-6Alkyl, -C (═ O) -C_1-6Alkylamino, -C (═ O) NH₂、-S(＝O)₂-C_1-6Alkyl, -S (═ O)₂-C_1-6Alkylamino, -S (═ O)₂NH₂、C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl or cyano C_1-6An alkyl group.

In some embodiments, R²Is H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, heterocyclic radical of 5-6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms.

In some embodiments, ring a is

Said E¹、E²、E³、R⁴X and R^yHaving the definitions set out in the present invention.

In some embodiments, X is N or CH.

In some embodiments, E₁Is- (CR)^aR^b)_q-、-C(＝O)-、-O-、-C(＝CR^jR^k)-、-S-、-S(＝O)-、-S(＝O)₂-or-NR^g-; the R is^a、R^b、R^j、R^k、R^gAnd q has the definitions stated in the present invention.

In some embodiments, E₂is-CR^cR^d-、-C(＝O)-、-C(＝CR^hRⁱ)-、-O-、-S-、-S(＝O)-、-S(＝O)₂-or-NR^g-, said R^c、R^d、R^h、RⁱAnd R^gHaving the definitions set out in the present invention.

In some embodiments, E₃is-CR^eR^f-、-C(＝O)-、-C(＝CR^mRⁿ)-、-O-、-S-、-S(＝O)-、-S(＝O)₂-or-NR^g-, said R^e、R^f、R^m、RⁿAnd R^gHaving the definitions set out in the present invention.

In some embodiments, each R is^a、R^b、R^c、R^d、R^e、R^f、R^h、Rⁱ、R^j、R^k、R^mAnd RⁿIndependently H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, any two R are^a、R^b、R^c、R^d、R^e、R^fTogether with the carbon atom to which they are attached form C_3-8A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-8The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^a、R^bTogether with the carbon atom to which they are attached form C_3-8A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-8The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^c、R^dTogether with the carbon atom to which they are attached form C_3-8A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-8The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^e、R^fTogether with the carbon atom to which they are attached form C_3-8A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-8The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, each R is⁴And R^gIndependently of one another H, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl radical、C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^a、R^cAnd together with the carbon atom to which they are each attached form-C ═ C-.

In some embodiments, R^c、R^eAnd together with the carbon atom to which they are each attached form-C ═ C-.

In some embodiments, R⁴、R^eAnd together with the atom to which they are each attached form-N ═ C-.

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

In some embodiments, each R is^yIndependently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_1-6Alkoxy or C_1-6An alkylamino group.

In some embodiments, each R is^y1Independently deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_1-6Alkoxy or C_1-6Alkyl ammoniaAnd (4) a base.

In some embodiments, R^3a、R^3b、R^3cAnd R^3dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, hydroxy C_1-4Alkyl, amino C_1-4Alkyl or cyano C_1-4An alkyl group.

In some embodiments, R¹Is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, -C (═ O) -C_1-4Alkoxy, -C (═ O) -C_1-4Alkyl, -C (═ O) -C_1-4Alkylamino, -C (═ O) NH₂、-S(＝O)₂-C_1-4Alkyl, -S (═ O)₂-C_1-4Alkylamino, -S (═ O)₂NH₂、C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, hydroxy C_1-4Alkyl, amino C_1-4Alkyl, carboxyl C_1-4Alkyl or cyano C_1-4An alkyl group.

In some embodiments, R²Is H, deuterium, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclic radical of 5-6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms.

In some embodiments, each R is^a、R^b、R^c、R^d、R^e、R^f、R^h、Rⁱ、R^j、R^k、R^mAnd RⁿIndependently H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkyl halidesBase, C_1-4Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, each R is^a、R^b、R^c、R^d、R^e、R^f、R^h、Rⁱ、R^j、R^k、R^mAnd RⁿIndependently H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂-SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃-C.ident.CH, methoxy, ethoxy, methylamino, -CF₃、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH₂-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-CH₂-, phenyl-CH₂CH₂-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH₂-, thienyl-CH₂-, imidazolyl-CH₂-, pyrimidinyl-CH₂-, pyridinyl-CH₂-or pyrrolyl-CH₂-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃-C.ident.CH, methoxy, ethoxy, methylamino, -CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH₂-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-CH₂-, phenyl-CH₂CH₂-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH₂-, thienyl-CH₂-, imidazolyl-CH₂-, pyrimidinyl-CH₂-, pyridinyl-CH₂-and pyrrolyl-CH₂Each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, any two R are^a、R^b、R^c、R^d、R^e、R^fTogether with the carbon atom to which they are attached form C_3-6Carbocyclic ring or heterocyclic ring of 5 to 6 atoms in which the ring forms C_3-6The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, any two R are^a、R^b、R^c、R^d、R^e、R^fTogether with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, ringPentyl, cyclohexyl, cycloheptyl or a 5-6 atom heterocycle wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^a、R^bTogether with the carbon atom to which they are attached form C_3-6A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-6The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^a、R^bTogether with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a 5-6 atom heterocycle wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^c、R^dTogether with the carbon atom to which they are attached form C_3-6A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-6The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^c、R^dTogether with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a 5-6 atom heterocycle wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^e、R^fTogether with the carbon atom to which they are attached formC_3-6A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-6The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, R^e、R^fTogether with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a 5-6 atom heterocycle wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, each R is⁴And R^gIndependently of one another H, deuterium, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, each R is⁴And R^gEach independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-CF₃、-CHF₂、-CH₂F、-CH₂CHF₂、-CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein the methyl, ethyl, n-propyl, isopropyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-CHF₂、-CH₂F、-CH₂CHF₂、-CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted, said R^y1Having the definitions set out in the present invention.

In some embodiments, each R is^yIndependently H, deuterium, F, Cl, Br, I, CN, OH, NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_1-4Alkoxy or C_1-4An alkylamino group.

In some embodiments, each R is^y1Independently deuterium, F, Cl, Br, I, CN, OH, NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_1-4Alkoxy or C_1-4An alkylamino group.

In some embodiments, each R is^yIndependently H, deuterium, F, Cl, Br, I, CN, OH, NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CHF₂Trifluoromethoxy, difluoromethoxy, methoxy, ethoxy or methylamino.

In some embodiments, each R is^y1Independently deuterium, F, Cl, Br, I, CN, OH, NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CHF₂Trifluoromethoxy, difluoromethoxy, methoxy, ethoxy or methylamino.

In another aspect, the invention relates to a structure of one of the following, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.

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

In another aspect, the invention relates to a method of agonizing a thyroid hormone receptor, or a method for preventing, treating or ameliorating a disease modulated by a thyroid hormone receptor, using a compound or a pharmaceutical composition of the invention, by administering a therapeutically effective amount of the compound or the pharmaceutical composition to a subject in need thereof. Also, the present invention provides the above-mentioned compounds or pharmaceutical compositions thereof can be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for agonizing a thyroid hormone receptor, or for the prevention, treatment or alleviation of a disease modulated by a thyroid hormone receptor.

In some embodiments, the disease modulated by a thyroid hormone receptor agonist according to the invention is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, a metabolic disorder, a lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer.

The dosage of a compound or pharmaceutical composition required to effect a therapeutic, prophylactic or delay-acting effect, etc., will generally depend on the particular compound being administered, the patient, the particular disease or condition and its severity, route and frequency of administration, etc., and will need to be determined on a case-by-case basis by the attending physician. For example, when a compound or pharmaceutical composition provided by the present invention is administered by intravenous route, administration may be performed once per week or at even longer intervals.

In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.

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

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

Pharmaceutical compositions, formulations and administration of the compounds of the invention

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

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

The pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle, as described herein, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular intended dosage form, as used herein. The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York disclose various carriers for use in formulating pharmaceutically acceptable compositions and methods for their preparation. In addition to conventional carrier vehicles which are incompatible with the compounds of the present invention, e.g., may produce undesirable biological effects or may deleteriously interact with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and its use are contemplated by the present invention.

Some examples of substances that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), celluloses and derivatives thereof (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), Powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl dodecanoate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffers, as well as other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, detackifiers, coating agents, sweetening and flavoring agents, preservatives and antioxidants, according to the judgment of the formulator, may also be present in the composition.

The pharmaceutical compositions of the present invention may be administered directly or in the form of pharmaceutical compositions or medicaments, together with suitable carriers or excipients, as is well known in the art. The methods of treatment of the present invention may comprise administering to a subject in need thereof an effective compound of the present invention. In some embodiments, the subject is a mammalian subject, and in other embodiments, the subject is a human subject.

Effective amounts of the compounds, pharmaceutical compositions or medicaments of the present invention can be readily determined by routine method tests, as can the most effective and convenient route of administration and the most appropriate formulation.

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

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

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

For example, injectable formulations can be sterilized by filtration through a bacteria retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

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

Compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, for example cocoa butter, polyethylene glycol or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or bulking agents such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

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

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

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

The compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the compositions are administered orally, intraperitoneally, or intravenously.

The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids, such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, carriers that are commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions may be prepared by mixing the agents and non-irritating excipients, such materials including, but not limited to, cocoa butter, beeswax and polyethylene glycols.

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

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

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

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or solutions in isotonic pH adjusted sterile saline in particular, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

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

Application of compound and pharmaceutical composition of the invention

The compound or the pharmaceutical composition provided by the invention can be used for preparing a medicament for exciting thyroid hormone receptors or preparing a medicament for preventing, treating or alleviating diseases modulated by the thyroid hormone receptors.

The compounds or pharmaceutical compositions provided by the present invention are useful for agonizing thyroid hormone receptors or for preventing, treating or ameliorating diseases modulated by thyroid hormone receptors.

The present invention provides a method for agonizing thyroid hormone receptors or for preventing, treating or alleviating disorders modulated by thyroid hormone receptors, which comprises administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutical composition thereof to a patient in need of treatment. Also, the present invention provides the above-mentioned compounds or pharmaceutical compositions thereof can be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.

The thyroid hormone receptor is a thyroid hormone beta receptor.

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

In addition to being beneficial for human therapy, the compounds of the present invention may also find use in veterinary therapy for pets, animals of the introduced species and animals in farms, including mammals, rodents, and the like. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

An "effective amount," "therapeutically effective amount," or "effective dose" of a compound of the invention or a pharmaceutically acceptable pharmaceutical composition refers to an effective amount to treat or reduce the severity of one or more of the conditions referred to herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. The methods, compounds and pharmaceutical compositions according to the present invention can be of any amount administered and any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compounds or pharmaceutical compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.

General Synthesis and detection methods

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

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

The structure of the compound is determined by nuclear magnetic resonance¹H-NMR、¹³C-NMR or/and¹⁹F-NMR).¹H-NMR、¹³C-NMR、¹⁹F-NMR chemical shifts (δ) are given in parts per million (ppm).¹H-NMR、¹³C-NMR、¹⁹F-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer in deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD or MeOH-d₄) Or deuterated dimethyl sulfoxide (DMSO-d)₆). TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), m (multiplets ), br (broadcasters, broad), dd (doublets of doublets), dt (doublets of triplets, doublets), td (triplets of doublets, triplet), brs (broad singlets). Coupling constant J, in Hertz (Hz).

Preparative purification or preparative resolution generally uses a Novasep pump 250 high performance liquid chromatograph.

The LC-MS was determined using an Agilen-6120Quadrupole LC/MS mass spectrometer.

The column chromatography generally uses 300-400 mesh silica gel in Qingdao ocean chemical industry as a carrier.

The starting materials of the present invention are known and commercially available, are available from Shanghai Accela Company, Annage Company, Bailingwei Company (J & K), Tianjin Afaha Angsa Company (Alfa Company), etc., or may be synthesized using or according to methods known in the art.

In the examples, the reaction was carried out in a nitrogen atmosphere unless otherwise specified;

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

the hydrogen atmosphere refers to that a reaction bottle is connected with a hydrogen balloon with the volume of about 1L or a stainless steel high-pressure reaction kettle with the volume of about 1L;

in the examples, unless otherwise specified, the solution means an aqueous solution;

in the examples, the reaction temperature is room temperature unless otherwise specified;

in the examples, the room temperature is 20 ℃ to 40 ℃ unless otherwise specified.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

The system of eluent for column chromatography comprises: a: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of ammonia water, acetic acid and the like can be added for adjustment.

HPLC refers to high performance liquid chromatography;

HPLC was carried out using an Agilent 1260 high pressure liquid chromatograph (column: Agilent ZORBAX Eclipse Plus C184.6 mm. times.150 mm,3.5 μm);

HPLC test conditions: operating time: 25min column temperature: detection wavelength at 35 ℃: 210 nm; 245 nm;

mobile phase: phase A: 0.05% phosphoric acid solution phase B: acetonitrile; flow rate: 1.0 ml/min;

mobile phase gradients are shown in table a:

TABLE A

Time	Gradient of mobile phase A	Gradient of mobile phase B
			0min	90％	10％
15min	10％	90％
			20min	10％	90％
25min	90％	10％

The analytical LC/MS/MS system in the biological test experiment includes Agilent 1200 series vacuum degassing furnace, binary injection pump, orifice plate automatic sampler, column thermostat, Agilent G6430 three-stage quadrupole mass spectrometer with Electric Spray Ionization (ESI) source. The quantitative analysis was performed in MRM mode, with the parameters of the MRM transition as shown in table B:

TABLE B

Full scan	50～1400
		Fragmentation voltage	230V
Capillary voltage	55V
		Dryer temperature	350℃
Atomizer	0.28MPa
		Flow rate of dryer	10L/min

Analysis 5. mu.L of sample was injected using an Agilent XDB-C18, 2.1X 30mm,3.5 μm column. Analysis conditions were as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4 mL/min. Mobile phase gradients are shown in table C:

watch C

Time	Gradient of mobile phase B
		0.5min	5％
1.0min	95％
		2.2min	95％
2.3min	5％
		5.0min	Terminate

The test conditions for low resolution Mass Spectrometry (MS) data were: agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1X 30mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) at 210nm/254nm with UV detection, using electrospray ionization mode (ESI).

The following acronyms are used throughout the invention:

DMSO-d₆：	deuterated dimethyl sulfoxide;	Boc：	a tert-butoxycarbonyl group;
				DCC：	dicyclohexylcarbodiimide;	DMSO：	dimethyl sulfoxide;
CDCl₃：	deuterated chloroform;	％wt,mass％：	weight percentage;
				CD₃OD：	deuterated methanol;	mL,ml：	ml;
μL,μl：	microliter;	mol/L,mol/l：	moles per liter;
				mol：	molar ratio;	mmol/L,mmol/l,mM：	millimoles per liter;
μmol/L,μmol/l,μM：	micromole/liter;	nmol/L,nmol/l,nM：	nanomole/liter;
				g：	g;	h：	hours;
mg：	mg;	μg：	microgram;
				ng：	nanogram;	nm：	nano;
μm：	micron size;	mm：	millimeter;
				H₂：	hydrogen gas;	N₂：	nitrogen gas;
min：	the method comprises the following steps of (1) taking minutes;	MPa：	megapascals;
				Me：	a methyl group;	ACN：	acetonitrile;
TFA：	trifluoroacetic acid;	H₂O：	and (3) water.

General synthetic methods

Typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. Unless otherwise stated, each E₁、E₂、E₃、R^3a、R^3dAnd R¹Having the definition as described in the present invention, X is halogen.

Synthesis scheme 1:

compounds having a structure as shown in general formula (I-A) can be prepared by general synthetic methods as described in FIG. 1. Firstly, reacting a compound (I-a) with a compound (I-b) under the action of a base (such as potassium carbonate and sodium hydride) to obtain a compound (I-c); reducing the nitro group of the compound (I-c) to obtain a compound (I-d); diazotizing the amino group of the compound (I-d) and reacting with the compound (I-e) to obtain a compound (I-f); and (3) closing the ring of the compound (I-f) under the action of alkali (such as potassium acetate) to obtain the target compound shown in the general formula (I-A).

Preparation examples

EXAMPLE 12- [3, 5-dichloro-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 1)

Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) -3, 4-dihydro-1H-quinolin-2-one 1b

6-hydroxy-3, 4-dihydro-1H-quinolin-2-one 1a (2.0g,12.3mmol) was dissolved in N, N-dimethylacetamide (5mL), and potassium carbonate (2.57g, 18.4mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (3.90g,12.3mmol) were added and reacted at 120 ℃ for 5.5 hours under nitrogen substitution. The reaction was cooled to room temperature, water (30mL) was added, stirred for 5 minutes, filtered, and the filter cake was collected and dried under vacuum to give the title compound 1b (4.0g, 93% yield) as an off-white solid.

¹HNMR(400MHz,CDCl₃)δ(ppm)8.43(s,1H),8.31(s,2H),6.73(d,J＝8.5Hz,1H),6.67(s,1H),6.63(dd,J＝8.5,2.6Hz,1H),2.93(t,J＝7.5Hz,2H),2.67-2.58(m,2H)。

Step 2)6- (4-amino-2, 6-dichloro-phenoxy) -3, 4-dihydroquinolin-2-one 1c

Reacting 6- (2, 6-dichloro-4-nitro-phenoxy) -3, 4-diHydrogenQuinolin-2-one 1b (1.7g,4.81mmol) was dissolved in ethanol (10mL), and sodium sulfide (3.79g,48.1mmol) was added to the solution, followed by reaction at 80 ℃ for 4 hours. The reaction was cooled to room temperature, poured into water (30mL), stirred for 15 minutes, filtered, and the collected cake was dried under vacuum to give the title compound 1c (1.20g, 77% yield) as a yellow solid.

MS(ESI,pos.ion)m/z:323.2[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆)δ(ppm)9.94(s,1H),6.77(d,J＝8.6Hz,1H),6.69(s,2H),6.62(d,J＝2.4Hz,1H),6.54(dd,J＝8.6,2.7Hz,1H),5.60(s,2H),2.81(t,J＝7.5Hz,2H),2.42-2.37(m,2H)。

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) oxy]Benzene and its derivatives Base of]Hydrazine fork]Acetyl group]Urethane 1d

6- (4-amino-2, 6-dichloro-phenoxy) -3, 4-dihydro-1H-quinolin-2-one 1c (0.80g,2.5mmol), N-cyanoacetylurethane (0.43g,2.7mmol) and concentrated hydrochloric acid (0.63mL) were added to acetic acid (5mL), and an aqueous solution (2mL) of sodium nitrite (0.19g,2.7mmol) was added dropwise at 3 deg.C, followed by continuing the reaction for 7 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 1d (0.40g, yield 33%) as a yellow solid.

MS(ESI,pos.ion)m/z:491.1[M+H]⁺。

Step 4)2- [3, 5-dichloro-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) oxy]Phenyl radical]-3, 5-bis Oxo-1, 2, 4-triazine-6-carbonitrile 1

Reacting N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 1d (0.40g,0.82mmol) was dissolved in N, N-dimethylacetamide (1mL), and potassium acetate (0.32g,3.3mmol) was added to react at 120 ℃ for 12 hours. Cooling the reaction solution to room temperature, filtering, and separating and purifying the filtrate by preparation and purification [ 50% ACN/50% H ]₂O (0.1% TFA), Philomena ACE specification C1810 μm X50 mm X250 mm, flow rate 100mL/min]To obtain the title compound 1(88mg, yield 24%, HPLC purity: 99.86%) as a white solid.

MS(ESI,neg.ion)m/z:442.0[M-H]^-；

¹HNMR(400MHz,DMSO-d₆)δ(ppm)10.01(s,1H),7.80(s,2H),6.82(d,J＝8.7Hz,1H),6.75(d,J＝2.5Hz,1H),6.64(dd,J＝8.6,2.7Hz,1H),2.84(t,J＝7.4Hz,2H),2.44-2.37(m,2H)。

Example 22- [3, 5-dichloro-4- [ (4, 4-dimethyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 2)

Step 1) N- (4-methoxyphenyl) -3-methyl-but-2-enamide 2b

P-methoxyaniline 2a (4.00g,32.5mmol), 3-methyl-but-2-ene-oic acid (3.69g,35.8mmol), triethylamine (6.8mL,49mmol) and 2- (7-azobenzotrifluorazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (15.6g,39.0mmol) were dissolved in N, N-dimethylformamide (10mL) and reacted at room temperature for 30 minutes. Water (100mL) was added to the reaction, stirred for 10min, filtered, the filter cake was washed with ethanol (10mL), collected and dried under vacuum to give the title compound 2b (4.6g, 69% yield) as a white solid.

Step 2) N- (4-hydroxyphenyl) -3-methyl-but-2-enamide 2c

N- (4-methoxyphenyl) -3-methyl-but-2-enamide 2b (4.6g,22.4mmol) was dissolved in dichloromethane (15mL), and boron tribromide (4.2mL,44mmol) was added dropwise at 5 ℃ to react for 2.5 hours. The reaction was poured into an ice-water mixture (30g), saturated sodium bicarbonate solution (30mL) was added, stirred for 10 minutes, extracted with dichloromethane (10mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration to give the title compound 2c (4.0g, yield 93%) as a white solid.

MS(ESI,pos.ion)m/z:192.3[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆)δ(ppm)9.54(s,1H),9.13(s,1H),7.39(d,J＝8.7Hz,2H),6.67(d,J＝8.8Hz,2H),5.81(s,1H),2.12(s,3H),1.83(s,3H)。

Step 3) 6-hydroxy-4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2d

N- (4-hydroxyphenyl) -3-methyl-but-2-enamide 2c (4.0g,20.9mmol) was dissolved in chlorobenzene (10mL), and aluminum trichloride (5.58g,41.8mmol) was added and reacted at 120 ℃ for 22 hours. The reaction solution was poured into ice water (40mL), extracted with ethyl acetate (20mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] to give the title compound 2d (1.4g, yield 35%) as a pale gray solid.

MS(ESI,pos.ion)m/z:192.3[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆)δ(ppm)9.84(s,1H),9.03(s,1H),6.67(d,J＝8.3Hz,2H),6.53(dd,J＝8.4,2.5Hz,1H),2.26(s,2H),1.17(s,6H)。

Step 4)6- (2, 6-dichloro-4-nitro-phenoxy) -4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2e

6-hydroxy-4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2d (0.80g, 4.2mmol) was dissolved in N, N-dimethylacetamide (5mL), and potassium carbonate (1.5g, 10mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (1.3g,4.2mmol) were added and reacted at 120 ℃ for 5.5 hours under nitrogen substitution. The reaction was cooled to room temperature, water (30mL) was added, stirred for 5 minutes, filtered, and the filter cake was collected and dried under vacuum to give the title compound 2e (1.2g, 75% yield) as a gray solid.

MS(ESI,pos.ion)m/z:381.0[M+H]⁺。

Step 5)6- (4-amino-2, 6-dichloro-phenoxy) -4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2f

6- (2, 6-dichloro-4-nitro-phenoxy) -4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2e (1.2g,3.15mmol) was dissolved in ethanol (5mL), and sodium sulfide (2.48g,31.5mmol) was added and reacted at 80 ℃ for 12 hours. The reaction solution was cooled to room temperature, poured into water (30mL), stirred for 15 minutes, filtered, and purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] collecting the cake to give the title compound 2f (0.50g, yield 45%) as an off-white solid.

¹HNMR(400MHz,DMSO-d₆)δ(ppm)10.02(s,1H),6.81(d,J＝2.7Hz,1H),6.77(d,J＝8.6Hz,1H),6.70(s,2H),6.43(dd,J＝8.6,2.7Hz,1H),5.61(s,2H),2.32(s,2H),1.17(s,6H)。

Step 6) N- [ 2-cyano-2 [ [3, 5-dichloro-4- [ (4, 4-methyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy Base of]Phenyl radical]Hydrazine fork]Acetyl group]2g of urethane

6- (4-amino-2, 6-dichloro-phenoxy) -4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2f (0.45g,1.3mmol), N-cyanoacetylurethane (0.22g,1.4mmol) and concentrated hydrochloric acid (0.33mL) were added to acetic acid (4mL), and an aqueous solution (2mL) of sodium nitrite (0.098g,1.4mmol) was added dropwise at 3 ℃ followed by reaction for 6 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give 2g (0.2g, yield 30%) of the title compound as a yellow solid.

MS(ESI,pos.ion)m/z:518.1[M+H]⁺。

Step 7)2- [3, 5-dichloro-4- [ (4, 4-dimethyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy]Phenyl radical]- 3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 2

Reacting N- [ 2-cyano-2 [ [3, 5-dichloro-4- [ (4, 4-methyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate (2 g, 0.20g,0.39mmol) was dissolved in N, N-dimethylacetamide (1mL), and potassium acetate (0.15g,1.5mmol) was added to react at 120 ℃ for 24 hours. Cooling the reaction solution to room temperature, filtering, separating and purifying the filtrate [ 50% ACN/50%H₂O (0.1% TFA), Philomena ACE specification C1810 μm X50 mm X250 mm, flow rate 100mL/min]To obtain the title compound 2(8mg, yield 4%, HPLC purity: 98.92%) as a white solid.

MS(ESI,pos.ion)m/z:472.0[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆)δ(ppm)9.01(s,1H),7.63(s,2H),7.03(d,J＝2.4Hz,1H),6.70(d,J＝8.6Hz,1H),6.44(dd,J＝8.6,2.5Hz,1H),2.05(s,6H)。

Example 32- [3, 5-dichloro-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 3)

Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) -1, 4-dihydro-3, 1-benzoxazine-2-one 3b

Under the protection of nitrogen, 6-hydroxy-1, 4-dihydro-3, 1-benzoxazine-2-one 3a (1.0g,6.1mmol) was dissolved in N, N-dimethylacetamide (7mL), and potassium carbonate (1.24g,8.97mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (1.9g,6.0mmol) were added in this order to react at 100 ℃ for 4.5 hours. The reaction solution was cooled to room temperature, water (30mL) was added, the mixture was stirred for 5 minutes, and the mixture was filtered, collected and purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 3b (1.33g, yield 62%) as a brown solid.

MS(ESI,neg.ion)m/z:353.0[M-H]^-。

¹HNMR(400MHz,CDCl₃)δ(ppm)8.73(s,1H),8.31(s,2H),6.82(d,J＝12.0Hz,1H),6.73(d,J＝12.0Hz,1H),6.64(d,J＝4.0Hz,1H),5.27(s,2H)。

Step 2)6- (4-amino-2, 6-dichloro-phenoxy) -1, 4-dihydro-3, 1-benzoxazine-2-one 3c

6- (2, 6-dichloro-4-nitro-phenoxy) -1, 4-dihydro-3, 1-benzoxazin-2-one 3b (1.2g,3.4mmol) was added to ethanol (20mL), sodium sulfide nonahydrate (8.29g,33.9mmol) was added, and the reaction was carried out at room temperature for 12 hours. The reaction was quenched by addition of water (40mL), extracted with ethyl acetate (50 × 3), the combined organic phases were washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/1] to give the title compound 3c (0.20g, yield 18%) as a yellow solid.

MS(ESI,pos.ion)m/z:325.0[M+H]⁺；

¹HNMR(400MHz,DMSO-d₆)δ(ppm)6.77(s,2H),6.59(s,J＝4.0Hz,1H),6.54(d,J＝8.0Hz,1H),6.43-6.40(m,1H),5.54(s,2H),4.56(s,2H)。

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) oxy Base of]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 3d

6- (4-amino-2, 6-dichloro-phenoxy) -1, 4-dihydro-3, 1-benzoxazin-2-one 3c (0.16g,0.49mmol) was dissolved in water (6mL) and concentrated hydrochloric acid (1mL), an aqueous solution (1mL) of sodium nitrite (40mg,0.57mmol) was added dropwise at 0 ℃, the reaction solution was then rapidly filtered, and the filtrate was added dropwise to a mixed solution of N-cyanoacetylurethane (84mg,0.54mmol) at 0 ℃ in pyridine (3mL) and water (9mL) and allowed to react at 0 ℃ for 30 minutes. The reaction was filtered, the collected filter cake was dissolved in dichloromethane (20mL), the organic phase was washed successively with water (10mL) and saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 3d (0.15g, 61% yield) as a red solid.

MS(ESI,neg.ion)m/z:489.9[M-H]^-。

Step 4)2- [3, 5-dichloro-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) oxy]Phenyl radical]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 3

Reacting N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) oxy group]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 3d (0.15g,0.30mmol) and sodium acetate (25mg,0.30mmol) were added to acetic acid (2.5mL) and reacted at 120 ℃ for 3.5 hours. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure, and water (7mL) was added dropwise to the residue to obtain a red solidSeparating out, filtering, collecting filter cake, separating and purifying [ 40% ACN/60% H ]₂O (0.1% TFA), Kromasil: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 100mL/min]To obtain the title compound 3(17mg, yield 13%, HPLC purity: 95.95%) as a yellow solid.

MS(ESI,pos.ion)m/z:446.0[M+H]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm)7.81(s,2H),7.37(d,J＝8.0Hz,1H),7.09(d,J＝4.0Hz,1H),6.92-9.89(m,1H),4.53(s,2H)。

Example 42- [3, 5-dichloro-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 4)

Step 1)7- (2, 6-dichloro-4-nitro-phenoxy) -4H-1, 4-benzoxazine-3-one 4b

7-hydroxy-4H-1, 4-benzoxazin-3-one 4a (3.6g,22mmol) was dissolved in N, N-dimethylacetamide (10mL), and potassium carbonate (4.56g,33mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (6.99g,22mmol) were added in this order to react at 120 ℃ for 12 hours. The reaction was cooled to room temperature, quenched by the addition of water (30mL), stirred for 5 minutes, filtered, the filter cake washed with water (10mL), collected and dried under vacuum to give the title compound 4b (6.7g, 87% yield) as a brown solid.

MS(ESI,neg.ion)m/z:354.1[M-H]^-。

¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.66(s,1H),8.51(s,2H),6.84(d,J＝8.0Hz,1H),6.58(d,J＝4.0Hz,1H),6.50-6.47(m,1H),4.57(s,2H)。

Step 2)7- (4-amino-2, 6-dichloro-phenoxy) -4H-1, 4-benzoxazine-3-one 4c

7- (2, 6-dichloro-4-nitro-phenoxy) -4H-1, 4-benzoxazin-3-one 4b (3.0g,8.4mmol) and sodium sulfide nonahydrate (5.6g,23.3mmol) were added to ethanol (20mL) and reacted at 80 ℃ for 15 hours. The reaction was quenched by the addition of water (40mL), stirred for 5 minutes, filtered, and the filter cake collected and dried in vacuo to give the title compound 4c (1.84g, 67% yield) as a brown solid.

MS(ESI,pos.ion)m/z:325.0[M+H]⁺。

¹HNMR(400MHz,CD₃OD)δ(ppm)6.80(d,J＝8.0Hz,1H),6.73(s.2H),6.41-6.36(m,2H),4.54(s,2H)。

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) oxy group]Benzene and its derivatives Base of]Hydrazine fork]Acetyl group]Urethane 4d

7- (4-amino-2, 6-dichloro-phenoxy) -4H-1, 4-benzoxazin-3-one 4c (1.0g,3.08mmol) was added to water (36mL) and concentrated hydrochloric acid (6mL), an aqueous solution (1mL) of sodium nitrite (0.24g,3.39mmol) was added dropwise at-5 deg.C, the reaction was allowed to react for 15 minutes, and the reaction solution was rapidly filtered. To the filtrate was added a mixed solution of N-cyanoacetylurethane (0.53g,3.38mmol) in pyridine (18mL) and water (42mL) at-5 ℃ to react for 30 minutes. The reaction was filtered and the filter cake was collected to give the title compound 4d (0.60g, 40% yield) as an orange solid.

MS(ESI,neg.ion)m/z:488.5[M-H]^-。

Step 4)2- [3, 5-dichloro-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) oxy group]Phenyl radical]-3, 5-dioxo Substituted-1, 2, 4-triazine-6-carbonitrile 4

Acetic acid (10mL) was added to N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) oxy ] group]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 4d (0.60g,1.22mmol) and sodium acetate (100mg,1.2073mmol) were reacted at 120 ℃ for 3 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was added with acetic acid (3mL) and water (15mL), stirred for 15 minutes, filtered, washed with water (5mL), and the filter cake was collected to isolate and purify [ 20% ACN/80% H ]₂O (0.1% ammonia), Kromasil: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 90mL/min]To obtain the title compound 4(61mg, yield 11%, HPLC purity: 97.95%) as a yellow solid.

MS(ESI,neg.ion)m/z:443.9[M-H]^-；

¹H NMR(400MHz,CD₃OD)δ(ppm)7.76(s,2H),6.85(d,J＝12.0Hz,1H),6.51(d,J＝2.6Hz,1H),6.46(dd,J＝8.6,2.7Hz,1H),4.57(s,2H)。

Example 52- [3, 5-dichloro-4- (3, 3-dimethyl-2-oxo-indolin-5-yl) oxy-phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 5)

Step 1)5- (2, 6-dichloro-4-nitro-phenoxy) -3, 3-dimethyl-indolin-2-one 5b

5-hydroxy-3, 3-dimethyl-indolin-2-one 5a (0.48g,2.7mmol) was dissolved in N, N-dimethylacetamide (5mL), and potassium carbonate (0.56g,4.05mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (0.86g,2.7mmol) were added and reacted at 120 ℃ for 18 hours. The reaction was cooled to room temperature, water (20mL) was added, stirred for 5 minutes, filtered, and the filter cake was collected and dried to give the title compound 5b (0.62g, yield 62%) as a yellow solid.

MS(ESI,pos.ion)m/z:367.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.29(s,1H),8.51(s,2H),7.06(d,J＝4.0Hz,1H),6.77(d,J＝8.0Hz,1H),6.61(dd,J＝8.4,2.6Hz,1H),1.23(s,6H)。

Step 2)5- (4-amino-2, 6-dichloro-phenoxy) -3, 3-dimethyl-indolin-2-one 5c

Reacting 5- (2, 6-dichloro-4-nitro-phenoxy) -3, 3-dimethyl-indoleQuinoline (III)-2-ketone 5b (0.62g,1.69mmol) was dissolved in ethanol (10mL), and sodium sulfide nonahydrate (1.20g,4.90mmol) was added and reacted at 80 ℃ for 11 hours. The reaction was cooled to room temperature, quenched by the addition of water (40mL), stirred for 5 minutes, filtered, and the filter cake was collected and dried to give the title compound 5c (0.33g, 57% yield) as a yellow solid.

MS(ESI,pos.ion)m/z:337.0[M+H]⁺。

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- (3, 3-dimethyl-2-oxo-indolin-5-yl) oxy-benzene Base of]Hydrazine fork]Acetyl group]Carbamic acid esterEthyl ester 5d

5- (4-amino-2, 6-dichloro-phenoxy) -3, 3-dimethyl-indolin-2-one 5c (0.15g,0.45mmol) was dissolved in water (5mL) and concentrated hydrochloric acid (2.3mL), an aqueous solution (1mL) of sodium nitrite (31mg,0.45mmol) was added dropwise at 0 ℃, followed by addition of a mixed solution of N-cyanoacetylurethane (78mg,0.50mmol) in pyridine (2.3mL) and water (5.4mL), and reacted at 0 ℃ for 30 minutes. The reaction was filtered, the filter cake was collected and dried to give the title compound 5d (0.13g, 56% yield) as a red solid.

MS(ESI,Pos.ion)m/z:504.0[M+H]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm)7.81(s,2H),6.84(dd,J＝7.5,5.6Hz,2H),6.58(dd,J＝8.4,2.5Hz,1H),4.28(q,J＝7.0Hz,2H),1.36-1.32(m,9H)。

Step 4)2- [3, 5-dichloro-4- (3, 3-dimethyl-2-oxo-indolin-5-yl) oxy-phenyl]-3, 5-bis Oxo-1, 2, 4-triazine-6-carbonitrile 5

Reacting N- [ 2-cyano-2- [ [3, 5-dichloro-4- (3, 3-dimethyl-2-oxo-indole)Quinoline (III)-5-yl) oxy-phenyl]Hydrazine fork]Acetyl group]Ethyl carbamate 5d (126mg,0.25mmol) was dissolved in acetic acid (3.5mL), and sodium acetate (20mg,0.24mmol) was added to react at 120 ℃ for 4 hours. Concentrating the reaction solution, adding water (30mL), filtering, collecting filter cake, drying, and separating and purifying by preparation method [ 47% ACN/53% H₂O (0.1% TFA), Kromasil: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 100mL/min]To obtain the title compound 5(52mg, yield 45%, HPLC purity: 98.82%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:455.9[M-H]^-；

¹H NMR(600MHz,DMSO-d₆)δ(ppm)10.29(s,1H),7.80(s,2H),7.07(s,1H),6.78(d,J＝8.2Hz,1H),6.51(d,J＝7.4Hz,1H),1.24(s,6H)。

EXAMPLE 62- [3, 5-dichloro-4- (2 '-oxospiro [ cyclopropane-1, 3' -indolin ] -5-yl) oxy-phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 6)

Step 1)5'- (2, 6-dichloro-4-nitro-phenoxy) spiro [ cyclopropane-1, 3' -indoline]-2' -keto 6b

5' -Hydroxyspiro [ cyclopropane-1, 3' -indolin ] -2' -one 6a (0.55g,3.14mmol) was dissolved in N, N-dimethylacetamide (5mL), and potassium carbonate (0.65g,4.65mmol) and 3-dichloro-2-iodo-5-nitrobenzene (0.99g,3.1mmol) were added and reacted at 120 ℃ for 14 hours. The reaction was cooled to room temperature, water (40mL) was added, stirred for 5 minutes, filtered, and the filter cake was collected and dried under vacuum to give the title compound 6b (0.88g, 77% yield) as a black solid.

MS(ESI,neg.ion)m/z:363.0[M-H]^-。

Step 2)5'- (4-amino-2, 6-dichloro-phenoxy) spiro [ cyclopropane-1, 3' -indoline]-2' -keto 6c

5- (2, 6-dichloro-4-nitro-phenoxy) spiro [ cyclopropane-1, 3' -indolin ] -2-one 6b (0.88g,2.3mmol) was dissolved in ethanol (12mL), and sodium sulfide nonahydrate (1.47g,6.00mmol) was added and reacted at 80 ℃ for 1 hour. The reaction was cooled to room temperature and quenched by the addition of water (40mL), stirred for 5 minutes, filtered, and the filter cake collected and dried in vacuo to give the title compound 6c (0.39g, 50% yield) as a brown solid.

MS(ESI,pos.ion)m/z:335.0[M+H]⁺。

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2 '-oxospiro [ cyclopropane-1, 3' -indoline)]-5' -yl) Oxy-phenyl]Hydrazine fork]Acetyl group]Urethane 6d

5' - (4-amino-2, 6-dichloro-phenoxy) spiro [ cyclopropane-1, 3' -indolin ] -2' -one 6c (0.39g,1.16mmol) was dissolved in water (12mL) and concentrated hydrochloric acid (6mL), an aqueous solution (2mL) of sodium nitrite (80mg,1.15mmol) was added dropwise at 0 ℃, and then the above reaction solution was rapidly filtered, and the filtrate was added dropwise to a mixed solution of N-cyanoacetylurethane (200mg,1.28mmol) at 0 ℃ in pyridine (6mL) and water (14mL) and kept at 0 ℃ for reaction for 30 minutes. The reaction was filtered, the filter cake collected and dried in vacuo to give the title compound 6d (0.112g, 19% yield) as a red solid.

MS(ESI,neg.ion)m/z:499.9[M-H]^-。

Step 4)2- [3, 5-dichloro-4- (2 '-oxospiro [ cyclopropane-1, 3' -indoleQuinoline (III)]-5' -yl) oxy-phenyl]- 3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 6

To N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2 '-oxospiro [ cyclopropane-1, 3' -indoline)]-5' -yl) oxy-phenyl]Hydrazine fork]Acetyl group]To ethyl carbamate 6d (112mg,0.223mmol) and sodium acetate (18.5mg,0.223mmol) was added acetic acid (3mL) and reacted at 120 ℃ for 4 hours. The reaction was cooled to room temperature, water (10mL) was added, stirred for 10min, filtered, the filter cake was collected and dried under vacuum to give a red solid which was purified by preparative separation [ 25% ACN/75% H₂O (0.1% ammonia), Kromasil: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 100mL/min]To obtain the title compound 6(22mg, yield 21%, HPLC purity: 97.98%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:455.9[M+H]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm)7.75(s,2H),6.89(d,J＝8.0Hz,1H),6.60(m,2H),1.65-1.56(m,4H)。

Example 72- [3, 5-dichloro-4- (2-oxospiro [1, 4-dihydroquinoline-3, 1' -cyclopropane)]-6-yl) oxy-benzene Base of]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile(Compound 7)

Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) spiro [1, 4-dihydroquinoline-3, 1' -cyclopropane]-2-one 7b

6-Hydroxyspiro [1, 4-dihydroquinolin-3, 1' -cyclopropane ] -2-one 7a (0.57g,3.01mmol) was dissolved in N, N-dimethylacetamide (3.5mL), and potassium carbonate (0.62g,4.49mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (0.95g,2.7mmol) were added in this order to react at 120 ℃ for 6 hours. The reaction was cooled to room temperature, water (20mL) was added, stirred for 30 minutes, filtered, and a yellow filter cake was collected to give the title compound 7b (1.1g, 96% yield) as a yellow solid.

MS(ESI,pos.ion)m/z:379.0[M+H]⁺。

Step 2)6- (4-amino-2, 6-dichloro-phenoxy) spiro [1, 4-dihydroquinoline-3, 1' -cyclopropane]-2-one 7c

6- (2, 6-dichloro-4-nitro-phenoxy) spiro [1, 4-dihydroquinoline-3, 1' -cyclopropane ] -2-one 7b (1.1g,2.9mmol) was dissolved in ethanol (20mL), and sodium sulfide nonahydrate (2.3g,9.4mmol) was added and reacted at 80 ℃ for 10 hours. The reaction was cooled to room temperature, and water (40mL) was added to quench the reaction, stirred for 5 minutes, filtered, and collected to give the title compound 7c (0.68g, 67% yield) as a brown solid.

MS(ESI,pos.ion)m/z:349.1[M+H]⁺。

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2-oxospiro [1, 4-dihydroquinoline-3, 1' -cyclopropane)]-6- Yl) oxy-phenyl]Hydrazine fork]Acetyl group]Urethane 7d

6- (4-amino-2, 6-dichloro-phenoxy) spiro [1, 4-dihydroquinoline-3, 1' -cyclopropane ] -2-one 7c (0.68g,1.94mmol) was dissolved in water (20mL) and concentrated hydrochloric acid (10mL), an aqueous solution (3mL) of sodium nitrite (135mg,1.94mmol) was added dropwise at 0 ℃, the reaction solution was then rapidly filtered, and the filtrate was added dropwise to a mixed solution of N-cyanoacetylurethane (334mg,2.13mmol) at 0 ℃ in pyridine (10mL) and water (23mL) and reacted at 0 ℃ for 30 minutes. The reaction was filtered, the collected filter cake was dried under vacuum to give the title compound 7d (83mg, yield 8.3%) as a yellow solid.

MS(ESI,pos.ion)m/z:516.0[M+H]⁺。

Step 4)2- [3, 5-dichloro-4- (2-oxaspiro (1, 4-dihydroquinoline-3, 1' -cyclopropane)]-6-yl-) oxy-benzene Base of]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 7

To N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2-oxospiro [1, 4-dihydroquinoline-3, 1' -cyclopropane)]-6-yl) oxy-phenyl]Hydrazine fork]Acetyl group]To ethyl carbamate 7d (83.1mg,0.161mmol) and sodium acetate (13.3mg,0.161mmol) was added acetic acid (3mL) and the reaction was carried out at 120 ℃ for 4 hours. Cooling the reaction solution to room temperature, adding water (10mL), stirring for 10min, filtering, collecting filter cake, vacuum drying to obtain red solid, and separatingPurification [ 47% ACN/53% H₂O (0.1% TFA), Kromasil: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 100mL/min]To obtain the title compound 7(37mg, yield 49%, HPLC purity: 95.95%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:470.0[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.07(s,1H),7.78(s,2H),6.85(d,J＝8.9Hz,1H),6.65(s,2H),2.81(s,2H),1.04(s,2H),0.69(s,2H)。

Example 82- [3, 5-dichloro-4- [ (2-oxo-1H-quinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 8)

Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) -1H-quinolin-2-one 8a

6- (2, 6-dichloro-4-nitro-phenoxy) -3, 4-dihydro-1H-quinolin-2-one 1b (0.74g,2.09mmol), 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (0.79g,3.14mmol) and N, O-bis (trimethylsilyl) trifluoroacetamide were dissolved in 1, 4-dioxane (15mL) and reacted at 100 ℃ for 21 hours. The reaction solution was cooled to room temperature, water (30mL) was poured into the reaction solution, extracted with ethyl acetate (10mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] to give the title compound 8a (0.21g, yield 29%) as a yellow solid.

MS(ESI,neg.ion)m/z:348.9[M-H]^-；

¹H NMR(400MHz,CDCl₃)δ(ppm)11.15(s,1H),8.34(s,2H),7.66(d,J＝9.6Hz,1H),7.32(d,J＝9.0Hz,1H),7.18(dd,J＝8.9,2.7Hz,1H),6.86(d,J＝2.7Hz,1H),6.71(d,J＝9.6Hz,1H)。

Step 2)6- (4-amino-2, 6-dichloro-phenoxy) -1H-quinolin-2-one 8b

6- (2, 6-dichloro-4-nitro-phenoxy) -1H-quinolin-2-one 8a (0.21g, 0.60mmol) and sodium sulfide (0.24g,3.00mmol) were dissolved in ethanol (3mL) and reacted at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (30mL) was added, stirred for 15 minutes, filtered, and the filter cake was collected and dried under vacuum to give the title compound 8b (0.10g, 52% yield) as a yellow solid.

MS(ESI,pos.ion)m/z:321.0[M+H]⁺。

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2-oxo-1H-quinolin-6-yl) oxy]Phenyl radical]Hydrazine fork]Second step Acyl radical]Urethane 8c

6- (4-amino-2, 6-dichloro-phenoxy) -1H-quinolin-2-one 8b (0.10g, 0.31mmol), N-cyanoacetylurethane (0.05g,0.34mmol) and concentrated hydrochloric acid (0.08mL) were added to acetic acid (2mL), and an aqueous solution (2mL) of sodium nitrite (0.02g,0.34mmol) was added dropwise at 3 ℃ followed by reaction for 2 hours. The reaction was concentrated to give the title compound 8c (0.15g, yield 99%) as a yellow solid.

MS(ESI,pos.ion)m/z:488.0[M+H]⁺。

Step 4)2- [3, 5-dichloro-4- [ (2-oxo-1H-quinolin-6-yl) oxy]Phenyl radical]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 8

Reacting N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2-oxo-1H-quinolin-6-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 8c (0.15g,0.31mmol) was dissolved in N, N-dimethylacetamide (1mL), and potassium acetate (0.12g,1.2mmol) was added to react at 120 ℃ for 5 hours. Cooling the reaction solution to room temperature, filtering, concentrating the filtrate, and separating and purifying the residue [ 39% ACN/61% H ]₂O (0.1% TFA), Philomena ACE specification C1810 μm X50 mm X250 mm, flow rate 100mL/min]To obtain the title compound 8(20mg, yield 15%, HPLC purity: 98.34%) as a white solid.

MS(ESI,neg.ion)m/z:440.3[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)13.30(s,1H),11.75(s,1H),7.87(d,J＝9.5Hz,1H),7.82(s,2H),7.34(d,J＝8.8Hz,1H),7.26(d,J＝9.6Hz,1H),7.09(s,1H),6.50(d,J＝9.4Hz,1H)。

Example 92- [3, 5-dichloro-4- [ (4, 4-dimethyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carboxamide (Compound 9)

Compound 2(0.15g,0.32mmol) was dissolved in concentrated hydrochloric acid (3mL) and reacted at 75 ℃ for 3.5 hours. The reaction was cooled to room temperature, quenched with water (10mL), adjusted to pH 9 with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (15mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration to give the title compound 9(62mg, yield 40%, HPLC purity: 95.00%) as a brown solid.

MS(ESI,pos.ion)m/z:490.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)13.00(s,1H),10.11(s,1H),9.56(d,J＝3.7Hz,1H),7.87(d,J＝2.5Hz,2H),7.67(d,J＝3.6Hz,1H),7.00-6.91(m,1H),6.82(d,J＝8.6Hz,1H),6.50(dd,J＝8.5,2.7Hz,1H),2.35(s,2H),1.21(s,6H)。

Example 102- [3, 5-dichloro-4- [ (4, 4-dimethyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carboxylic acid (Compound 10)

Compound 2(0.15g,0.32mmol) was dissolved in concentrated hydrochloric acid (3mL) and reacted at 75 ℃ for 3.5 hours. The reaction was cooled to room temperature, quenched with water (10mL), adjusted to pH 9 with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (15mL × 3); the aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (3mol/L,30mL), followed by extraction with ethyl acetate (15mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15mL × 2), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 10(50mg, yield 32%, HPLC purity: 99.26%) as a pale yellow solid. MS (ESI, neg. ion) M/z 488.9[ M-H [ ]]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)12.72(s,1H),10.09(s,1H),7.84(s,2H),6.98(d,J＝2.6Hz,1H),6.82(d,J＝8.7Hz,1H),6.50(dd,J＝8.6,2.7Hz,1H),2.35(s,2H),1.22(s,6H)。

EXAMPLE 112- [3, 5-dichloro-4- [ (1-methyl-2-oxo-3, 4-dihydroquinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 11)

Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) -1-methyl-3, 4-dihydroquinolin-2-one 11a

Sodium hydride (0.57g,14mmol,60 mass%) was added portionwise to a solution of 6- (2, 6-dichloro-4-nitro-phenoxy) -3, 4-dihydro-1H-quinolin-2-one 1b (2.00g,5.66mmol) in tetrahydrofuran (30mL) under nitrogen blanket in an ice-water bath, and iodomethane (0.47mL,7.4mmol) was added dropwise, followed by reaction at room temperature for 12 hours. The reaction solution was quenched by adding water (30mL) under an ice-water bath, extracted with ethyl acetate (30mL × 3), the combined organic phases were washed with a saturated sodium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 11a (1.15g, yield 55%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:367.0[M+H]⁺。

Step 2)6- (4-amino-2, 6-dichloro-phenoxy) -1-methyl-3, 4-dihydroquinolin-2-one 11b

6- (2, 6-dichloro-4-nitro-phenoxy) -1-methyl-3, 4-dihydroquinolin-2-one 11a (0.70g,1.90mmol) was dissolved in acetic acid (15mL), and iron powder (0.43g,7.5mmol) was added and reacted at 60 ℃ for 4 hours. The reaction was cooled to room temperature, iron powder was removed, water (40mL) was added, stirring was carried out for 30 minutes, filtration was carried out, and the collected cake was dried under vacuum to give the title compound 11b (0.52g, yield 81%) as an off-white solid.

MS(ESI,pos.ion)m/z:337.1[M+H]⁺。

Step 3) [ 2-cyano-2- [ [3, 5-dichloro-4- [ (1-methyl-2-oxo-3, 4-dihydroquinolin-6-yl) oxy] Phenyl radical]Hydrazine fork]Acetyl group]Urethane 11c

6- (4-amino-2, 6-dichloro-phenoxy) -1-methyl-3, 4-dihydroquinolin-2-one 11b (0.50g,1.48mmol) and N-cyanoacetylurethane (0.26g,1.63mmol) were dissolved in acetic acid (10mL), and an aqueous solution (1.5mL) of sodium nitrite (0.16g,2.23mmol) was added at 0 ℃ to react for 4.5 hours. Water (30mL) was added to the reaction, stirred for 30 min, filtered, and the filter cake was collected and dried under vacuum to give the title compound 11c (0.64g, 86% yield) as a yellow solid.

MS(ESI,neg.ion)m/z:502.1[M-H]^-。

Step 4)2- [3, 5-dichloro-4- [ (1-methyl-2-oxo-3, 4-dihydroquinolin-6-yl) oxy]Phenyl radical]-3,5- Dioxo-1, 2, 4-triazine-6-carbonitrile 11

Ethyl [ 2-cyano-2- [ [3, 5-dichloro-4- [ (1-methyl-2-oxo-3, 4-dihydroquinolin-6-yl) oxy ] phenyl ] hydrazono ] acetyl ] carbamate 11c (0.75g,1.49mmol) was dissolved in N, N-dimethylacetamide (10mL), and sodium acetate (0.62g,7.43mmol) was added and reacted at 120 ℃ for 4.5 hours. The reaction was cooled to room temperature, water (40mL) was added, the pH was adjusted to 7 with dilute hydrochloric acid (2mol/L), stirring was carried out for 30 minutes, filtration was carried out, the collected cake was dried in vacuo, and the resulting reddish brown solid was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/2] to give the title compound 11(0.12g, yield 17%, HPLC purity: 98.14%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:456.1[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)13.28(s,1H),7.82(s,2H),7.05(d,J＝8.9Hz,1H),6.85(d,J＝1.8Hz,1H),6.75-6.69(m,1H),3.23(s,3H),2.85(t,J＝7.0Hz,2H),2.52(t,J＝7.0Hz,2H)。

Example 122- [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 12)

Step 1)7- (2, 6-dichloro-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12b

7-hydroxy-1, 3,4, 5-tetrahydro-1-benzazepin-2-one 12a (0.50g,2.8mmol), 1, 3-dichloro-2-iodo-5-nitro-benzene (0.99g,3.1mmol) were dissolved in N, N-dimethylformamide (8mL), and potassium carbonate (0.79g,5.7mmol) was added to react at 100 ℃ for 16 hours. The reaction was cooled to room temperature, water (15mL) was added, stirred for 15 minutes, filtered, the filter cake was collected, and the resulting yellow solid was recrystallized at 85 ℃ (ethanol/ethyl acetate/petroleum ether ═ 1/5/10,16mL), filtered, and the filter cake was dried to give the title compound 12b (0.70g, yield 68%) as a gray solid.

Step 2)7- (4-amino-2, 6-dichloro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12c

7- (2, 6-dichloro-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12b (0.70g,1.9mmol) was dissolved in acetic acid (8mL), and iron powder (0.43g,7.7mmol) was added and reacted at 70 ℃ for 4 hours. The reaction was cooled to room temperature, water (30mL) was added, stirred for 10 minutes, filtered, rinsed with water (10mL), and the solid collected and dried under vacuum to give the title compound 12c (0.64g, 100% yield) as a brown solid. MS (ESI, pos.ion) M/z 337.0[ M + H ]]⁺。

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepine-7- Radical) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 12d

7- (4-amino-2, 6-dichloro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12c (0.20g,0.54mmol), N-cyanoacetylurethane (94mg,0.59mmol) was dissolved in acetic acid (4mL) and a solution of sodium nitrite (75mg,1.08mmol) in water (2mL) was added at 0 ℃. Water (10mL) was added to the reaction mixture at 0 ℃, stirred for 10 minutes, filtered, rinsed with water (2mL), the filter cake was collected and dried under vacuum to give the title compound 12d (0.27g, 100% yield) as a brown solid.

Step 4)2- [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy]Benzene and its derivatives Base of]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 12

Ethyl N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] hydrazono ] acetyl ] carbamate 12d (0.27g,0.54mmol) was dissolved in N, N-dimethylacetamide (3mL), and sodium acetate (48mg,0.59mmol) was added and reacted at 120 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (20mL) was added, extraction was performed with ethyl acetate (20mL × 5), the combined organic phases were washed with a saturated sodium chloride solution (10mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (100% ethyl acetate), and the resulting red solid was recrystallized (ethanol/ethyl acetate/petroleum ether ═ 1/6/12,9.5mL) at 85 ℃ to give the title compound 12(36mg, yield 15%, HPLC purity: 85.61%) as a red brown solid.

MS(ESI,neg.ion)m/z:456.5[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)13.29(s,1H),9.42(s,1H),7.81(s,2H),6.94(d,J＝8.7Hz,1H),6.87(d,J＝2.6Hz,1H),6.70(dd,J＝8.6,2.8Hz,1H),2.67(t,J＝6.4Hz,2H),2.11(dd,J＝17.3,4.6Hz,4H)。

EXAMPLE 132- [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carboxylic acid methyl ester (Compound 13)

Hydrogen chloride is reacted withTo a solution of compound 12(0.10g,0.22mmol) in methanol (2mL) was added and reacted at 50 ℃ for 4.5 hours (2mL,4.5 mol/L). Cooling the reaction solution to room temperature, concentrating, and separating and purifying the residue [ 40% ACN/60% H ]₂O (0.1% TFA), Philomena ACE specification C1810 μm X50 mm X250 mm, flow rate 100mL/min]To obtain the title compound 13(62mg, yield 58%, HPLC purity: 98.48%) as an off-white solid.

MS(ESI,neg.ion)m/z:490.0[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.81(s,2H),7.05(d,J＝7.9Hz,1H),6.77(s,1H),6.67(d,J＝7.5Hz,1H),3.59(s,3H),2.54(d,J＝4.2Hz,2H),2.41-2.29(m,2H),1.85-1.65(m,2H)。

EXAMPLE 142- [3, 5-dichloro-4- [ (1-methyl-2-oxo-4, 5-dihydro-3H-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 14)

Step 1)7- (2, 6-dichloro-4-nitro-phenoxy) -1-methyl-4, 5-dihydro-3H-1-benzazepin-2-one 14a

7- (2, 6-dichloro-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12b (0.80g,2.2mmol) was dissolved in tetrahydrofuran (15mL), and sodium hydride (0.17g,4.3mmol,60 mass%) was added at 0 ℃ to react for 10 minutes, followed by methyl iodide (0.20mL,3.2mmol) and reacted at room temperature for 1 hour. The reaction was quenched by the addition of water (10mL), extracted with ethyl acetate (50mL × 2), the combined organic phases were washed with saturated sodium chloride (20mL), dried over anhydrous sodium sulfate, concentrated with suction filtration, and the resulting yellow solid was recrystallized from 85 ℃ (petroleum ether/ethyl acetate ═ 3/2,15mL) to give the title compound 14a (0.60g, yield 72%) as a yellow solid.

Step 2)7- (4-amino-2, 6-dichloro-phenoxy) -1-methyl-4, 5-dihydro-3H-1-benzazepin-2-one 14b

7- (2, 6-dichloro-4-nitro-phenoxy) -1-methyl-4, 5-dihydro-3H-1-benzazepin-2-one 14a (0.72g,1.9mmol) was dissolved in acetic acid (8mL), and iron powder (0.21g,3.8mmol) was added and reacted at 60 ℃ for 2 hours. The reaction was cooled to room temperature, water (48mL) was added, stirred for 10min, filtered, rinsed with water (10mL), and the solid was collected and dried under vacuum to give 14b as a yellow solid (0.66g, 99% yield).

Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (1-methyl-2-oxo-4, 5-dihydro-3H-1-benzazepine Zepin-7-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 14c

7- (4-amino-2, 6-dichloro-phenoxy) -1-methyl-4, 5-dihydro-3H-1-benzazepin-2-one 14b (0.56g,1.6mmol) was dissolved in acetic acid (11mL), a solution of sodium nitrite (0.22g,3.2mmol) in water (5.6mL) was added at 0 ℃ and reacted for 1 hour, N-cyanoacetylurethane (0.33g,2.1mmol) was added and the reaction was continued for 3.5 hours. Water (10mL) was added to the reaction mixture at 0 ℃, stirred for 10 minutes, filtered, rinsed with water (10mL), the cake collected and dried under vacuum to give the title compound 14c (0.83g, 100% yield) as a yellow solid.

Step 4)2- [3, 5-dichloro-4- [ (1-methyl-2-oxo-4, 5-dihydro-3H-1-benzazepin-7-yl) oxy Base of]Phenyl radical]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 14

Ethyl N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (1-methyl-2-oxo-4, 5-dihydro-3H-1-benzazepin-7-yl) oxy ] phenyl ] hydrazono ] acetyl ] carbamate 14c (0.86g,1.7mmol) was dissolved in N, N-dimethylformamide (8mL), and sodium acetate (0.20g,2.4mmol) was added and reacted at 120 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (20mL) was added, stirred for 10 minutes, filtered, washed with water (10mL), and the collected solid was slurried with ethanol/ethyl acetate/petroleum ether (5/5/10,20mL) to give the title compound 14(0.41g, yield 52%, HPLC purity: 88.67%) as a yellow solid.

MS(ESI,neg.ion)m/z:469.9[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.82(s,2H),7.30(d,J＝8.8Hz,1H),6.88(d,J＝2.8Hz,1H),6.79(dd,J＝8.7,2.9Hz,1H),3.20(s,3H),2.64(t,J＝6.8Hz,2H),2.13(t,J＝6.6Hz,2H),2.02(t,J＝11.5Hz,2H)。

Example 152- [3, 5-dimethyl-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 15)

Step 1)7- (2, 6-dimethyl-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 15a

7-hydroxy-1, 3,4, 5-tetrahydro-1-benzazepin-2-one 12a (0.30g,1.7mmol), 2-fluoro-1, 3-dimethyl-5-nitro-benzene (0.32g,1.9mmol) were dissolved in N, N-dimethylformamide (2.4mL), and potassium carbonate (0.47g,3.4mmol) was added to react at 70 ℃ for 16 hours. After the reaction solution was cooled to room temperature, water (10mL) was added, stirred for 15 minutes, filtered, and the filter cake was collected and dried to give the title compound 15a (0.55g, yield 100%) as an off-white solid.

Step 2)7- (4-amino-2, 6-dimethyl-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 15b

7- (2, 6-dimethyl-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 15a (0.55g,1.7mmol) was dissolved in acetic acid (3.3mL), and iron powder (0.28g,5.0mmol) was added to the solution to react at 60 ℃ for 5 hours. The reaction was cooled to room temperature, water (10mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), the combined organic phases were washed with saturated sodium chloride (10 mL. times.3), dried over anhydrous sodium sulfate, concentrated by suction filtration, slurried with petroleum ether/ethyl acetate (1/1,10mL), filtered, the cake was collected and dried to give the title compound 15b (0.50g, 100% yield) as an off-white solid.

Step 3) N- [ 2-cyano-2- [ [3, 5-dimethyl-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepine- 7-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 15c

7- (4-amino-2, 6-dimethyl-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 15b (0.50g,1.7mmol) was dissolved in acetic acid (10mL), a solution of sodium nitrite (0.24g,3.4mmol) in water (5mL) was added at 0 deg.C, and after half an hour of reaction, N-cyanoacetylurethane (0.35g,2.2mmol) was added and the reaction was continued for 3 hours. To the reaction mixture was added water (10mL) at 0 deg.C, stirred for 10min, filtered, rinsed with water (10mL), the filter cake was collected and dried to give the title compound 15c (0.47g, 60% yield) as a yellow solid.

Step 4)2- [3, 5-dimethyl-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy]Benzene and its derivatives Base of]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 15

Ethyl N- [ 2-cyano-2- [ [3, 5-dimethyl-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] hydrazono ] acetyl ] carbamate 15c (0.47g,1.0mmol) was dissolved in N, N-dimethylformamide (4mL), and sodium acetate (0.12g,1.5mmol) was added and reacted at 120 ℃ for 5 hours. The reaction was cooled to room temperature, water (10mL) was added, the filter cake was collected and dried, and the resulting solid was recrystallized at 85 ℃ (ethanol/ethyl acetate/petroleum ether ═ 2.5/5/10,17.5mL), filtered, and the filter cake was collected and dried under vacuum to give the title compound 15(0.23g, 54% yield, 98.59% HPLC purity) as a yellow solid.

MS(ESI,neg.ion)m/z:416.2[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)9.35(s,1H),7.29(s,2H),6.90(d,J＝8.6Hz,1H),6.74(d,J＝2.6Hz,1H),6.57(dd,J＝8.6,2.8Hz,1H),3.42(s,2H),2.63(t,J＝6.6Hz,2H),2.11(s,6H),2.10-2.03(m,2H)。

Example 162- [3, 5-bromo-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 16)

Step 1)7- (2, 6-dibromo-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 16a

7-hydroxy-1, 3,4, 5-tetrahydro-1-benzazepin-2-one 12a (0.10g,0.56mmol), 1, 3-dibromo-2-fluoro-5-nitro-benzene (0.20g,0.67mmol) were dissolved in N, N-dimethylformamide (5mL), and potassium carbonate (0.16g,1.2mmol) was added to react at 60 ℃ for 10 hours. After the reaction solution was cooled to room temperature, water (5mL) was added, stirred for 10 minutes, filtered, and the filter cake was collected and dried to give the title compound 16a (0.25g, yield 97%) as a pale yellow solid.

Step 2)7- (4-amino-2, 6-dibromo-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 16b

7- (2, 6-dibromo-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 16a (0.25g,0.55mmol) was dissolved in acetic acid (3mL), and iron powder (0.10g,1.6mmol) was added to the solution, followed by reaction at 60 ℃ for 5 hours. The reaction was cooled to room temperature, water (5mL) was added, stirred for 10min, filtered, washed with water (3mL × 2), and the filter cake was collected and dried to give the title compound 16b (0.19g, yield 81%) as a yellow solid.

Step 3) N- [ 2-cyano-2- [ [3, 5-dibromo-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepine-7- Radical) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 16c

7- (4-amino-2, 6-dibromo-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 16b (0.19g,0.45mmol) was dissolved in acetic acid (3mL), a solution of sodium nitrite (46mg,0.67mmol) in water (1mL) was added at 0 ℃, and after 10 minutes of reaction, N-cyanoacetylurethane (90mg,0.56mmol) was added, followed by continuing the reaction at 0 ℃ for 1 hour. To the reaction was added water (3mL), stirred for 10min, filtered, washed with water (3mL), and the filter cake was collected and dried to give the title compound 16c (0.20g, 76% yield) as a yellow solid.

Step 4)2- [3, 5-dibromo-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy) benzene Base of]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 16

Reacting N- [ 2-cyano-2- [ [3, 5-dibromo-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy group]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 16c (0.20g,0.34mmol) was dissolved in N, N-dimethylformamide (3mL), and sodium acetate (33mg,0.40mmol) was added to react at 120 ℃ for 5 hours. The reaction mixture was cooled to room temperature, water (5mL) was added, stirred for 10 minutes, filtered and collectedThe collected solid was separated and purified by preparative liquid chromatography [ 47% ACN/53% H ]₂O (0.1% TFA), Kromasil standard: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 100mL/min]To obtain the title compound 16(50mg, yield 27%, HPLC purity: 98.04%) as a white solid.

MS(ESI,neg.ion)m/z:546.0[M-H]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)13.25(s,1H),9.42(s,1H),7.95(s,2H),6.94(d,J＝8.8Hz,1H),6.85(d,J＝2.4Hz,1H),6.64(dd,J＝2.8,2.8Hz,1H),2.67(t,J＝6.4Hz,2H),2.72-2.62(m,4H)。

Activity test examples

Firstly, the compounds of the invention detect the agonist activity of TR alpha or TR beta in a dual-luciferase reporter gene experiment

Test materials:

HEK293 cells, purchased from ATCC, Cat No. CRL-1573;

fugene HD transfection reagent, available from Promega, Cat No. E231A;

DMEM, available from Gibco, Cat No. 11995;

FBS, purchased from Biosera, Cat No. FB-1280/500;

0.25% Trypsin-EDTA, available from Gibco, Cat No. 25200-072;

Dual-Luciferase Reporter Assay System, available from Promega, Cat No. E1960;

96-well plate (round bottom) available from Corning, Cat No. 3365.

The test method comprises the following steps:

HEK293 cells were cultured in 10% FBS + DMEM in whole medium. pBind-TR alpha or pBind-TR beta (100 ng/. mu.l), pG5Luc (100 ng/. mu.l), FuGENE HD and Opti-MEM were mixed well and incubated at room temperature for 15min, while HEK293 cells were digested with 0.25% Trypsin-EDTA, resuspended in whole medium, the cell density was calculated, adjusted to 500,000cells/ml, the transcription mixture was added to mix well with the cell suspension, plated in 96-well plates (100. mu.L/well), and cultured at 37 ℃ for 24 h. After 24h, test compounds were dissolved in DMSO and diluted 3-fold for 10 concentrations, followed by dilution of the compounds with DMEM to 10% DMSOCompound solution, 5 μ L of compound was put in a 96-well plate, the compound DMSO content was 0.5% final, and the compound was co-cultured with cells for 18 h. After 18h, firefly fluorescence signal and renilla fluorescence signal were detected using the Dual-Luciferase Reporter Assay System. The F/R ratio was calculated by dividing the firefly fluorescence signal (F) by the Renilla fluorescence signal (R), and EC was calculated by plotting using Graph Pad Prism software₅₀The value is obtained.

The test results show that: the compound has obvious agonistic activity and selectivity on TR beta.

Secondly, the in vitro binding activity detection of the compound of the invention to TR alpha or TR beta

Test materials:

LanthaScreen TR-FRET thyoid Receptor beta activator Assay kit purchased from Invitrogen, Cat.No. PV4686;

LanthaScreen TR-FRET Thyroid Receptor alfa Coactivator Assay kit was purchased from Invitrogen, Cat.No. PV4687.

The test method comprises the following steps:

the method uses the LanthaScreen TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit to perform the experiment. Test compounds were dissolved in DMSO and diluted 3-fold for 10 concentrations, followed by dilution with TR-FRET Coregulator Buffer C in the kit to a compound solution containing 2% DMSO. mu.L of compound solution containing 2% DMSO was placed in 384 well plates, then 5. mu.L of 4 XTR beta/alfa-LBD, 5. mu.L of a mixture containing 0.4. mu.M fluoroescein-SRC 2-2 and 8nM Tb anti-GST antibody was added to each well, mixed well and incubated at room temperature for 1h in the dark. After 1h, fluorescence values (RFU) were read at excitation 520nm and emission 495nm using a PHERAStar FSX microplate reader from BMG LABTECH. The TR-FRET ratio was calculated by dividing the emission signal at 520nm by the emission signal at 495 nm. Curve generation and EC calculation Using Graph Pad Prism 5 software₅₀The value is obtained. The results of the experiment are shown in table 1.

Table 1:

the test results show that: the compound has stronger binding affinity and selectivity to TR beta.

Third, pharmacokinetic determination of the Compounds of the invention

For purposes of the test the following method was used to determine the pharmacokinetics of the compounds of the present invention.

Test materials:

the used experimental reagents and test articles are as follows: propranolol (internal standard)), methanol, ammonium acetate, K₂EDTA (potassium ethylenediaminetetraacetate), formic acid, acetonitrile, MTBE (methyl tert-butyl ether), KolliphorHS15 (polyethylene glycol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available;

SD rat: male, 180-.

The test method comprises the following steps:

1. preparation of test article

The test solutions were prepared from 5% DMSO + 5% KolliphorHS15+ 90% physiological saline, and were adjusted to the solubility of each compound so that the compound was completely dissolved.

2. Design of animal experiments

3. Animal administration dose meter

Group of	Sex	Number of animals	Dosage to be administered	Concentration of drug administration	Volume of administration
						I.v. was injected intravenously.	Male sex	3	1mg/kg	1mg/mL	1mL/kg
P.O is administered orally.	Male sex	3	5mg/kg	1mg/mL	5mL/kg

4. Solution preparation

(1) Preparation of a stock solution of a test article: accurately weighing a proper amount of a test sample, dissolving the test sample in DMSO, diluting the test sample to 1mg/mL by using acetonitrile, and shaking up the test sample to obtain the test sample. Storing at-20 deg.C for use.

(2) Preparing an internal standard substance solution: a certain amount of 1mg/mL Propranol stock solution was precisely aspirated and diluted to 100ng/mL with water.

5. Sample analysis

Processing a sample by adopting a liquid-liquid extraction method, carrying out chromatographic separation, carrying out quantitative analysis on the sample by a triple quadrupole tandem mass spectrometer in a multiple reactive ion monitoring (MRM) mode, and calculating the concentration of the result by using instrument quantitative software.

6. Plasma sample pretreatment

Accurately sucking 30 μ L of plasma sample, adding 250 μ L of internal standard, and mixing by vortex. The extract was extracted once with 1mL of MTBE, centrifuged at 13,000rpm for 2min at 4 ℃, 800. mu.L of the supernatant was aspirated, evaporated in a 96-well nitrogen blower, and the residue was reconstituted with 150. mu.L of methanol/water (v/v. 50/50), vortexed, and injected in an amount of 8. mu.L.

7. Preparation of Standard samples

Accurately sucking a proper amount of compound stock solution, and adding acetonitrile to dilute to prepare a standard series solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, uniformly mixing by vortex, preparing plasma samples with plasma concentrations of 3,5, 10, 30, 100, 300, 1,000, 3,000, 5,000 and 10,000ng/mL, performing double-sample analysis according to the operation of 'plasma sample pretreatment', and establishing a standard curve.

8. Analytical method

The LC/MS method was used to determine the amount of test compound in rat plasma after administration of the different compounds.

9. Data processing

Pharmacokinetic parameters were calculated using WinNonlin 6.1 software, a non-compartmental model method.

The test results show that the compound of the invention shows excellent pharmacokinetic properties when administered by intravenous injection or oral administration.

Fourthly, pharmacodynamic evaluation of the compound of the invention

Test materials:

western diet: purchased from Research die, cat #: D12079B;

MCD die: purchased from southbound telofil fodder science ltd, cat #: TP 3006R;

ALT, AST, ALP, TG, CHO, HDL, LDL and GLU: purchased from Roche, and the respective cargo numbers are: 20764957322, 20764949322, 03333701190, 20767107322, 0303973190, 04399803190, 03038866322 and 04404483190;

male OB/OB mice 8 weeks old: purchased from Jiangsu Jiejiaokang Biotech limited;

8 week old male db/db mice: purchased from Jiangsu Jiejiaokang Biotech limited.

A. Compound on OB/OB mouse nonalcoholic steatohepatitis (NASH) model induced by Western diet Evaluation of pharmacodynamics of (1)

OB/OB mice are mice with leptin gene deletion, and OB/OB mouse NASH model induced by Western diet is a common NASH in vivo efficacy evaluation model. The experiment was started 1 week after the animals were acclimated. OB/OB mice were fed Western diet, which was changed three times a week (Monday, three, five), and mice were dosed starting at the fifth week after feeding, once a day orally for 6 weeks, for a total experimental period of 10 weeks. The animals were monitored daily for baseline performance during the experiment and mouse body weights were recorded weekly. After the experiment, the test was performed overnight, and the mice were anesthetized, subjected to orbital bleeding to collect whole blood, centrifuged at 4 ℃ and 4,000rpm for 10min to obtain serum, and stored at-80 ℃. The serum was used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. The mice were dissected, livers were removed and weighed. Liver midlobes were stored at-80 ℃ in EP tubes and used for intrahepatic TG and CHO content determination. Left lobe of liver was fixed in 10% formalin, HE stained and scored for NAS.

B. Efficacy of Compounds in MCD diet-induced db/db mouse non-alcoholic steatohepatitis (NASH) model Evaluation of science

The db/db mouse is a leptin receptor gene deletion mouse, and the db/db mouse NASH model induced by MCD diet is a commonly used NASH in-vivo efficacy evaluation model. The experiment was started 1 week after the animals were acclimated. db/db mice were fed with MCD feed, which was changed three times a week (monday, wednesday, friday), and the mice were tested by dosing while molding, once a day for 8 weeks, with the entire test period of 8 weeks. The animals were monitored daily for baseline performance during the experiment and mouse body weights were recorded weekly. After the experiment, the mice were anesthetized, subjected to orbital bleeding to collect whole blood, centrifuged at 4 ℃ and 4,000rpm for 10min to obtain serum, and stored at-80 ℃. The serum was used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. The mice were dissected, livers were removed and weighed. Liver midlobes were stored at-80 ℃ in EP tubes and used for intrahepatic TG and CHO content determination. Left lobe of liver was fixed in 10% formalin, HE stained and scored for NAS.

Test results show that the compound can effectively reduce fat accumulation in liver, relieve inflammation and improve hepatic fibrosis.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,

wherein,

y is-O-),-NH-、-CH₂-、-CH＝CH-、-C(＝O)-、-CH(OH)-、-CH(CH₃)-、-C(CH₃)₂-or-S-;

R¹is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (═ O) -C_1-6Alkoxy, -C (═ O) -C_1-6Alkyl, -C (═ O) -C_1-6Alkylamino, -C (═ O) NH₂、-S(＝O)₂-C_1-6Alkyl, -S (═ O)₂-C_1-6Alkylamino, -S (═ O)₂NH₂、C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl or cyano C_1-6An alkyl group;

ring A is

X is N or CH;

or R^a、R^bTogether with the carbon atom to which they are attached form C_3-8Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R^c、R^dAnd the carbon atoms to which they are attachedTogether form C_3-8Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R^e、R^fTogether with the carbon atom to which they are attached form C_3-8A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C_3-8The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted;

2. The compound of claim 1, wherein R is^3a、R^3b、R^3cAnd R^3dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂-SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF₃、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl or cyanomethyl.

3. The compound of claim 1 or 2, wherein R is¹Is H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂-SH, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-C(＝O)-OCH₃、-C(＝O)-OCH₂CH₃、-C(＝O)-OCH(CH₃)₂、-C(＝O)-OCH₂CH₂CH₃、-C(＝O)-O(CH₂)₃CH₃、-C(＝O)-OCH₂CH(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-CH₂CH₃、-C(＝O)-NHCH₃、-C(＝O)-N(CH₃)₂、-C(＝O)NH₂、-S(＝O)₂-CH₃、-S(＝O)₂-CH₂CH₃、-S(＝O)₂-NHCH₃、-S(＝O)₂NH₂Methylamino, ethylamino, methoxy, ethoxy, -CF₃、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Trifluoromethoxy group, difluoromethoxy group, hydroxymethyl group, aminomethyl groupCarboxymethyl or cyanomethyl.

4. A compound according to any one of claims 1-3, wherein R is²Is H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃C ≡ CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl with 5-6 atoms, phenyl, naphthyl or heteroaryl with 5-6 atoms.

5. The compound of any one of claims 1-4, wherein each R is^a、R^b、R^c、R^d、R^e、R^f、R^h、Rⁱ、R^j、R^k、R^mAnd RⁿIndependently H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂、-SH、C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene is each independently unsubstituted or substituted by 1,2 or3R^y1Substituted;

6. The compound of any one of claims 1-5, wherein each R is^a、R^b、R^c、R^d、R^e、R^f、R^h、Rⁱ、R^j、R^k、R^mAnd RⁿIndependently H, deuterium, F, Cl, Br, I, -CN, -NO₂、-COOH、-OH、-NH₂-SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃-C.ident.CH, methoxy, ethoxy, methylamino, -CF₃、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH₂-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-CH₂-, phenyl-CH₂CH₂-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH₂-, thienyl-CH₂-, imidazolyl-CH₂-, pyrimidinyl-CH₂-, pyridinyl-CH₂-or pyrrolyl-CH₂-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butylButyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃-C.ident.CH, methoxy, ethoxy, methylamino, -CHF₂、-CH₂F、-CH₂CF₃、-CH₂CHF₂Difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH₂-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-CH₂-, phenyl-CH₂CH₂-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH₂-, thienyl-CH₂-, imidazolyl-CH₂-, pyrimidinyl-CH₂-, pyridinyl-CH₂-and pyrrolyl-CH₂Each independently unsubstituted or substituted by 1,2 or 3R^y1Substituted;

or R^a、R^bTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a heterocyclic ring of 5 to 6 atoms, or R^c、R^dTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a heterocyclic ring of 5 to 6 atoms, or R^e、R^fTogether with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a 5-6 atom heterocycle wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R^y1And (4) substituting.

7. The compound of any one of claims 1-6, wherein each R is⁴And R^gEach independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-CF₃、-CHF₂、-CH₂F、-CH₂CHF₂、-CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene, wherein the methyl, ethyl, n-propyl, isopropyl, -CH ═ CH₂、-CH₂CH＝CH₂、-CH＝CHCH₃、-C≡CH、-CHF₂、-CH₂F、-CH₂CHF₂、-CH₂CF₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C_3-6cycloalkyl-C_1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C_1-2Alkylene, phenyl-C_1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C_1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3R^y1And (4) substituting.

8. The compound according to any one of claims 1-7, each R^yIndependently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CHF₂Trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, or methylamino;

each R^y1Independently deuterium, F, Cl, Br, I, -CN, -OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CHF₂Trifluoromethoxy, difluoromethoxy, methoxy, ethoxy or methylamino.

9. The compound according to any one of claims 1-8, having one of the following structures:

or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

10. A pharmaceutical composition comprising a compound of any one of claims 1-9, optionally further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or any combination thereof.

11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for agonising a thyroid hormone receptor; or for the prevention, treatment or alleviation of diseases modulated by thyroid hormone receptors.

12. The use of claim 11, wherein the thyroid hormone receptor is thyroid hormone beta receptor.

13. The use according to claim 11, wherein the disease modulated by thyroid hormone receptors is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer;

wherein the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.