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

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a compound as a thyroid hormone beta receptor agonist and its use, and further relates to a pharmaceutical composition comprising the compound. The present invention further relates to the use of the compound and the pharmaceutical composition in preparing a drug for preventing, treating or alleviating a disease regulated by the thyroid hormone beta receptor, especially in preparing a drug for treating non-alcoholic fatty liver disease. Background Art

[0002] Thyroid hormone (TH) plays an extremely important role in growth, differentiation, development and maintaining metabolic balance. Thyroid hormone is synthesized by the thyroid gland and secreted into the circulation in two main forms: triiodothyronine (T3) and tetraiodothyronine (T4). Although T4 is the main form secreted by the thyroid gland, T3 is the more physiologically active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues, but mainly in the liver and kidneys.

[0003] The physiological effects of TH are mainly carried out through the thyroid hormone receptor (TR). TR is a member of the nuclear receptor superfamily and is a transcription factor induced by the ligand T3. It plays a core role in mediating the action of T3. TR is mainly located in the cell nucleus, and forms a heterodimer with the retinoid X receptor (RXR) and other nuclear receptors to bind to the thyroid hormone response element (TRE) in the promoter region of the target gene, thereby regulating gene transcription. TR has two subtypes: TRα and TRβ. TRα can be divided into TRα1 and TRα2, and TRβ can be divided into TRβ1 and TRβ2. Among them, only TRα1, TRβ1 and TRβ2 can bind to the ligand T3. TRα mainly regulates heart rate, and TRβ plays a key role in controlling liver cholesterol metabolism and inhibiting the release of thyroid stimulating hormone (TSH), which may be related to the high expression of TRβ in the liver and pituitary gland.

[0004] If side effects can be minimized or eliminated, thyroid hormone has certain therapeutic benefits (Paul M. Yen Physiological Reviews, Vol. 81 (3): pp. 1097-1126 (2001); Paul Webb Expert Opin. Investig. Drugs, Vol. 13 (5): pp. 489-500 (2004)). For example, thyroid hormone can increase metabolic rate, oxygen consumption and heat production, thereby reducing body weight. Reducing body weight will improve co-morbidities associated with obesity and have a beneficial effect on obese patients, and can also have a beneficial effect on glycemic control in obese patients with type 2 diabetes.

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

[0006] In addition, non-alcoholic fatty liver disease (NAFLD) is also closely related to thyroid hormones. On the one hand, NAFLD patients have an impact on the conversion and inactivation of thyroid hormones, which can lead to a decrease in serum thyroid hormone levels; on the other hand, the decrease in thyroid hormone levels further causes lipid metabolism disorders and sugar metabolism disorders, which are involved in the occurrence of NAFLD. Studies have shown that the use of a choline-methionine deficient diet to induce fatty liver formation in rats can reverse fatty liver after feeding T3 (Perra A, et al. Faseb, 2008, 22 (8): 2981).

[0007] However, endogenous thyroid hormones are non-selective and have side effects, such as hyperthyroidism, particularly those related to cardiovascular toxicity. Therefore, 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 hormones would open new avenues for treating patients with diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic fatty liver disease, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, and related conditions and diseases. Summary of the invention

[0008] The present invention provides a class of compounds with good stimulating activity of thyroid hormone beta receptors. Such compounds and pharmaceutical compositions thereof can be used to prepare drugs for preventing, treating or alleviating patients' non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer.

[0009] On the one hand, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I),

[0010]

[0011] in,

[0012] Y is -O-, -NH-, -CH2- or -S-;

[0013] L is -O-, -CH2-, -CH=CH-, *-NR 0 C(=O)-, *-C(=O)NR 0 -、-NR 0 - or -S-; * indicates the end connected to the benzene ring;

[0014] X is a bond or C 1-6 Alkylene;

[0015] R 1 , R 2 , R 3 and R 4 Each independently represents H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl or cyano C 1-6 alkyl;

[0016] A is

[0017] Among them, ring C is C 3-8 A carbon ring or a heterocyclic ring consisting of 3 to 8 atoms;

[0018] p, r and t are each independently 0, 1, 2, 3 or 4;

[0019] Z 3 is -CH= or -N=;

[0020] Z 1 and Z 2 Each is independently a key, -CR 5c R 5d -、-NR n -, -O-, -S-, -C(=O)-, -S(=O)-, or -S(=O)2-;

[0021] U 1 For-CR U1 =or-N=;U 2 For-CR U2 = or -N =;

[0022] U 3 and U 4 Each is independently a key, -CR U3 R U4 -、-NR n1 -, -O-, -S-, -C(=O)-, -S(=O)-, or -S(=O)2-;

[0023] T 1 For-CR T1 = or -N =; T 2 For-CR T2= or -N =; T 3 For-CR T3 = or -N =; T 4 For-CR T4 = or -N =;

[0024] Each R 5a , R 5b , R 5c , R 5d , R U1 , R U2 , R U3 , R U4 , R T1 , R T2 , R T3 and R T4 are independently H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-4 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-4 Alkylene;

[0025] Each R 5 are independently H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-4 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C6-10 Aryl-C 1-4 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-4 Alkylene, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-4 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene and (heteroaryl consisting of 5-6 atoms)-C 1-4 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 It is substituted by a substituent of an aryl group or a heteroaryl group consisting of 5 to 6 atoms;

[0026] or two R attached to adjacent atoms 5 Together with the atoms to which they are attached, they form C 3-8 A carbon ring or a heterocyclic ring consisting of 3 to 8 atoms;

[0027] or two R attached to the same carbon atom 5 Together with the atoms to which they are attached, they form C 3-8 A carbon ring or a heterocyclic ring consisting of 3 to 8 atoms;

[0028] R 0 , R n and R n1 Each independently is H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C3-6 Cycloalkyl-C 1-4 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-4 Alkylene; wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-4 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene and (heteroaryl consisting of 5-6 atoms)-C 1-4 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 It is substituted by a substituent of an aryl group or a heteroaryl group consisting of 5 to 6 atoms;

[0029] B is

[0030] V 1 、V 6 and V 7 Each is independently -CH= or -N=;

[0031] V 2 、V 3 、V 4 and V 5 Each is independently -CH2-, -NH-, -O-, -S-, -C(=O)-, -S(=O)- or -S(=O)2-;

[0032] Each R 6 and R 6a are independently deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl or heteroaryl consisting of 5-6 atoms;

[0033] n and q are each independently 0, 1, 2, 3 or 4;

[0034] Wherein, the compound does not include the following compounds:

[0035]

[0036] In some embodiments, each R 6 and R 6a are independently deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, N,N-dimethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, phenyl, naphthyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, imidazolyl, pyrimidinyl, pyridinyl or pyrrolyl;

[0037] R 0 , R n and R n1 Each independently is H, deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-3 Alkylene; wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and (heteroaryl consisting of 5-6 atoms)-C 1-3 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 The aryl group or the heteroaryl group consisting of 5-6 atoms is substituted.

[0038] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II).

[0039]

[0040] In some embodiments, A is

[0041] Among them, X 1 , X 2 , X 3 and X 4 Each independently represents -CH2- or -NH-; X 5 and X 6 Each is independently -CH= or -N=.

[0042] In some embodiments, A is

[0043] Each R 5 are independently H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-2 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-2 Alkylene, C 6-10 Aryl-C 1-2 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-2 Alkylene, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-2 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-2 Alkylene, C 6-10 Aryl-C 1-2 Alkylene and (heteroaryl consisting of 5-6 atoms)-C 1-2 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 It is substituted by a substituent of an aryl group or a heteroaryl group consisting of 5 to 6 atoms;

[0044] or two R attached to adjacent atoms 5 Together with the atoms to which they are attached, they form C 3-6 A carbon ring or a heterocyclic ring consisting of 3 to 6 atoms;

[0045] or two R attached to the same carbon atom 5 Together with the atoms to which they are attached, they form C 3-6 A carbon ring or a hetero ring consisting of 3 to 6 atoms.

[0046] In some embodiments, each R 5are independently H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, N,N-dimethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, phenyl, naphthyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrrolyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl-CH2CH2-, cyclopentyl-CH2CH2-, cyclohexyl-CH2CH2-, cyclopentadienyl-CH2-, phenyl-CH2-, phenyl-CH2CH2-, phenyl-CH2CH2-, phenyl-CH2CH2CH2-, naphthyl-CH2-, tetrahydropyranyl-CH2-, pyrrolidinyl-CH2-, pyrazolidinyl-CH2- 2-, tetrahydrofuranyl-CH2-, tetrahydrothienyl-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, thiomorpholinyl-CH2-, piperazinyl-CH2-, furanyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, thiazolyl-CH2-, pyrimidinyl-CH2-, pyrazinyl-CH2-, pyridazinyl-CH2-, pyridinyl-CH2- or pyrrolyl-CH2-; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, N,N-dimethylamino, -CF3, -CHF 2, -CH2F, -CH2CF3, -OCF3, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, phenyl, naphthyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridyl and pyrrolyl are each independently unsubstituted or substituted by 1, 2 or 3 independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 It is substituted by a substituent of an aryl group or a heteroaryl group consisting of 5 to 6 atoms;

[0047] or two R attached to adjacent atoms 5 Together with the atoms to which they are attached, they form C 3-6 A carbon ring or a heterocyclic ring consisting of 3 to 6 atoms;

[0048] or two R attached to the same carbon atom 5 Together with the atoms to which they are attached, they form C 3-6 A carbon ring or a hetero ring consisting of 3 to 6 atoms.

[0049] In some embodiments, R 0 , R n and R n1 each independently represents H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, trifluoroethyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrothiophenyl, morpholinyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, C 1-2 Alkylene, cyclobutyl C 1-2 Alkylene, cyclopentyl C 1-2 Alkylene, cyclohexyl C 1-2 Alkylene, tetrahydropyranyl C 1-2 Alkylene, tetrahydrofuranyl C 1-2 Alkylene, piperidinyl C 1-2 Alkylene, piperazine C 1-2 Alkylene, pyrrolidyl C 1-2 Alkylene, tetrahydrothienyl C 1-2 Alkylene, morpholinyl C 1-2 Alkylene, phenyl C 1-2 Alkylene, naphthyl C 1-2 Alkylene, furanyl C 1-2 Alkylene, thienyl C 1-2 Alkylene, thiazolyl C 1-2 Alkylene, pyrazolyl C 1-2 Alkylene, imidazolyl C 1-2 Alkylene, pyrrolyl C 1-2 Alkylene, pyridyl C 1-2 Alkylene, pyrimidinyl C 1-2 Alkylene, pyrazinyl C 1-2 Alkylene or pyridazinyl C 1-2Alkylene; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoroethyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrothiophenyl, morpholinyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl C 1-2 Alkylene, cyclobutyl C 1-2 Alkylene, cyclopentyl C 1-2 Alkylene, cyclohexyl C 1-2 Alkylene, tetrahydropyranyl C 1-2 Alkylene, tetrahydrofuranyl C 1-2 Alkylene, piperidinyl C 1-2 Alkylene, piperazine C 1-2 Alkylene, pyrrolidyl C 1-2 Alkylene, tetrahydrothienyl C 1-2 Alkylene, morpholinyl C 1-2 Alkylene, phenyl C 1-2 Alkylene, naphthyl C 1-2 Alkylene, furanyl C 1-2 Alkylene, thienyl C 1-2 Alkylene, thiazolyl C 1-2 Alkylene, pyrazolyl C 1-2 Alkylene, imidazolyl C 1-2 Alkylene, pyrrolyl C 1-2 Alkylene, pyridyl C 1-2 Alkylene, pyrimidinyl C 1-2 Alkylene, pyrazinyl C 1-2 Alkylene and pyridazinyl C 1-2 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Substituted by a substituent of a cycloalkyl group, a heterocyclic group consisting of 3 to 6 atoms, a phenyl group or a heteroaryl group consisting of 5 to 6 atoms;

[0050] Each R 5a , R 5b , R 5c , R 5d , R U1 , R U2 , R U3 , R U4 , R T1 , RT2 , R T3 and R T4 are independently H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, N,N-dimethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, phenyl, naphthyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thiophenyl, imidazolyl, pyrimidinyl, pyridinyl, pyrrolyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-3 Alkylene, phenyl-C 1-3 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-3 Alkylene.

[0051] On the other hand, the present invention relates to a pharmaceutical composition comprising the compound of the present invention, and optionally, further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or any combination thereof.

[0052] On the other hand, the present invention relates to the use of the compound described in the present invention or the pharmaceutical composition described in the present invention in the preparation of a drug, wherein the drug is used to stimulate thyroid hormone receptors, or to prevent, treat or alleviate diseases regulated by thyroid hormone receptors.

[0053] In some embodiments, the thyroid hormone receptor described herein is a thyroid hormone beta receptor.

[0054] In some embodiments, the disease modulated by thyroid hormone receptor described in the present invention is a neurodegenerative disease, non-alcoholic fatty liver disease, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer.

[0055] In some embodiments, the non-alcoholic fatty liver disease described in the present invention is non-alcoholic simple fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.

[0056] In some embodiments, the neurodegenerative disease described herein is a demyelinating disease, a chronic demyelinating disease, a leukodystrophy, dementia, an ischemic stroke, a lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenal dystrophy (ALD), amyotrophic lateral sclerosis (ALS), or Alzheimer's disease.

[0057] The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and complete below.

[0058] Definitions and general terms

[0059] Certain embodiments of the present invention are now described in detail, and examples thereof are illustrated by the accompanying structural formula and chemical formula. The present invention is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included within the scope of the present invention. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is by no means limited to the methods and materials described herein, and in the case where one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0060] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0061] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0062] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0063] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. 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 the implementation of the described embodiment.

[0064] Unless otherwise stated, the terms used in the specification and claims of the present invention have the following definitions.

[0065] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0066] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in the embodiments. It should be understood that the term "optionally substituted" can be used interchangeably with the term "unsubstituted or substituted by..." The term "optionally", "optional" or "optionally" means that the event or situation described subsequently may but may not occur, and the description includes situations in which the event or situation occurs, as well as situations in which the event or situation does not occur. In general, unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner. The substituents described herein can be, but are not limited to, -H, -D, -F, -Cl, -Br, -I, -CN, -NO2, -COOH, -OH, -NH2, -SH, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkylene, heterocyclyl-alkylene, carbocyclyl, heterocyclyl, aryl, aryl-alkylene, heteroaryl, heteroaryl-alkylene, and the like.

[0067] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each...is independently" and "...are each independently" and "...are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0068] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to independently disclosed C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl; "heterocyclic group consisting of 3-6 atoms" refers to heterocyclic group consisting of 3 atoms, heterocyclic group consisting of 4 atoms, heterocyclic group consisting of 5 atoms and heterocyclic group consisting of 6 atoms.

[0069] In various parts of this specification, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.

[0070] The term "alkyl" or "alkyl group" refers to a saturated, linear or branched, 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 to 8 carbon atoms, i.e., C 1-8 In some embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C 1-6 In some embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 In some embodiments, the alkyl group contains 1-3 carbon atoms, i.e., C 1-3 In some embodiments, the alkyl group contains 1-2 carbon atoms, i.e., C 1-2 alkyl.

[0071] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), and the like.

[0072] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation is carbon-carbon sp 2 In some embodiments, the alkenyl group contains 2-8 carbon atoms; in some embodiments, the alkenyl group contains 2-6 carbon atoms, i.e., C 2-6 In some embodiments, the alkenyl group contains 2-4 carbon atoms, i.e., C 2-4 Alkenyl.

[0073] Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), propenyl (-CH=CHCH3), butenyl (-CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=C(CH3)2, -CH=C(CH3)2, -CH2C(CH3)=CH2), and the like.

[0074] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein at least one unsaturated site is a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in some embodiments, the alkynyl group contains 2-6 carbon atoms, i.e., C 2-6 In some embodiments, the alkynyl group contains 2-4 carbon atoms, i.e., C 2-4Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propynyl (—C≡CH—CH), propargyl (—CHC≡CH), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like.

[0075] The term "alkoxy" refers to an alkyl group attached to the rest of the molecule through an oxygen atom, i.e., alkyl-O-, 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, the alkoxy group contains 1-10 carbon atoms; in some embodiments, the alkoxy group contains 1-8 carbon atoms; in some embodiments, the alkoxy group contains 1-6 carbon atoms, i.e., C 1-6 Alkoxy; In some embodiments, the alkoxy group contains 1-4 carbon atoms, i.e., C 1-4 Alkoxy; In some embodiments, the alkoxy group contains 1-3 carbon atoms, i.e., C 1-3 Alkoxy.

[0076] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), n-propyloxy (n-PrO, n-propoxy, -OCH2CH2CH3), isopropyloxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-isopropyloxy (t-BuO, t-butoxy, -OC(CH3)3), and the like.

[0077] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", which means that the amino group is independently substituted by one or two alkyl groups, and the alkyl groups have the definition described in the present invention. Wherein, the alkylamino group can be optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkylamino group is one or two C 1-6 The alkyl group is attached to the nitrogen atom, i.e., C 1-6 Alkylamino; in some embodiments, the alkylamino group is one or two C 1-4 The alkyl group is attached to the nitrogen atom, i.e., C 1-4 Alkylamino; in some embodiments, the alkylamino group is one or two C 1-3 The alkyl group is attached to the nitrogen atom, i.e., C1-3 Alkylamino; in some embodiments, the alkylamino group is one or two C 1-2 The alkyl group is attached to the nitrogen atom, i.e., C 1-2 Alkylamino. Examples of alkylamino groups include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), N,N-dimethylamino, and the like.

[0078] The term "haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the haloalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the haloalkyl group contains 1-10 carbon atoms, i.e., C 1-10 In some embodiments, the haloalkyl group contains 1-8 carbon atoms, i.e., C 1-8 In some embodiments, the haloalkyl group contains 1-6 carbon atoms, i.e., C 1-6 In some embodiments, the haloalkyl group contains 1-4 carbon atoms, i.e., C 1-4 In some embodiments, the haloalkyl group contains 1-3 carbon atoms, i.e., C 1-3 In some embodiments, the haloalkyl group contains 1-2 carbon atoms, i.e., C 1-2 Haloalkyl. Examples of haloalkyl include, but are not limited to, fluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), fluoroethyl (-CHFCH3, -CH2CH2F), difluoroethyl (-CF2CH3, -CFHCFH2, -CH2CHF2), perfluoroethyl (trifluoroethyl, -CH2CF3), fluoropropyl (-CHFCH2CH3, -CH2CHFCH3, -CH2CH2CH2F), difluoropropyl (-CF2CH2CH3, -CFHCFHCH3, -CH2CH2CHF2, -CH2CF2CH3, -CH2CHFCH2F), trifluoropropyl (e.g., 3,3,3-trifluoropropyl), 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

[0079] 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, the haloalkoxy group contains 1-10 carbon atoms, i.e., C 1-10 In some embodiments, the haloalkoxy group contains 1-8 carbon atoms, i.e., C 1-8 In some embodiments, the haloalkoxy group contains 1-6 carbon atoms, i.e., C 1-6In some embodiments, the haloalkoxy group contains 1-4 carbon atoms, i.e., C 1-4 In some embodiments, the haloalkoxy group contains 1-3 carbon atoms, i.e., C 1-3 In some embodiments, the haloalkyl group contains 1-2 carbon atoms, i.e., C 1-2 Haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like.

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

[0081] The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3-12 atoms, wherein at least one ring atom is selected from nitrogen, sulfur, oxygen and phosphorus atoms, wherein the heterocyclyl is non-aromatic and the ring system has one or more points of attachment to the rest of the molecule. The heterocyclyl group may be optionally substituted with one or more substituents described herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems, and also includes polycyclic ring systems in which a monocyclic ring is fused to one or more non-aromatic rings or one or more aromatic rings. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. Unless otherwise specified, the heterocyclyl group may be carbonyl or nitrogenyl, and the -CH2- group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to S-oxide. The nitrogen atom of the ring may be optionally oxidized to N-oxide. The phosphorus atom of the ring may be optionally oxidized to P-oxide. In some embodiments, the heterocyclyl is a ring system consisting of 3-10 atoms, i.e., a heterocyclyl consisting of 3-10 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 3-8 atoms, i.e., a heterocyclyl consisting of 3-8 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 5-10 atoms, i.e., a heterocyclyl consisting of 5-10 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 5-6 atoms, i.e., a heterocyclyl consisting of 5-6 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 3-6 atoms, i.e., a heterocyclyl consisting of 3-6 atoms; in some embodiments, the heterocyclyl is a system consisting of 3 ring atoms, i.e., a heterocyclyl consisting of 3 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 4 atoms, i.e., a heterocyclyl consisting of 4 atoms; in other embodiments, the heterocyclyl is a ring system consisting of 5 atoms, i.e., a heterocyclyl consisting of 5 atoms; in other embodiments, the heterocyclyl is a ring system consisting of 6 atoms, i.e., a heterocyclyl consisting of 6 atoms.

[0082] Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, oxepanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and the like. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. Bridged heterocyclic groups include, but are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and the like.

[0083] The term "aryl" refers to monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein each ring contains 3-6 ring atoms and has one or more points of attachment to the rest of the molecule. The aryl group may be optionally substituted with one or more substituents described herein. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl and anthracenyl, etc.

[0084] The term "heteroaryl" refers to a monocyclic, bicyclic and tricyclic aromatic ring system containing 5-10 ring atoms, wherein at least one ring contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms, and at the same time, the heteroaryl has one or more attachment points connected to the rest of the molecule. The heteroaryl group may be optionally substituted with one or more substituents described in the present invention. Unless otherwise specified, the heteroaryl group may be connected to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable site (which may be C in CH, or N in NH). When a -CH2- group is present in a heteroaryl group, the -CH2- group may be optionally replaced by -C(=O)-. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a 5-8 atom heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in some embodiments, the heteroaryl group is a 5-6 atom heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in some embodiments, the heteroaryl group is a 5 atom heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in some embodiments, the heteroaryl group is a 6 atom heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0085] Examples of heteroaryl groups include, but are not limited to, the following monocyclic groups: furanyl (2-furanyl, 3-furanyl), imidazolyl (N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrrolyl (N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl), thiazolyl (2-thiazolyl, 4- The invention also includes, but is not limited to, the following bicyclic or tricyclic groups: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), dibenzimidazolyl, dibenzofuranyl, dibenzothiophenyl.

[0086] The term "cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3-12 atoms, having one or more points of attachment to the rest of the molecule, wherein the cycloalkyl group is optionally substituted with substituents as described herein. The terms "carbocycle", "carbocyclyl", "cycloalkyl" or "carbocyclic" are used interchangeably herein. In some embodiments, a cycloalkyl is a ring system containing 3-10 ring carbon atoms, i.e., C 3-10 Cycloalkyl; In some embodiments, cycloalkyl is a ring system containing 3-8 ring carbon atoms, i.e., C 3-8 Cycloalkyl; In some embodiments, cycloalkyl is a ring system containing 3-6 ring carbon atoms, i.e., C 3-6 Cycloalkyl. "Cycloalkyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which a monocyclic ring is fused to one or more non-aromatic rings or one or more aromatic rings. Bicyclic carbocyclic groups include bridged bicyclic carbocyclic groups, fused bicyclic carbocyclic groups and spiro bicyclic carbocyclic groups, and "fused" bicyclic ring systems contain two rings that share 2 adjacent ring atoms. Bridged bicyclic groups include two rings that share 3 or 4 adjacent ring atoms. Spiro bicyclic ring systems share 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloalkenyl and cycloalkynyl. Further included, but in no way limited to, cyclopentadienyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. 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, etc.

[0087] The term "cycloalkyl-alkylene" means a cycloalkyl group connected to the rest of the molecule via an alkyl group, wherein cycloalkyl and alkyl have the meanings as defined herein. The cycloalkyl-alkylene may be optionally substituted with one or more substituents as defined herein. 3-6 Cycloalkyl-C 1-4 "Alkylene" means C 3-6 Cycloalkyl groups through C 1-4 The alkyl group is connected to the rest of the molecule. 3-6 Cycloalkyl-C 1-2 "Alkylene" means C 3-6 Cycloalkyl groups through C 1-2The alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl-CH2CH2-, cyclopentyl-CH2CH2-, cyclohexyl-CH2CH2-, etc.

[0088] The term "heterocyclyl-alkylene" means a heterocyclyl group attached to the rest of the molecule via an alkyl group, wherein heterocyclyl and alkyl have the meanings as defined herein. The heterocyclyl-alkylene may be optionally substituted with one or more substituents as defined herein. 1-4 "Alkylene" means a heterocyclic group consisting of 5 to 6 atoms connected by C 1-4 The alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, pyrrolidinyl-CH2-, pyrazolidinyl-CH2-, tetrahydrofuranyl-CH2-, tetrahydrothienyl-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, thiomorpholinyl-CH2-, piperazinyl-CH2-, and the like.

[0089] The term "aryl-alkylene" means an aryl group attached to the rest of the molecule via an alkyl group, wherein aryl and alkyl have the meanings as described herein. The aryl-alkylene may be optionally substituted with one or more substituents as described herein. For example, the "C 6-10 Aryl-C 1-4 "Alkylene" means C 6-10 Aryl groups through C 1-4 The alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, phenyl-CH2-, phenyl-CH2CH2-, phenyl-CH2CH2CH2-, naphthyl-CH2-, etc.

[0090] The term "heteroaryl-alkylene" means a heteroaryl group attached to the rest of the molecule via an alkyl group, wherein heteroaryl and alkyl have the meanings as described herein. The heteroaryl-alkylene group may be optionally substituted with one or more substituents as described herein. The "(5-6 atoms composed of heteroaryl)-C 1-4 "Alkylene" means a heteroaryl group consisting of 5 to 6 atoms connected by C 1-4 The alkyl group is connected to the rest of the molecule. 1-2 "Alkylene" means a heteroaryl group consisting of 5 to 6 atoms connected by C 1-2The alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, furanyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, pyridinyl-CH2-, pyrrolyl-CH2-, and the like.

[0091] The term "heteroatom" refers to O, S, N, P and Si, including S, N and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl, R is a substituent on N).

[0092] The term "carbonyl", whether used alone or in combination with other terms (such as "aminocarbonyl" or "acyloxy"), refers to -(C=O)-.

[0093] The term "deuterium" refers to deuterated 2 H or D.

[0094] As described in the present invention, a ring connected to other parts of the molecule by a bond means that the ring can be connected to other parts of the molecule through any possible connection site on the ring. For example, formula a represents that the imidazole ring can be connected to other parts of the molecule at any possible connection site on the ring, as shown in formulas a-1 to a-4:

[0095]

[0096] As described in the present invention, a bicyclic ring system in which one ring is connected to the rest of the molecule by a bond means that the ring can be connected to the rest of the molecule through any connectable site on the ring. For example, formula b represents that the bicyclic structure can be connected to the rest of the molecule through any possible connection site on ring K, as shown in formulas b-1 to b-4:

[0097]

[0098] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammals treated therewith. Preferably, the "pharmaceutically acceptable" of the present invention refers to those approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, particularly humans.

[0099] The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or a combination thereof, which are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except for the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is covered.

[0100] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, other components such as physiologically / pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and other auxiliary materials, and additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[0101] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following documents: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0102] The term "metabolite" refers to a product obtained by the metabolism of a specific compound or its salt in vivo. The metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.

[0103] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19.

[0104] The term "solvate" refers to an association formed by one or more solvent molecules and the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0105] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. A special example of an N-oxide is an N-oxide of a tertiary amine or an N-oxide of a nitrogen-containing heterocyclic nitrogen atom. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA).

[0106] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the invention may exist in a racemic or enantiomerically enriched form, such as in 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 with unsaturated double bonds may exist in cis-(Z)- or trans-(E)-form, if possible.

[0107] Therefore, as described herein, the compounds of the present invention may exist in the form of one or a mixture of possible isomers, rotamers, atropisomers, tautomers, for example, in the form of substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0108] Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the components into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0109] Any racemates of the resulting final products or intermediates can be separated into their optical antipodes by known methods by methods familiar to those skilled in the art, for example, by separation of the diastereomeric salts thereof obtained. The racemic products can also be separated by chiral chromatography, for example, by high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972)).

[0110] The present invention also includes isotopically labeled compounds of the present invention which are identical to those described 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 may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 Oh, 17 Oh, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0111] Compounds of the invention containing the aforementioned isotopes and / or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are included within the scope of the invention. Isotopically labeled compounds of the invention, for example radioactive isotopes, such as 3 H and 14C incorporation into the compounds of the present invention can be used for drug and / or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, heavy isotopes, such as deuterium, 2 H substitution may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0112] The stereochemical definitions and conventions used herein are generally in accordance with those set forth in SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore 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 and mixtures thereof such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes d and l or (+) and (–) are the signs used to designate the rotation of plane polarized light caused by a compound, where (–) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0113] Depending on the choice of starting materials and processes, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as isomer mixtures, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral agents, 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 cycloalkyl substituents may be in the cis- or trans- configuration.

[0114] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore 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 and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0115] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomers, diastereomers, atropisomers, and geometric (or conformational)) forms of such structures; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric isomer (or conformational) mixtures of the compounds of the invention are within the scope of the invention.

[0116] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0117] The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the fact that double bonds (including olefin double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms cannot rotate freely.

[0118] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects also refer to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0119] The terms "subject" and "patient" used in the present invention are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails or turkeys or mammals), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs and mice) and primates (e.g., monkeys, chimpanzees and humans), more particularly humans. In one embodiment, the subject is a non-human animal, such as livestock (e.g., horses, cows, pigs or sheep) or a pet (e.g., dogs, cats, guinea pigs or rabbits). In other embodiments, "patient" refers to humans.

[0120] Additionally, unless otherwise indicated, structural formulae of compounds described herein may include enriched isotopes of one or more different atoms.

[0121] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0122] Description of the compounds of the present invention

[0123] The present invention provides a class of compounds with good stimulating thyroid hormone beta receptors, which are used to prepare drugs for treating non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds and pharmaceutical compositions to prepare drugs for treating the above-mentioned diseases in mammals, especially humans. Compared with existing similar compounds, the compounds of the present invention not only have good pharmacological activity and selectivity, but also have excellent in vivo metabolic kinetics and in vivo pharmacodynamics. The preparation method of the compounds of the present invention is simple and easy, the process method is stable, and it is suitable for industrial production. Therefore, the compounds provided by the present invention have better drugability than the currently existing similar compounds.

[0124] Specifically:

[0125] On the one hand, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I),

[0126]

[0127] Among them, A, B, X, Y, L, R 1 , R 2 , R 3 and R 4 Has the definition as described in the present invention.

[0128] In some embodiments, Y is -O-, -NH-, -CH2-, or -S-.

[0129] In some embodiments, L is -O-, -CH2-, -CH=CH-, *-NR 0 C(=O)-, *-C(=O)NR 0 -、-NR 0 -or -S-; * indicates the end connected to the benzene ring.

[0130] In some embodiments, X is a bond or C 1-6 Alkylene.

[0131] In some embodiments, B is Where V 1 、V 6 、V 7 、V 2 、V 3、V 4 、V 5 , R 6 , R 6a , n and q have the meanings as defined in the present invention.

[0132] In some embodiments, V 1 、V 6 and V 7 Each is independently -CH= or -N=; V 2 、V 3 、V 4 and V 5 Each is independently -CH2-, -NH-, -O-, -S-, -C(=O)-, -S(=O)- or -S(=O)2-.

[0133] In some embodiments, the compound of the present invention is a structure as shown in formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the structure as shown in formula (II).

[0134]

[0135] Among them, A, Y, R 1 , R 2 , R 3 , R 4 、V 1 、V 2 、V 3 、V 4 , R 6 and n have the meanings described in the present invention, wherein the compound does not include the following compounds:

[0136]

[0137] In some embodiments, R 1 , R 2 , R 3 and R 4 Each independently represents H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl or cyano C 1-6 alkyl.

[0138] In some embodiments, A is The T 1 , T 2 , T 3 , T 4 , Z 1 , Z 2 , Z 3 , U 1 , U 2 , U 3 , U 4 , R 5a , R 5b , R 5 , p, r and t have the definitions described in the present invention.

[0139] In some embodiments, Ring C is C 3-8 A carbon ring or a heterocyclic ring consisting of 3 to 8 atoms.

[0140] In some embodiments, Z 3 It is -CH= or -N=.

[0141] In some embodiments, Z 1 and Z 2 Each is independently a key, -CR 5c R 5d -、-NR n -, -O-, -S-, -C(=O)-, -S(=O)- or -S(=O)2-; wherein R 5c , R 5d and R n Has the definition described in the present invention.

[0142] In some embodiments, U 1 For-CR U1 =or-N=;U 2 For-CR U2 = or -N =; wherein the R U1 and R U2 Has the definition described in the present invention.

[0143] In some embodiments, U 3 and U 4 Each is independently a key, -CR U3 R U4 -、-NR n1 -, -O-, -S-, -C(=O)-, -S(=O)- or -S(=O)2-; wherein R U3 , R U4 and R n1 Has the definition described in the present invention.

[0144] In some embodiments, T 1For-CR T1 = or -N =; T 2 For-CR T2 = or -N =; T 3 For-CR T3 = or -N =; T 4 For-CR T4 = or -N =; wherein the R T1 , R T2 , R T3 and R T4 Has the definition described in the present invention.

[0145] In some embodiments, A is

[0146] Among them, the X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , T 1 , T 2 , T 3 , T 4 , Z 1 , Z 3 , U 1 , U 2 , U 3 , U 4 , R 5a , R 5b , R 5 , p, r and t have the definitions described in the present invention.

[0147] In some embodiments, A is

[0148] Wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , T 1 , T 2 , T 3 , T 4 , Z 1 , Z 3 , U 2 , U 3 , U 4 , R 5a , R 5b , R 5, p, r and t have the definitions described in the present invention.

[0149] In some embodiments, X 1 , X 2 , X 3 and X 4 Each independently represents -CH2- or -NH-; X 5 and X 6 Each is independently -CH= or -N=.

[0150] In some embodiments, each R 5 are independently H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-2 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-2 Alkylene, C 6-10 Aryl-C 1-2 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-2 Alkylene, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-2 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-2 Alkylene, C 6-10 Aryl-C 1-2 Alkylene and (heteroaryl consisting of 5-6 atoms)-C 1-2 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-3 Alkyl, C1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 The aryl group or the heteroaryl group consisting of 5-6 atoms is substituted.

[0151] In some embodiments, each R 5are independently H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, N,N-dimethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, phenyl, naphthyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl , piperazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrrolyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl-CH2CH2-, cyclopentyl-CH2CH2-, cyclohexyl-CH2CH2-, cyclopentadienyl-CH2-, phenyl-CH2-, phenyl-CH2CH2-, phenyl-CH2CH2-, phenyl-CH2CH2CH2-, naphthyl-CH2-, tetrahydropyranyl-CH2-, pyrrolidinyl-CH2-, pyrazolidinyl-CH2- 2-, tetrahydrofuranyl-CH2-, tetrahydrothienyl-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, thiomorpholinyl-CH2-, piperazinyl-CH2-, furanyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, thiazolyl-CH2-, pyrimidinyl-CH2-, pyrazinyl-CH2-, pyridazinyl-CH2-, pyridinyl-CH2- or pyrrolyl-CH2-; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, N,N-dimethylamino, -CF3, -CHF 2, -CH2F, -CH2CF3, -OCF3, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, phenyl, naphthyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridyl and pyrrolyl are each independently unsubstituted or substituted by 1, 2 or 3 independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 The aryl group or the heteroaryl group consisting of 5-6 atoms is substituted.

[0152] In some embodiments, two R attached to adjacent atoms 5 Together with the atoms to which they are attached, they form C 3-8 A carbon ring or a heterocyclic ring consisting of 3 to 8 atoms.

[0153] In some embodiments, two R attached to adjacent atoms 5 Together with the atoms to which they are attached, they form C 3-6 A carbon ring or a hetero ring consisting of 3 to 6 atoms.

[0154] In some embodiments, two R 5 Together with the atoms to which they are attached, they form C 3-8 A carbon ring or a heterocyclic ring consisting of 3 to 8 atoms.

[0155] In some embodiments, two R 5 Together with the atoms to which they are attached, they form C 3-6 A carbon ring or a hetero ring consisting of 3 to 6 atoms.

[0156] In some embodiments, R 0 , R n and R n1 Each independently is H, deuterium, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-3 Alkylene; wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 Aryl, 5-6 atoms of heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and (heteroaryl consisting of 5-6 atoms)-C1-3 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 The aryl group or the heteroaryl group consisting of 5-6 atoms is substituted.

[0157] In some embodiments, R 0 , R n and R n1 each independently represents H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, trifluoroethyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrothiophenyl, morpholinyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, C 1-2 Alkylene, cyclobutyl C 1-2 Alkylene, cyclopentyl C 1-2 Alkylene, cyclohexyl C 1-2 Alkylene, tetrahydropyranyl C 1-2 Alkylene, tetrahydrofuranyl C 1-2 Alkylene, piperidinyl C 1-2 Alkylene, piperazine C 1-2 Alkylene, pyrrolidyl C 1-2 Alkylene, tetrahydrothienyl C 1-2 Alkylene, morpholinyl C 1-2 Alkylene, phenyl C 1-2 Alkylene, naphthyl C 1-2 Alkylene, furanyl C 1-2 Alkylene, thienyl C 1-2 Alkylene, thiazolyl C 1-2 Alkylene, pyrazolyl C 1-2 Alkylene, imidazolyl C 1-2 Alkylene, pyrrolyl C 1-2 Alkylene, pyridyl C 1-2 Alkylene, pyrimidinyl C 1-2 Alkylene, pyrazinyl C 1-2 Alkylene or pyridazinyl C 1-2Alkylene; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoroethyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrothiophenyl, morpholinyl, phenyl, naphthyl, furanyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl C 1-2 Alkylene, cyclobutyl C 1-2 Alkylene, cyclopentyl C 1-2 Alkylene, cyclohexyl C 1-2 Alkylene, tetrahydropyranyl C 1-2 Alkylene, tetrahydrofuranyl C 1-2 Alkylene, piperidinyl C 1-2 Alkylene, piperazine C 1-2 Alkylene, pyrrolidyl C 1-2 Alkylene, tetrahydrothienyl C 1-2 Alkylene, morpholinyl C 1-2 Alkylene, phenyl C 1-2 Alkylene, naphthyl C 1-2 Alkylene, furanyl C 1-2 Alkylene, thienyl C 1-2 Alkylene, thiazolyl C 1-2 Alkylene, pyrazolyl C 1-2 Alkylene, imidazolyl C 1-2 Alkylene, pyrrolyl C 1-2 Alkylene, pyridyl C 1-2 Alkylene, pyrimidinyl C 1-2 Alkylene, pyrazinyl C 1-2 Alkylene and pyridazinyl C 1-2 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 The cycloalkyl group may be substituted by a substituent consisting of a cycloalkyl group, a heterocyclic group consisting of 3 to 6 atoms, a phenyl group or a heteroaryl group consisting of 5 to 6 atoms.

[0158] In some embodiments, each R 5a , R 5b , R 5c , R 5d , R U1 , R U2 , R U3 , R U4 , RT1 , R T2 , R T3 and R T4 are independently H, deuterium, F, Cl, Br, I, CN, NO2, COOH, OH, NH2, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylamino, ethylamino, N,N-dimethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentadienyl, phenyl, naphthyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thiophenyl, imidazolyl, pyrimidinyl, pyridinyl, pyrrolyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, (heterocyclic group consisting of 3-6 atoms)-C 1-3 Alkylene, phenyl-C 1-3 Alkylene or (heteroaryl consisting of 5-6 atoms)-C 1-3 Alkylene.

[0159] In another aspect, the present invention relates to one of the following structures, or a stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0160]

[0161]

[0162]

[0163] In another aspect, the present invention relates to a pharmaceutical composition comprising the compound of the present invention.

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

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

[0166] On the other hand, the present invention relates to a method for exciting thyroid hormone receptors using the compounds or pharmaceutical compositions of the present invention, or a method for preventing, treating or alleviating diseases regulated by thyroid hormone receptors, wherein the method is to administer an effective therapeutic amount of the compound or pharmaceutical composition to an individual in need thereof. In addition, the above-mentioned compound or pharmaceutical composition provided by the present invention can be co-administered with other therapies or therapeutic agents. The administration can be performed simultaneously, sequentially or at certain time intervals.

[0167] In another aspect, the present invention relates to the use of the compound or pharmaceutical composition of the present invention for stimulating thyroid hormone receptors, or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

[0168] In some embodiments, the thyroid hormone receptor described herein is a thyroid hormone beta receptor.

[0169] In some embodiments, the disease modulated by thyroid hormone receptor described in the present invention is a neurodegenerative disease, non-alcoholic fatty liver disease, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer;

[0170] In some embodiments, the non-alcoholic fatty liver disease described in the present invention is non-alcoholic simple fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.

[0171] In some embodiments, the neurodegenerative disease described herein is a demyelinating disease, a chronic demyelinating disease, a leukodystrophy, dementia, an ischemic stroke, a lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenal dystrophy (ALD), amyotrophic lateral sclerosis (ALS), or Alzheimer's disease.

[0172] The dosage of the compound or pharmaceutical composition required for the treatment, prevention or delay of the effect usually depends on the specific compound, patient, specific disease or condition and its severity, administration route and frequency, etc., and needs to be determined by the attending physician according to the specific circumstances. For example, when the compound or pharmaceutical composition provided by the present invention is administered by intravenous route, it can be administered once a week or even at longer intervals.

[0173] In some embodiments, the salt is a pharmaceutically acceptable salt.

[0174] The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for preparing and / or purifying the compounds of the present invention and / or for separating the enantiomers of the compounds of the present invention.

[0175] Moreover, the compounds of the present invention, including their salts, may also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.

[0176] Any structural formula given herein is also intended to represent unlabeled forms of these compounds as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number.

[0177] Pharmaceutical compositions, formulations and administration of compounds of the present invention

[0178] The present invention relates to a pharmaceutical composition, which includes the compound of the present invention or the compound of the structure shown in the examples, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or combination thereof, and optionally, other therapeutic and / or preventive ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention and at least one pharmaceutically acceptable carrier, excipient, adjuvant or vehicle. The amount of the compound in the pharmaceutical composition of the present invention can effectively and detectably excite the thyroid hormone beta receptor in a biological specimen or a patient.

[0179] The pharmaceutically acceptable carrier may contain inert ingredients that do not excessively inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or have no other adverse reactions or side effects once administered to a patient. Standard pharmaceutical techniques can be used.

[0180] As described in the present invention, the pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle, such as the one used in the present invention, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc. suitable for the specific target dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in the preparation of pharmaceutically acceptable compositions and their known preparation methods. In addition to conventional carrier media that are incompatible with the compounds of the present invention, such as those that produce adverse biological effects or have harmful interactions with any other components in the pharmaceutically acceptable composition, any other conventional carrier media and their uses are also within the scope of the present invention.

[0181] Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphates, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropyl methylcellulose, lanolin, sugars (e.g., lactose, glucose and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium 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 and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and, according to the judgment of the formulator, coloring agents, anti-adherents, coating agents, sweetening and flavoring agents, preservatives and antioxidants may also be present in the composition.

[0182] The pharmaceutical composition of the present invention can be administered directly or in the form of a pharmaceutical composition or drug along with a suitable carrier or excipient, which is well known in the art. The treatment method of the present invention may include administering an effective compound of the present invention to an individual in need thereof. In some embodiments, the individual is a mammalian individual, and in other embodiments, the individual is a human individual.

[0183] The effective amount of the compound, pharmaceutical composition or drug of the present invention can be easily determined by conventional methods, and the most effective and convenient route of administration and the most suitable formulation can also be determined by conventional experiments.

[0184] The compounds or pharmaceutical compositions of the present invention can be administered by any suitable means, and can be administered to humans or other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (such as by powders, ointments or drops), orally as an oral or nasal spray, etc., depending on the severity of the disease.

[0185] 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 compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, dimethylformamide, oils (especially cottonseed oil, peanut oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavor enhancers.

[0186] Injectable preparations can be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable water or oil suspensions. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are used as solvents or suspension media as a rule. For this reason, any tasteless fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used to prepare injections.

[0187] For example, the injectable formulation can be sterilized by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0188] In order to prolong the effect of the compound or pharmaceutical composition of the present invention, it is often desirable to slow down the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystal or amorphous substance. Then, the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. An injectable storage form can be prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The compound release rate can be controlled according to the ratio of the compound to the polymer and the properties of the special polymer used. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable storage preparations can also be prepared by trapping the compound in a liposome or microemulsion compatible with body tissues.

[0189] Compositions for rectal or vaginal administration are particularly suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as 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.

[0190] 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 expanders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarder such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0191] Also can use the solid composition of similar type as filler in soft and hard gel capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Available coating and shell, for example enteric coating and other well-known coatings in the pharmaceutical field prepare solid dosage forms of tablets, lozenges, capsules, pills and granules. They can optionally contain opacifiers and can also have the properties of the composition, so that optionally only release active ingredients in a delayed manner, or preferably, release in a certain part of the intestinal tract. The example of spendable embedded composition includes polymer and wax.

[0192] The active compound may also be in a microencapsulated form with one or more of the above excipients. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Typically, such dosage forms may also contain additional substances in addition to the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also contain a buffer.

[0193] The topical or transdermal dosage forms of the compounds of the present invention include ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic preparations, ear drops and eye drops are also considered within the scope of the present invention. In addition, the present invention contemplates the use of skin patches with the additional advantage of providing controlled compound delivery to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flow 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.

[0194] The compositions of the present invention may also be administered orally, parenterally, topically, rectally, nasally, buccally, vaginally, or by implanted kits via inhalation sprays. 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 may be administered orally, intraperitoneally, or intravenously.

[0195] The sterile injectable form of the composition of the present invention may be an aqueous or oil suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution may be used. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any odorless fixed oil may be used, including synthetic monoglycerides 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 to prepare injections. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0196] The pharmaceutical composition of the present invention can be taken orally in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, common carriers include but are not limited to lactose and starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavor enhancers or coloring agents may also be added.

[0197] 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 reagents and non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0198] For topical drip application, the pharmaceutical composition can be formulated as a suitable ointment containing an active component suspended or dissolved in one or more carriers. Carriers suitable for topical drip application of the compound of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0199] The pharmaceutical composition 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.

[0200] Uses of the compounds and pharmaceutical compositions of the present invention

[0201] The compound or pharmaceutical composition provided by the present invention can be used to prepare a drug for exciting thyroid hormone receptors, or to prepare a drug for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

[0202] The compound or pharmaceutical composition provided by the present invention can be used to stimulate thyroid hormone receptors, or to prevent, treat or alleviate diseases regulated by thyroid hormone receptors.

[0203] The present invention provides a method for exciting thyroid hormone receptors, or a method for preventing, treating or alleviating diseases regulated by thyroid hormone receptors, the method comprising administering a therapeutically effective amount of the above-mentioned compound or its pharmaceutical composition to a patient in need of treatment. In addition, the above-mentioned compound or its pharmaceutical composition provided by the present invention can be co-administered with other therapies or therapeutic agents. The administration method can be simultaneous, sequential or at a certain time interval.

[0204] The thyroid hormone receptor described in the present invention is a thyroid hormone β receptor.

[0205] The disease described in the present invention is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer, wherein the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic fatty hepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.

[0206] The compounds of the present invention are useful for human treatment and are also useful for veterinary treatment of pets, imported species of animals and farm animals, including mammals, rodents, etc. Other examples of animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0207] An "effective amount", "effective therapeutic amount" or "effective dose" of a compound or pharmaceutically acceptable pharmaceutical composition of the present invention refers to an effective amount for treating or alleviating the severity of one or more of the conditions mentioned herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly wide dosage range. For example, the daily dosage is about 0.1 mg-1000 mg / person, divided into one or more administrations. The methods, compounds and pharmaceutical compositions of the present invention can be effectively used to treat or alleviate the severity of the disease in any dosage and any route of administration. The exact amount required will vary depending on the patient's condition, depending on age, the patient's general condition, the severity of the infection, special factors, mode of administration, etc. The compounds or pharmaceutical compositions of the present invention can be administered in combination with one or more other therapeutic agents, as discussed herein.

[0208] General synthesis and detection methods

[0209] To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0210] In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure prevails.

[0211] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following reaction schemes and examples are provided to further illustrate the present invention.

[0212] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many 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 non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known drugs in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0213] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or / and 19 F-NMR). 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR, 19 F-NMR measurements were performed using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer. The solvents used were deuterated chloroform (CDCl3), deuterated methanol (CD3OD or MeOH-d4) or deuterated dimethyl sulfoxide (DMSO-d6). TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard. When multiple peaks appeared, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), qd (quartet of doublets), brs (broadened singlet). The coupling constant J is expressed in Hertz (Hz).

[0214] Novasep pump 250 high performance liquid chromatograph was generally used for preparative purification or preparative resolution.

[0215] LC-MS was measured using Agilen-6120 Quadrupole LC / MS mass spectrometer.

[0216] Column chromatography generally uses Qingdao Ocean Chemical 300-400 mesh silica gel as the carrier.

[0217] The starting materials of the present invention are known and can be purchased on the market from companies such as Shanghai Accela Company, Energy Company, J&K, and Alfa Company, or can be synthesized by methods known in the art.

[0218] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere;

[0219] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon or steel kettle with a volume of about 1L;

[0220] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L or a stainless steel high-pressure reactor with a volume of about 1L;

[0221] In the examples, unless otherwise specified, solution refers to aqueous solution; the reaction temperature is room temperature; and room temperature is 20°C to 40°C.

[0222] The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction included: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent was adjusted according to the polarity of the compound.

[0223] The eluent systems for column chromatography include: A: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of ammonia water and acetic acid.

[0224] HPLC refers to high performance liquid chromatography; HPLC determination was performed using an Agilent 1260 high pressure liquid chromatograph (chromatographic column: Agilent ZORBAX Eclipse Plus C18 4.6 mm × 150 mm, 3.5 μm);

[0225] HPLC test conditions: running time: 25min column temperature: 35℃ detection wavelength: 210nm; 245nm;

[0226] Mobile phase: Phase A: 0.05% phosphoric acid solution Phase B: acetonitrile; Flow rate: 1.0 ml / min;

[0227] The mobile phase gradient is shown in Table A:

[0228] Table A

[0229] time Gradient of mobile phase A Gradient of mobile phase B 0min 90％ 10％ 15min 10％ 90％ 20min 10％ 90％ 25min 90％ 10％

[0230] The LC / MS / MS system used for the analysis in the biological test experiments included an Agilent 1200 series vacuum degassing oven, a binary syringe pump, a well plate autosampler, a column thermostat, and an Agilent G6430 triple quadrupole mass spectrometer with an electrospray ionization source (ESI). Quantitative analysis was performed in MRM mode, and the parameters of the MRM transitions are shown in Table B:

[0231] Table B

[0232] Full Scan 50→1400 Fragmentation voltage 230V Capillary voltage 55V Dryer temperature 350℃ Atomizer 0.28MPa Dryer flow rate 10L / min

[0233] The analysis was performed using an Agilent XDB-C18, 2.1×30 mm, 3.5 μM column, and 5 μL of sample was injected. Analysis conditions: The mobile phase was 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4 mL / min. The mobile phase gradient is shown in Table C:

[0234] Table C

[0235] time Gradient of mobile phase B 0.5min 5％ 1.0min 95％ 2.2min 95％ 2.3min 5％ 5.0min termination

[0236] In addition, an Agilent 6330 series LC / MS / MS spectrometer equipped with a G1312A binary syringe pump, a G1367A autosampler, and a G1314C UV detector was used for the analysis; the LC / MS / MS spectrometer used an ESI radiation source. Standard solutions were used to perform appropriate cation model processing and MRM transitions for each analyte for optimal analysis. A Capcell MP-C18 column with the specifications of 100×4.6 mm ID, 5 μM (Phenomenex, Torrance, California, USA) was used during the analysis. The mobile phase was 5 mM ammonium acetate, 0.1% methanol in water (A): 5 mM ammonium acetate, 0.1% methanol in acetonitrile (B) (70 / 30, v / v); the flow rate was 0.6 mL / min; the column temperature was maintained at room temperature; and 20 μL of sample was injected.

[0237] The following abbreviations are used throughout this invention:

[0238] <![CDATA[DMSO-d6]]> Deuterated dimethyl sulfoxide DMSO Dimethyl sulfoxide <![CDATA[CDCl3]]> Deuterated chloroform %wt,mass% Weight Percent <![CDATA[CD3OD]]> Deuterated methanol mL ml μL microliter mol / L Mole / liter mol Moore mmol mmol g gram h Hour <![CDATA[H2]]> hydrogen <![CDATA[N2]]> Nitrogen min minute MPa MPa ACN Acetonitrile TFA Trifluoroacetic acid N mol / L DETAILED DESCRIPTION

[0239] The present invention provides a class of compounds with good stimulating thyroid hormone beta receptors, preparation methods, pharmaceutical compositions and uses thereof. Those skilled in the art can refer to the contents of this article and appropriately improve the process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the scope of the present invention.

[0240] Typical synthetic steps for preparing the compounds disclosed in the present invention are shown in the following synthetic scheme. Unless otherwise specified, each ring A, Y, R 1 , R 2 , R 3 , R 4 , R 6 、V 1 、V 2 、V 3 、V 4 and n are as defined in the present invention, R s It is Cl or OH, etc.

[0241] Synthesis Scheme 1

[0242]

[0243] The compound having the structure shown in the general formula (II) can be prepared by the general synthesis method described in Synthesis Scheme 1, and the specific steps can be referred to in the Examples. First, compound (S-1) is subjected to nitro reduction to obtain compound (S-2); compound (S-2) reacts with compound (S-3) to obtain the target compound shown in the general formula (II).

[0244] Preparation Example

[0245] Intermediate 15-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride

[0246]

[0247] Step 1) Synthesis of 2-amino-2-oxime-ethyl acetate S2

[0248] Take ethyl cyanoformate S1 (1.50 g, 15.10 mmol), sodium carbonate (3.21 g, 30.30 mmol) and hydroxylamine hydrochloride (1.581 g, 22.70 mmol) and dissolve them in ethanol (10 mL) and react at room temperature for 2 hours. Filter the reaction solution, collect the filtrate and concentrate it, and purify the residue by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 3) to obtain compound S2 (1.48 g, yield 74%) as a white solid.

[0249] Step 2) Synthesis of ethyl 2-amino-2-(((isopropoxyacyl)oxy)imino)acetate S3

[0250] Take 2-amino-2-oximino-acetic acid ethyl ester S2 (0.83 g, 2.40 mmol), triethylamine (2.12 mL) and isopropyl chloroformate (0.93 g, 7.57 mmol) and dissolve in dichloromethane (8 mL), react at 0°C for 1 hour. Add saturated sodium bicarbonate solution (20 mL) to the reaction solution, extract with ethyl acetate (10 mL×3), dry the combined organic layer with anhydrous sodium sulfate, filter and concentrate to obtain compound S3 (1.20 g, yield 73%) as a white solid.

[0251] Step 3) Synthesis of 5-oxo-4H-1,2,4-oxadiazole-3-carboxylic acid ethyl ester S4

[0252] Ethyl 2-amino-2-(((isopropoxyacyl)oxy)imino)acetate S3 (0.80 g, 3.70 mmol) was dissolved in acetic acid (3 mL) and reacted at 120° C. for 5 hours. The reaction solution was cooled to room temperature and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound S4 (0.50 g, yield 86%) as a colorless oil.

[0253] Step 4) Synthesis of 5-oxo-4H-1,2,4-oxadiazole-3-sodium carboxylate S5

[0254] Take 5-oxo-4H-1,2,4-oxadiazole-3-carboxylic acid ethyl ester S4 (1.00 g, 6.32 mmol) and dissolve it in ethanol (20 mL), add sodium hydroxide (1.02 g, 25.30 mmol) in water (5 mL), and react at room temperature for 1 hour. Filter the reaction solution, collect the filter cake and vacuum dry to obtain compound S5 (0.90 g, yield 94%) as a white solid.

[0255] Step 5) Synthesis of 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride intermediate 1

[0256] Sodium 5-oxo-4H-1,2,4-oxadiazole-3-carboxylate S5 (0.10 g, 0.66 mmol) was dissolved in thionyl chloride (1.9 mL) and reacted at 80° C. for 6 hours. The reaction solution was concentrated to obtain intermediate 1 (0.11 g, yield 100%) as a white solid.

[0257] Example 1 N-(3,5-dichloro-4-((1-(3,4-difluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 1

[0258]

[0259] Step 1) Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-2-methoxypyridine 1b

[0260] 3-Hydroxy-6-methoxypyridine 1a (0.20 g, 1.6 mmol) and 1,3-dichloro-2-iodo-5-nitrobenzene (0.51 g, 1.6 mmol) were dissolved in N,N-dimethylacetamide (2 mL), potassium carbonate (0.56 g, 4.0 mmol) was added, and the mixture was reacted at 120°C for 1 hour. The reaction solution was cooled to room temperature, water (20 mL) was added, stirred for 5 minutes, filtered, and the filter cake was collected and dried under vacuum to obtain compound 1b (0.30 g, yield 60%) as a yellow solid.

[0261] MS (ESI, pos.ion) m / z: 315.0 [M+H] + .

[0262] Step 2) Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-1H-pyridin-2-one 1c

[0263] 5-(2,6-dichloro-4-nitrophenoxy)-2-methoxypyridine 1b (0.35 g, 1.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), p-toluenesulfonic acid (0.86 g, 4.7 mmol) and lithium chloride (0.20 g, 4.7 mmol) were added, and the mixture was reacted at 120°C for 30 minutes. The reaction solution was cooled to room temperature, saturated sodium carbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 1c (0.30 g, yield 90%) as a light yellow solid.

[0264] MS (ESI, pos.ion) m / z: 301.1 [M+H] + ;

[0265] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.25 (s, 1H), 8.50 (s, 2H), 7.40 (dd, J = 9.6, 3.3Hz, 1H), 7.24 (d, J = 2.6Hz, 1H), 6.46 (d, J = 9.6Hz, 1H).

[0266] Step 3) Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-1-(3,4-difluorobenzyl)-1H-pyridin-2-one 1d

[0267] 5-(2,6-dichloro-4-nitrophenoxy)-1H-pyridin-2-one 1c (5.0 g, 17 mmol) and cesium carbonate (11 g, 33.6 mmol) were dissolved in acetonitrile (50 mL), 4-(bromomethyl)-1,2-difluorobenzene (3.2 mL, 25 mmol) was added dropwise, and the mixture was reacted at 60° C. for 7 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The obtained residue was recrystallized (petroleum ether / ethyl acetate (v / v) = 3 / 1, 20 mL) to obtain compound 1d (3.5 g, yield 49%) as a yellow solid.

[0268] Step 4) Synthesis of 5-(4-amino-2,6-dichlorophenoxy)-1-(3,4-difluorobenzyl)-1H-pyridin-2-one 1e

[0269] 5-(2,6-dichloro-4-nitrophenoxy)-1-(3,4-difluorobenzyl)-1H-pyridin-2-one 1d (3.5 g, 8.2 mmol) was dissolved in acetic acid (21 mL), iron powder (1.1 g, 20 mmol) was added, and the mixture was reacted at 60°C for 1 hour. The reaction solution was cooled to room temperature, the iron powder was removed by filtration, water (150 mL) was added to the filtrate, stirred for 10 minutes, filtered, rinsed with water (50 mL), and the filter cake was collected and dried in vacuo to obtain compound 1e (3.3 g, yield 100%) as an off-white solid.

[0270] Step 5) Synthesis of N-(3,5-dichloro-4-((1-(3,4-difluorobenzyl)-6-oxo-1H-pyridin-3-yl)oxy) Phenyl)-5-oxo-4H-1,2,4-oxadiazole-3-carboxamide 1

[0271] 5-(4-amino-2,6-dichlorophenoxy)-1-(3,4-difluorobenzyl)-1H-pyridin-2-one 1e (0.10 g, 0.25 mmol) and triethylamine (0.11 mL) were dissolved in tetrahydrofuran (10 mL), and intermediate 1 (0.11 g, 0.74 mmol) was added and reacted at room temperature for 2 hours. The reaction solution was concentrated, and the obtained residue was purified by preparative separation [47% ACN / 53% H2O (0.1% TFA), Kromasil specification: C18 10μm×50mm×250mm, flow rate: 100mL / min] to obtain compound 1 (60 mg, yield 47%) as a white solid.

[0272] MS (ESI, pos.ion) m / z: 509.2 [M+H] + ;

[0273] 1H NMR (600MHz, DMSO-d6) δ (ppm) 11.36 (s, 1H), 8.03 (s, 2H), 7.52 (d, J = 3.0Hz, 1H), 7.47-7. 37(m,3H),7.34-7.28(m,1H),7.09(d,J=1.4Hz,1H),6.47(d,J=9.9Hz,1H),5.00(s,2H).

[0274] Example 2 N-(3,5-dichloro-4-((2-oxo-1,3,4,5-tetrahydro-1H-benzazepine -7-yl)oxy)phenyl)-5-oxo-2H-1,2,4-oxadiazole-3-carboxamide 2

[0275]

[0276] Step 1) Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-1,3,4,5-tetrahydro-1H-benzazepine -2-Keto 2b

[0277] 7-Hydroxy-1,3,4,5-tetrahydro-1H-benzazepine -2-ketone 2a (0.50 g, 2.8 mmol) and 1,3-dichloro-2-iodo-5-nitrobenzene (0.99 g, 3.1 mmol) were dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (0.79 g, 5.7 mmol) was added, and the mixture was reacted at 100°C for 16 hours. After the reaction solution cooled to room temperature, water (15 mL) was added and stirred for 15 minutes. A yellow solid precipitated, which was filtered and the filter cake was collected to obtain a yellow solid, which was recrystallized with ethanol / ethyl acetate / petroleum ether ((v / v) = 1 / 5 / 10, 16 mL), filtered, the filter cake was collected and dried to obtain a gray solid 2b (0.70 g, yield 68%).

[0278] Step 2: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-1,3,4,5-tetrahydro-1H-benzazepine -2-Keto 2c

[0279] 7-(2,6-dichloro-4-nitrophenoxy)-1,3,4,5-tetrahydro-1H-benzazepine -2-Ketone 2b (0.70 g, 1.9 mmol) was dissolved in AcOH (8 mL), iron powder (0.43 g, 7.7 mmol) was added, and the mixture was reacted at 70°C for 4 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was stirred for 10 minutes. Solids precipitated, which were filtered and rinsed with water (10 mL). The solids were collected and dried in vacuo to obtain brown solids 2c (0.64 g, yield 100%).

[0280] MS (ESI, pos.ion) m / z: 337.0 [M+H] +.

[0281] Step 3) Synthesis of N-(3,5-dichloro-4-((2-oxo-1,3,4,5-tetrahydro-1H-benzazepine -7-yl)oxy 2-(2-(2-(2-(phenyl)-5-oxo-2H-1,2,4-oxadiazole-3-carboxamide))

[0282] Take 7-(4-amino-2,6-dichloro-phenoxy)-1,3,4,5-tetrahydro-1H-benzazepine -2-Ketone 2c (0.10 g, 0.25 mmol) and triethylamine (0.11 mL) were dissolved in tetrahydrofuran (10 mL), and intermediate 1 (98 mg, 0.66 mmol) was added and reacted at 25°C for 22 hours. The reaction solution was concentrated, and the obtained crude product was purified by preparative separation [37% ACN / 63% H2O (0.1% TFA), Kromasil specification: C18 10 μm×50mm×250mm, flow rate: 100 mL / min] to obtain the title compound 2 (50.0 mg, yield 38%) as a white solid.

[0283] MS(ESI,pos.Scan)m / z:449.0[M+H] + ;

[0284] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.34 (s, 1H), 9.39 (s, 1H), 8.04 (s, 2H), 6.91 (d, J = 8.7Hz, 1H), 6.81 (d, J=2.8Hz, 1H), 6.64 (dd, J=8.6, 2.9Hz, 1H), 2.64 (t, J=6.5Hz, 2H), 2.09 (dt, J=23.7, 6.8Hz, 4H).

[0285] Example 3 N-(4-((1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 3

[0286]

[0287] Step 1) Synthesis of 1-benzyl-5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one 3a

[0288] 5-(2,6-Dichloro-4-nitrophenoxy)pyridin-2(1H)-one 1i (3.00 g, 9.96 mmol) and potassium carbonate (2.78 g, 19.9 mmol) were dissolved in N,N-dimethylformamide (15 mL), and benzyl bromide (1.74 g, 9.97 mmol) was added, and the mixture was reacted at room temperature for 5 hours. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a white solid 3a (2.76 g, yield 71%).

[0289] Step 2) Synthesis of 5-(4-amino-2,6-dichlorophenoxy)-1-benzylpyridin-2(1H)-one 3b

[0290] 1-Benzyl-5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one 3a (2.0 g, 5.1 mmol) was dissolved in acetic acid (12 mL), iron powder (0.86 g, 15 mmol) was added, and the mixture was reacted at 60°C for 4 hours. The reaction solution was cooled to room temperature, the iron powder was removed, water (30 mL) was added, stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to obtain a yellow solid 3b (1.8 g, yield 97%).

[0291] Step 3) Synthesis of N-(4-((1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-3,5-dichlorophenyl)- 5-Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0292] At 0°C, triethylamine (0.62 mL, 4.4 mmol) was added dropwise to 5-(4-amino-2,6-dichlorophenoxy)-1-benzylpyridin-2(1H)-one 3b (0.20 g, 0.55 mmol) and intermediate 1 (0.57 g, 3.84 mmol) in tetrahydrofuran (10 mL), and the mixture was reacted at room temperature for 12 hours. The reaction solution was concentrated, methanol (4 mL) was added and stirred, water (1 mL) was slowly added dropwise, stirred for 10 minutes, filtered, and the collected filter cake was slurried with ethyl acetate / petroleum ether ((v / v) = 1 / 1, 2 mL) to obtain a gray solid 3 (0.12 g, yield 46%).

[0293] MS (ESI, neg.ion) m / z: 470.9 [MH] - ;

[0294] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.29 (s, 1H), 8.02 (s, 2H), 7.5-7.16 (m, 7H), 6.47 (d, J = 9.8Hz, 1H), 5.04 (s, 2H).

[0295] Example 4 N-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine -7-yl)oxy)phenyl)-5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-carboxamide 4

[0296]

[0297] Step 1) Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -1- Keto 4b

[0298] 7-Hydroxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine -1-Ketone 4a (0.60 g, 3.4 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.77 g, 3.4 mmol) were dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (1.2 g, 8.6 mmol) was added, and the mixture was reacted at 120°C for 16 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, stirred for 15 minutes, filtered, and the collected filter cake was slurried with ethanol / ethyl acetate / petroleum ether ((v / v / v)=1 / 2 / 4, 28 mL), filtered, and the collected filter cake was dried to obtain a brown solid 4b (0.90 g, yield 72%).

[0299] Step 2) Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -1- Keto 4c

[0300] 7-(2,6-dichloro-4-nitrophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -1-Ketone 4b (0.50 g, 1.4 mmol) was dissolved in acetic acid (5 mL), iron powder (91 mg, 1.63 mmol) was added, and the mixture was reacted at 70°C for 2 hours. The reaction solution was cooled to room temperature, the iron powder was removed, water (48 mL) was added, stirred for 10 minutes, filtered, rinsed with water (10 mL), and the solid was collected and dried to obtain a yellow solid 4c (0.36 g, yield 78%).

[0301] Step 3) Synthesis of N-(3,5-dichloro-4-((1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine -7-yl) 4-(2 ...

[0302] At 0°C, triethylamine (0.60 mL, 4.3 mmol) was added dropwise to 7-(4-amino-2,6-dichlorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine. -1-ketone 4c (0.20 g, 0.59 mmol) and intermediate 1 (0.57 g, 3.84 mmol) in tetrahydrofuran (10 mL) were reacted at room temperature for 12 hours. The reaction solution was concentrated, and the residue was purified by preparative separation [38% ACN / 62% H2O (0.1% TFA), Kromasil specification: C18 10 μm × 50 mm × 250 mm, flow rate: 100 mL / min] to obtain a light yellow solid 4 (55 mg, yield 21%).

[0303] MS (ESI, neg.ion) m / z: 447.0 [MH] - ;

[0304] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.50 (s, 1H), 8.15 (s, 2H), 7.95 (t, J = 5.6Hz, 1H), 7.48 (d, J = 8.5Hz, 1H), 6.79 ( d, J=2.3Hz, 1H), 6.73 (dd, J=8.5, 2.5Hz, 1H), 2.92 (d, J=6.0Hz, 2H), 2.72 (t, J=6.9Hz, 2H), 1.92-1.82 (m, 2H).

[0305] Example 5 N-(3,5-dichloro-4-((1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 5

[0306]

[0307] Step 1) Synthesis of 5-(4-amino-2,6-dichlorophenoxy)pyridin-2(1H)-one 5a

[0308] 5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one 1i (5.00 g, 1.6 mmol) was dissolved in acetic acid (10 mL), iron powder (2.79 g, 49.8 mmol) was added, and the mixture was reacted at 75°C for 3 hours. The reaction solution was cooled to room temperature, water (100 mL) was added, stirred for 15 minutes, filtered, and the filter cake was collected and dried under vacuum to obtain a light yellow solid 5a (2.00 g, yield 44%).

[0309] Step 2) Synthesis of 5-(2,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)phenoxy)pyridin-2(1H)-one 5b

[0310] 5-(4-amino-2,6-dichlorophenoxy)pyridin-2(1H)-one 5a (1.60 g, 5.9 mmol), p-toluenesulfonic acid (0.11 g, 0.59 mmol) and 2,5-hexanedione (0.69 g, 5.9 mmol) were dissolved in toluene (5 mL) and reacted at 110°C for 2 hours. The reaction solution was cooled to room temperature, quenched by adding saturated sodium carbonate solution (50 mL), extracted with ethyl acetate (10 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a gray solid 5b (1.90 g, yield 92%).

[0311] Step 3) Synthesis of 5-(2,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)phenoxy)-1-(2-methoxy Ethyl)pyridin-2(1H)-one 5c

[0312] 5-(2,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)phenoxy)pyridin-2(1H)-one 5b (2.0 g, 5.7 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1.6 g, 11 mmol) and 2-bromoethyl methyl ether (0.66 mL, 6.9 mmol) were added, and the mixture was reacted at 70°C for 5 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (80 mL×2). The combined organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain a reddish brown oil 5c (1.2 g, yield 51%).

[0313] Step 4) Synthesis of 5-(4-amino-2,6-dichlorophenoxy)-1-(2-methoxyethyl)pyridin-2(1H)-one 5d

[0314] 5-(2,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)phenoxy)-1-(2-methoxyethyl)pyridin-2(1H)-one 5c (0.50 g, 1.2 mmol) and hydroxylamine hydrochloride (1.3 g, 19 mmol) were dissolved in ethanol (4 mL), triethylamine (0.51 mL, 3.7 mmol) was added, and the mixture was reacted at 85°C for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate (20 mL) was added, stirred for 10 minutes, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 3) to obtain a yellow solid 5d (0.20 g, yield 49%).

[0315] Step 5) Synthesis of N-(3,5-dichloro-4-((1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl) Oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 5

[0316] At 0°C, triethylamine (0.60 mL, 4.3 mmol) was added dropwise to 5-(4-amino-2,6-dichlorophenoxy)-1-(2-methoxyethyl)pyridin-2(1H)-one 5d (0.20 g, 0.61 mmol) and intermediate 1 (0.57 g, 3.84 mmol) in tetrahydrofuran (10 mL), and the reaction was allowed to proceed at room temperature for 12 hours. The reaction solution was concentrated, and the residue was purified by preparative separation [38% ACN / 62% H2O (0.1% TFA), Kromasil specification: C18 10 μm×50 mm×250 mm, flow rate: 100 mL / min] to obtain a light yellow solid 5 (40 mg, yield 15%).

[0317] MS (ESI, neg.ion) m / z: 439.0 [MH] - ;

[0318] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.27 (s, 1H), 8.03 (s, 2H), 7.38 (dd, J = 9.9, 3.2Hz, 1H), 7.23 (d ,J=3.0Hz,1H),6.42(d,J=9.9Hz,1H),3.99(t,J=5.1Hz,2H),3.51-3.49(m,2H),3.19(s,3H).

[0319] Example 6 N-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 6

[0320]

[0321] Step 1) Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 6b

[0322] 7-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one 6a (1.5 g, 9.2 mmol) and 1,2,3-trichloro-5-nitrobenzene (2.3 g, 10 mmol) were dissolved in N,N-dimethylformamide (40 mL), potassium carbonate (2.6 g, 19 mmol) was added, and the mixture was reacted at 80°C for 4 hours. The reaction solution was cooled to room temperature, water (80 mL) was added, stirred for 15 minutes, filtered, and the collected filter cake was slurried with ethanol / ethyl acetate / petroleum ether ((v / v / v)=1 / 3 / 6, 50 mL), filtered, and the collected filter cake was dried to obtain a gray solid 6b (2.4 g, yield 74%).

[0323] Step 2) Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 6c

[0324] 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 6b (2.4 g, 6.8 mmol) was dissolved in acetic acid (15 mL), iron powder (1.5 g, 3.9 mmol) was added, and the mixture was reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, the iron powder was removed, water (30 mL) was added, stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to obtain a white solid 6c (1.00 g, yield 46%).

[0325] Step 3) Synthesis of N-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)phenyl)- 5-Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 6

[0326] 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 6c (0.15 g, 0.46 mmol) and intermediate 1 (0.65 g, 3.5 mmol) were dissolved in tetrahydrofuran (3 mL), and triethylamine (0.45 mL, 3.2 mmol) was added dropwise at 0°C. The reaction was allowed to react for 3 hours at room temperature. The reaction solution was concentrated, and the crude product was purified by preparative separation [37% ACN / 63% H2O (0.1% TFA), Kromasil specification: C18 10 μm×50 mm×250 mm, flow rate: 100 mL / min], and a white solid 6 (0.13 g, yield 66%) was obtained.

[0327] MS (ESI, negative ion) m / z: 433.0 [MH] - ;

[0328] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.35 (s, 1H), 8.08 (s, 2H), 8.04 (s, 1H), 7.33 (d, J = 8 .3Hz, 1H), 7.12 (d, J = 8.1Hz, 1H), 7.06 (s, 1H), 3.43 (s, 2H), 2.86 (t, J = 5.2Hz, 2H).

[0329] Example 7 N-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 7

[0330]

[0331] Step 1) Synthesis of 6-(benzyloxy)-3,4-dihydroisoquinolin-1(2H)-one 7b

[0332] 6-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one 7a (5.0 g, 31 mmol) was dissolved in N,N-dimethylformamide (50 mL), potassium carbonate (6.4 g, 46 mmol) was added, and the mixture was reacted at room temperature for 15 minutes, and benzyl bromide (4.4 mL, 37 mmol) was added dropwise, and the mixture was reacted at room temperature for 48 hours. Water (100 mL) was added to quench the reaction, and the mixture was stirred for 20 minutes, filtered, and the solid was collected and dried to obtain a white solid 7b (6.2 g, yield 80%).

[0333] Step 2) Synthesis of 6-(benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 7c

[0334] 6-(Benzyloxy)-3,4-dihydroisoquinolin-1(2H)-one 7b (3.0 g, 12 mmol) was dissolved in tetrahydrofuran (24 mL) and N,N-dimethylformamide (6 mL), sodium hydride (1.4 g, 35 mmol, 60% in oil) was added, and the mixture was reacted at room temperature for 15 minutes, 1-bromo-2-methoxyethane (1.7 mL, 18 mmol) was added dropwise, and the mixture was reacted at 60°C for 4 hours. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with saturated sodium chloride (20 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oil 7c (3.7 g, yield 100%).

[0335] Step 3) Synthesis of 6-hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 7d

[0336] 6-(Benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 7c (3.7 g, 12 mmol) was dissolved in ethanol (30 mL), 10% palladium carbon (0.37 g) was added, hydrogen (3 MPa) was replaced, and the hydrogenation reaction was carried out for 16 hours. The reaction solution was filtered, and the filtrate was collected and concentrated to obtain a yellow solid 7d (2.6 g, yield 99%).

[0337] Step 4) Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1 (2H)-Keto 7e

[0338] 6-Hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 7d (0.50 g, 2.3 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.56 g, 2.5 mmol) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (0.63 g, 4.5 mmol) was added, and the mixture was reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, stirred for 15 minutes, filtered, and the filter cake was collected and recrystallized (ethyl acetate / petroleum ether (v / v) = 3 / 5, 12 mL) to obtain a yellow solid 7e (0.49 g, yield 53%).

[0339] Step 5) Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinoline-1 (2H)-Ketone 7f

[0340] 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 7e (0.40 g, 0.97 mmol) was dissolved in acetic acid (4 mL), iron powder (0.14 g, 2.48 mmol) was added, and the mixture was reacted at 60°C for 5 hours. The reaction solution was cooled to room temperature, water (12 mL) was added to quench the reaction, stirred for 10 minutes, filtered, rinsed with water (20 mL), and the solid was collected and dried to obtain an off-white solid 7f (0.33 g, yield 89%).

[0341] Step 6) Synthesis of N-(3,5-dichloro-4-((2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline- 6-amino)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 7

[0342] 6-(4-amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 7f (0.13 g, 0.33 mmol) and intermediate 1 (0.49 g, 3.28 mmol) were dissolved in tetrahydrofuran (3 mL), triethylamine (0.45 mL, 3.2 mmol) was added dropwise at 0°C, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, and the obtained residue was purified by preparative separation [35% ACN / 65% H2O (0.1% TFA), Kromasil specification: C18 10 μm × 50 mm × 250 mm, flow rate: 100 mL / min] to obtain a white solid 7 (71 mg, yield 44%).

[0343] MS (ESI, neg.ion) m / z: 491.0 [MH] - ;

[0344] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 8.08 (s, 2H), 7.84 (d, J = 8.2Hz, 1H), 6.75 (d, J = 24.4Hz, 2H), 3.66-3.47 (m, 6H), 3.26 (s, 3H), 2.91 (s, 2H).

[0345] Example 8 N-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 8

[0346]

[0347] Step 1) Synthesis of 2-benzyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 8b

[0348] At 0°C, 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 8a (3.0 g, 17 mmol) was added to a mixed solution of sodium hydride (0.81 g, 20 mmol, 60% in oil) in N,N-dimethylformamide (24 mL) and tetrahydrofuran (18 mL), and benzyl bromide (2.2 mL, 19 mmol) was added dropwise. The mixture was reacted at room temperature for 6 hours. Water (120 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated by suction to obtain a light yellow oil 8b (4.51 g, yield 100%).

[0349] Step 2) Synthesis of 2-benzyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 8c

[0350] Boron tribromide (3.2 mL, 34 mmol) was added dropwise to a solution of 2-benzyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 8b (4.5 g, 17 mmol) in dichloromethane (36 mL) at 0°C, followed by reaction at room temperature for 5 hours. The reaction solution was poured into ice water (100 mL) for quenching, stirred for 10 minutes, filtered, and the filter cake was washed with water (20 mL × 2), and the filter cake was collected and dried to obtain a white solid 8c (3.8 g, yield 89%).

[0351] Step 3) Synthesis of 2-benzyl-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 8d

[0352] 2-Benzyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 8c (3.80 g, 15.0 mmol) and 1,2,3-trichloro-5-nitrobenzene (3.74 g, 16.5 mmol) were dissolved in N,N-dimethylformamide (23 mL), potassium carbonate (3.14 g, 22.5 mmol) was added, and the mixture was reacted at 70°C for 7 hours. The reaction solution was cooled to room temperature, water (50 mL) was added, stirred for 10 minutes, filtered, and the filter cake was washed with water (20 mL × 2). The filter cake was collected and recrystallized with ethyl acetate / petroleum ether ((v / v) = 1 / 2, 30 mL) to obtain an off-white solid 8d (6.10 g, yield 92%).

[0353] Step 4) Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-benzyl-3,4-dihydroisoquinolin-1(2H)-one 8e

[0354] Synthesized 2-benzyl-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 8d (1.0 g, 2.3 mmol) was dissolved in acetic acid (12 mL), iron powder (0.50 g, 9.0 mmol) was added, and the mixture was reacted at 55°C for 4 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL × 3), and the filter cake was collected and dried to obtain a white solid 8e (0.93 g, yield 98%).

[0355] Step 5) Synthesis of N-(4-((2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichloro Phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide8

[0356] 6-(4-amino-2,6-dichlorophenoxy)-2-benzyl-3,4-dihydroisoquinolin-1(2H)-one 8e (0.30 g, 0.73 mmol) and intermediate 1 (1.0 g, 6.7 mmol) were dissolved in tetrahydrofuran (8 mL), triethylamine (0.70 mL, 5.0 mmol) was added dropwise at 0°C, and then reacted at room temperature for 2 hours. The reaction solution was concentrated, and the obtained residue was purified by preparative separation [40% ACN / 60% H2O (0.1% TFA), Kromasil specification: C18 10 μm×50 mm×250 mm, flow rate: 100 mL / min] to obtain a white solid 8 (0.15 g, yield 38%).

[0357] MS (ESI, neg.ion) m / z: 523.0 [MH] - ;

[0358] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.34 (s, 1H), 8.07 (s, 2H), 7.91 (d, J = 8.3Hz, 1H), 7.37-7.23 ( m, 5H), 6.82 (d, J = 2.5Hz, 1H), 6.79 (s, 1H), 4.69 (s, 2H), 3.48 (s, 2H), 2.93 (t, J = 6.4Hz, 2H).

[0359] Example 9 N-(4-((1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-3,5-dichlorophenyl)-1H-pyrazole-3-carboxamide 9

[0360]

[0361] Step 1) Synthesis of 1H-pyrazole-3-carboxylic acid 9b

[0362] 1H-pyrazole-3-carboxylic acid ethyl ester 9a (2.00 g, 14.3 mmol) and lithium hydroxide (1.20 g, 28.6 mmol) were dissolved in a mixed solution of water (5 mL) and toluene (10 mL) and reacted at room temperature for 4.5 hours. 3N hydrochloric acid was slowly added dropwise at 0°C to adjust the pH to 3, and the mixed solution was concentrated. Methanol / ethyl acetate (1 / 2, 15 mL) was added to the residue, stirred at 0°C for 30 minutes, filtered, and the filtrate was collected and concentrated to obtain a white solid 9b (1.58 g, yield 99%).

[0363] Step 2) Synthesis of 1H-pyrazole-3-carbonyl chloride 9c

[0364] 1H-pyrazole-3-carboxylic acid 9b (1.78 g, 15.9 mmol) was dissolved in tetrahydrofuran (6 mL), stirred at 60°C for 2 minutes, thionyl chloride (8 mL, 110 mmol) was added, and the reaction was continued for 30 minutes. The reaction solution was concentrated to obtain a white solid 9c (2.03 g, yield 98%).

[0365] Step 3) Synthesis of N-(4-((1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-3,5-dichlorophenyl)- 1H-Pyrazole-3-carboxamide 9

[0366] 5-(4-amino-2,6-dichlorophenoxy)-1-benzylpyridin-2(1H)-one 3b (0.15 g, 0.42 mmol) and 1H-pyrazole-3-carbonyl chloride 9c (1.90 g, 14.6 mmol) were dissolved in tetrahydrofuran (8 mL), triethylamine (2.2 mL, 16 mmol) was added dropwise at 0°C, and then reacted at room temperature for 2 hours. Saturated sodium chloride solution (50 mL) was added to the reaction solution, stirred for 10 minutes, filtered, the filtrate was collected and extracted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain a white solid 9 (0.10 g, yield 53%).

[0367] MS (ESI, negative ion) m / z: 453.0 [MH] - ;

[0368] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.55 (s, 1H), 10.53 (s, 1H), 8.16 (s, 2H), 7.93 (d, J = 2.4Hz, 1H), 7.47 (d, J = 3.3Hz ,1H),7.42(dd,J=9.8,3.3Hz,1H),7.36-7.18(m,5H),6.81(d,J=2.4Hz,1H),6.47(d,J=9.8Hz,1H),5.05(s,2H).

[0369] Example 10 N-(4-((1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-3,5-dichlorophenyl)-1H-imidazole-5-carboxamide 10

[0370]

[0371] Carbonyldiimidazole (99 mg, 0.61 mmol) was added to a solution of 1H-imidazole-5-carboxylic acid 10a (80 mg, 0.70 mmol) in dichloromethane (2.0 mL) at 0°C, stirred for 30 minutes, 5-(4-amino-2,6-dichlorophenoxy)-1-benzylpyridin-2(1H)-one 3b (0.25 g, 0.69 mmol) was added, and then reacted at room temperature for 24 hours. Water (8 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative separation [35% ACN / 65% H2O (0.1% TFA), Kromasil specification: C18 10 μm × 50 mm × 250 mm, flow rate: 100 mL / min] to give a yellow solid 10 (30 mg, yield 9.5%).

[0372] MS (ESI, negative ion) m / z: 453.0 [MH] - ;

[0373] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.69 (s, 1H), 8.27 (s, 1H), 8.16 (s, 2H), 8.11 (s, 1H), 7.47 (d, J = 3.1Hz, 1H), 7.41 (dd, J = 9 .8, 3.2Hz, 1H), 7.33 (t, J = 7.2Hz, 2H), 7.27 (d, J = 7.0Hz, 1H), 7.21 (d, J = 7.4Hz, 2H), 6.47 (d, J = 9.8Hz, 1H), 5.05 (s, 2H).

[0374] Example 11 N-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 11

[0375]

[0376] Step 1) Synthesis of 6-(2,6-dichloro-4-nitro-phenoxy)-3,4-dihydro-2H-isoquinolin-1-one 11b

[0377] 6-Hydroxy-3,4-dihydro-2H-isoquinolin-1-one 11a (1.00 g, 6.13 mmol) and 1,2,3-trichloro-5-nitro-benzene (1.39 g, 6.14 mmol) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (2.14 g, 15.3 mmol) was added, and the mixture was reacted at 120°C for 16 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was stirred for 15 minutes. A yellow solid precipitated, which was filtered and the filter cake was collected to obtain a yellow solid with a wet weight of 2.60 g. The yellow solid was recrystallized with ethanol / ethyl acetate / petroleum ether ((v / v / v)=1 / 2 / 4, 35 mL), filtered, the filter cake was collected, and dried to obtain a yellow solid 11b (1.41 g, yield 65%).

[0378] MS (ESI, pos.ion) m / z: 353.1 [M+H] + .

[0379] Step 2) Synthesis of 6-(4-amino-2,6-dichloro-phenoxy)-3,4-dihydro-2H-isoquinolin-1-one 11c

[0380] 6-(2,6-dichloro-4-nitro-phenoxy)-3,4-dihydro-2H-isoquinolin-1-one 11b (1.4 g, 4.0 mmol) was dissolved in acetic acid (8 mL), iron powder (0.22 g, 3.9 mmol) was added, and the mixture was reacted at 70°C for 2 hours. The reaction solution was cooled to room temperature, the stirring magnet was removed, the iron powder was removed and then put back into the reaction solution, water (30 mL) was added, and the mixture was stirred for 10 minutes. Solids precipitated, which were filtered, rinsed with water (10 mL), and the solids were collected and dried in vacuo to obtain yellow solids 11c (1.00 g, yield 78%).

[0381] MS (ESI, pos.ion) m / z: 323.2 [M+H] + .

[0382] Step 3) Synthesis of N-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)- 5-Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 11

[0383] 6-(4-amino-2,6-dichloro-phenoxy)-3,4-dihydro-2H-isoquinolin-1-one 11c (0.30 g, 0.93 mmol) and intermediate 1 (0.83 g, 5.57 mmol) were dissolved in tetrahydrofuran (20 mL) and reacted at 75°C for 3 hours. The reaction solution was cooled to room temperature, water (20 mL) was added to quench the reaction, and it was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was purified by preparative separation [38% ACN / 62% H2O (0.1% TFA), Kromasil specification: C18 10μm×50mm×250mm, flow rate: 100mL / min] to obtain a white solid 11 (0.24 g, yield 59%).

[0384] MS (ESI, neg.ion) m / z: 433.4 [MH] - ;

[0385] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.43 (s, 1H), 11.38 (s, 1H), 8.06 (s, 2H), 7.92-7.55 (m, 2H), 6. 80(d,J=2.5Hz,1H), 6.76(dd,J=8.5,2.6Hz,1H), 3.33(d,J=6.7Hz,2H), 2.86(t,J=6.5Hz,2H).

[0386] Example 13 N-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 13

[0387]

[0388] Step 1) Synthesis of 2-ethyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 13a

[0389] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 8a (2.05 g, 11.6 mmol) was dissolved in a mixed solution of tetrahydrofuran (40 mL) and N,N-dimethylacetamide (15 mL). Sodium hydride (0.58 g, 14.5 mmol, 60% in oil) was added in batches at 0°C, and then iodoethane (1.13 mL, 13.8 mmol) was added dropwise. The mixture was reacted at 50°C for 24 hours. The reaction solution was cooled to room temperature, ice water (40 mL) was added to the reaction solution to quench, and tetrahydrofuran was removed by concentration under reduced pressure. The remaining solution was extracted with ethyl acetate (50 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (45 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a light yellow oil 13a (2.30 g, yield 97%).

[0390] MS (ESI, pos.ion) m / z: 206.2 [M+H] + .

[0391] Step 2) Synthesis of 2-ethyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 13b

[0392] 2-Ethyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 13a (2.40 g, 11.7 mmol) was dissolved in dichloromethane (50 mL), and boron tribromide (2.28 mL, 23.4 mmol) was slowly added dropwise at 0°C, and stirring was continued for 3.5 hours. Methanol (10 mL) was slowly added dropwise at 0°C to quench the reaction, and the mixture was concentrated under reduced pressure. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phases were washed with saturated sodium chloride solution (40 mL×2), dried over anhydrous sodium sulfate, and concentrated by suction to obtain a brown solid 13b (2.01 g, yield 90%).

[0393] MS (ESI, neg.ion) m / z: 190.1 [MH] - .

[0394] Step 3) Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one 13c

[0395] 2-Ethyl-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 13b (2.00 g, 10.5 mmol) was dissolved in N,N-dimethylacetamide (25 mL), and 1,2,3-trichloro-5-nitrobenzene (2.37 g, 10.5 mmol) and potassium carbonate (5.61 g, 40.2 mmol) were added in sequence, and the mixture was reacted at 80°C for 7 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), stirred for 20 minutes, and then hydrochloric acid (3N, 15 mL) was added dropwise, filtered, and the solid was collected and dried. The obtained solid was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain a white solid 13c (3.42 g, yield 86%).

[0396] MS (ESI, pos.ion) m / z: 381.0 [M+H] + .

[0397] Step 4) Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one 13d

[0398] 6-(2,6-dichloro-4-nitrophenoxy)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one 13c (2.05 g, 5.38 mmol) was dissolved in acetic acid (25 mL), iron powder (1.23 g, 21.6 mmol) was added, and the mixture was reacted at 60°C for 4 hours. The reaction solution was cooled to room temperature, the iron powder was removed, water (50 mL) was added, stirred for 10 minutes, filtered, rinsed with water (10 mL), and the filter cake was collected and dried to obtain a white solid 13d (1.80 g, yield 95%).

[0399] MS (ESI, pos.ion) m / z: 351.1 [M+H] + .

[0400] Step 5) Synthesis of N-(3,5-dichloro-4-((2-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy) Phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 13

[0401] 6-(4-amino-2,6-dichlorophenoxy)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one 13d (0.35 g, 1.00 mmol) and intermediate 1 (0.90 g, 4.12 mmol) were dissolved in tetrahydrofuran (8 mL) and reacted at 75°C for 2.5 hours. The reaction solution was cooled to room temperature, water (10 mL) was added to quench the reaction, and it was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative separation [47% ACN / 53% H2O (0.1% TFA), Kromasil specification: C18 10 μm×50 mm×250 mm, flow rate: 100 mL / min] to obtain a white solid 13 (0.31 g, yield 67%).

[0402] MS (ESI, neg.ion) m / z: 461.1 [MH] - ;

[0403] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.50 (s, 1H), 11.37 (s, 1H), 8.07 (s, 2H), 7.84 (d, J = 8.2Hz, 1H), 6.78 (s, 1H), 6 .76(d,J=2.8Hz,1H),3.52(d,J=6.6Hz,2H),3.50-3.44(m,2H),2.93(t,J=6.5Hz,2H),1.09(t,J=7.0Hz,3H).

[0404] Example 14 N-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 14

[0405]

[0406] Step 1) Synthesis of 6-(2,6-dimethyl-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 14b

[0407] 6-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one 26a (3.0 g, 18 mmol) and 2-fluoro-1,3-dimethyl-5-nitrobenzene 14a (3.5 g, 21 mmol) were dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (2.8 g, 28 mmol) was added, and the mixture was reacted at 80°C for 12 hours. The reaction solution was cooled to room temperature, water (150 mL) was added, stirred for 10 minutes, filtered, the filter cake was rinsed with water (30 mL × 2), the filter cake was collected, slurried with ethyl acetate / petroleum ether ((v / v) = 1 / 6, 70 mL), filtered, the filter cake was collected and dried to obtain a white solid 14b (4.2 g, yield 73%).

[0408] Step 2) Synthesis of 6-(4-amino-2,6-dimethylphenoxy)-3,4-dihydroisoquinolin-1(2H)-one 14c

[0409] 6-(2,6-dimethyl-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 14b (0.50 g, 1.60 mmol) was dissolved in acetic acid (10 mL), iron powder (0.36 g, 6.41 mmol) was added, and the mixture was reacted at 55°C for 21 hours. The reaction solution was cooled to room temperature, the iron powder was removed, ethyl acetate (100 mL) was added, and the mixture was washed with water (50 mL) and saturated sodium bicarbonate solution (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to obtain a yellow solid 14c (0.32 g, yield 70%).

[0410] Step 3) Synthesis of N-(3,5-dimethyl-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)benzene 14-(2-(2-(2-nitro-4-(2-nitro-1-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide)

[0411] 6-(4-Amino-2,6-dimethylphenoxy)-3,4-dihydroisoquinolin-1(2H)-one 14c (0.35 g, 1.24 mmol) and intermediate 1 (1.08 g, 4.95 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 75°C for 2 hours. The reaction solution was cooled to room temperature and concentrated, and the obtained residue was purified by preparative separation [38% ACN / 62% H2O (0.1% TFA), Kromasil specification: C18 10μm×50mm×250mm, flow rate: 100mL / min] to obtain a white solid 14 (0.43 g, yield 89%).

[0412] MS (ESI, neg.ion) m / z: 393.2 [MH] - ;

[0413] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.34 (s, 1H), 10.96 (s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.78-7.74 (m, 1H), 7.58(s,2H),6.68(s,1H),6.67-6.63(m,1H),3.49-3.41(m,2H),2.85(t,J=6.6Hz,2H),2.06(s,6H).

[0414] Example 15 N-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 15

[0415]

[0416] Step 1) Synthesis of 6-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinoline-1(2H)- Ketone 15a

[0417] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 8a (3.0 g, 16.9 mmol) was dissolved in tetrahydrofuran (30 mL) and N,N-dimethylformamide (30 mL). Sodium hydride (0.85 g, 21.2 mmol, 60% in oil) was added in batches at 0°C, and then bromomethylpyran (1.13 mL, 13.8 mmol) was added dropwise. After the addition, the reaction was continued at room temperature for 24 hours. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a light yellow oil 15a (4.35 g, yield 93%).

[0418] MS (ESI, pos.ion) m / z: 276.2 [M+H] + .

[0419] Step 2) Synthesis of 6-hydroxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 15b

[0420] 6-Methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 15a (0.81 g, 2.94 mmol) was dissolved in dichloromethane (20 mL), and boron tribromide (0.57 mL, 5.89 mmol) was slowly added dropwise at 0°C, and the reaction was maintained at 0°C for 2.5 hours. Methanol (5 mL) was added at 0°C to quench the reaction, and the mixture was concentrated. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phases were washed with saturated sodium chloride solution (40 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain a light yellow solid 15b (0.42 g, yield 55%).

[0421] Step 3) Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4- Dihydroisoquinolin-1(2H)-one 15c

[0422] 6-Hydroxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 15b (0.33 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), 1,2,3-trichloro-5-nitrobenzene (0.39 g, 1.7 mmol) and potassium carbonate (0.55 g, 3.9 mmol) were added, and the mixture was reacted at 80°C for 5 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The combined organic phase was washed with saturated sodium chloride solution (15 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain a yellow solid 15c (0.31 g, yield 54%).

[0423] Step 4) Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4- Dihydroisoquinolin-1(2H)-one 15d

[0424] 6-(2,6-dichloro-4-nitrophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 15c (0.31 g, 0.69 mmol) was dissolved in acetic acid (10 mL), iron powder (0.19 g, 3.3 mmol) was added, and the mixture was reacted at 60°C for 3.5 hours. The reaction mixture was cooled to room temperature, the iron powder was removed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The combined organic phases were washed with saturated sodium chloride solution (15 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a light yellow solid 15d (0.18 g, yield 62%).

[0425] MS (ESI, pos.ion) m / z: 421.1 [M+H] + .

[0426] Step 5) Synthesis of N-(3,5-dichloro-4-((1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4- Tetrahydroisoquinolin-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide 15

[0427] 6-(4-amino-2,6-dichlorophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 15d (0.30 g, 0.71 mmol) and intermediate 1 (0.62 g, 2.85 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, water (20 mL) was added to quench the reaction, and it was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative separation [47% ACN / 53% H2O (0.1% TFA), Kromasil specification: C18 10μm×50mm×250mm, flow rate: 100mL / min] to obtain a white solid 15 (0.25 g, yield 67%).

[0428] MS (ESI, neg.ion) m / z: 531.1 [MH] - ;

[0429] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.45 (s, 1H), 11.38 (s, 1H), 8.07 (s, 2H), 7.84 (d, J= 8.3Hz,1H),6.78(s,1H),6.76(d,J=2.7Hz,1H),3.83(d,J=9.0Hz,2H),3.52(t,J=6 .5Hz,2H),3.37(d,J=30.4Hz,2H),3.25(td,J=11.6,2.0Hz,2H),2.93(t,J=6.5Hz, 2H), 1.97-1.85 (m, 1H), 1.53 (dd, J=13.3, 3.6Hz, 2H), 1.21 (qd, J=12.1, 4.6Hz, 2H).

[0430] Activity Test Example

[0431] 1. Method for detecting the agonist activity of compounds on TRα or TRβ in dual luciferase reporter gene assay

[0432] Test Materials:

[0433] HEK293 cells were purchased from ATCC, Cat No. CRL-1573;

[0434] Fugene HD transfection reagent, purchased from Promega, Cat No. E231A;

[0435] DMEM, purchased from Gibco, Cat No. 11995;

[0436] FBS, purchased from Biosera, Cat No. FB-1280 / 500;

[0437] 0.25% Trypsin-EDTA, purchased from Gibco, Cat No. 25200-072;

[0438] Dual-Luciferase Reporter Assay System, purchased from Promega, Cat No. E1960;

[0439] 96-well plate (round bottom), purchased from Corning, Cat No.3365.

[0440] Test method:

[0441] HEK293 cells were cultured in a complete medium of 10% FBS + DMEM. pBind-TRα or pBind-TRβ (100ng / μl), pG5Luc (100ng / μl), FuGENE HD and Opti-MEM were thoroughly mixed and incubated at room temperature for 15min. At the same time, HEK293 cells were digested with 0.25% Trypsin-EDTA and resuspended in complete medium. The cell density was calculated and adjusted to 500,000 cells / ml. Then, the transcription mixture was added and mixed with the cell suspension, plated in a 96-well plate (100μL / well), and cultured at 37°C for 24h. After 24h, the test compound was dissolved in DMSO and diluted 3 times for a total of 10 concentrations. Subsequently, the compound was diluted with DMEM to a compound solution containing 10% DMSO. 5μL of the compound was taken in a 96-well plate. The final concentration of the compound DMSO was 0.5%. The compound and cells were co-cultured for 18h. After 18 hours, the firefly fluorescence signal and the Renilla fluorescence signal were detected using the Dual-Luciferase Reporter Assay System. The firefly fluorescence signal was divided by the Renilla fluorescence signal to calculate the F / R ratio, and the curve was drawn using Graph Pad Prism software to calculate the EC 50 The compounds of the present invention have good TRβ agonist activity. Specifically, the EC value of the compounds of the present invention for TRβ agonist activity is 50 The value is less than 0.1 μM. At the same time, the compounds of the present invention have good selectivity for TRβ. Specifically, the EC of the compounds of the present invention for stimulating TRβ 50 EC values ​​of TRα 50 The ratio of values ​​is greater than 10.

[0442] The test results show that the compounds of the present invention have obvious agonist activity and selectivity to TRβ.

[0443] II. In vitro binding activity detection method of compounds to TRα or TRβ

[0444] Test Materials:

[0445] LanthaScreen TR-FRET Thyroid Receptor beta Coactivator Assay kit was purchased from Invitrogen, Cat. No. PV4686;

[0446] LanthaScreen TR-FRET Thyroid Receptor alfa Coactivator Assay kit was purchased from Invitrogen, Cat. No. PV4687.

[0447] Test method:

[0448] The method was performed using the LanthaScreen TR-FRET Thyroid Receptor beta / alfa Coactivator Assay kit. The test compound was dissolved in DMSO and diluted 3-fold for a total of 10 concentrations, followed by dilution into a compound solution containing 2% DMSO using TR-FRET Coregulator Buffer C in the kit. 10 μL of the compound solution containing 2% DMSO was added to a 384-well plate, and then 5 μL of 4×TRα-LBD or TRβ-LBD, 5 μL of a mixture containing 0.4 μMfluorescein-SRC2-2 and 8 nM Tb anti-GST antibody were added to each well, mixed thoroughly, and incubated at room temperature in the dark for 1 hour. After 1 hour, the fluorescence value (RFU) was read using a BMG LABTECH PHERAstar FSX microplate reader at excitation 520 nm and emission 495 nm. The TR-FRET ratio was calculated by dividing the emission signal at 520 nm by the emission signal at 495 nm. Graph Pad Prism 5 software was used to draw curves and calculate EC 50 The results of the in vitro binding activity test of the compounds of the present invention to TRα or TRβ are shown in Table 1 below.

[0449] Table 1 In vitro binding activity test results of the compounds of the present invention to TRα or TRβ

[0450]

[0451] The test results show that the compounds of the present invention have strong binding affinity and selectivity to TRβ.

[0452] III. Pharmacokinetics of the compounds of the present invention

[0453] Purpose of the study: The following method was used to determine the pharmacokinetic properties of the compounds of the present invention.

[0454] Test Materials:

[0455] The experimental reagents and test products used: Propranolol (internal standard), methanol, ammonium acetate, K2EDTA (potassium ethylenediaminetetraacetate), formic acid, acetonitrile, MTBE (methyl tert-butyl ether), Kolliphor HS15 (polyethylene glycol 12-hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available;

[0456] SD rats: male, 180-220 g, 7-8 weeks old, purchased from Hunan Slake Experimental Animal Co., Ltd.

[0457] Test method:

[0458] 1. Preparation of test samples

[0459] The test solution was prepared according to 5% DMSO + 5% Kolliphor HS15 + 90% normal saline, and the solution was adjusted according to the solubility of each compound so that the compound could be completely dissolved.

[0460] 2. Animal Experiment Design

[0461]

[0462] 3. Animal Dosage Table

[0463] Group gender Number of animals Dosage Dosing concentration Dosing volume IV male 3 1mg / kg 1mg / mL 1mL / kg Oral male 3 5mg / kg 1mg / mL 5mL / kg

[0464] 4. Solution preparation

[0465] (1) Preparation of test sample stock solution: Accurately weigh an appropriate amount of test sample, dissolve it in DMSO, dilute it to 1 mg / mL with acetonitrile, and shake well. Store at -20°C until use.

[0466] (2) Preparation of internal standard solution: Accurately pipette a certain amount of 1 mg / mL Propranolol stock solution and dilute it to 100 ng / mL with water.

[0467] 5. Sample analysis

[0468] The samples were treated by liquid-liquid extraction and chromatographic separation. The quantitative analysis was performed on a triple quadrupole tandem mass spectrometer using multiple reaction ion monitoring (MRM). The concentration of the results was calculated using instrument quantitative software.

[0469] 6. Plasma sample pretreatment

[0470] Accurately pipette 30 μL of plasma sample, add 250 μL of internal standard, vortex mix evenly. Extract once with 1 mL of MTBE, centrifuge at 13,000 rpm, 4 ° C for 2 min, pipette 800 μL of supernatant, evaporate in a 96-well nitrogen blower, re-dissolve the residue with 150 μL of methanol / water (v / v=50 / 50), vortex mix, and inject, the injection volume is 8 μL.

[0471] 7. Preparation of standard samples

[0472] Accurately pipette an appropriate amount of compound stock solution, add acetonitrile to dilute and prepare a standard series of solutions. Accurately pipette 20 μL of each of the above standard series solutions, add 180 μL of blank plasma, vortex mix, and prepare plasma samples equivalent to plasma concentrations of 3, 5, 10, 30, 100, 300, 1000, 3000, 5000 and 10000 ng / mL. All operations are performed according to the "plasma sample pretreatment". Double sample analysis is performed for each concentration to establish a standard curve.

[0473] 8. Analysis methods

[0474] The LC / MS / MS method was used to determine the content of the test compound in the plasma of SD rats after administration of different compounds.

[0475] 9. Data Processing

[0476] WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental method.

[0477] The test results show that the compound of the present invention exhibits excellent pharmacokinetic properties in SD rats when administered by intravenous injection or oral administration.

[0478] IV. Pharmacodynamic Evaluation of the Compounds of the Invention

[0479] Test Materials:

[0480] Western diet: purchased from Research diet, catalog number: D12079B;

[0481] MCD diet: purchased from Nantong Trofi Feed Technology Co., Ltd., product number: TP3006R;

[0482] ALT, AST, ALP, TG, CHO, HDL, LDL and GLU were purchased from Roche with the catalog numbers: 20764957322, 20764949322, 03333701190, 20767107322, 03039773190, 04399803190, 03038866322 and 04404483190, respectively;

[0483] 8-week-old male OB / OB mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0484] 8-week-old male db / db mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0485] A. Effect of compounds on Western diet-induced non-alcoholic steatohepatitis (NASH) model in OB / OB mice Pharmacodynamic evaluation in OB / OB mice are leptin gene-deficient mice. The OB / OB mouse NASH model induced by Western diet is a commonly used NASH in vivo drug efficacy evaluation model. The experiment began after the animals adapted for 1 week. OB / OB mice were fed with Western diet, and the feed was changed three times a week (Monday, Wednesday, and Friday). The mice began to be administered in the fifth week after feeding, and were orally administered once a day for 6 weeks. The entire experimental period was 10 weeks. During the experiment, the basic conditions of the animals were monitored every day, and the weight of the mice was recorded once a week. After the experiment, the mice were fasted overnight, and the mice were anesthetized and whole blood was collected from the orbital cavity. Serum was obtained by centrifugation at 4°C, 4,000rpm, and stored at -80°C. Serum was used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL, and GLU. The mice were dissected, and the liver was taken and weighed. The middle lobe of the liver was placed in an EP tube and stored at -80°C for the determination of TG and CHO content in the liver. The left liver lobe was fixed in 10% formalin, and then stained with HE and NAS was scored.

[0486] B. Efficacy of the compound in the MCD diet-induced db / db mouse nonalcoholic steatohepatitis (NASH) model Academic Evaluation

[0487] The db / db mouse is a leptin receptor gene-deficient mouse. The db / db mouse NASH model induced by MCD diet is a commonly used NASH in vivo drug efficacy evaluation model. The experiment began after the animals adapted for 1 week. The db / db mice were fed with MCD feed, and the feed was changed three times a week (Monday, Wednesday, and Friday). The mice were experimented by drug administration while modeling, and oral administration was performed once a day for 8 weeks. The entire experimental period was 8 weeks. During the experiment, the basic conditions of the animals were monitored every day, and the weight of the mice was recorded once a week. After the experiment, the mice were fasted overnight, and the mice were anesthetized and whole blood was collected from the orbital cavity. The serum was obtained by centrifugation at 4°C, 4,000rpm, and stored at -80°C. The serum was used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL, and GLU. The mice were dissected, and the liver was taken and weighed. The middle lobe of the liver was placed in an EP tube and stored at -80°C for the determination of TG and CHO content in the liver. The left liver lobe was fixed in 10% formalin, and then stained with HE and NAS was scored.

[0488] The test results show that the compound of the present invention can effectively reduce fat accumulation in the liver, alleviate inflammation, and improve liver fibrosis.

[0489] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, unless they are contradictory.

[0490] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound having a structure as shown in formula (II), or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of the structure as shown in formula (II), in, Y is -O- or -S-; R 1 , R 2 , R 3 and R 4 Each independently represents H, deuterium, F, Cl, Br, I, CN, OH, NH2, SH, C 1-6 Alkyl or C 1-6 Haloalkyl; A is Among them, X 1 is -NH-; X 2 , X 3 and X 4 Each is independently -CH2-; t is 0, 1, 2, 3, or 4; T 1 For-CR T1 =;T 2 For-CR T2 =;T 4 For-CR T4 =; Each R T1 , R T2 and R T4 are independently H, deuterium, F, Cl, Br or I; Each R 5 are independently H, deuterium, F, Cl, Br, I, CN, OH, NH2, SH, C 1-3 Alkyl, C 1-3 Haloalkyl, (3-6 atoms composed of heterocyclic) -C 1-2 Alkylene or C 6-10 Aryl-C 1-2 Alkylene, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, (3-6 atoms composed of heterocyclic) -C 1-2 Alkylene and C 6-10 Aryl-C 1-2 Each alkylene group is independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, SH, C 1-3 Alkyl and C 1-3 substituted by an alkoxy substituent; V 1 is -N=; V 2 for -O-; V 3 is -C(=O)-; V 4 is -NH-; R 6 Deuterium, F, Cl, Br, I, CN, OH, NH2, SH or C 1-6 alkyl; n is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, wherein R 6 is deuterium, F, Cl, Br, I, CN, OH, NH2, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

3. The compound according to claim 1, wherein each R 5 are independently H, deuterium, F, Cl, Br, I, CN, OH, NH2, SH, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, phenyl-CH2-, phenyl-CH2CH2-, naphthyl-CH2-, tetrahydropyranyl-CH2-, pyrrolidinyl-CH2-, pyrazolidinyl-CH2-, tetrahydrofuranyl-CH2-, tetrahydrothiophenyl-CH2-, piperidinyl-CH2-, wherein the methyl, ethyl, n-propyl, isopropyl, -CHF2, -CH2F, -CH2CF3, phenyl, naphthyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted by 1, 2 or 3 independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, SH, C 1-3 Alkyl and C 1-3 The alkoxy group is substituted with an alkoxy substituent.

4. A compound having one of the following structures: or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or any combination thereof.

6. Use of the compound according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a drug, wherein: The drug is used for stimulating thyroid hormone receptors; or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

7. The use according to claim 6, wherein the thyroid hormone receptor is a thyroid hormone β receptor; wherein the disease regulated by thyroid hormone receptor is a neurodegenerative disease, nonalcoholic fatty liver disease, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, dyslipidemia, obesity, diabetes, metabolic disorder, type 1A glycogen storage disease or hypothyroidism; The non-alcoholic fatty liver disease is non-alcoholic simple fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer; The neurodegenerative disease is a demyelinating disease, leukodystrophy, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenocortical dystrophy, amyotrophic lateral sclerosis or Alzheimer's disease.

Images