Thyroid hormone receptor beta selective agonist compounds, pharmaceutical compositions thereof, and uses

Abstract

This invention relates to thyroxine receptor β-selective agonist compounds represented by general formula I, pharmaceutical compositions thereof, and uses. These compounds maintain good THR-β agonist activity while improving selectivity for THR-α and druggability, and exhibit certain activity in in vivo pharmacodynamic studies.

Description

β-selective thyroxine receptor agonist compounds, their pharmaceutical compositions and uses

[0001] This application is a divisional application of patent application No. 202111482622.9, filed on December 7, 2021, entitled "Thyroxine Receptor β Selective Agonist Compound, Pharmaceutical Composition Thereof and Uses". Technical Field

[0002] This invention relates to thyroid hormone receptor β-selective agonists. More specifically, this invention relates to a thyroid hormone receptor β-subtype agonist compound of general formula (I), pharmaceutical compositions thereof, and their use in the preparation of medicaments for treating related diseases. Background Technology

[0003] Thyroid hormones (TH) are produced by the thyroid gland and secreted into the circulatory system (hypothalamic / pituitary / thyroid system) in two different forms: 3,5,3',5'-tetraiodo-L-thyroxine (T4) and 3,5,3'-triiodo-L-thyroxine (T3). Although T4 is the predominant form secreted by the thyroid gland, T3 is the physiologically more active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues, but primarily in the liver and kidneys. The biological activity of thyroid hormones is mediated by thyroid hormone receptors (THRs). THRs are encoded by the α and β expression of different genes located on human chromosomes 17 and 3, respectively. Different protein isoforms are produced by selective splicing of the primary transcript, with each gene producing two isoforms: THRα1, THRα2, THRβ1, and THRβ2. THRβ1 and THRβ2 are derived by promoter differential expression, and these two isoforms differ only in their amino terminus. THRα1 and THRα2 are derived from differentially spliced ​​precursor mRNA, with the main difference being at the C-terminus. THRα1, THRβ1, and THRβ2 can bind thyroid hormones. It has been shown that thyroid hormone receptor subtypes can differ in their contribution to specific physiological responses. THRβ1 plays an important role in regulating thyroid-stimulating hormone (TSH) and thyroid hormones in the liver. THRβ2 plays a major role in regulating thyroid-stimulating hormone. Thyroid hormones have the effect of lowering serum low-density lipoprotein (LDL). Hyperthyroidism is associated with low total serum cholesterol, attributed to increased hepatic LDL receptor expression and stimulation of cholesterol metabolism to bile acids by thyroid hormones. Hypothyroidism is associated with hypercholesterolemia, and thyroid hormone replacement therapy is known to lower total cholesterol. Thyroid hormones can also reduce the risk of atherosclerosis and other cardiovascular diseases. The incidence of atherosclerotic vascular disease is directly related to LDL cholesterol levels. Thyroid hormones have beneficial effects on obese patients by increasing metabolic rate, oxygen consumption, and heat release, thereby reducing body weight and improving obesity-related comorbidities. They can also have beneficial effects on glycemic control in obese patients with type 2 diabetes.

[0004] The development of thyroid analogs that avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones will open new avenues for treating patients with the following conditions: metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, and diabetes; and other conditions such as hepatic steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid diseases, and related conditions and diseases.

[0005] MGL-3196 is a first-in-class, orally administered, small-molecule selective agonist of the hepatic thyroid hormone receptor β subtype (THR-β). Preclinical toxicology and Phase 1 clinical data suggest that MGL-3196 significantly reduces LDL cholesterol, triglycerides, and lipoproteins as a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemia (Journal of Hepatology, 2018, vol. 68, S37-S64), making it an ideal candidate for reducing cardiovascular risk in NASH patients and for dyslipidemia patients who are taking moderate doses of statins or are intolerant to statins (European Heart Journal, Volume 39, Issue suppl_l, August 2018, ehy566. P5387). Phase 2 clinical data showed that adverse reactions (AEs) were mainly mild (85%) and moderate (15%), with 3 cases of serious AEs unrelated to treatment (Journal of Hepatology, 2018, vol.68, S37-S64).

[0006]

[0007] While MGL-3196 is an effective THR-β agonist for treating a variety of diseases, discovering novel compounds that possess the beneficial effects of thyroid hormones while avoiding adverse effects, have good oral bioavailability, and are druggable remains a challenging task. Therefore, the art still needs to develop selective THR-β agonists with better specificity, efficacy, and pharmacokinetic properties, and this invention provides such compounds. Summary of the Invention

[0008] One object of the present invention is to provide a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, an enantiomer, a diastereomer, a transisomer, a racemic mixture, a polymorph, a solvate, or an isotopically labeled compound (including deuterium-substituted compounds).

[0009] Another object of the present invention is to provide a method for preparing the compound.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising the said compound.

[0011] Another object of the present invention is to provide the use of the compound in pharmaceutical manufacturing.

[0012] According to one aspect of the invention, a compound represented by general formula (I), its pharmaceutically usable salt, stereoisomer, enantiomer, diastereomer, transisomer, racemic mixture, polymorph, solvate, or isotopically labeled compound is provided:

[0013]

[0014] in,

[0015] Ring A is selected from:

[0016] Ring B is selected from:

[0017] R0 is selected from hydrogen and C. 1-10 alkyl;

[0018] R1 is selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl and substituted or unsubstituted 5-10 heteroaryl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, =O, C. l-6 Alkoxy, C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, Halogenated C 6-10 Aryl, C 1-10 Alkyl C 6-10 Aryl, C 1-10 Alkoxy C 6-10 Aryl, 5-10 heteroaryl, C 1-10 Alkyl 5-10-membered heteroaryl, halogenated 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl and -NR 10 R 11 ;

[0019] R2, R3, and Y are each independently selected from hydrogen, halogen atoms, substituted or unsubstituted carbon atoms. 1-6 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C l-6 alkoxy, wherein the substituent is selected from halogen atoms, hydroxyl groups, C 1-6 Alkyl and C l-6 Alkoxy;

[0020] R4 is selected from hydrogen, cyano, and -NR. 10 R 11 C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 3-6cycloalkyl and substituted or unsubstituted C 2-8 Alkyne group, wherein the substituent is selected from halogen atoms, hydroxyl groups, cyano groups, and C. l-6 Alkoxy;

[0021] R5 is selected from hydrogen, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0022] R6 is selected from hydrogen and substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0023] L does not exist, or is -NR 10 C(O)- or -NR 10 CR 11 R 11 -;

[0024] Each R 10 Independently selected from hydrogen and substituted or unsubstituted C 1-3 Alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-3 Alkoxy;

[0025] Each R 11 Independently selected from hydrogen and substituted or unsubstituted C 1-6 Alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0026] X1 and X2 are each independently selected from N and CR. 12 R 12 Selected from hydrogen, halogens, cyano, -NR b R c -C(=O)R a -C(=O)OR b -C(=O)NR b R c C, substituted or unsubstituted 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl and substituted or unsubstituted 5-10-membered heteroaryl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0027] X3 and X4 are each independently selected from N and CR. 13 R 13 Selected from hydrogen, halogen, cyano, hydroxyl, -ORa -NR b R c -C(=O)R a -C(=O)OR b -C(=O)NR b R c C, substituted or unsubstituted 1-4 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0028] Each R a Independently for C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl, and heterocyclic alkyl are independently optionally selected from halogen, hydroxyl, amino, and C. 1-6 One or more substituents of the alkyl group are used for substitution;

[0029] Each R b and R c Independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl, and heterocyclic alkyl are independently optionally selected from halogen, hydroxyl, amino, and C. 1-6 One or more substituents of the alkyl group are used for substitution;

[0030] Or R b and R c Together with the nitrogen atoms to which they are attached, they form 3-10 membered heterocyclic alkyl groups, which are optionally selected from halogens, hydroxyl groups, amino groups, and C-membered alkyl groups. 1-6 One or more substituents of the alkyl group are used for substitution;

[0031] n is 1, 2, or 3 independently each time it appears.

[0032] According to another aspect of the present invention, a method for preparing the compound of the present invention is provided, wherein the method is one of the following:

[0033] Option 1:

[0034]

[0035] Compound Ia of general formula is dissolved in a polar solvent, and a base is added to react with compound Ib of general formula to give compound Ic of general formula. The base under these conditions includes inorganic bases (sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, or potassium hydroxide, etc.) and organic bases (triethylamine, N,N-diisopropylethylamine, or pyridine, etc.), with potassium carbonate being preferred. The polar solvent under these conditions includes (N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, or acetonitrile, etc.), with N,N-dimethylformamide being preferred.

[0036] Compound Ic of general formula reacts with a reducing agent to yield compound Id of general formula. The reducing agent under these conditions includes iron powder, sulfides, stannous chloride, or zinc powder, with stannous chloride being the preferred reducing agent.

[0037] Compound Id of general formula reacts with a nitrite ester in an acidic acetonitrile solution, followed by the addition of compound Ie for further reaction, and then ring closure at high temperature to yield compound I-S1 of general formula. The acid under these conditions is an organic acid, including carboxyl or sulfonic acids, with acetic acid being preferred. The nitrite ester under these conditions includes isoamyl nitrite or tert-butyl nitrite, with tert-butyl nitrite being preferred. The A ring, Y, and R rings are described. 2 R 3 and R 4 As defined in this article. Or

[0038] Option 2:

[0039]

[0040] Under acidic conditions, the compound of general formula Id reacts with a nitrite ester to form a diazonium salt compound. The addition of a halide anion yields the compound of general formula If. The resulting compound of general formula If is then coupled with an intermediate Ig under transition metal catalysis to yield the compound of general formula I-S1. The acid under these conditions is an organic acid, including carboxyl or sulfonic acids, with acetic acid being preferred. The nitrite ester under these conditions includes isoamyl nitrite or tert-butyl nitrite, with tert-butyl nitrite being preferred. X is a halogen, and rings A, Y, and R... 2 R 3 and R 4 As defined in this article. Or

[0041] Option 3:

[0042]

[0043] Compound II-a of general formula undergoes a condensation reaction with compound Id of general formula under basic conditions, forming an amide bond, to yield compound II of general formula. The base under these conditions includes organic bases such as triethylamine or N,N-diisopropylethylamine, and the condensing agent includes carbodiimide-type, phosphocation-type, or urea-type condensing agents. A ring, Y, R 2 and R 3 As defined in this article. Or

[0044] Option 4:

[0045]

[0046] Compound of general formula Id reacts with a compound of general formula II-b acyl chloride under basic conditions to form an amide bond, yielding compound of general formula II. The base under these conditions includes organic bases such as triethylamine or N,N-diisopropylethylamine, with triethylamine being preferred. A ring, Y, R 2 and R 3 As defined in this article. Or

[0047] Option 5:

[0048]

[0049] Compound III-a of general formula undergoes a substitution reaction with compound Ia of general formula under basic conditions to give compound III-b. Subsequently, under conventional conditions, the methyl ether protection on the oxygen atom is removed, followed by a substitution reaction with a haloalkane substituted with an R1 group under basic conditions to give intermediate III-d of general formula. The base under these conditions includes inorganic bases such as potassium carbonate, cesium carbonate, and sodium hydroxide, as well as organic bases such as triethylamine or N,N-diisopropylethylamine. The reaction temperature is 50-150°C, and the reaction can be carried out under heating or microwave conditions. The organic solvents include, but are not limited to, dioxane, DMF, DMSO, tetrahydrofuran, and NMP. R1, R2, R3, X1, X2, X3, and X4 are as defined herein.

[0050] Then, following the method in Scheme 1, III-d is reduced to obtain the key intermediate III-e, which is then reacted with nitrite ester, and then further reacted with compound Ie to cyclize and obtain the general formula compound III-f.

[0051] According to another aspect of the invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of one or more selected from the compounds described above, pharmaceutically acceptable salts thereof, stereoisomers, enantiomers, diastereomers, transisomers, racemates, polymorphs, solvates, and isotopically labeled compounds (including deuterium-substituted compounds), and optionally, pharmaceutically acceptable excipients.

[0052] According to another aspect of the invention, the use of said compound, its pharmaceutically usable salt, stereoisomer, enantiomer, diastereomer, transisomer, racemic, polymorph, solvate, or isotopically labeled compound (including deuterium-substituted) or said composition in the preparation of a medicament for treating metabolic-related diseases is provided.

[0053] According to another aspect of the present invention, a method for treating metabolic-related diseases is provided, the method comprising administering to a subject an effective amount of one or more selected from the compounds described above, pharmaceutically acceptable salts thereof, stereoisomers, enantiomers, diastereomers, transisomers, racemates, polymorphs, solvates, and isotopically labeled compounds (including deuterium-substituted compounds), or a pharmaceutical composition comprising one or more selected from the compounds described above, pharmaceutically acceptable salts thereof, stereoisomers, enantiomers, diastereomers, transisomers, racemates, polymorphs, solvates, and isotopically labeled compounds (including deuterium-substituted compounds) as an active ingredient.

[0054] Beneficial effects

[0055] This disclosure effectively develops a THR-β selective agonist with better specificity, efficacy, and pharmacokinetic properties, which shows potential for treating a variety of diseases. Detailed Implementation

[0056] To enable those skilled in the art to understand the features and effects of this invention, the terms and expressions used in the specification and claims are explained and defined in general below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art regarding this invention, and in case of conflict, the definitions in this specification shall prevail.

[0057] In this document, the terms “comprising,” “including,” “having,” “containing,” or any similar terms are open-ended transitional phrases intended to encompass non-exclusive inclusions. For example, a composition or article containing a plural element is not limited to the elements listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated otherwise, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously encompassing closed or semi-closed transitional phrases such as “composed of” and “substantially composed of.”

[0058] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0059] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0060] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0061] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0062] The following detailed embodiments are merely illustrative in nature and are not intended to limit the invention or its uses. Furthermore, this document is not limited to the foregoing prior art or the invention itself, or to any theory described in the following detailed embodiments or examples.

[0063] According to one embodiment of this disclosure, a compound represented by general formula (I), its pharmaceutically usable salt, stereoisomer, enantiomer, diastereomer, transisomer, racemic mixture, polymorph, solvate, or isotopically labeled compound is provided:

[0064]

[0065] in,

[0066] Ring A is selected from:

[0067] Ring B is selected from:

[0068] R0 is selected from hydrogen and C. 1-10 alkyl;

[0069] R1 is selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl and substituted or unsubstituted 5-10 heteroaryl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, =O, C. l-6 Alkoxy, C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10Aryl, Halogenated C 6-10 Aryl, C 1-10 Alkyl C 6-10 Aryl, C 1-10 Alkoxy C 6-10 Aryl, 5-10 heteroaryl, C 1-10 Alkyl 5-10-membered heteroaryl, halogenated 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl and -NR 10 R 11 ;

[0070] R2, R3, and Y are each independently selected from hydrogen, halogen atoms, substituted or unsubstituted carbon atoms. 1-6 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C l-6 alkoxy, wherein the substituent is selected from halogen atoms, hydroxyl groups, C 1-6 Alkyl and C l-6 Alkoxy;

[0071] R4 is selected from hydrogen, cyano, and -NR. 10 R 11 C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl and substituted or unsubstituted C 2-8 Alkyne group, wherein the substituent is selected from halogen atoms, hydroxyl groups, cyano groups, and C. l-6 Alkoxy;

[0072] R5 is selected from hydrogen, substituted or unsubstituted C. 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0073] R6 is selected from hydrogen and substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0074] L does not exist, or is -NR 10 C(O) or -NR 10 CR 11 R 11 ;

[0075] Each R 10 Independently selected from hydrogen and substituted or unsubstituted C 1-3 Alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-3 Alkoxy;

[0076] Each R 11Independently selected from hydrogen and substituted or unsubstituted C 1-6 Alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0077] X1 and X2 are each independently selected from N and CR. 12 R 12 Selected from hydrogen, halogens, cyano, -NR b R c -C(=O)R a -C(=O)OR b -C(=O)NR b R c C, substituted or unsubstituted 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl and substituted or unsubstituted 5-10-membered heteroaryl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0078] X3 and X4 are each independently selected from N and CR. 13 R 13 Selected from hydrogen, halogen, cyano, hydroxyl, -OR a -NR b R c -C(=O)R a -C(=O)OR b -C(=O)NR b R c C, substituted or unsubstituted 1-4 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0079] Each R a Independently for C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl, and heterocyclic alkyl are independently optionally selected from halogen, hydroxyl, amino, and C. 1-6 One or more substituents of the alkyl group are used for substitution;

[0080] Each R b and R c Independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl, and heterocyclic alkyl are independently optionally selected from halogen, hydroxyl, amino, and C. 1-6 One or more substituents of the alkyl group are used for substitution;

[0081] Or R b and R c Together with the nitrogen atoms to which they are attached, they form 3-10 membered heterocyclic alkyl groups, which are optionally selected from halogens, hydroxyl groups, amino groups, and C-membered alkyl groups. 1-6 One or more substituents of the alkyl group are used for substitution;

[0082] n is 1, 2, or 3 independently each time it appears.

[0083] According to one embodiment of this disclosure, the compound of general formula (I) is selected from the compounds shown in formula (Ia) or (Ib):

[0084]

[0085] R0 is hydrogen;

[0086] R1 is selected from hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl and substituted or unsubstituted C 3-8 Heterocyclic alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, =O, and C. l-6 Alkoxy;

[0087] R2 and R3 are each independently selected from halogen atoms, substituted or unsubstituted carbon atoms. 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups, C... 1-4 Alkyl and C l-4 Alkoxy;

[0088] n is 1 or 2 independently each time it appears;

[0089] X1 and X2 are each independently selected from N and CR. 12 R 12 Selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0090] X3 and X4 are each independently selected from N and CR. 13 R 13 Selected from hydrogen, substituted or unsubstituted C 1-4 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0091] The definitions of R5 and B rings are the same as those above.

[0092] According to one embodiment of this disclosure, the compound of general formula (I) is selected from the compounds represented by formula (Ic):

[0093]

[0094] R2 and R3 are each independently selected from halogen atoms, substituted or unsubstituted carbon atoms. 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituent is selected from halogen atoms, hydroxyl groups, C... 1-4 Alkyl and C l-4 Alkoxy;

[0095] X1 and X2 are each independently selected from N and CR. 12 R 12 Selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0096] X3 and X4 are each independently CR 13 R 13 Selected from hydrogen, substituted or unsubstituted C 1-4 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0097] The definitions of R1 and B rings are the same as those above.

[0098] According to one embodiment of this disclosure, the compound of general formula (I) is selected from the compounds represented by formula (Id):

[0099]

[0100] R2 and R3 are each independently selected from halogen atoms;

[0101] L is -NHC(O)- or -NHCHR 11 -;R 11 Selected from hydrogen and substituted or unsubstituted C 1-6 Alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0102] X1 and X2 are each independently selected from N and CR. 12 R12 Selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0103] R1 is defined the same as above.

[0104] According to one embodiment of this disclosure, the compound of general formula (I) is selected from the compounds represented by formula (Ie):

[0105]

[0106] R2 and R3 are each independently selected from halogen atoms;

[0107] X1 and X2 are each independently selected from N and CR. 12 R 12 Selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0108] R1 and R4 are defined the same as those in the above text.

[0109] According to one embodiment of this disclosure, the compound of general formula (I) is selected from the compounds represented by formula (If):

[0110]

[0111] R2 and R3 are each independently selected from halogen atoms;

[0112] X1 and X2 are each independently selected from N and CR. 12 R 12 Selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, wherein the substituents are selected from halogen atoms, hydroxyl groups, and C. l-6 Alkoxy;

[0113] R1 and R6 are defined the same as those in the above text.

[0114] In this invention, the heteroatoms in the heterocyclic alkyl and heteroaryl groups are selected from one or more of O, N and S, and the sulfur atom is not necessarily oxidized to form sulfoxide and sulfone groups.

[0115] According to one embodiment of this disclosure, the compound of general formula I is selected from the following compounds:

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] According to one embodiment of the present disclosure, a pharmaceutical composition is provided comprising one or more selected from the above-described compounds, pharmaceutically acceptable salts thereof, stereoisomers, enantiomers, diastereomers, transisomers, racemates, polymorphs, solvates, and isotopically labeled compounds, and optionally, pharmaceutically acceptable excipients.

[0125] According to one embodiment of this disclosure, the use of the above-described compounds, their pharmaceutically acceptable salts, stereoisomers, enantiomers, diastereomers, transisomers, racemates, polymorphs, solvates, or isotopically labeled compounds, or the above-described pharmaceutical compositions, in the preparation of a medicament for treating metabolic-related diseases is provided.

[0126] According to one embodiment of this disclosure, a method for treating metabolic-related diseases is provided, the method comprising administering to a subject an effective amount of one or more selected from the compound, pharmaceutically acceptable salts thereof, stereoisomers, enantiomers, diastereomers, transisomers, racemic mixtures, polymorphs, solvates, and isotopically labeled compounds, or a pharmaceutical composition thereof.

[0127] According to one embodiment of this disclosure, the metabolic-related diseases are selected from: obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic fatty liver disease (NASH), hepatic steatosis, atherosclerosis, hypothyroidism, and thyroid cancer.

[0128] According to one embodiment of this disclosure, the metabolic-related disease is selected from: non-alcoholic fatty liver disease (NASH), hypothyroidism, and thyroid cancer.

[0129] Example

[0130] In the following examples, the optimal reaction conditions and reaction time for each individual step may be varied depending on the specific reactants used and the substituents present in all reactants. Unless otherwise specified, solvents, temperatures, and other reaction conditions may be readily selected by those skilled in the art. Specific steps are provided in the Synthesis Examples section. The reaction may be further processed in a conventional manner, for example by removing the solvent from the residue and further purifying it according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, grinding, and chromatography. Unless otherwise stated, the starting materials and reactants are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature.

[0131] Routine experiments, including appropriate adjustment of reaction conditions, reactants and sequence of synthetic routes, protection of arbitrary chemical functional groups (which may not be adapted to reaction conditions), and deprotection at appropriate points in the reaction sequence of the method, are all included within the scope of this invention. Appropriate protecting groups and methods for protecting and deprotecting different substituents using such appropriate protecting groups are well known to those skilled in the art; examples of which are found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which are incorporated herein by reference in their entirety. The synthesis of the compounds of this invention can be carried out by methods similar to those described in the synthetic schemes described above and in the specific examples.

[0132] If the starting materials are not commercially available, they may be prepared by steps selected from: standard organic chemistry techniques, techniques similar to those used to synthesize known structural analogs, or techniques similar to those described in the foregoing embodiments or synthesis examples. When an optically active form of the compounds of the present invention is desired, it may be obtained by performing one of the steps described herein using optically active starting materials (e.g., asymmetric induction via appropriate reaction steps), or by resolving a mixture of stereoisomers of the compound or intermediates using standard steps (e.g., chromatographic separation, recrystallization, or enzymatic resolution).

[0133] Similarly, when pure geometric isomers of the compounds of the present invention are required, they can be obtained by performing one of the above steps using pure geometric isomers as starting materials, or by using standard steps, such as chromatographic separation to resolve mixtures of geometric isomers of the compounds or intermediates.

[0134] For illustrative purposes, the following embodiments can be used. These embodiments are only used to explain the technical solutions of the present invention and are not intended to limit the present invention to these embodiments.

[0135] Example 1: Preparation of compounds ZB-H-01 and ZB-H-02

[0136]

[0137] Step 1: Preparation of compound 1b

[0138] To a solution of compound 5-methoxy-1H-indole (1a, 1.47 g, 10 mmol) in N,N-dimethylformamide (20 mL), 1,3-dichloro-2-fluoro-5-nitrobenzene (2.5 g, 12 mmol) and potassium carbonate (2 g, 15 mmol) were added sequentially. After the addition was complete, the mixture was heated to 100 °C and stirred overnight. The reaction was then stopped, allowed to cool naturally to room temperature, and saturated brine (100 mL) was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain compound 1b (3 g). This product was used directly in the next reaction. LC-MS [M+H] + :338.

[0139] Step 2: Preparation of compound 1c

[0140] To a 20 mL ethanol solution of compound 1b (1 g, 2.98 mmol), stannous chloride dihydrate (3.4 g, 14.9 mmol) was added. After the addition was complete, the temperature was raised to 80 °C and stirred for 6 hours. After the reaction was stopped, the mixture was allowed to cool naturally to room temperature. The solvent was concentrated under reduced pressure, and then dissolved in 200 mL ethyl acetate. The organic phase was washed three times with an aqueous sodium hydroxide solution (2 M). After concentrating the organic phase, column chromatography was used to obtain compound 1c (750 mg). 1 H NMR(400MHz, CDCl3)δ7.16(s,1H),7.05(d,J=3.2Hz,1H),6.90–6.82(m,2H),6.74(s,2H),6.62(d,J=3.2Hz,1H),3.96(s,2H),3.87(s,3H); LC-MS[M+H] + :307.

[0141] Step 3: Preparation of compound ZB-H-01

[0142] 202 mg (1.9 mmol) of tert-butyl nitrite was dissolved in acetic acid (3 mL). This solution was slowly added at 0 °C to a solution of compound 1c (500 mg, 1.63 mmol) in acetic acid (20 mL) and acetonitrile (10 mL). The mixture was stirred at 0 °C for 30 minutes. Then, an acetonitrile solution of N-cyanoacetylurane (1d, 330 mg, 2.1 mmol) was added dropwise, followed by stirring for 3 hours. After the reaction was stopped, the reaction mixture was added to a saturated sodium bicarbonate aqueous solution (150 mL), and the resulting red solid was filtered off. The solid was washed with water and petroleum ether and dried. N,N-dimethylacetamide (5 mL) and potassium acetate (1.9 mmol) were added to the solid, and the mixture was heated to 120 °C and stirred for 6 hours. After cooling to room temperature, 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the solvent, and purified by column chromatography to obtain compound ZB-H-01 (520 mg). LC-MS[M+H] + :428.

[0143] Step 4: Preparation of compound ZB-H-02

[0144] Compound ZB-H-01 (30 mg) was dissolved in 20 mL of DCM and purged three times with argon. At -78 °C, a 2 M, 0.7 mL solution of boron tribromide in dichloromethane was slowly added to this solution, followed by gradual heating to -10 °C. The reaction was monitored by TLC until the starting material spot disappeared. Then, 10 mL of saturated sodium bicarbonate aqueous solution was added, and the mixture was stirred until it returned to room temperature. After standing and separating the layers, the dichloromethane layer was separated and extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and purified by thin-layer chromatography (DCM:MeOH = 8:1) to obtain compound ZB-H-02 (18 mg). 1 H NMR (400MHz, DMSO-d6) δ8.89 (s, 1H), 7.89 (s, 2H), 7.36 (d, J = 3.2Hz, 1H), 6.96 (s, 1 H),6.75(d,J=8.7Hz,1H),6.65(d,J=8.7Hz,1H),6.55(d,J=3.2Hz,1H); LC-MS[M+H] + 414.

[0145] Example 2: Preparation of compound ZB-H-07

[0146]

[0147] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 2a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-07 was finally prepared. 1 H NMR(400MHz, DMSO-d6)δ9.41(s,1H),8.25(s,1H),7.92(s,2H),7.20–7.05(m,2H),7.03–6.93(m,1H); LC-MS[M+H] + 415.

[0148] Example 3: Preparation of compound ZB-H-08

[0149]

[0150] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 3a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-08 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ13.30(s,1H),9.30(s,1H),7.79(s,2H),7.45(d,J=8.6Hz,1H),6. 72(s,1H),6.61(d,J=7.3Hz,1H),4.26(t,J=8.4Hz,2H),3.18(t,J=8.4Hz,2H); LC-MS[M+H] + :416.

[0151] Example 4: Preparation of compound ZB-H-09

[0152]

[0153] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 4a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-09 was finally prepared. 1 H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.89(s,2H),7.27(d,J=3.2Hz,1H),6.98(s,1H),6 .61(s,1H),6.51(d,J=3.2Hz,1H),3.26–3.21(m,1H),1.12(d,J=6.9Hz,6H); LC-MS[M+H] + :456.

[0154] Example 5: Preparation of compound ZB-H-11

[0155]

[0156] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 5a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-11 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),7.98(s,2H),7.63(d,J=8.7Hz,1H),6.87(d,J=8.7Hz,1H),6.50(s,1H); LC-MS[M+H] + 415.

[0157] Example 6: Preparation of compound ZB-H-15

[0158]

[0159] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 6a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-15 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.89(s,1H),7.87(s,2H),7.27(d,J=3.2H z,1H),6.98(s,1H),6.65(s,1H),6.52(d,J=3.1Hz,1H),2.15(s,3H); LC-MS[M+H] + 428.

[0160] Example 7: Preparation of compound ZB-H-16

[0161]

[0162] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 7a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-16 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.18(s,1H),7.92(s,2H),7.11(s,1H),6.98(s,1H),2.21(s,3H); LC-MS[M+H] + :429.

[0163] Example 8: Preparation of compound ZB-H-17

[0164]

[0165] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 8a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-17 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),8.66(s,1H),7.36(d,J=3.3Hz,1H),6.71(d,J =8.6Hz,1H),6.63(d,J=3.3Hz,1H),6.58(d,J=8.6Hz,1H),2.32(s,3H); LC-MS:[M+H] + :428.

[0166] Example 9: Preparation of compound ZB-H-18

[0167]

[0168] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 9a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-18 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ13.37(s,1H),9.12(s,1H),8.36(s,1H),7.92(s,2H),7.02(d,J=8.8Hz,1H),6.91(d,J=8.8Hz,1H),2.40(s,3H); LC-MS[M+H] + :429.

[0169] Example 10: Preparation of compound ZB-H-19

[0170]

[0171] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 10a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-19 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),7.86(s,2H),7.14(s,1H),6.88(s,1H),6.71(d,J=8.7Hz,1H),6.65(d,J=8.7Hz,1H),2.24(s,3H); LC-MS[M+H] + :428.

[0172] Example 11: Preparation of compounds ZB-H-22 and ZB-H-23

[0173]

[0174] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 11a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target products ZB-H-22 and ZB-H-23 were finally prepared.

[0175] Compound ZB-H-22: 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),7.89(s,2H),7.41(d,J=3.1Hz,1H),7.30(d,J=9.5Hz,1H),6.28(d,J=3.0Hz,1H),6.06(d,J=9.4Hz,1H); LC-MS[M+H] + :415.

[0176] Compound ZB-H-23: LC-MS [M+H] + :429.

[0177] Example 12: Preparation of compound ZB-H-24

[0178]

[0179] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 12a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-24 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ8.90 (s, 1H), 7.86 (s, 2H), 7.11 (s, 1H), 6.96 (d, J = 2.1Hz, 1H), 6.71 ( d,J=8.7Hz,1H),6.63(d,J=8.7Hz,1H),3.15–3.02(m,1H),1.31(d,J=6.8Hz,6H); LC-MS[M+H] + :456.

[0180] Example 13: Preparation of compound ZB-H-31

[0181]

[0182] Using the synthetic route of Example 1, the first step raw material 1a was replaced with 13a, and the remaining steps and conditions were carried out in accordance with the description in Example 1, and the target product ZB-H-31 was finally prepared. 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),9.38(s,1H),7.86(s,2H),7.81(s,1H),7.58(d,J=3.6Hz,1H),7.41(s,1H),6.61(d,J=3.6Hz,1H); LC-MS:[M+H] + :415.

[0183] Example 14: Preparation of compound 14e

[0184]

[0185] Step 1: Preparation of intermediate 14b

[0186] Following the synthetic route of the first step in Example 1, intermediate 14b was prepared by replacing starting material 1a with 11a. LC-MS [M+H] + :339.

[0187] Step 2: Preparation of intermediate 14c

[0188] Compound 14b (337 mg, 1 mmol) was dissolved in anhydrous acetonitrile (10 mL). Under argon protection, the mixture was stirred, and sodium iodide (750 mg, 5 mmol) and trimethylchlorosilane (0.6 mL, 5 mmol) were added separately. The mixture was refluxed and monitored by TLC. After the starting material spot disappeared, the mixture was cooled to room temperature, stirred continuously, and quenched with methanol (5 mL). The solvent was concentrated under reduced pressure, and the mixture was purified by column chromatography to obtain compound 14c (249 mg). 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),8.61(s,2H),7.40(d,J=3.2Hz,1H),7.29(d,J=9.5Hz,1H),6.32(d,J=3.1Hz,1H),6.09(d,J=9.5Hz,1H); LC-MS[M+H] + :325.

[0189] Step 3: Preparation of intermediate 14d

[0190] Compound 14c (323 mg, 1 mmol) was dissolved in 1,4-dioxane (5 mL) in a microwave-safe reaction tube. Iodomethane (3 mmol) and cesium carbonate (3 mmol) were added separately. The reaction was carried out under microwave conditions (150 °C, 12 h). After the reaction was complete, the solvent was concentrated under reduced pressure, and the solution was purified by column chromatography to obtain compound 14d (288 mg). LC-MS: [M+H] + :338.

[0191] Step 4: Preparation of compound 14e

[0192] To a 20 mL ethanol solution of compound 14d (1 g, 2.98 mmol), stannous chloride dihydrate (3.4 g, 14.9 mmol) was added. After the addition was complete, the temperature was raised to 80 °C and stirred for 6 hours. After the reaction was stopped, the mixture was allowed to cool naturally to room temperature. The solvent was concentrated under reduced pressure, and then dissolved in 200 mL ethyl acetate. The organic phase was washed three times with a 2 M sodium hydroxide aqueous solution. After concentrating the organic phase, column chromatography was used to obtain compound 14e. LC-MS [M+H] + :308.

[0193] Example 15: Preparation of compound 15e

[0194]

[0195] Following the synthetic route of Example 14, iodomethane was replaced with iodoisopropane in the third step to prepare compound 15e. LC-MS: [M+H] + :336.

[0196] Example 16: Preparation of compound 16e

[0197]

[0198] Step 1: Hydroxylamine hydrochloride (11 g, 159 mmol) and sodium carbonate (11 g, 106 mmol) were added to a solution of ethyl cyanoformate (16a, 9 g, 106 mmol) in ethanol (100 mL) and water (80 mL). The mixture was stirred at room temperature for 2 hours. The organic solvent was removed under vacuum, and the aqueous layer was extracted with dichloromethane (8 × 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give compound 16b (5.7 g) as a white solid. LC-MS [M+H] + :133.

[0199] Step 2: N,N'-carbonyldiimidazole (9.4 g, 58 mmol) and 1,8-diazabicycloundec-7-ene (8.7 g, 58 mmol) were added to a solution of compound 16b (5.7 g, 48 mmol) in 1,4-dioxane (50 mL), and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was quenched with HCl, concentrated, and extracted with dichloromethane (8 × 100 mL). The combined organic layers were concentrated and purified by column chromatography (DCM:EA = 8:1) to give compound 16c (3 g) as a yellow oil. 1 HNMR (400MHz, DMSO-d6) δ13.41 (s, 1H), 4.37 (q, J = 7.1Hz, 2H), 1.30 (t, J = 7.1Hz, 3H); LC-MS [MH] -: 157.

[0200] Step 3: Lithium hydroxide (0.5 g, 20.8 mmol) was added to compound 2 (3 g, 20.8 mmol) in a mixed solution of tetrahydrofuran (30 mL) and water (30 mL), and stirred at room temperature for 3 hours. The mixture was washed with ethyl acetate (2 × 20 mL), then acidified to pH 3 with 1 M HCl, concentrated, extracted with ethyl acetate (8 × 20 mL), dried, and concentrated under reduced pressure to give compound 16d (2 g) as a white solid. LC-MS [MH] - :129.

[0201] Step 4: Compound 16d (2 g, 15.4 mmol) was dissolved in anhydrous tetrahydrofuran, one drop of N,N-dimethylformamide was added, and the mixture was stirred at 0 °C. Oxaloyl chloride (1.3 mL, 15.4 mmol) was added dropwise, and the mixture was allowed to return to room temperature. The stirring was continued for 30 minutes. The solvent was concentrated under reduced pressure to obtain compound 16e (1.8 g).

[0202] Example 17: Preparation of compound ZB-H-25

[0203]

[0204] Using the synthetic route of steps three and four in Example 1, the target compound ZB-H-25 was prepared by replacing 1c in step three with compound 14e. 1 H NMR (400MHz, DMSO-d6) δ7.90 (s, 2H), 7.51 (d, J = 3.2Hz, 1H), 7.32 (d, J = 9.4Hz, 1H), 6.61 (d, J = 3.0Hz, 1H), 6.15 (d, J = 9.4Hz, 1H), 3.55 (s, 3H); LC-MS: [M+H] + :429.

[0205] Example 18: Preparation of compound ZB-H-26

[0206]

[0207] Using the synthetic route of steps three and four in Example 1, the target compound ZB-H-26 was prepared by replacing 1c in step three with compound 15e. 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),7.89(s,2H),7.50(d,J=3.2Hz,1H),7.27(d,J=9.4Hz,1H),6 .76(d,J=3.2Hz,1H),6.12(d,J=9.4Hz,1H),5.47–5.06(m,1H),1.51(d,J=7.0Hz,6H); LC-MS[M+H] + :458.

[0208] Example 19: Preparation of compound ZB-H-32

[0209]

[0210] Compound 15e (63 mg, 0.19 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and triethylamine (0.6 mL, 0.9 mmol) was added. After stirring and cooling to 0 degrees Celsius, anhydrous tetrahydrofuran (2 mL) of intermediate 16e (125 mg, 0.9 mmol) was added dropwise. The mixture was then brought back to room temperature and stirred for 30 minutes. The solvent was concentrated under reduced pressure, and the mixture was purified by column chromatography to obtain compound ZB-H-32 (48 mg). 1 H NMR (400MHz, DMSO-d6) δ13.49(s,1H),11.52(s,1H),8.12(s,2H),7.41(d,J=3.2Hz,1H),7.17(d,J=9.3Hz ,1H),6.70(d,J=3.3Hz,1H),6.10(d,J=9.4Hz,1H),5.40–5.17(m,1H),1.50(d,J=7.0Hz,6H); LC-MS[M+H] + 449.

[0211] Example 20: Preparation of compound 20e

[0212]

[0213] Step 1: Preparation of compound 20d

[0214] Compound 14c (323 mg, 1 mmol) was dissolved in toluene (5 mL) and placed in a microwave reaction tube. Cyclopropylboronic acid (3 mmol), copper acetate (1 mmol), pyridine (5 mmol), and sodium bis(trimethylsilyl)amino (1 mmol) were added separately. Oxygen was blown in and the mixture was microwaved (120 °C, 3 h). After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography to obtain compound 20d (300 mg).

[0215] Step 2: Preparation of compound 20e

[0216] Following the synthetic route of the first step in Example 1, compound 20e was prepared by replacing starting material 1b with 20d. LC-MS [M+H] + :334.

[0217] Example 21: Preparation of compound 21e

[0218]

[0219] Following the synthetic route of Example 14, iodomethane was replaced with iodocyclohexane in the third step to prepare compound 21e. LC-MS [M+H] + :376.

[0220] Example 22: Preparation of compound 22e

[0221]

[0222] Following the synthetic route of Example 14, the starting material iodomethane in the third step was replaced with 4-bromotetrahydropyran to prepare compound 22e. LC-MS [M+H] + :378.

[0223] Example 23: Preparation of compound 23e

[0224]

[0225] Following the synthetic route of Example 14, the starting material iodomethane in the third step was replaced with 4-bromotetrahydrothiopyran to prepare compound 23e. LC-MS [M+H] + :394.

[0226] Example 24: Preparation of compound 24e

[0227]

[0228] Following the synthetic route of Example 14, the starting material iodomethane in the third step was replaced with 4-bromotetrahydro-2H-thiopyran 1,1-dioxide to prepare compound 24e. LC-MS: [M+H] + :426.

[0229] Example 25: Preparation of compound 25e

[0230]

[0231] Following the synthetic route of Example 14, the starting material iodomethane in the third step was replaced with tert-butyl 4-iodopiperidine-1-carboxylate to prepare compound 25e. LC-MS [M+H] + :477.

[0232] Example 26: Preparation of compound 26e

[0233]

[0234] Following the synthetic route of Example 14, iodomethane was replaced with iodocyclopentane in the third step to prepare compound 26e. LC-MS [M+H] + :362.

[0235] Example 27: Preparation of compound 27e

[0236]

[0237] Following the synthetic route of Example 14, the starting material iodomethane in the third step was replaced with iodocyclobutane to prepare compound 27e. LC-MS [M+H] + :348.

[0238] Example 28: Preparation of compound ZB-H-33

[0239]

[0240] Using the synthetic route of steps three and four in Example 1, the raw material 1c in step three was replaced with compound 20e to prepare the target compound ZB-H-33. 1H NMR (400MHz, DMSO-d6) δ13.35(s,1H),7.89(s,2H),7.48(d,J=3.2Hz,1H),7.29(d,J=9.5Hz,1H),6.61(d,J=3. 2Hz,1H),6.08(d,J=9.5Hz,1H),3.05(tt,J=7.2,4.1Hz,1H),1.21–1.11(m,2H),0.91–0.82(m,2H); LC-MS[M+H] + :456.

[0241] Example 29: Preparation of compound ZB-H-34

[0242]

[0243] Using the synthetic route of Example 19, compound 15e was replaced with compound 20e to prepare the target compound ZB-H-34. 1 H NMR (400MHz, DMSO-d6) δ13.57(s,1H),11.51(s,1H),8.12(s,2H),7.39(d,J=3.1Hz,1H),7.19(d,J=9.5Hz,1H),6.56( d,J=3.1Hz,1H),6.07(d,J=9.4Hz,1H),3.03(tt,J=7.1,4.0Hz,1H),1.21–1.12(m,2H),0.91–0.83(m,2H); LC-MS[M+H] + :447.

[0244] Example 30: Preparation of compound ZB-H-38

[0245]

[0246] Using the synthetic route of steps three and four in Example 1, the target compound ZB-H-38 was prepared by replacing the raw material 1c in step three with compound 21e. 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),7.89(s,2H),7.49(d,J=3.2Hz,1H),7.25(d,J=9.4Hz,1H), 6.80(d,J=3.0Hz,1H),6.13(d,J=9.4Hz,1H),2.41–2.28(m,1H),1.95–1.09(m,10H); LC-MS[M+H] + :498.

[0247] Example 31: Preparation of compound ZB-H-44

[0248]

[0249] Following the synthetic route of steps three and four in Example 1, the target compound ZB-H-44 was prepared by replacing starting material 1c in step three with compound 26e. LC-MS [M+H] + :484.

[0250] Example 32: Preparation of compound ZB-H-42

[0251]

[0252] Following the synthetic route of steps three and four in Example 1, the target compound ZB-H-42 was prepared by replacing starting material 1c in step three with compound 27e. LC-MS [M+H] + :470.

[0253] Example 33: Preparation of compound ZB-H-46

[0254]

[0255] Following the synthetic route of steps three and four in Example 1, the target compound ZB-H-46 was prepared by replacing starting material 1c in step three with compound 22e. LC-MS [M+H] + :500.

[0256] Example 34: Preparation of compound ZB-H-48

[0257]

[0258] Following the synthetic route of steps three and four in Example 1, the target compound ZB-H-48 was prepared by replacing starting material 1c in step three with compound 23e. LC-MS [M+H] + :516.

[0259] Example 35: Preparation of compound ZB-H-55

[0260]

[0261] Following the synthetic route of steps three and four in Example 1, the target compound ZB-H-49 was prepared by replacing starting material 1c in step three with compound 24e. LC-MS [M+H] + :548.

[0262] Example 36: Preparation of compound ZB-H-50

[0263]

[0264] Following the synthetic route of steps three and four in Example 1, the starting material 1c in step three was replaced with compound 25e, and the Boc protecting group was further removed to prepare the target compound ZB-H-50. LC-MS [M+H] + :499.

[0265] Example 37: Preparation of compound ZB-H-52

[0266]

[0267] Step 1: Preparation of intermediate 37a

[0268] To a solution of compound 15e (1 mmol) in acetonitrile (4 mL), 2-bromoacetonitrile (3.66 mmol, 243 μL), NaI (219 mg, 1.46 mmol), and K₂CO₃ (202 mg, 1.46 mmol) were added. The mixture was then sealed in a tube and stirred at 100 °C for 16 hours. LC-MS showed that the starting material was completely consumed. The suspension was filtered through a diatomaceous earth filter, and the filter cake was washed with ethyl acetate. The combined washes were concentrated to dryness and purified by column chromatography to give compound 37a. LC-MS [M+H] + :374.

[0269] Step 2: Preparation of intermediate 37b

[0270] To a tetrahydrofuran solution (3 mL) of substrate 37a (571.9 mmol), di-tert-butyl dicarbonate (374 mg, 1.72 mmol) and DMAP (70 mg, 571.85 mmol) were added, and the mixture was stirred at 40 °C for 3 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give compound 37b. LC-MS [M+H] + :474.

[0271] Step 3: Preparation of intermediate 37c

[0272] Hydroxylamine hydrochloride (297 mg, 4.28 mmol) and NaOAc (351 mg, 4.28 mmol) were added to a solution of compound 37b (534.9 mmol) in DMF (3 mL). The mixture was stirred at 80 °C for 1 hour. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give compound 37c, which could be used directly for the next step without further purification. LC-MS [M+H] + :507.

[0273] Step 4: Preparation of intermediate 37d

[0274] DSC (173 mg) and TEA (105 mg, 1.04 mmol) were added to a 3 mL solution of tetrahydrofuran (520 mmol) at 37°C. The mixture was stirred at 60°C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired MS was detected. The mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue, which was purified by column chromatography to give compound 37d. LC-MS [M+H] + :533.

[0275] Step 5: Preparation of compound ZB-H-52

[0276] Compound 37d (323.0 mmol) was placed in hydrogen chloride / ethyl acetate (2 mL) and stirred at 25 °C for 2 h. LC-MS showed complete consumption of the starting material and detection of the desired MS. The mixture was diluted with water (0.5 mL) and the pH was adjusted to 8 with an aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue. The crude product was purified by preparative HPLC column chromatography to give the title compound ZB-H-52. LC-MS [M+H] + 433.

[0277] Example 38: Preparation of compound ZB-H-53

[0278]

[0279] Step 1: Preparation of intermediate 38a

[0280] Compound 15e (1 mmol) was dissolved in acetonitrile (5 mmol), and cuprous iodide (2 mmol) was added. Tert-butyl nitrite (2 mmol) was then added dropwise under an ice-water bath. The mixture was stirred overnight at room temperature, the solvent was evaporated, and the solution was purified by column chromatography to give compound 38a. LC-MS: [M+H] + :398.

[0281] Step 2: Preparation of intermediate 38b

[0282] Compound 38a (1 mmol) was dissolved in dry 1,4-dioxane. Under argon protection, 2 mmol of boron pinacol ester, 3 mmol of potassium acetate, and 0.05 mmol of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride were added. The mixture was reacted overnight at 80 °C. The solvent was evaporated, and the solution was purified by column chromatography to obtain compound 38b. LC-MS: [M+H] + :447.

[0283] Step 3: Preparation of compound ZB-H-53

[0284] Compound 38b (1 mmol) and 5-bromo-6-azouridine (38c, 1 mmol) were dissolved together in 1,4-dioxane (5 mL), and 2M sodium carbonate aqueous solution (2.5 mL) was added. Under argon protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.1 mmol) was added, and the mixture was refluxed at 110 °C for 3 hours under argon protection. After cooling to room temperature, 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure to remove the solvent, and purified by column chromatography to obtain compound ZB-H-53. LC-MS [M+H] + :432; 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),12.32(s,1H),8.15(s,2H),7.46(d,J=3.2Hz,1H),7.18(d,J =9.4Hz,1H),6.73(d,J=3.2Hz,1H),6.11(d,J=9.4Hz,1H),5.51–5.00(m,1H),1.51(d,J=7.0Hz,6H)

[0285] Example 39: Preparation of compound ZB-H-54

[0286]

[0287] Following the synthetic route of step 3 in Example 38, compound ZB-H-54 was prepared by replacing starting material 38c with compound 39a. LC-MS [M+H]+ :498. 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.20(s,2H),7.46(d,J=3.2Hz,1H),7.19(d,J=9.4Hz,1H),6 .74(d,J=3.1Hz,1H),6.11(d,J=9.4Hz,1H),5.47–5.00(m,1H),3.60(s,3H),1.51(d,J=7.0Hz,6H).

[0288] Example 40: Preparation of compound ZB-H-39

[0289]

[0290] Using the synthetic route of Example 19, compound 15e was replaced with compound 21e to prepare the target compound ZB-H-39. LC-MS [M+H] + :488.

[0291] Example 41: Preparation of compound ZB-H-43

[0292]

[0293] Following the synthetic route of Example 19, compound 15e was replaced with compound 27e to prepare the target compound ZB-H-43. LC-MS [M+H] + :460.

[0294] Example 42: Preparation of compound ZB-H-45

[0295]

[0296] Using the synthetic route of Example 19, compound 15e was replaced with compound 26e to prepare the target compound ZB-H-45. LC-MS [M+H] + :474. 1 H NMR (400 MHz, DMSO-d6) δ13.35(s,1H),7.89(s,2H),7.50(d,J=3.2 Hz,1H),7.27(d,J=9.4 Hz,1H),6.62(d,J=3.2 Hz,1H),6.12(d,J=9.4 Hz,1H),5.45–5.04(m,1H),2.27–2.11(m,2H),2.04–1.82(m,4H),1.75–1.60(m,2H).

[0297] Example 43: Preparation of compound ZB-H-47

[0298]

[0299] Using the synthetic route of Example 19, compound 15e was replaced with compound 22e to prepare the target compound ZB-H-47. LC-MS [M+H] + :490. 1 H NMR (400 MHz, DMSO-d6) δ13.34(s,1H),7.89(s,2H),7.50(d,J=3.2 Hz,1H),7.28(d,J=9.4 Hz,1H),6.76(d,J=3.2 Hz,1H),6.14(d,J=9.4 Hz,1H),5.22–4.90(m,1H),4.11–3.88(m,2H),3.56–3.51(m,2H),2.76–2.57(m,2H),1.65–1.54(m,2H).

[0300] Example 44: Preparation of compound ZB-H-49

[0301]

[0302] Using the synthetic route of Example 19, compound 15e was replaced with compound 23e to prepare the target compound ZB-H-49. LC-MS [M+H] + :506.

[0303] Example 45: Preparation of compound ZB-H-51

[0304]

[0305] Following the synthetic route of Example 19, compound 15e was replaced with compound 25e, and the Boc protecting group was further removed to prepare compound ZB-H-51. LC-MS [M+H] + :489.

[0306] Example 46: Preparation of compound ZB-H-56

[0307]

[0308] Following the synthetic route of Example 19, compound 15e was replaced with compound 24e to prepare compound ZB-H-56. LC-MS [M+H]+ :538.

[0309] Example 47: Preparation of compound 47b

[0310]

[0311] Using the synthetic route of Example 20, cyclopropylboronic acid in the first step was replaced with phenylboronic acid, and the remaining steps and conditions were performed as described in Example 20, to prepare the target compound 47b. LC-MS: [M+H] + :371.

[0312] Example 48: Preparation of compound ZB-H-57

[0313]

[0314] Following the synthetic route of steps three and four in Example 1, the target compound ZB-H-57 was prepared by replacing starting material 1c in step three with compound 47b. LC-MS: [M+H] + :492.

[0315] Example 49: Preparation of compound ZB-H-58

[0316]

[0317] Using the synthetic route of Example 19, compound 15e was replaced with compound 47b to prepare the target compound ZB-H-58. LC-MS [M+H] + :483.

[0318] Example 50: Preparation of compound 50e

[0319]

[0320] Following the synthetic route of Example 14, the starting material 11a in the first step was replaced with compound 50a, and the starting material iodomethane in the third step was replaced with iodoisopropane. The remaining steps and conditions were performed as described in Example 14, yielding the target compound 50e. LC-MS [M+H] + :338.

[0321] Example 51: Preparation of compound ZB-H-35

[0322]

[0323] Using the synthetic route of steps three and four in Example 1, the starting compound 1c in step three was replaced with compound 50e to prepare the target compound ZB-H-35. 1 H NMR (400MHz, DMSO-d6) δ13.38(s,1H),8.42(s,1H),7.93(s,2H),7.64(d,J=9.6Hz ,1H),6.48(d,J=9.6Hz,1H),5.42–5.13(m,1H),1.51(d,J=7.0Hz,6H); LC-MS[M+H] + :459.

[0324] Example 52: Preparation of compound ZB-H-36

[0325]

[0326] Using the synthetic route of Example 19, compound 15e was replaced with compound 50e to prepare the target compound ZB-H-36. LC-MS [M+H] + :450.

[0327] Example 53: Preparation of compound ZB-H-59

[0328]

[0329] Following the synthetic route of Example 38, compound ZB-H-59 was prepared by replacing starting material 38c in step 3 with compound 53a. LC-MS [M+H] + :475.

[0330] Example 54: Preparation of compound ZB-H-76

[0331]

[0332] Step 1: Preparation of compound 54a

[0333] Compound 50c (500 mg, 1.54 mmol) was dissolved in 1,4-dioxane (10 mL) in a microwave reaction tube. Benzyl bromide (800 mg, 4.63 mmol) and potassium carbonate (640 mg, 4.63 mmol) were added, and the mixture was microwaved at 150 °C for 12 hours. After the reaction was complete, the solvent was concentrated under reduced pressure, and the mixture was purified by column chromatography to obtain compound 54a (1.2 g). 1H NMR(600MHz,Chloroform-d)δ8.38(s,2H),7.78(d,J=1.0Hz,1H),7.42–7.38(m,2H),7.38–7.34(m,2 H),7.33–7.29(m,1H),7.18(dd,J=9.6,0.9Hz,1H),6.73(d,J=9.6Hz,1H),5.37(s,2H).LC-MS:[M+H] + :416.

[0334] Step 2: Preparation of compound 54b

[0335] To a 20 mL ethanol solution of compound 54a (1 g, 2.41 mmol), stannous chloride dihydrate (2.7 g, 12.0 mmol) was added. After the addition was complete, the temperature was raised to 80 °C and stirred for 6 hours. After the reaction was stopped, the mixture was allowed to cool naturally to room temperature. The solvent was concentrated under reduced pressure, and then dissolved in 200 mL ethyl acetate. The organic phase was washed three times with a 2 M sodium hydroxide aqueous solution. After concentrating the organic phase, column chromatography was performed to obtain compound 54b, which was directly used in the next step. 1 H NMR(400MHz, DMSO-d6)δ8.08(s,1H),7.49(d,J=9.6Hz,1H),7.46–7.41(m,2H),7.39–7 .30(m,3H),6.76(s,2H),6.54(d,J=9.6Hz,1H),6.21(s,2H),5.30(s,2H).LC-MS[M+H] + :386.

[0336] Step 3: Preparation of compound 54c

[0337] 53 mg (0.514 mmol) of tert-butyl nitrite was dissolved in 1 mL of acetic acid. This solution was slowly added at 0 °C to a solution of compound 54b (180 mg, 0.47 mmol) in 10 mL of acetic acid and 10 mL of acetonitrile. The mixture was stirred at 0 °C for 30 minutes. Then, an acetonitrile solution of N-cyanoaceturane (80 mg, 0.514 mmol) was added dropwise, followed by stirring for 3 hours. After the reaction was complete, the reaction mixture was added to a saturated sodium bicarbonate aqueous solution (70 mL), and the resulting red solid was filtered off. The solid was washed with water and petroleum ether and dried. The product was used directly in the next step. 1H NMR (400MHz, DMSO-d6) δ12.26(s,1H),11.02(s,1H),8.20(s,1H),8.12(s,2H),7.59(d,J=9.6Hz,1H),7.43(d,J=7.2Hz,2H),7.36 (t,J=7.5Hz,2H),7.33–7.24(m,1H),6.59(d,J=9.6Hz,1H),5.32(s,2H),4.21(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).LC-MS[M+H] + :553.

[0338] Step 4: Preparation of compound ZB-H-76

[0339] N,N-dimethylacetamide (5 mL) and potassium acetate (2.0 mmol) were added to the solid compound 54c (1.0 mmol), and the mixture was heated to 120 °C and stirred for 6 hours. After the reaction was completed, the mixture was directly used to prepare and purify compound ZB-H-76. 1 HNMR (400MHz, Methanol-d4) δ8.07 (d, J = 0.9 Hz, 1H), 7.97 (s, 2H), 7.61 (dd, J = 9. 6,0.9Hz,1H),7.47–7.32(m,5H),6.74(d,J=9.5Hz,1H),5.47(s,2H).LC-MS[M+H] + :507.

[0340] Example 55: Preparation of compound ZB-H-60

[0341]

[0342] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with methyl iodide (MeI) to prepare compound ZB-H-60. LC-MS [M+H] + :431.

[0343] Example 56: Preparation of compound ZB-H-61

[0344]

[0345] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with ethane iodide to prepare compound ZB-H-61. LC-MS [M+H] + :445.

[0346] Example 57: Preparation of compound ZB-H-62

[0347]

[0348] Referring to the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with iodocyclobutane to prepare compound ZB-H-62. LC-MS [M+H] + :472.

[0349] Example 58: Preparation of compound ZB-H-63

[0350]

[0351] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with iodocyclopentane to prepare compound ZB-H-63. LC-MS [M+H] + :485.

[0352] Example 59: Preparation of compound ZB-H-64

[0353]

[0354] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 1-Boc-3-iodopyrrolidine, followed by further removal of the Boc protecting group to prepare compound ZB-H-64. LC-MS [M+H] + :485.

[0355] Example 60: Preparation of compound ZB-H-65

[0356]

[0357] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with iodocyclohexane to prepare compound ZB-H-65. LC-MS [M+H] + :499.

[0358] Example 61: Preparation of compound ZB-H-66

[0359]

[0360] Referring to the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with 4-iodotetrahydropyran to prepare compound ZB-H-66. LC-MS [M+H] + :501.

[0361] Example 62: Preparation of compound ZB-H-67

[0362]

[0363] Referring to the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with tetrahydro-4-iodo-2H-thiaran to prepare compound ZB-H-67. LC-MS [M+H] + :517.

[0364] Example 63: Preparation of compound ZB-H-68

[0365]

[0366] Compound ZB-H-67 (1.0 mmol) was dissolved in dichloromethane (5 mL). A solution of m-chloroperoxybenzoic acid (0.9 mmol) in dichloromethane (5 mL) was added dropwise to the solution under ice bath conditions. The reaction was carried out under ice bath conditions for 30 minutes. After the reaction was complete, the solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, and the organic phases were combined. After the solvent was evaporated, the mixture was purified by column chromatography to obtain compound ZB-H-68. LC-MS [M+H] + :533.

[0367] Example 64: Preparation of compound ZB-H-69

[0368]

[0369] Compound ZB-H-67 (1.0 mmol) was dissolved in dichloromethane (5 mL). A solution of m-chloroperoxybenzoic acid (2.0 mmol) in dichloromethane (5 mL) was added dropwise to the solution under ice bath conditions. The reaction was carried out for 30 min under ice bath conditions. After the reaction was complete, the solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane. The organic phases were combined, the solvent was evaporated, and the mixture was purified by column chromatography to obtain compound ZB-H-69. LC-MS [M+H] + :549.

[0370] Example 65: Preparation of compound ZB-H-70

[0371]

[0372] Following the synthetic routes of Examples 47 and 54, compound ZB-H-70 was prepared. LC-MS [M+H] + :593.

[0373] Example 66: Preparation of compound ZB-H-71

[0374]

[0375] Step 1: Preparation of compound 66a

[0376] Compound 50c (200 mg, 0.615 mmol) was dissolved in 1,4-dioxane (10 mL) and placed in a microwave reaction tube. Bromomethylcyclopropane (250 mg, 1.845 mmol) and potassium carbonate (170 mg, 1.231 mmol) were added, respectively. The mixture was microwaved at 150 °C for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography to obtain compound 66a. 1 H NMR(400MHz,Chloroform-d)δ8.37(s,2H),7.88(s,1H),7.16(d,J=9.6Hz,1H),6.67( d,J=9.6Hz,1H),4.04(d,J=7.1Hz,2H),2.02(m,1H),1.30–1.15(m,4H).LC-MS:[M+H] + :379.

[0377] Step 2: Preparation of compound 66b

[0378] To a 10 mL ethanol solution of compound 66a (80 mg, 0.212 mmol), stannous chloride dihydrate (238 mg, 1.058 mmol) was added. After the addition was complete, the temperature was raised to 80 °C and stirred for 6 hours. After the reaction was stopped, the mixture was allowed to cool naturally to room temperature. The solvent was concentrated under reduced pressure, and then dissolved in 10 mL ethyl acetate. The organic phase was washed three times with 2 M, 10 mL sodium hydroxide aqueous solution. After concentrating the organic phase, column chromatography was performed to obtain compound 66b, which was directly used in the next step. 1 H NMR (400MHz, Methanol-d4) δ8.01 (s, 1H), 7.39 (d, J = 9.5Hz, 1H), 6.74 (s, 2H), 6.58 ( d,J=9.5Hz,1H),4.07(d,J=7.1Hz,2H),1.95(m,1H),0.57–0.46(m,4H).LC-MS[M+H] + 350.

[0379] Step 3: Preparation of compound 66c

[0380] 16.2 mg of tert-butyl nitrite (0.1573 mmol) was dissolved in acetic acid (2 mL). This solution was slowly added at 0 °C to a solution of compound 66b (50 mg, 0.143 mmol) in acetic acid (2 mL) and acetonitrile (2 mL). The mixture was stirred at 0 °C for 30 minutes. Then, a solution of N-cyanoaceturane (25 mg, 0.1573 mmol) in acetonitrile (2 mL) was added dropwise. After the addition was complete, the mixture was stirred for 3 hours. After the reaction was complete, the reaction solution was added to a saturated sodium bicarbonate aqueous solution (20 mL). The resulting red solid was filtered off, washed with water (10 mL) and petroleum ether (10 mL), and dried. The product was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),11.02(s,1H),8.25(d,J=0.9Hz,1H),8.13(s,2H),7.54(dd,J=9.6,0.9Hz,1H),6.51(d, J=9.6Hz,1H),4.21(q,J=7.1Hz,2H),3.99(d,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H),1.23(m,1H),0.52–0.44(m,4H).LC-MS[M+H] + :517.

[0381] Step 4: Preparation of compound ZB-H-71

[0382] N,N-dimethylacetamide (5 mL) and potassium acetate (17 mg, 0.1716 mmol) were added to the solid compound 66c (81 mg, 0.1571 mmol), and the mixture was heated to 120 °C and stirred for 6 hours. After the reaction was completed, the mixture was directly used to prepare and purify compound ZB-H-71. 1 H NMR(400MHz,Methanol-d4)δ8.19(d,J=0.9Hz,1H),7.96(s,2H),7.56(dd,J=9.6,0.9Hz,1H),6 .66(d,J=9.5Hz,1H),4.14(d,J=7.1Hz,2H),1.48–1.36(m,1H),0.64–0.49(m,4H).LC-MS[M+H] + :471.

[0383] Example 67: Preparation of compound ZB-H-72

[0384]

[0385] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with (iodomethyl)cyclobutane to prepare compound ZB-H-72. LC-MS [M+H] + :485.

[0386] Example 68: Preparation of compound ZB-H-73

[0387]

[0388] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with (iodomethyl)cyclopentane to prepare compound ZB-H-73. LC-MS [M+H] + :489.

[0389] Example 69: Preparation of compound ZB-H-74

[0390]

[0391] Step 1: Synthesis of compound 69a

[0392] Following the first step of the synthetic route of Example 54, compound 50c was replaced with compound 14c to obtain compound 69a. 1 H NMR(400MHz,Chloroform-d)δ8.38(s,2H),7.40–7.27(m,5H),7.03(dd,J=9.6,0.8Hz,1H),6.9 2(d,J=3.3Hz,1H),6.49(d,J=9.5Hz,1H),6.37(dd,J=3.3,0.8Hz,1H),5.41(s,2H).LC-MS[M+H] + :415.

[0393] Step 2: Synthesis of compound 69b

[0394] Following the second step of the synthetic route in Example 54, compound 69b was obtained. 1 H NMR (400MHz, DMSO-d6) δ7.42–7.37(m,2H),7.33(t,J=7.4Hz,2H),7.28–7.22(m,2H),7.18(d,J=9.4Hz ,1H),6.75(s,2H),6.46(d,J=3.2Hz,1H),6.18(d,J=9.4Hz,1H),6.08(s,2H),5.28(s,2H).LC-MS[M+H] + :385.

[0395] Step 3: Synthesis of compound 69c

[0396] Following the synthetic route of Example 54, step 3 yielded compound 69c. LC-MS [M+H] + :552.

[0397] Step 4: Synthesis of compound ZB-H-74

[0398] Following the fourth step of the synthetic route in Example 54, compound ZB-H-74 was obtained. 1 H NMR(400MHz, Methanol-d4)δ7.92(s,2H),7.40–7.28(m,7H),6.56(dd,J=3.3,0.8Hz,1H),6.45(d,J=9.4Hz,1H),5.48(s,2H)..LC-MS[M+H] + :506.

[0399] Example 70: Preparation of compound ZB-H-75

[0400]

[0401] Step 1: Synthesis of Compound 70a

[0402] Compound 50c (500 mg, 1.54 mmol) was dissolved in toluene (20 mL), and potassium cyclopropyltrifluoroborate (4.62 mmol), copper acetate (0.385 mmol), potassium carbonate (3.08 mmol), 1,10-phenanthroline (0.1925 mmol), and water (2 mL) were added. The gas was replaced with oxygen three times, and the reaction was carried out overnight at 80 °C. After the reaction was completed, the solvent was concentrated under reduced pressure, and the mixture was purified by column chromatography to obtain compound 70a. 1 H NMR(400MHz,Chloroform-d)δ8.42(s,2H),8.07(d,J=0.9Hz,1H),7.14(dd,J=9.7,0.9Hz,1H),6.6 2(d,J=9.6Hz,1H),3.20(tt,J=7.3,4.0Hz,1H),1.37–1.30(m,2H),1.14–1.08(m,2H).LC-MS[M+H] + :366.

[0403] Step 2: Synthesis of compound 70b

[0404] Following the second step of the synthetic route in Example 54, compound 70b was obtained. 1H NMR(600MHz,DMSO-d6)δ8.00(d,J=0.9Hz,1H),7.38(dd,J=9.5,0.9Hz,1H),6.76(s,2H),6.38(d,J=9.5Hz,1H), 6.27–6.03(br.s,2H),3.10(tt,J=7.3,4.0Hz,1H),1.16(td,J=7.4,5.6Hz,2H),0.93–0.87(m,2H).LC-MS[M+H] + :336.

[0405] Step 3: Synthesis of compound 70c

[0406] Following the synthetic route of Example 54, step 3, compound 70c was obtained. 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),11.00(s,1H),8.12(s,J=1.9Hz,2H),8.10(m,1H),7.49(d,J=9.6Hz,1H),6.43(d,J=9.6Hz, 1H),4.21(q,J=7.1Hz,2H),3.12(tt,J=7.2,3.9Hz,1H),1.27(t,J=7.1Hz,3H),1.23–1.13(m,2H),0.94–0.86(m,2H).LC-MS[M+H] + :503.

[0407] Step 4: Synthesis of compound ZB-H-75

[0408] Following the fourth step of the synthetic route in Example 54, compound ZB-H-75 was obtained. 1 H NMR (500MHz, DMSO-d6) δ8.18(d,J=0.9Hz,1H),7.93(s,2H),7.63(d,J=9.6Hz,1H),6.44(d,J=9.6 Hz,1H),3.13(td,J=7.1,3.7Hz,1H),1.18(td,J=7.4,5.6Hz,2H),0.95–0.88(m,2H).LC-MS[M+H] + :457.

[0409] Example 71: Preparation of compound ZB-H-77

[0410]

[0411] Step 1: Preparation of compound 71a

[0412] Compound 50c (200 mg, 0.615 mmol) was dissolved in 1,4-dioxane (10 mL) and placed in a microwave reaction tube. 4-fluorobenzyl bromide (233 mg, 1.231 mmol) and potassium carbonate (170 mg, 1.231 mmol) were added, respectively. The mixture was microwaved at 150 °C for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography to obtain compound 71a. 1 H NMR (400MHz, Methanol-d4) δ6.98 (s, 2H), 6.57 (d, J = 0.9Hz, 1H), 6.04 (dd, J = 9.5, 0.9Hz, 1 H),5.92–5.86(m,2H),5.57–5.49(m,2H),5.14(d,J=9.5Hz,1H),3.85(s,2H).LC-MS:[M+H] + :434.

[0413] Step 2: Preparation of compound 77b

[0414] To a 10 mL ethanol solution of compound 77a (92 mg, 0.212 mmol), stannous chloride dihydrate (238 mg, 1.058 mmol) was added. After the addition was complete, the temperature was raised to 80 °C and stirred for 6 hours. After the reaction was stopped, the mixture was allowed to cool naturally to room temperature. The solvent was concentrated under reduced pressure, and then dissolved in 10 mL ethyl acetate. The organic phase was washed three times with 2 M, 10 mL sodium hydroxide aqueous solution. After concentrating the organic phase, column chromatography was performed to obtain compound 71b, which was directly used in the next step. LC-MS [M+H] + :404.

[0415] Step 3: Preparation of compound 71c

[0416] 16.2 mg of tert-butyl nitrite (0.1573 mmol) was dissolved in acetic acid (2 mL). This solution was slowly added at 0 °C to a solution of compound 71b (58 mg, 0.143 mmol) in acetic acid (2 mL) and acetonitrile (2 mL). The mixture was stirred at 0 °C for 30 minutes. Then, a solution of N-cyanoaceturane (25 mg, 0.1573 mmol) in acetonitrile (2 mL) was added dropwise. After the addition was complete, the mixture was stirred for 3 hours. After the reaction was complete, the reaction solution was added to a saturated sodium bicarbonate aqueous solution (20 mL). The resulting red solid was filtered off, washed with water (10 mL) and petroleum ether (10 mL), and dried. The product was used directly in the next step. 1H NMR (400MHz, DMSO-d6) δ12.27(s,1H),11.01(s,1H),8.25(d,J=0.9Hz,1H),8.12(s,2H),7.59(d,J=9.6Hz,1H),7.56–7.4 7(m,2H),7.23–7.16(m,2H),6.58(d,J=9.6Hz,1H),5.30(s,2H),4.21(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).LC-MS[M+H] + :571.

[0417] Step 4: Preparation of compound ZB-H-77

[0418] N,N-dimethylacetamide (5 mL) and potassium acetate (17 mg, 0.1716 mmol) were added to the solid compound 71c (89 mg, 0.157 mmol), and the mixture was heated to 120 °C and stirred for 6 hours. After the reaction was completed, the mixture was directly used to prepare and purify compound ZB-H-77. 1 H NMR (400MHz, DMSO-d6) δ13.36(s,1H),8.32(s,1H),7.93(s,2H),7.74(d,J=9.6Hz,1 H),7.56–7.47(m,2H),7.20(m,2H),6.59(d,J=9.6Hz,1H),5.31(s,2H).LC-MS[M+H] + :525.

[0419] Example 72: Preparation of compound ZB-H-78

[0420]

[0421] Referring to the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 3-fluorobenzyl bromide to prepare compound ZB-H-78. LC-MS [M+H] + :525.

[0422] Example 73: Preparation of compound ZB-H-79

[0423]

[0424] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 4-methylbenzyl bromide to prepare compound ZB-H-79. LC-MS [M+H] + :521.

[0425] Example 74: Preparation of compound ZB-H-80

[0426]

[0427] Referring to the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 4-methoxybenzyl bromide to prepare compound ZB-H-80. LC-MS [M+H] + :537.

[0428] Example 75: Preparation of compound ZB-H-81

[0429]

[0430] Step 1: Synthesis of compound 75a

[0431] In the first step of the synthetic route of Example 54, benzyl bromide was replaced with (bromomethyl)cyclohexane to obtain compound 75a. 1 H NMR(600MHz,Chloroform-d)δ8.36(s,2H),7.82(s,1H),7.13(d,J=9.6Hz,1H),6.62(d,J=9.6Hz,1H),3.9 5(d,J=7.4Hz,2H),1.97(dqt,J=10.6,6.9,3.2Hz,1H),1.78–1.60(m,5H),1.24–1.11(m,5H).LC-MS[M+H] + :422.

[0432] Step 2: Synthesis of compound 75b

[0433] Following the second step of the synthetic route in Example 54, compound 75b was obtained. 1 H NMR(400MHz, Methanol-d4)δ7.88(s,1H),7.36(d,J=9.6Hz,1H),6.78(s,2H),6.63(d,J =9.6Hz,1H),4.03(d,J=7.3Hz,2H),2.00(m,1H),1.73(m,5H),1.24(m,5H).LC-MS[M+H] + :392.

[0434] Step 3: Synthesis of compound 75c

[0435] Following the third step of the synthetic route in Example 54, compound 75c was obtained. 1H NMR (600MHz, DMSO-d6) δ12.26(s,1H),11.01(s,1H),8.21(s,1H),8.13(s,2H),7.52(d,J=9.6Hz,1H),6.49(d,J=9.6Hz,1H), 4.21(q,J=7.1Hz,2H),3.93(d,J=7.3Hz,2H),1.90(m,1H),1.71–1.57(m,5H),1.27(t,J=7.1Hz,3H),1.14(m,5H).LC-MS[M+H] + :559.

[0436] Step 4: Synthesis of compound ZB-H-81

[0437] Following the fourth step of the synthetic route in Example 54, compound ZB-H-81 was obtained. 1 H NMR (600MHz, DMSO-d6) δ13.35(s,1H),8.28(s,1H),7.93(s,2H),7.67(d,J=9.5Hz,1H),6.51(d,J=9.5Hz,1H) ,3.94(d,J=7.3Hz,2H),1.90(dtt,J=12.9,8.9,4.6Hz,1H),1.71–1.58(m,5H),1.19–1.07(m,5H).LC-MS[M+H] + :513.

[0438] Example 76: Preparation of compound ZB-H-82

[0439]

[0440] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 4-bromomethyltetrahydropyran to prepare compound ZB-H-82. LC-MS [M+H] + :515.

[0441] Example 77: Preparation of compound ZB-H-83

[0442]

[0443] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 4-(bromomethyl)-tetrahydro-2H-thiaran to prepare compound ZB-H-83. LC-MS [M+H] + :531.

[0444] Example 78: Preparation of compound ZB-H-84

[0445]

[0446] Compound ZB-H-83 (1.0 mmol) was dissolved in dichloromethane (5 mL). A solution of m-chloroperoxybenzoic acid (2.0 mmol) in dichloromethane (5 mL) was added dropwise to the solution under ice bath conditions. The reaction was carried out for 30 min under ice bath conditions. After the reaction was complete, the solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, and the organic phases were combined. After the solvent was evaporated, the mixture was purified by column chromatography to obtain compound ZB-H-84. LC-MS [M+H] + :563.

[0447] Example 79: Preparation of compound ZB-H-85

[0448]

[0449] Referring to the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with 4-(bromomethyl)-pyridine to prepare compound ZB-H-85. LC-MS [M+H] + :508.

[0450] Example 80: Preparation of compound ZB-H-86

[0451]

[0452] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 3-bromomethylthiophene to prepare compound ZB-H-86. LC-MS [M+H] + :513.

[0453] Example 81: Preparation of compound ZB-H-87

[0454]

[0455] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 2-bromomethylthiophene to prepare compound ZB-H-87. LC-MS [M+H] + :513.

[0456] Example 82: Preparation of compound ZB-H-88

[0457]

[0458] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 2-bromomethylfuran to prepare compound ZB-H-88. LC-MS [M+H] + :497.

[0459] Example 83: Preparation of compound ZB-H-89

[0460]

[0461] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 3-(bromomethyl)-5-methylisoxazole to prepare compound ZB-H-89. LC-MS [M+H] + :512.

[0462] Example 84: Preparation of compound ZB-H-90

[0463]

[0464] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 4-(bromomethyl)-pyridine, and compound 50c was replaced with compound 14c to prepare compound ZB-H-90. LC-MS [M+H] + :507.

[0465] Example 85: Preparation of compound ZB-H-91

[0466]

[0467] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 3-bromomethylthiophene, and compound 50c was replaced with compound 14c, to prepare compound ZB-H-91. LC-MS [M+H] + :512.

[0468] Example 86: Preparation of compound ZB-H-92

[0469]

[0470] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 2-bromomethylthiophene, and compound 50c was replaced with compound 14c, to prepare compound ZB-H-92. LC-MS [M+H] + :512.

[0471] Example 87: Preparation of compound ZB-H-93

[0472]

[0473] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 2-bromomethylfuran, and compound 50c was replaced with compound 14c, to prepare compound ZB-H-93. LC-MS [M+H] + :496.

[0474] Example 88: Preparation of compound ZB-H-94

[0475]

[0476] Following the synthetic route of Example 54, benzyl bromide in step 1 of Example 54 was replaced with 3-(bromomethyl)-5-methylisoxazole, and compound 50c was replaced with compound 14c, to prepare compound ZB-H-94. LC-MS [M+H] + :511.

[0477] Example 89: Preparation of compound ZB-H-95

[0478]

[0479] Step 1: Synthesis of compound 89a

[0480] Following the synthetic route of Example 54, in the first step, benzyl bromide was replaced with 1-iodo-2-methylpropane to obtain compound 89a. 1 H NMR(600MHz,Chloroform-d)δ8.37(s,2H),7.82(s,1H),7.14(d,J=9.6Hz,1H),6.63(d,J =9.6Hz,1H),3.95(d,J=7.6Hz,2H),1.28–1.15(m,1H),1.00(d,J=6.7Hz,6H).LC-MS[M+H] + :382.

[0481] Step 2: Synthesis of compound 89b

[0482] Following the second step of the synthetic route in Example 54, compound 89b was obtained. 1H NMR (400MHz, Methanol-d4) δ8.02 (s, 1H), 7.42 (d, J = 9.5, 1H), 6.78 (s, 2H), 6.61 (d, J=9.5Hz,1H),4.03(d,J=7.6Hz,2H),2.31(m,1H),0.99(d,J=6.7Hz,6H).LC-MS[M+H] + :352.

[0483] Step 3: Synthesis of compound 89c

[0484] Following the third step of the synthetic route in Example 54, compound 89c was obtained. 1 H NMR (600MHz, DMSO-d6) δ8.22(s,1H),8.12(s,2H),7.53(d,J=9.6Hz,1H),6.50(d,J=9.6Hz,1H),4.21(q,J=7. 1Hz,2H),3.92(d,J=7.5Hz,2H),2.28–2.16(m,1H),1.27(t,J=7.1Hz,3H),0.92(d,J=6.7Hz,6H).LC-MS[M+H] + :519.

[0485] Step 4: Synthesis of compound ZB-H-95

[0486] Following the fourth step of the synthetic route in Example 54, compound ZB-H-95 was obtained. 1 H NMR (600MHz, DMSO-d6) δ13.35(s,1H),8.29(d,J=1.0Hz,1H),7.93(s,2H),7.68(d,J=9.6Hz,1H ),6.51(d,J=9.6Hz,1H),3.93(d,J=7.5Hz,2H),2.21(m,1H),0.93(d,J=6.7Hz,6H).LC-MS[M+H] + :473.

[0487] Example 90: Preparation of compound ZB-H-96

[0488]

[0489] Referring to the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with 4-chlorobenzyl bromide to prepare compound ZB-H-96. LC-MS [M+H] + :541.

[0490] Example 91: Preparation of compound ZB-H-97

[0491]

[0492] Referring to the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with 3-chlorobenzyl bromide to prepare compound ZB-H-97. LC-MS [M+H] + :541.

[0493] Example 92: Preparation of compound ZB-H-98

[0494]

[0495] Referring to the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with 2-chlorobenzyl bromide to prepare compound ZB-H-98. LC-MS [M+H] + :541.

[0496] Example 93: Preparation of compound ZB-H-99

[0497]

[0498] Referring to the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with 2-fluorobenzyl bromide to prepare compound ZB-H-99. LC-MS [M+H] + :525.

[0499] Example 94: Preparation of compound ZB-H-100

[0500]

[0501] Following the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with 2,4-difluorobenzyl bromide to prepare compound ZB-H-100. LC-MS [M+H] + :543.

[0502] Example 95: Preparation of compound ZB-H-101

[0503]

[0504] Following the synthetic route of Example 54, the benzyl bromide in step 1 of Example 54 was replaced with 1-bromo-trifluoro-p-xylene to prepare compound ZB-H-101. LC-MS [M+H] + :575.

[0505] Example 96: Detection of the agonistic activity of compounds on THRα and THRβ using the THR reporter gene assay

[0506] Huh7 cells were cultured in DMEM medium containing 10% FBS. Cells were seeded into 10cm cell culture dishes and allowed to proliferate to approximately 90% confluence. They were then co-transfected with human THRα eukaryotic expression plasmid or human THRβ eukaryotic expression plasmid and the reporter gene plasmid PGL4.26-DR4-Luc containing a THR response sequence driven by liposome Lipofectamine 2000. The procedure was performed according to the Lipofectamine 2000 manufacturer's instructions. The day after transfection, cells were seeded into 96-well cell culture plates with phenol red-free DMEM medium (containing 5% activated charcoal-treated FBS) at a density of 20,000 cells per well and a volume of 135 μL per well. Six hours after seeding, cells adhered. The compound dissolved in DMSO was diluted 20-fold to 10-fold with phenol red-free DMEM medium (containing 5% activated charcoal-treated FBS) and added to each well at a final concentration of 15 μL, thus achieving a final concentration after a further 10-fold dilution. The positive control was set as triiodothyronine (T3) (100 nM), and the blank control was 0.5% DMSO. After drug addition, the cells were cultured overnight (16 hours) at 37°C in a 5% CO2 incubator. After incubation, the culture medium was discarded, and 35 μL of serum-free and phenol red-free DMEM culture medium and 35 μL of Steady-Glo were added to each well. After shaking at room temperature in the dark for 10 minutes, the chemiluminescence value of the samples was detected.

[0507] The agonistic activity of a compound is calculated as follows: Effect % = (Compound - Blank Control) / (Positive Control - Blank Control) × 100%. The EC50 of the compound... 50 EC was obtained by fitting the agonistic activity of the compound to the logarithm of the compound concentration using GraphPad Prism. 50 The lower the value, the better the activity.

[0508] EC50 of the compound’s agonistic activity against THRα and THRβ 50 The values ​​were first calculated using the EC50 values ​​of T3 on the agonistic activity of THRα and THRβ in the same experiment. 50 After value correction, the fold increase, i.e., receptor selectivity, is calculated based on the obtained value. The specific calculation method is as follows: Selectivity = (compound THRαEC) / (receptor selectivity) * (receptor selectivity ... 50 / T3 THRαEC 50 ) / (compound THRβEC 50 / T3THRβEC 50 The higher the value, the higher the selectivity of the compound for the THRβ receptor.

[0509] The positive control drug was Resmetirom (MGL-3196), which is a highly selective THR-β agonist. (Reference: J Med Chem. 2014, 57(10): 3912-3923).

[0510]

[0511]

[0512] Experimental results show that some compounds with the disclosed structure (such as ZB-H-02, ZB-H-17, ZB-H-18, ZB-H-25, ZB-H-26, ZB-H-33, ZB-H-38, ZB-H-74, ZB-H-75, ZB-H-76, ZB-H-81, ZB-H-95, etc.) have significantly higher activity or selectivity than the positive compound, and most other compounds have activity or selectivity comparable to the positive compound (MGL-3196).

[0513] Example 97: Effect of a single administration of the compound on serum cholesterol levels in ICR mice.

[0514] ICR mice were used as test animals to test changes in serum cholesterol levels after gavage administration of the compound. Male ICR mice (7-8 weeks old) were randomly divided into groups according to body weight. The solvent control group was administered 0.25% CMC-Na by gavage, while the compound groups were administered the corresponding test compound, with a single dose. Mice were fasted overnight on the day of administration. Blood and serum were collected 24 hours after administration. Serum cholesterol levels were measured using a total cholesterol assay kit (Zhejiang Dongou Diagnostic Products Co., Ltd.). The percentage decrease in serum cholesterol levels in each group was calculated with the solvent control group as 100%.

[0515]

[0516] The results of the experiment 24 hours after administration showed that the compound had certain in vivo efficacy in animals.

Claims

1. The following compounds or their medicinal salts: 。 2. A pharmaceutical composition comprising one or more compounds selected from the compounds of claim 1, or pharmaceutically acceptable salts thereof, and optionally, pharmaceutically acceptable excipients.

3. Use of the compound of claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a medicament for treating metabolic-related diseases.

4. The use according to claim 3, wherein the metabolic-related diseases are selected from: obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic fatty liver disease, hepatic steatosis, atherosclerosis, hypothyroidism, and thyroid cancer.

5. The use according to claim 3, wherein the metabolic-related disease is selected from: non-alcoholic fatty liver disease, hypothyroidism, and thyroid cancer.

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