Compound with fused ring pyridazinone structure as well as preparation method and application of compound

Abstract

The invention relates to the technical field of medicines, in particular to a compound with a fused ring pyridazinone structure and a preparation method and application thereof. The structural formula of the compound is shown as a formula I. The compound disclosed by the invention has a selective excitation effect on a THR-beta receptor, is remarkable in activity, is relatively weak in excitation activity on a THR-alpha receptor, and has excellent safety. # imgabs0 #

Description

Field of the Invention

[0001] The present invention relates to the field of medical technology, and in particular to a compound having a cyclopyridazinone structure, a preparation method and an application thereof. Background Art

[0002] Thyroid hormones are essential for normal growth and development and for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly regulated through feedback mechanisms in the hypothalamus-pituitary-thyroid (HPT) axis. Abnormal thyroid function can result in either hypothyroidism or hyperthyroidism. Thyroid hormones have profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior.

[0003] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (THRs). THR subtypes differ in their contribution to specific physiological responses. There are two main subtypes of thyroid hormone receptors: THR-α and THR-β. In humans, the former are mainly found in the heart, brain and bones, while THR-β is mainly found in the liver, kidneys, pituitary gland and brain, and is a receptor that has an effect on metabolism. THR-β plays an important role in the liver in regulating thyroid stimulating hormone and modulating the action of thyroid hormones. 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 metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other conditions such as hepatic steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease and related conditions and diseases.

[0004] In recent years, a series of THR-β receptor agonists have been developed, such as Resmetirom and TERN-501, which have the effects of reducing liver fat accumulation and inhibiting liver fibrosis. Their structural formulas are as follows:

[0005]

[0006] However, since the structure-activity relationship of drug compounds is not obvious, how to develop compounds with better efficacy and better selectivity remains a daunting challenge.

[0007] In view of this, the present invention is proposed. Summary of the invention

[0008] The object of the present invention is to provide a compound as shown in general formula I, II or III, which exhibits excellent selective agonist effect on THR-β receptor.

[0009] The present invention provides a compound as shown in Formula I or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0010]

[0011] Wherein, X is hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, alkyl, deuterated alkyl, halogenated alkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, substituted silicon, alkenyl or alkynyl, wherein the alkyl, aryl and heteroaryl are independently and optionally substituted by one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl, C3-C6 cycloalkyl, C2-C8 alkynyl, C2-C8 alkenyl;

[0012] Y is a nitrogen atom, an oxygen atom or a sulfur atom;

[0013] Z is a nitrogen atom, an oxygen atom, a sulfur atom or a carbon atom;

[0014] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl or alkynyl;

[0015] Ring A is a substituted or unsubstituted aromatic ring, heteroaromatic ring, heterocyclic ring, or 4- to 8-membered carbon ring.

[0016] The present invention provides a compound as shown in Formula II or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0017]

[0018] Wherein, X is hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; wherein the alkyl, aryl and heteroaryl are independently and optionally substituted by one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl, C3-C6 cycloalkyl, C2-C8 alkynyl, C2-C8 alkenyl;

[0019] R 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, cyano, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl.

[0020] The present invention also provides a compound as shown in formula III or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0021]

[0022] Wherein, X is hydrogen, deuterium, fluorine, chlorine, bromine, alkenyl, alkynyl;

[0023] R 2 , R 3 , R 7 , R A1 , R A2 , R A3 and R A4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, cyano, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl.

[0024] The technical solution provided by the embodiment of the present invention has the following advantages compared with the prior art:

[0025] The compound of the present invention has a good stimulating effect on THR-β receptors, has significant stimulating activity, and has a good therapeutic effect for treating metabolic diseases. At the same time, the stimulating activity on THR-α receptors is relatively weak, and has excellent safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The results of the weight measurement of mice after drug administration;

[0027] Figure 2 The results of serum triglyceride and transaminase levels in the blood of mice in groups G1-G6 on day 28;

[0028] Figure 3 These are the results of the detection of total cholesterol and triglyceride levels in the livers of mice in groups G1-G6 on the 28th day. DETAILED DESCRIPTION

[0029] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the specification.

[0030] The compounds provided in the embodiments of the present invention can be prepared by standard synthetic methods known in the art, and this specification provides a general method for preparing the compounds of the present invention. The starting materials can usually be obtained commercially or prepared by methods well known to those skilled in the art.

[0031] All technical and scientific terms used in this specification have the meanings commonly understood by those of ordinary skill in the art.

[0032] Table 1:

[0033]

[0034] The term "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms in this article, and further refers to a saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. The term includes straight and branched hydrocarbon groups. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkyloxy, heterocyclic oxygen, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0035] The term "aryl" herein refers to a 6-10 membered all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group having a conjugated π electron system. The aryl group can be covalently linked to the defined chemical structure at any carbon atom that produces a stable structure. The aryl group described herein can be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0036] The term "heterocyclic group" refers to a ring system containing a nitrogen atom or an oxygen atom, which can be "concatenated" with aromatic and non-aromatic ring systems, or linked to other ring systems through a "spiro carbon atom", such as the following structure:

[0037]

[0038] etc.

[0039] The term "heteroaryl" herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through the atoms of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy.

[0040] The term "alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and having at least one alkenyl unsaturated site in this article, and further refers to an alkenyl group having 2 to 6 carbon atoms and having at least one alkenyl unsaturated site. The non-limiting examples of alkenyl include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc. Alkenyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfydryl, alkyl sulfydryl, deuterated alkyl sulfydryl, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0041] The term "alkynyl" herein refers to an alkyl group having 2 to 8 carbon atoms, wherein two adjacent carbon atoms are connected by a triple bond, and further refers to an alkynyl group having 2 to 6 carbon atoms and having at least one alkynyl unsaturation site. The alkyl group is as defined herein. Alkyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylthiol, deuterated alkylthiol, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0042] The term "pharmaceutically acceptable carrier" herein refers to a non-toxic solid, semi-solid or liquid filler, diluent, adjuvant, packaging material or other formulation excipient. The carrier used may be adapted to the corresponding administration form, and may be formulated into injection, (injection) lyophilized powder, spray, oral solution, oral suspension, tablet, capsule, enteric-coated tablet, pill, powder, granule, sustained release or delayed release formulations using carriers known to those skilled in the art.

[0043] The terms "prevention" and "treatment" herein have the meanings conventionally understood by those skilled in the art, i.e., "prevention" refers to the administration of a pharmaceutical composition or active compound before the onset of a disease or before the onset of symptoms to prevent, delay and / or alleviate the onset of a corresponding disease or the onset of symptoms; "treatment" refers to the administration of a pharmaceutical composition or active compound at the time of or after the onset of a disease, or at the time of or after the onset of symptoms, to eliminate the corresponding condition, alleviate the severity of the corresponding symptoms, or delay the development of the corresponding disease.

[0044] The term "subject" herein preferably refers to a mammal, especially a human or an experimental animal (such as a mouse, rat or rabbit, etc.).

[0045] The term "effective amount" herein refers to the appropriate dose of a drug or treatment method required to produce the desired effect. Among them, a therapeutically effective dose refers to a dose of a drug that can treat a disease or symptom, while a preventive effective dose refers to a dose of a drug or measure that can prevent the occurrence of a disease or reduce the risk of a disease. Those skilled in the art can determine the effective dose based on specific factors, such as individual age, weight, severity of the disease, etc.

[0046] The present invention provides a compound as shown in Formula I or its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0047]

[0048] Wherein, X is hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, alkyl, deuterated alkyl, halogenated alkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, substituted silicon, alkenyl or alkynyl, wherein the alkyl, aryl and heteroaryl are independently and optionally substituted by one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl, C3-C6 cycloalkyl, C2-C8 alkynyl, C2-C8 alkenyl;

[0049] Y is a nitrogen atom, an oxygen atom or a sulfur atom;

[0050] Z is a nitrogen atom, an oxygen atom, a sulfur atom or a carbon atom;

[0051] R 1, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl or alkynyl;

[0052] Ring A is a substituted or unsubstituted aromatic ring, heteroaromatic ring, heterocyclic ring, or 4- to 8-membered carbon ring.

[0053] As an improvement of an embodiment of the present invention, in Formula I, X is hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl or C2-C8 alkynyl; C1-C6 alkyl, C6-C10 aryl and C4-C9 heteroaryl are independently and optionally substituted with one or more substituents selected from the following: halogen, hydroxyl, methoxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl.

[0054] As an improvement of an embodiment of the present invention, X is hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl; wherein the C1-C6 alkyl is substituted by one or more substituents selected from the following: halogen, hydroxyl, methoxy, amino, cyano, trifluoromethyl.

[0055] As an improvement of an embodiment of the present invention, X is hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkenyl or C2-C8 alkynyl; the C1-C6 alkyl is substituted by one or more substituents selected from the following: halogen, methoxy.

[0056] As an improvement of the embodiment of the present invention, X is hydrogen, deuterium, halogen, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, vinyl or ethynyl.

[0057] As an improvement of the embodiment of the present invention, it is hydrogen, deuterium, fluorine, bromine, and chlorine.

[0058] As an improvement of the embodiment of the present invention, Y is an oxygen atom or a sulfur atom.

[0059] As an improvement of the embodiment of the present invention, Y is an oxygen atom.

[0060] As an improvement of the embodiment of the present invention, Z is an oxygen atom or a carbon atom.

[0061] As an improvement of the embodiment of the present invention, Z is an oxygen atom.

[0062] As an improvement of the embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkane substituted with mono- or poly-halogen, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl.

[0063] As an improvement of the embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, mono- or poly-halogen-substituted C1-C6 alkane, C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl.

[0064] As an improvement of the embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or deuterated C1-C6 alkyl.

[0065] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 6 Each is independently halogen, C1-C6 alkyl, monohalogen or polyhalogen substituted C1-C6 alkyl.

[0066] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 6Each is independently halogen, methyl, ethyl, propyl, mono- or poly-halogen-substituted methyl, mono- or poly-halogen-substituted ethyl, or mono- or poly-halogen-substituted propyl.

[0067] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 6 Each is independently fluorine, chlorine or bromine.

[0068] As an improvement of the embodiment of the present invention, R 1 , R 4 , R 5 , R 7 Each is independently hydrogen, deuterium, or C1-C6 alkyl.

[0069] As an improvement of the embodiment of the present invention, R 1 , R 4 , R 5 , R 7 Each is independently hydrogen, deuterium, methyl, ethyl or propyl.

[0070] As an improvement of the embodiment of the present invention, R 1 , R 4 , R 5 , R 7 are each independently hydrogen or deuterium.

[0071] As an improvement of an embodiment of the present invention, ring A is a substituted or unsubstituted C6-C10 aromatic ring, a C4-C9 heteroaromatic ring, a C4-C9 heterocycle, or a C4-C8 carbocycle; the substituted substituent is selected from halogen, cyano, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, monohalogen or polyhalogen substituted C1-C6 alkyl, or deuterated C1-C6 alkyl.

[0072] As an improvement of an embodiment of the present invention, ring A is a substituted or unsubstituted C6-C10 aromatic ring; the substituted substituent is selected from halogen, cyano, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, monohalogen or polyhalogen substituted C1-C6 alkyl, deuterated C1-C6 alkyl.

[0073] As an improvement of an embodiment of the present invention, ring A is a substituted or unsubstituted benzene ring; the substituted substituent is selected from halogen, cyano, methyl, ethyl, propyl, ethynyl, trifluoromethyl, and trideuterated methyl.

[0074] The present invention provides a compound as shown in Formula II or its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0075]

[0076] Wherein, X is hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; wherein the alkyl, aryl and heteroaryl are independently and optionally substituted by one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl, C3-C6 cycloalkyl, C2-C8 alkynyl, C2-C8 alkenyl;

[0077] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, cyano, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl.

[0078] As an improvement of an embodiment of the present invention, X is hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl; wherein, C1-C6 alkyl, C6-C10 aryl, C4-C9 heteroaryl are independently and optionally substituted with one or more substituents selected from the following: halogen, hydroxyl, methoxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl.

[0079] As an improvement of an embodiment of the present invention, X is hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; wherein the C1-C6 alkyl is substituted by one or more substituents selected from the following: halogen, hydroxyl, methoxy, amino, cyano, trifluoromethyl.

[0080] As an improvement of an embodiment of the present invention, X is hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkenyl or C2-C8 alkynyl; the C1-C6 alkyl is substituted by one or more substituents selected from the following: halogen, methoxy.

[0081] As an improvement of the embodiment of the present invention, X is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, vinyl or ethynyl.

[0082] As an improvement of the embodiment of the present invention, X is hydrogen, deuterium, fluorine, chlorine or bromine.

[0083] As an improvement of the embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkane substituted with mono- or poly-halogen, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl.

[0084] As an improvement of the embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, mono- or poly-halogen-substituted C1-C6 alkane, C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl.

[0085] As an improvement of the embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, or C2-C8 alkynyl.

[0086] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 6 Each is independently halogen, C1-C6 alkyl, monohalogen or polyhalogen substituted C1-C6 alkyl.

[0087] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 6 Each is independently halogen, methyl, ethyl, propyl, mono- or poly-halogen-substituted methyl, mono- or poly-halogen-substituted ethyl, or mono- or poly-halogen-substituted propyl.

[0088] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 6 Each is independently fluorine, chlorine or bromine.

[0089] As an improvement of the embodiment of the present invention, R 1 , R 4 , R 5 , R 7 Each is independently hydrogen, deuterium, or C1-C6 alkyl.

[0090] As an improvement of the embodiment of the present invention, R 1 , R 4 , R 5 , R 7 Each is independently hydrogen, deuterium, methyl, ethyl or propyl.

[0091] As an improvement of the embodiment of the present invention, R 1 , R 4 , R 5 , R 7 are each independently hydrogen or deuterium.

[0092] As an improvement of the embodiment of the present invention, R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, cyano, C1-C3 alkyl, deuterated C1-C3 alkyl, monohalogen or polyhalogen substituted C1-C3 alkane, C2-C4 alkenyl, C2-C4 alkynyl.

[0093] As an improvement of the embodiment of the present invention, R A1 , R A2 For hydrogen.

[0094] As an improvement of the embodiment of the present invention, R A3 , R A4Each is independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, trideuterium, or ethynyl.

[0095] The present invention also provides a compound as shown in Formula III or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

[0096]

[0097] Wherein, X is hydrogen, deuterium, fluorine, chlorine, bromine, alkenyl, alkynyl;

[0098] R 2 , R 3 , R 7 , R A1 , R A2 , R A3 and R A4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, cyano, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl.

[0099] As an improvement of the embodiment of the present invention, X is hydrogen, deuterium, fluorine, chlorine, bromine, C2-C8 alkenyl or C2-C8 alkynyl;

[0100] R 2 , R 3 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkane substituted with mono- or poly-halogen, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl or C2-C8 alkynyl.

[0101] As an improvement of the embodiment of the present invention, X is hydrogen, deuterium, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, vinyl or ethynyl.

[0102] As an improvement of the embodiment of the present invention, X is hydrogen, deuterium, fluorine, chlorine or bromine.

[0103] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 7 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, monohalogen or polyhalogen substituted C1-C6 alkyl.

[0104] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 7 Each is independently hydrogen, deuterium, halogen, methyl, ethyl, propyl, mono- or poly-halogen-substituted methyl, mono- or poly-halogen-substituted ethyl, or mono- or poly-halogen-substituted propyl.

[0105] As an improvement of the embodiment of the present invention, R 2 , R 3 , R 7 Each is independently hydrogen, deuterium, fluorine, chlorine or bromine.

[0106] As an improvement of the embodiment of the present invention, R 2 , R 3 Each is independently fluorine, chlorine or bromine.

[0107] As an improvement of the embodiment of the present invention, R 7 is hydrogen or deuterium.

[0108] As an improvement of the embodiment of the present invention, R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-C3 alkyl, deuterated C1-C3 alkyl, monohalogen or polyhalogen substituted C1-C3 alkane, C2-C4 alkenyl, C2-C4 alkynyl.

[0109] As an improvement of the embodiment of the present invention, R A1 , R A2 For hydrogen.

[0110] As an improvement of the embodiment of the present invention, R A3 , R A4 Each is independently hydrogen, deuterium, halogen, cyano, methyl, trifluoromethyl, trideuteriomethyl, or ethynyl.

[0111] The present invention also provides a compound as shown in the following structural formula or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0112]

[0113]

[0114] In the embodiments of the present invention, compounds of the present invention having the same molecular formula but different properties or sequences of their atomic bonds or different spatial arrangements of their atoms are referred to as "isomers". Isomers with different spatial arrangements of atoms are referred to as "stereoisomers". All isomers of the compounds described herein (e.g., cis-, trans-, or diastereomers) alone or in any mixture thereof are included within the scope of the embodiments of the present invention. All of these forms include enantiomers, diastereomers, cis, trans, syn, anti, tautomers, and mixtures thereof. Stereoisomeric mixtures (e.g., mixtures of diastereomers) can be separated into their corresponding isomers in a known manner using suitable separation methods.

[0115] In an embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula I can include acid addition salts and basic salts. Suitable acid addition salts are formed by the acid that can form non-toxic salts. For example, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, sucrose acid salt, stearate, succinate, tannate, tartrate. Suitable basic salts are formed by the alkali that forms non-toxic salts. Examples thereof include salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc.

[0116] The present invention also proposes a pharmaceutical composition, which includes a therapeutically effective dose of the above-mentioned compound or its stereoisomer, tautomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be prepared by methods known in the art. The pharmaceutical composition used in the present invention can be prepared using one or more pharmaceutically acceptable carriers according to conventional methods, and the carrier includes excipients and adjuvants, which are conducive to processing the active compound into a pharmaceutically usable preparation. Suitable preparations depend on the selected route of administration. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the scope of the present invention. The pharmaceutical composition of the embodiment of the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and the compounds of the embodiment of the present invention can be present in suitable solid or liquid carriers or diluents. The pharmaceutical composition of the present invention can also be stored in suitable sterile equipment for injection or infusion. Usually, the amount of active ingredient in the pharmaceutical composition is 0.01% by weight to 99% by weight of the pharmaceutical composition.

[0117] The compounds of the embodiments of the present invention or pharmaceutical compositions comprising the compounds of the embodiments of the present invention can be used clinically in mammals (including humans) through oral, nasal, skin, lung or gastrointestinal administration routes. The preferred route of administration is oral. The preferred daily dose is 0.5-200 mg / kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined according to the specific treatment. Usually, it starts with a small dose and gradually increases the dose until the most suitable dose is found. The effective dose of the active ingredient used may vary with the compound used, the mode of administration and the severity of the disease to be treated. However, generally, when the compound of the present invention is administered at a dose of about 1-300 mg / kg animal body weight per day, satisfactory results can be obtained, preferably administered in 1-3 divided doses per day, or administered in a sustained release form. For most large mammals, the total daily dose is about 5-1000 mg, preferably about 10-500 mg. A dosage form suitable for oral administration comprises about 1-200 mg of an active compound intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as required by the exigencies of the therapeutic situation.

[0118] Embodiments of the present invention also provide methods for treating or preventing disorders or conditions associated with THR-β receptors, and disorders or conditions associated with THR-β receptors include metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic fatty hepatitis, cardiovascular disease, hypothyroidism, and thyroid cancer. Among them, cardiovascular disease includes atherosclerosis. Specific treatment and prevention methods include: administering an effective amount of a compound comprising an embodiment of the present invention or a pharmaceutically acceptable salt thereof to an individual. The compound of the present invention or its pharmaceutical composition can be administered orally, parenterally, topically, rectally, mucosally or intestinally. Parenteral administration includes indirect injection to produce systemic effects or direct injection into the affected part. Topical administration includes treatment of the skin or organs (such as eyes or ears) that can be easily reached by topical application. It also includes transdermal delivery to produce systemic effects. Rectal administration includes the form of suppositories. Preferred routes of administration are oral and parenteral.

[0119] The embodiments of the present invention also provide the use of the above-mentioned compound or its stereoisomer, tautomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a drug for treating metabolic diseases; metabolic diseases are diseases related to thyroid hormone receptors. Specifically, metabolic diseases include obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic fatty hepatitis, cardiovascular disease, hypothyroidism and thyroid cancer; wherein cardiovascular disease includes atherosclerosis.

[0120] The present invention also provides a method for treating a disease with a thyroid hormone receptor agonist, which comprises administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0121] The embodiment of the present invention further provides a thyroid hormone receptor agonist, which is the compound described in the embodiment of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt.

[0122] The present invention also provides a preparation method of the general formula I, for example, the following synthetic route can be used:

[0123]

[0124] In the embodiment of the present invention, SM-1 is used as the starting material, and the cyano group is hydrolyzed to obtain compound IM1, which is then subjected to esterification to obtain compound IM2, which is reduced to obtain compound IM-3, and then subjected to functional group conversion reaction to obtain compound I, wherein rings A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7The definitions are the same as described for Formula I.

[0125] Functional group transformation reactions include: fluorination reaction of hydroxyl, bromination reaction, chlorination reaction, esterification reaction and other common functional group transformation reactions.

[0126] The following further explains and lists the compounds of the embodiments of the present invention and the corresponding preparation methods by examples and preparation. It should be understood that although typical or preferred reaction conditions are given in the specific examples, other reaction conditions can also be used by those skilled in the art. Optimum reaction conditions can change with the specific reaction substrate or solvent used, but the conditions can be determined by conventional optimization by those skilled in the art.

[0127]

[0128] Add anhydride (5.0 g) and hydrazine sulfate (4.4 g) to water (150 mL), heat to 100°C and react for 3 hours. After the reaction is complete, cool to room temperature and filter. Collect the solid to obtain 4 g of white solid. m / z: 177.10 (M+1), 175.10 (M-1).

[0129] Weigh the intermediate (4 g) from the previous step and add POCl 3 (30 mL), heated to 85 ° C for 1 hour, concentrated, added dichloromethane (40 mL) to the residue, slowly added dropwise to ice water (40 mL), and then washed with saturated Na 2 CO 3 Adjust the pH to weak acid, separate the liquids, and use anhydrous Na 2 SO 4 Dry, filter, concentrate and column chromatograph to obtain 1.5 g of light yellow solid. m / z: 213.00 (M+1).

[0130] Using similar starting materials and similar preparation schemes, the following intermediates can be prepared:

[0131]

[0132] The preparation examples of the compounds proposed in the examples of the present invention are as follows:

[0133] Embodiment 1:

[0134]

[0135]

[0136] first step:

[0137] 1,4-Dichlorophthalazine (10 g) and 2,6-dichloro-4-aminophenol (9.8 g) were dissolved in acetonitrile (200 mL), cesium carbonate (40.9 g) was added, stirred at 90°C for 3 hours, filtered, concentrated to remove the solvent, extracted with dichloromethane and water, dried over anhydrous sodium sulfate, filtered, spin-dried, and column chromatography to obtain 5 g of a yellow solid. m / z: 339.15 (M+H).

[0138] Step 2:

[0139] Intermediate 1-1 (2 g) was dissolved in acetic acid (20 mL), sodium acetate (4.84 g) was added and reacted at 130°C overnight, solid was precipitated, filtered, filter cake was collected, water and ethyl acetate were added to the filtrate for extraction, solid was precipitated again in the organic phase, filtered, filter cake was collected, the filtrate was spin-dried, 50 mL of ethanol was added for pulping, filtered, filter cake was collected, and a total of 1.2 g of white solid was obtained. m / z: 363.95 (M+H), 362.05 (MH).

[0140] Step 3:

[0141] Intermediate 1-2 (1.2 g) was dissolved in 36 mL of ethanol and 18 mL of water, sodium hydroxide (13.2 g) was added, and the mixture was reacted at 110° C. overnight to precipitate a solid, which was filtered and the filter cake was collected. The filtrate was separated into layers, the upper layer was separated, 10 mL of ethanol was added for slurrying, filtered, and the filter cake was collected. A total of 910 mg of brown solid was obtained. m / z: 321.95 (M+H), 320.00 (MH).

[0142] Step 4:

[0143] Intermediate 1-3 (0.9 g) was suspended in 90 mL of water, and concentrated hydrochloric acid (45 mL) was added. An aqueous solution of sodium nitrite (580.4 mg) was added under ice bath, and the mixture was reacted at 0°C for 1 hour to obtain a yellow solution A. Cyanoacetylurea (525.3 mg) was dissolved in 25 mL of water and 37.5 mL of pyridine, and the mixture was stirred at 0°C to obtain a solution B. Solution A was added to solution B, and the mixture was reacted at 0°C for 1 hour to precipitate an orange solid, which was filtered and dried to obtain 655 mg of an orange solid. m / z: 489.05 (M+H), 487.05 (MH).

[0144] Step 5:

[0145] Intermediate 1-4 (650 mg) was dissolved in acetic acid (32.5 mL), sodium acetate (1.1 g) was added, and the mixture was reacted at 130 ° C for 3 hours. Water and ethyl acetate were added for extraction, and solids were precipitated from the organic phase, filtered, and the filter cake was collected to obtain 300 mg of crude product, which was then subjected to reverse preparative chromatography (water, 40% to 54% acetonitrile) to obtain 110 mg of compound X (same as Example 9 (Compound No. 9) in WO2020123827A1, i.e., TERN-501) as a white solid.

[0146] MS: m / z 442.95(M+H), 441.00(MH). 1 H-NMR(400MHz,DMSO-d6)δ:13.27(s,1H),12.04(s,1H),8.33(dd,1H,J=7.6&0.8Hz),8.27(d d,1H,J=8.0&0.8Hz), 8.12~8.08(td,1H,J=15.2&1.2Hz), 8.06~8.01(td,1H,J=15.2&1.2Hz).

[0147] Step 6:

[0148] Intermediate 1-5 (3 g) was dissolved in glacial acetic acid (100 mL), and concentrated hydrochloric acid (20 mL) was added under stirring. After the addition was completed, the temperature was raised to 120°C and the reaction was allowed to react for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature and H 2 O (200 mL), stirred at room temperature for 1 hour, filtered, and the filter cake was washed with H 2 O (20 mL × 2) was used for elution, and the solid was collected and dried at 45°C to obtain 2.0 g of a brown solid. m / z: 462.00 / 464.00 (M+H), 460.00 / 462.00 (MH).

[0149] Step 7:

[0150] Intermediate 1-6 (2 g) was dissolved in methanol (100 mL) and SOCl was added dropwise under ice bath. 2 (10 mL), after addition, the temperature was raised to 100°C for 5 hours, after the reaction was completed, the mixture was concentrated under reduced pressure, the residue was pulped, filtered, the filter cake was rinsed with petroleum ether, the solid was collected, and dried at 45°C to obtain 2.3 g of yellow solid. m / z: 476.00 / 477.95 (M+H), 473.95 / 475.95 (MH).

[0151] Step 8:

[0152] Intermediate 1-7 (2 g) was dissolved in tetrahydrofuran (40 mL), sodium borohydride (0.82 g) was added, methanol (4 mL) was slowly added dropwise, a large number of bubbles were generated, and the reaction was stirred for 1 hour. After the reaction was completed, the reaction was quenched with ice water, and the pH was adjusted to about 6 with 1M HCl, extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to obtain 1.6 g of a light yellow solid. m / z: 447.95 / 449.95 (M+H), 446.00 / 448.00 (MH).

[0153] Step 9:

[0154] Intermediate 1-8 (100 mg) was dissolved in dichloromethane (20 mL), and diethylaminosulfur trifluoride (DAST, 8 drops) was added dropwise under ice bath. After the addition, the mixture was stirred in ice bath for 30 min. After the reaction was completed, the reaction solution was slowly added dropwise to ice water, separated, the organic phase was temporarily stored, the aqueous phase was extracted with dichloromethane (15 mL), the organic phases were combined, washed with saturated sodium chloride (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was slurried with ethyl acetate to obtain 20 mg of compound 1 as a white solid. m / z: 450.00 / 452.00 (M+H), 448.00 / 450.00 (MH).

[0155] 1 H-NMR (400MHz, DMSO-d6) δ: 12.02 (s, 1H), 8.33 (d, 1H, J = 7.2Hz), 8.28 (d, 1H, J = 7.6Hz), 8.11~8.07 (td,1H,J=15.2&1.2Hz), 8.05~8.01(td,1H,J=15.2&1.2Hz), 7.86(s,2H), 5.34(d,2H,J=46.8Hz).

[0156] Embodiment 2:

[0157]

[0158] first step:

[0159] Methyl-1,4-dichlorophthalazine (1.5 g) and 2,6-dichloro-4-aminophenol (1.26 g) were placed in a three-necked flask and Cs 2 CO 3 (5.76 g), heated to 90°C for 3 hours, cooled, concentrated the filtrate, added anhydrous ethanol (4 mL) to the residue, slurried, filtered, and obtained 500 mg of a yellow solid. m / z: 353.95 (M+1).

[0160] Step 2:

[0161] Intermediate 2-1 (475 mg) and sodium ethoxide (440 mg) were placed in a three-necked flask, ethanol (5 mL) was added, and the temperature was raised to 120°C for 16 hours, then cooled, concentrated to dryness, and used directly in the next step. m / z: 378.05 (M+1), 376.05 (M-1).

[0162] Step 3:

[0163] Methanol (7 mL) was added to the product of the previous step, and NaOH aqueous solution was added at room temperature. The temperature was raised to 100 °C for 5 hours, and most of the methanol was concentrated. Ethyl acetate (20 mL) was added, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (10 mL). The organic phases were combined and washed with saturated NaCl aqueous solution (30 mL). The organic phase was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to obtain 400 mg of solid. m / z: 336.00 (M+1), 334.00 (M-1).

[0164] Step 4:

[0165] Dissolve the intermediate 2-3 (201 mg) in 6 mL of water, add 6 mL of hydrochloric acid, then cool to 0-10 ° C and add a solution of sodium nitrite (125 mg) in water (0.8 mL). After adding, stir for 1 hour in an ice-water bath, which is recorded as solution A. Add the raw material (112 mg) to 3.75 mL of water, then add 6 mL of pyridine, which is recorded as solution B. Control the temperature at 5-15 ° C, slowly add solution A to solution B, and continue stirring for 1.5 hours after the addition is complete. Filter the reaction solution, wash the filter cake with water and n-hexane, and dry to obtain 300 mg of orange-red solid. m / z: 503.00 (M+1), 501.00 (M-1).

[0166] Step 5:

[0167] Add intermediate 2-4 (300 mg), sodium acetate (490 mg) and 10 mL acetic acid to the reaction flask, heat to 100 ° C and react for 3 hours. The reaction solution is cooled, concentrated, 25 mL of water is added, extracted with ethyl acetate (25 mL × 2), the combined organic phases are washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried to obtain 200 mg of light yellow solid. Take 50 mg and purify it by column chromatography to obtain 25 mg of off-white solid.

[0168] m / z:457.00(M+1),454.95(M-1). 1 H-NMR(400MHz,DMSO-d6)δ:12.05(s,1H),8.16(dd,1H,J=7.2&

[0169] 2.0Hz),7.86~7.81(m,2H),7.78(s,2H),2.88(s,3H).

[0170] Step 6:

[0171] Add intermediate 2-5 (150 mg) and 1.5 mL of acetic acid to a reaction flask, add concentrated hydrochloric acid (2 mL) and heat to 120 ° C for 16 hours. The reaction solution was cooled, poured into 10 mL of water, filtered, and the filter cake was washed with water and dried to obtain 138 mg of light yellow solid. m / z: 476.00 (M+1), 473.95 (M-1).

[0172] Step 7:

[0173] Intermediate 2-6 (138 mg) and 7 mL of methanol were added to the reaction flask, thionyl chloride (1.5 mL) was slowly added dropwise under ice bath, and the temperature was raised to 100°C for 6 hours. The reaction solution was cooled, concentrated, slurried, filtered, and the filter cake was dried to obtain 150 mg of light yellow solid. m / z: 490.00 (M+1), 488.00 (M-1).

[0174] Step 8:

[0175] Weigh intermediate 2-7 (150 mg), add THF (15 mL), then add NaBH 4 (60 mg), methanol (1.5 mL) was added dropwise under ice bath, and the reaction was allowed to react at room temperature for 2 hours. H 2 O (10 mL) was added to quench the reaction, concentrated, adjusted to pH 6 with 1 M HCl, extracted with ethyl acetate, separated, the organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 mg of a white solid. m / z: 462.00 (M+1), 460.00 (M-1).

[0176] Step 9:

[0177] Weigh the intermediate 2-8 (100 mg), add dichloromethane (20 mL), add DAST (0.2 mL) dropwise under ice bath, and after addition, warm to room temperature naturally for 1 hour, slowly dropwise add the reaction solution into ice water, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by column chromatography to obtain 25 mg of white solid. m / z: 464.00 (M+1), 462.00 (M-1).

[0178] 1 H-NMR (400MHz, DMSO-d6) δ: 12.04 (s, 1H), 8.16 (dd, 1H, J = 7.2&2.0Hz), 7.87 ~ 7.83 (m, 2H), 7.82 (s, 2H), 5.37 (d, 2H, J = 46.8Hz), 2.88 (s, 3H).

[0179] Using a similar preparation route as above, replacing "methyl-1,4-dichlorophthalazine" with "cyano-1,4-dichlorophthalazine" or "deuterated methyl-1,4-dichlorophthalazine", the following compounds can be prepared respectively:

[0180]

[0181] Compound 8: 1 H-NMR (400MHz, DMSO-d6) δ: 12.00 (s, 1H), 8.12 (m, 1H), 7.84~7.80 (m, 2H), 7.82 (s, 2H), 5.35 (d, 2H). m / z:475.00(M+1),473.00(M-1).

[0182] Compound 9: 1 H-NMR (400MHz, DMSO-d6) δ: 11.98 (s, 1H), 8.18 (m, 1H), 7.88~7.79 (m, 2H), 7.81 (s, 2H), 5.32 (d, 2H). m / z:467.10(M+1),465.20(M-1).

[0183] Embodiment 3:

[0184]

[0185]

[0186] first step:

[0187] Add m-methyl-1,4-dichlorophthalazine (5.2 g), 2,6-dichloro-4-aminophenol (4.4 g), cesium carbonate (20.0 g), and acetonitrile (100 mL) to the reaction bottle in sequence and react at 90°C for 3 hours. Filter with suction, spin dry the filtrate, and slurry with anhydrous ethanol at room temperature for 1 hour. Filter with suction, and dry the filter cake to obtain 2.7 g of brown-black solid. m / z: 353.95 (M+H), 351.95 (MH).

[0188] Step 2:

[0189] Intermediate 3-1 (2.7 g), sodium acetate (6.3 g), and acetic acid (54 mL) were added to the reaction flask in sequence and reacted at 130°C for 16 hours. The reaction solution was concentrated and slurried with ethyl acetate at room temperature for 1 hour. After suction filtration, the filter cake was air-dried to obtain 2.8 g of gray solid. m / z: 378.05 (M+H), 376.05 (MH).

[0190] Step 3:

[0191] Add intermediate 3-2 (2.8 g) and ethanol (90 mL) to the reaction flask and stir, then add sodium hydroxide aqueous solution (sodium hydroxide (30.6 g), water (45 mL)), and react at 110°C for 18 hours. Separate the liquid, concentrate the upper layer until a large amount of solid precipitates, filter, and air-dry the filter cake to obtain 2.6 g of gray solid. m / z: 336.00 (M+H), 334.00 (MH).

[0192] Step 4:

[0193] Add intermediate 3-3 (2.6 g), water (260 mL), concentrated hydrochloric acid (130 mL) to the reaction bottle in sequence, add sodium nitrite aqueous solution [sodium nitrite (1.61 g), water (7 mL)] under stirring, control the temperature at 0-5 ° C and stir for 1 hour, record as solution A. Take another reaction bottle and add raw materials (1.46 g), water (87 mL), pyridine (130 mL), cool the ice bath to 0-5 ° C, drop solution A into the system, keep 0-10 ° C and add dropwise. After the dropwise addition, stir at 0-5 ° C for 1 hour. Filter by suction, and air-dry the filter cake to obtain 2.4 g of orange solid. m / z: 503.05 (M+H), 501.05 (MH).

[0194] Step 5:

[0195] Add intermediate 3-4 (2.4 g), sodium acetate (3.93 g), acetic acid (120 mL) to the reaction flask in sequence, and react at 130 ° C for 3 hours. Cool down and concentrate until no solvent flows out. Add water and ethyl acetate to extract, wash the organic layer with saturated sodium chloride aqueous solution, and dry it over anhydrous sodium sulfate. Filter, spin dry the filtrate and purify it with a column to obtain 90 mg of a yellow solid. m / z: 457.00 (M+H), 455.00 (MH). 1 H-NMR (400MHz, DMSO-d6) δ: 11.96 (s, 1H), 8.16 (d, 1H, J = 8.4Hz), 8.13 (s, 1H), 7.92 (d, 1H, J = 8.0Hz), 7.82 (s, 2H), 2.59 (s, 3H).

[0196] Step 6:

[0197] Add intermediate 3-5 (100 mg) and 1.5 mL of acetic acid to a reaction flask, add concentrated hydrochloric acid (2 mL) and heat to 120 ° C for 16 hours. The reaction solution was cooled, poured into 10 mL of water, filtered, and the filter cake was washed with water and dried to obtain 108 mg of light yellow solid. m / z: 476.00 (M+1), 473.05 (M-1).

[0198] Step 7:

[0199] Add intermediate 3-6 (108 mg) and 7 mL of methanol to a reaction flask, slowly drop thionyl chloride (1.5 mL) under ice bath, and heat to 100 °C for 6 hours. The reaction solution was cooled, concentrated, slurried, filtered, and the filter cake was dried to obtain 100 mg of light yellow solid. m / z: 490.00 (M+1), 488.05 (M-1).

[0200] Step 8:

[0201] Weigh intermediate 3-7 (100 mg), add THF (15 mL), then add NaBH 4 (60 mg), methanol (1.5 mL) was added dropwise under ice bath, and the reaction was allowed to react at room temperature for 2 hours. H 2 O (10 mL) was added to quench the reaction, concentrated, adjusted to pH 6 with 1 M HCl, extracted with ethyl acetate, separated, the organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 80 mg of a white solid. m / z: 462.00 (M+1), 460.05 (M-1).

[0202] Step 9:

[0203] Weigh the intermediate 3-8 (80 mg), add dichloromethane (10 mL), add DAST (0.2 mL) dropwise under ice bath, and after the addition, naturally warm to room temperature to react for 1 hour. Slowly dropwise add the reaction solution into ice water, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by column chromatography to obtain 20 mg of white solid compound 3. m / z: 464.05 (M+1), 462.00 (M-1).

[0204] Embodiment 4:

[0205]

[0206] first step:

[0207] Methyl-1,4-dichlorophthalazine (2.4 g) and 2,6-dichloro-4-aminophenol (1.5 g) were dissolved in acetonitrile (48 mL), cesium carbonate (7 g) was added, stirred at 90°C for 3 hours, filtered, concentrated to remove the solvent, and 6 mL of ethanol was added to slurry to obtain 1.5 g of a yellow solid. m / z: 417.90 (M+H).

[0208] Step 2:

[0209] Intermediate 4-1 (1.5 g) was dissolved in acetic acid (15 mL), sodium acetate (2.9 g) was added and reacted at 130°C overnight, solid precipitated, filtered, the filter cake was collected, the filtrate was dried, 3 mL of ethyl acetate was added to slurry, filtered, the filter cake was collected, and a total of 3.5 g of gray solid was obtained. m / z: 443.90 (M+H), 441.90 (MH).

[0210] Step 3:

[0211] Intermediate 4-2 (3.5 g) was dissolved in 105 mL of ethanol, and a solution of sodium hydroxide (13.2 g) and water (52.5 mL) was added. The reaction was allowed to react overnight at 110°C. The reaction solution was separated into layers, the upper layer was separated, most of the solvent was removed by vortexing, ethyl acetate was added for extraction, the organic phase was dried, and 1.2 g of a black solid was obtained by vortexing. m / z: 399.90 (M+H), 398.00 (MH).

[0212] Step 4:

[0213] Intermediate 4-3 (1 g) was suspended in 100 mL of water, and concentrated hydrochloric acid (50 mL) was added. A solution of sodium nitrite (516 mg) in water (2 mL) was added under ice bath, and the mixture was reacted at 0°C for 1 hour to obtain a yellow solution A. Cyanoacetylurea (467 mg) was dissolved in 25 mL of water and 37.5 mL of pyridine, and the mixture was stirred at 0°C to obtain a solution B. Solution A was added to solution B, and the mixture was reacted at 0°C for 1 hour to precipitate an orange solid, which was filtered and dried to obtain 600 mg of an orange solid. m / z: 567.00 (M+H), 565.00 (MH).

[0214] Step 5:

[0215] Intermediate 4-4 (600 mg) was dissolved in acetic acid (30 mL), sodium acetate (868 mg) was added, and the mixture was reacted at 130°C for 3 hours. Most of the acetic acid was dried, and water and ethyl acetate were added for extraction. The organic phase was dried, filtered, and dried, and 200 mg of off-white solid was obtained by reverse flash chromatography (water, acetonitrile). m / z: 520.90 (M+H), 518.90 (MH).

[0216] 1H-NMR (600MHz, DMSO-d6) δ12.21(s,1H),8.41(s,1H),8.28~8.27(m,1H),8.22~8.19(m,1H),7.84(s,2H).

[0217] Step 6:

[0218] Intermediate 4-5 (120 mg) and 1.5 mL of acetic acid were added to the reaction flask, and concentrated hydrochloric acid (2 mL) was added and the temperature was raised to 120°C for 16 hours. The reaction solution was cooled, poured into 10 mL of water, filtered, and the filter cake was washed with water and dried to obtain 88 mg of a light yellow solid. m / z: 539.00 (M+1).

[0219] Step 7:

[0220] Intermediate 4-6 (88 mg) and 7 mL of methanol were added to the reaction flask, thionyl chloride (1.5 mL) was slowly added dropwise under ice bath, and the temperature was raised to 100°C for 6 hours. The reaction solution was cooled, concentrated, slurried, filtered, and the filter cake was dried to obtain 70 mg of light yellow solid. m / z: 553.00 (M+1).

[0221] Step 8:

[0222] Weigh intermediate 4-7 (70 mg), add THF (15 mL), then add NaBH 4 (60 mg), methanol (1.5 mL) was added dropwise under ice bath, and the reaction was allowed to react at room temperature for 2 hours. H 2 O (10 mL) to quench the reaction, concentrate, adjust the pH to about 6 with 1M HCl, add ethyl acetate for extraction, separate the layers, wash the organic phase with saturated NaCl, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 50 mg of a white solid. m / z: 525.00 (M+1).

[0223] Step 9:

[0224] Weigh the intermediate 4-8 (50 mg), add dichloromethane (10 mL), add DAST (0.2 mL) dropwise under ice bath, and after the addition, naturally warm to room temperature for 1 hour, slowly dropwise add the reaction solution into ice water, separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by column chromatography to obtain 30 mg of white solid compound 3. m / z: 527.05 (M+1), 525.05 (M-1).

[0225] The abbreviations of the terms used in the following biological activity experiments are shown in Table 2:

[0226] Table 2: Abbreviations of nouns

[0227]

[0228]

[0229] Experimental example: Biological activity experiment

[0230] 1. Compound THR-β and THR-α binding assay

[0231] Test principle: The HTRF method is used to detect the effect of the test compound on THR-α and THR-β. MAbAnti GST-Eu cryptate antibody is labeled with THR-α-LBD (THR-β-LBD) by binding to the GST tag, and Streptavidin-XL665 is labeled with SRC3-2 coactivator peptide by binding to the biotin tag. The binding of the agonist to THR-α-LBD (THR-β-LBD) causes the conformation of THR-α-LBD (THR-β-LBD) to change, thereby increasing the recruitment ability of SRC3-2 coactivator peptide. At the same time, the distance between XL665-labeled SRC3-2 and Eu-anti-GST antibody caused by this decreases, increasing the THRFRET signal. The agonist ability of this target is evaluated by the effect of the compound on the activity of THR-α-LBD (THR-β-LBD) at different concentrations.

[0232] Test method:

[0233] THR-β testing process:

[0234] (1) Prepare 1× reaction solution.

[0235] (2) Compound preparation: The compound test concentration is 20 μM, 3-fold dilution, 10 concentrations, and each concentration is set up for duplicate well testing. The test concentration is 20 μM, 3-fold dilution, 10 concentrations, and each concentration is set up for duplicate well testing. Dilute the solution to the corresponding 100-fold final concentration in the 384-well Source plate, and then transfer 200 nL to the 384-well reaction plate for testing using Echo550. Transfer 200 nL of 100% DMSO and test sample to the Min and Max wells, respectively.

[0236] (3) Use 1× reaction solution to prepare 2× protein solution.

[0237] (4) Use 1× reaction solution to prepare 4× SRC3-2 solution.

[0238] (5) Use 1× reaction solution to prepare 4× GST-Eu cryptate and XL665 mixed solution.

[0239] (6) Add 10 μL of 2× protein solution to each well of the reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 30 min.

[0240] (7) Add 5 μL of 4×SRC3-2 solution to each well of the reaction plate and centrifuge at 1000 rpm for 1 min.

[0241] (8) Add 5 μL of 4×GST-Eu cryptate and XL665 solution to each well of the reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C.

[0242] (9) Use EnVision to read the fluorescence signal.

[0243] The THR-α test process is the same as above.

[0244] Among them, compound X is Example 9 in WO2020123827A1 (compound number 9, clinical research code TERN-501), and the preparation method is shown in Example 1, that is, intermediate 1-5.

[0245] The test results are shown in Table 3:

[0246] Table 3: Agonistic activity of the compounds of the present invention on THRβ and THRα

[0247] Example Compound No. <![CDATA[THR-β(EC 50 ,nM)]]> <![CDATA[THR-α(EC 50 ,nM)]]> 1 11 >5000 3 45 >5000 5 40 >5000 6 6.5 >5000 8 33 >5000 9 12 >5000 X(TERN-501) 139 1288 Resmetirom 243 2780

[0248] The above data show that compounds 1, 3, 5, 6, 8, and 9 of the present invention have good agonistic effects on THR-β, and their agonistic activity on THR-β is significantly better than that of Resmetirom and compound X (TERN-501); on the other hand, compounds 1, 3, 5, and 6 have weak agonistic activity on THR-α, and almost no agonistic activity, indicating that compounds 1, 3, 5, 6, 8, and 9 have selective agonistic effects on THR-β and have excellent potential safety.

[0249] 2. Compound B-DIO efficacy test in NASH mouse model

[0250] Purpose:

[0251] The purpose of this experiment was to evaluate the pharmacodynamics of the compounds of the present invention using the NASH model of B-DIO mice.

[0252] The experimental consumables are shown in Table 4:

[0253] Table 4: Name of instruments used

[0254] Reagent / Instrument Name factory Model / Article No. Storage conditions TC Nanjing Jiancheng Bioengineering Institute A111-1-1 2-8℃ TG Nanjing Jiancheng Bioengineering Institute A110-1-1 2-8℃ ALT Nanjing Jiancheng Bioengineering Institute C009-2-1 2-8℃ AST Nanjing Jiancheng Bioengineering Institute C010-2-1 2-8℃ Balance Ningbo Jiming Weighing Equipment Co., Ltd. JM-B10002 Room temperature High-speed centrifuge GENE 1524 Room temperature High-throughput tissue grinder Ningbo Xinzhi Biotechnology Co., Ltd. EI-A-240 Room temperature Multifunctional ELISA reader GENE ELX800 Room temperature

[0255] The experimental animals are shown in Table 5 and Table 6:

[0256] Table 5: Normal experimental animal information

[0257] Species Mus musculus strain C57BL / 6 name C57BL / 6 gender male weight About 30g Age 30 weeks quantity The number of participants is 5 Laboratory Animal Providers Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0258] Table 6: NASH model animal information

[0259] Species Mus musculus strain C57BL / 6 name B-DIO mice gender male weight About 30g Age 30 weeks (28 weeks for high-fat diet induction) quantity The number of participants is 25 Laboratory Animal Providers Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0260] Experimental methods:

[0261] Five C57BL / 6 mice fed a normal diet were assigned to the G1 experimental group (normal group), and 25 B-DIO mice induced by a high-fat diet were randomly assigned to five experimental groups (HFD groups) from G2 to G6 according to their body weight, with five mice in each group. The experimental grouping is shown in Table 7 below:

[0262] Table 7: Experimental animal grouping

[0263]

[0264]

[0265] Dosing started on Day 0. Body weight was measured twice a week after grouping. At the end of the experiment (Day 28), mice were fasted for 4 hours, non-anticoagulated blood was collected from mice in groups G1-G6, and serum was obtained by centrifugation for blood biochemical detection; livers from groups G1-G6 were collected and weighed, and 20 mg was weighed for TC and TG determination.

[0266] Results and Analysis:

[0267] During the study, no abnormal death or obvious clinical symptoms were observed in animals. On Day 28, the average body weight of the G2 model group was significantly higher than that of the G1 solvent control group; compared with the G2 model group, the body weight of the other drug-treated groups did not change significantly. Figure 1 .

[0268] On Day 28, compared with the G1 solvent control, the serum AST and TG values ​​of the G2 model control group were significantly increased, and compared with the G2 model group, the above indicators of the mice in the G3-G6 drug administration groups were significantly reduced. The experimental results are as follows Figure 2 shown.

[0269] On Day 28, compared with the G1 solvent control, the values ​​of TC and TG in the liver of the G2 model control group were significantly increased. Compared with the G2 model group, the above indicators in the G3-G6 administration groups were significantly reduced. The experimental results are as follows: Figure 3 shown.

[0270] Experimental conclusion:

[0271] In this experiment, a high-fat diet-induced NASH model of C57 mice was used. During the experiment, Resmetirom (G3), Compound X (G4) and Compound 1 (G5-G6) were able to improve the abnormal blood lipids and liver lipids of mice caused by modeling, which was manifested in the ability to significantly reduce serum TG, liver TC and TG. Under the same experimental conditions, Compound 1 (G5-G6) showed better effects on reducing liver total cholesterol and liver triglycerides than Resmetirom (G3) and Compound X (G4).

[0272] The above description is only a specific embodiment of the present invention, so that those skilled in the art can understand or implement the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments described herein, but should conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A compound as shown in formula I or its stereoisomers, tautomers, and pharmaceutically acceptable salts, in, X is hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, substituted silicon, alkenyl or alkynyl, wherein the alkyl, aryl and heteroaryl are independently and optionally substituted by one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl, C3-C6 cycloalkyl, C2-C8 alkynyl, C2-C8 alkenyl; Y is a nitrogen atom, an oxygen atom or a sulfur atom; Z is a nitrogen atom, an oxygen atom, a sulfur atom or a carbon atom; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl or alkynyl; Ring A is a substituted or unsubstituted aromatic ring, heteroaromatic ring, heterocyclic ring, or 4- to 8-membered carbon ring.

2. The compound according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: X is hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl or C2-C8 alkynyl; the C1-C6 alkyl, the C6-C10 aryl and the C4-C9 heteroaryl are independently and optionally substituted with one or more substituents selected from the following: halogen, hydroxyl, methoxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; Optionally, X is hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl; wherein the C1-C6 alkyl is substituted by one or more substituents selected from the following: halogen, hydroxyl, methoxy, amino, cyano, trifluoromethyl; Optionally, X is hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkenyl or C2-C8 alkynyl; the C1-C6 alkyl is substituted by one or more substituents selected from the following: halogen, methoxy; Alternatively, X is hydrogen, deuterium, halogen, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, vinyl or ethynyl; Optionally, X is hydrogen, deuterium, fluorine, bromine or chlorine.

3. The compound according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: Y is an oxygen atom or a sulfur atom; Optionally, Y is an oxygen atom; Optionally, Z is an oxygen atom or a carbon atom; Optionally, Z is an oxygen atom.

4. The compound according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkane substituted with mono- or poly-halogen, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl; Optionally, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, monohalogen or polyhalogen substituted C1-C6 alkane, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; Optionally, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or deuterated C1-C6 alkyl.

5. The compound according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R 2 , R 3 , R 6 Each is independently halogen, C1-C6 alkyl, monohalogen or polyhalogen substituted C1-C6 alkyl; Optionally, R 2 , R 3 , R 6 Each is independently halogen, methyl, ethyl, propyl, monohalogen- or polyhalogen-substituted methyl, monohalogen- or polyhalogen-substituted ethyl, monohalogen- or polyhalogen-substituted propyl; Optionally, R 2 , R 3 , R 6 are each independently fluorine, chlorine, or bromine; Optionally, R 1 , R 4 , R 5 , R 7 Each is independently hydrogen, deuterium, or C1-C6 alkyl; Optionally, R 1 , R 4 , R 5 , R 7 are each independently hydrogen, deuterium, methyl, ethyl or propyl; Optionally, R 1 , R 4 , R 5 , R 7 are each independently hydrogen or deuterium.

6. The compound according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: Ring A is a substituted or unsubstituted C6-C10 aromatic ring, C4-C9 heteroaromatic ring, C4-C9 heterocycle, or C4-C8 carbocycle; the substituted substituent is selected from halogen, cyano, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, monohalogen or polyhalogen substituted C1-C6 alkyl, deuterated C1-C6 alkyl; Optionally, Ring A is a substituted or unsubstituted C6-C10 aromatic ring; the substituted substituent is selected from halogen, cyano, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, monohalogen or polyhalogen substituted C1-C6 alkyl, deuterated C1-C6 alkyl; Optionally, ring A is a substituted or unsubstituted benzene ring; the substituted substituent is selected from halogen, cyano, methyl, ethyl, propyl, ethynyl, trifluoromethyl, trideuteriomethyl.

7. A compound as shown in formula II or its stereoisomers, tautomers, and pharmaceutically acceptable salts, in, X is hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; wherein the alkyl, aryl and heteroaryl are independently and optionally substituted by one or more substituents selected from the following: C1-C6 alkyl, halogen, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, trifluoromethyl, C3-C6 cycloalkyl, C2-C8 alkynyl, C2-C8 alkenyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, cyano, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl.

8. The compound according to claim 7 or its stereoisomer, tautomer, pharmaceutically acceptable salt, characterized in that: X is hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl; wherein the C1-C6 alkyl, the C6-C10 aryl, the C4-C9 heteroaryl are independently and optionally substituted with one or more substituents selected from the following: halogen, hydroxyl, methoxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; Optionally, X is hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; wherein the C1-C6 alkyl is substituted by one or more substituents selected from the following: halogen, hydroxyl, methoxy, amino, cyano, trifluoromethyl; Optionally, X is hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C8 alkenyl or C2-C8 alkynyl; the C1-C6 alkyl is substituted by one or more substituents selected from the following: halogen, methoxy; Alternatively, X is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, vinyl or ethynyl; Optionally, X is hydrogen, deuterium, fluorine, chlorine, or bromine.

9. The compound according to claim 7 or its stereoisomer, tautomer, pharmaceutically acceptable salt, characterized in that: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkane substituted with mono- or poly-halogen, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl, C2-C8 alkynyl; Optionally, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, monohalogen or polyhalogen substituted C1-C6 alkane, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; Optionally, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, or C2-C8 alkynyl.

10. The compound according to claim 7 or its stereoisomer, tautomer, pharmaceutically acceptable salt, characterized in that: R 2 , R 3 , R 6 Each is independently halogen, C1-C6 alkyl, monohalogen or polyhalogen substituted C1-C6 alkyl; Optionally, R 2 , R 3 , R 6 Each is independently halogen, methyl, ethyl, propyl, monohalogen- or polyhalogen-substituted methyl, monohalogen- or polyhalogen-substituted ethyl, monohalogen- or polyhalogen-substituted propyl; Optionally, R 2 , R 3 , R 6 are each independently fluorine, chlorine, or bromine; Optionally, R 1 , R 4 , R 5 , R 7 Each is independently hydrogen, deuterium, or C1-C6 alkyl; Optionally, R 1 , R 4 , R 5 , R 7 are each independently hydrogen, deuterium, methyl, ethyl or propyl; Optionally, R 1 , R 4 , R 5 , R 7 each independently is hydrogen or deuterium; Optionally, R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, cyano, C1-C3 alkyl, deuterated C1-C3 alkyl, monohalogen or polyhalogen substituted C1-C3 alkane, C2-C4 alkenyl, C2-C4 alkynyl; Optionally, R A1 , R A2 is hydrogen; Optionally, R A3 , R A4 Each is independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, trideuterium, or ethynyl.

11. A compound of formula III or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in, X is hydrogen, deuterium, fluorine, chlorine, bromine, alkenyl, or alkynyl; R 2 , R 3 , R 7 , R A1 , R A2 , R A3 and R A4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, cyano, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl.

12. The compound according to claim 11 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: X is hydrogen, deuterium, fluorine, chlorine, bromine, C2-C8 alkenyl or C2-C8 alkynyl; R 2 , R 3 , R 7 , R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, sulfone, phosphorus carbonyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkane substituted with mono- or poly-halogen, C3-C8 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, C2-C8 alkenyl or C2-C8 alkynyl.

13. The compound according to claim 11 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: X is hydrogen, deuterium, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, vinyl or ethynyl; Optionally, X is hydrogen, deuterium, fluorine, chlorine, or bromine; Optionally, R 2 , R 3 , R 7 Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, monohalogen or polyhalogen substituted C1-C6 alkyl; Optionally, R 2 , R 3 , R 7 Each is independently hydrogen, deuterium, halogen, methyl, ethyl, propyl, mono- or poly-halogen-substituted methyl, mono- or poly-halogen-substituted ethyl, mono- or poly-halogen-substituted propyl; Optionally, R 2 , R 3 , R 7 are each independently hydrogen, deuterium, fluorine, chlorine, or bromine; Optionally, R 2 , R 3 are each independently fluorine, chlorine, or bromine; Optionally, R A1 , R A2 , R A3 , R A4 Each is independently hydrogen, deuterium, halogen, cyano, C1-C3 alkyl, deuterated C1-C3 alkyl, monohalogen or polyhalogen substituted C1-C3 alkane, C2-C4 alkenyl, C2-C4 alkynyl; Optionally, R A1 , R A2 is hydrogen; Optionally, R A3 , R A4 Each is independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, trideuterium, or ethynyl.

14. A compound represented by the following structural formula or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

15. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 14 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. Use of the compound according to any one of claims 1 to 14 or its stereoisomer, tautomer or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 15 for preparing a thyroid hormone receptor agonist.

17. Use of the compound according to any one of claims 1 to 14 or its stereoisomer, tautomer or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating metabolic diseases; the metabolic diseases are thyroid hormone receptor-related diseases; Preferably, the metabolic disease includes obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis, cardiovascular disease, hypothyroidism and thyroid cancer; preferably, the cardiovascular disease includes atherosclerosis.

18. A thyroid hormone receptor agonist, which is the compound according to any one of claims 1 to 14 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

19. A method for preparing the compound according to any one of claims 1 to 6, characterized in that: The process comprises the following reaction steps: The compound represented by SM-1 is subjected to cyanohydrolysis reaction to obtain compound IM-1, the IM-1 compound is subjected to esterification reaction to obtain compound IM-2, the IM-2 compound is subjected to reduction reaction to obtain compound IM-3, and the IM-3 compound is subjected to functional group conversion reaction to obtain compound I; Among them, ring A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 Definition as in claim 1.

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