CN111484481A

CN111484481A - Pyridazinone derivative, preparation method and medical application thereof

Info

Publication number: CN111484481A
Application number: CN201910075437.4A
Authority: CN
Inventors: 郑苏欣; 王中利; 赵雯雯
Original assignee: Chaluesheng Pharmaceutical Technology Shanghai Co ltd
Current assignee: Chaluesheng Pharmaceutical Technology Shanghai Co ltd
Priority date: 2019-01-26
Filing date: 2019-01-26
Publication date: 2020-08-04

Abstract

The invention relates to pyridazinone derivatives, a preparation method thereof and application thereof in medicines. Specifically, the invention relates to a pyridazinone derivative shown as a general formula (I), a preparation method thereof, a pharmaceutically acceptable salt thereof and application thereof as a therapeutic agent, in particular to a thyroid hormone receptor agonist, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Pyridazinone derivative, preparation method and medical application thereof

Technical Field

The invention relates to a preparation method of pyridazinone derivatives, a pharmaceutical composition containing the pyridazinone derivatives and application of the pyridazinone derivatives as a therapeutic agent, in particular to the treatment of metabolic diseases such as obesity, non-alcoholic fatty liver disease, hypercholesterolemia, hyperlipidemia, diabetes, cardiovascular diseases, hypothyroidism, thyroid cancer and related diseases and diseases.

Background

Thyroid Hormones (TH) are thyroid stimulating hormones secreted in response to the pituitary and play key roles in growth, development, metabolism and homeostasis.they are produced by the thyroid gland as thyroxine (T4) and 3,5,3' -triiodo-L-thyronine (T3). thyroid hormones are iodinated tyrosine analogs that are secreted into the circulation primarily in the form of T4. T4 is the major secretory form in humans and is enzymatically deiodinated to the more active form T3 in peripheral tissues by deiodinase, T3 is the strongest thyroid hormone.t 3 plays an important role in normal development, differentiation and maintenance of metabolic balance, control of cholesterol levels by interacting with Thyroid Hormone Receptors (THR).

THR is expressed in most tissues, there are two distinct isoforms THR α and THR β evaluation of patients with thyroid hormone Resistance (RTH) syndrome has established THR β as the predominant isoform in the heart and regulating most heart function, while the THR β isoform predominates in the liver and pituitary and regulates cholesterol metabolism and production of thyroid stimulating hormones, respectively T3 maintains weight, metabolic rate, body temperature, mood and regulates serum cholesterol at normal levels, hypothyroidism is associated with weight gain, high levels of low density lipoprotein (β D β) cholesterol and associated with hyperthyroidism leads to weight loss, hypermetabolism, reduced serum β D β levels, arrhythmia, heart failure, muscle weakness, loss of bone and anxiety, native thyroid hormone T3 shows no selective effect on the binding of the two THR isoforms (THR α and THR β) in animal models, thus, T3 and T358 administration of a patient has no effect on reducing cholesterol, bone loss and bone formation in animals, reducing effects of cholesterol, reducing blood lipid levels, reducing side effects of blood lipid levels, reducing blood lipid levels, treating liver cancer, and liver cancer (THR 4642), and reducing side effects of liver cancer, such as a selective effect of treating liver cancer, and side effects of cardiovascular diseases (THR 4642) in liver cancer, and cardiovascular side effects of treating liver cancer, such as well as liver cancer, and side effects of liver cancer (L) on liver cancer, and side effects of liver cancer, including the same on liver cancer, and side effects of treating liver cancer, and side effects of liver cancer, including selective treatment of liver cancer, etc. on liver cancer, and side effects of liver cancer, which are not including hypertension of liver cancer, and side effects of kidney deficiency, and liver cancer, and side effects of chemotherapy of kidney deficiency, such as a liver cancer, and kidney.

Currently, a variety of compounds have been disclosed as possible agonists of THR β, including WO0039077, WO2004067482, US6344481, US6787652, US20070173548, WO2006128058, WO2007009913, WO20080221210, WO2009089093, WO2009037172, etc., but the compounds disclosed in these prior arts as well as the experimental drugs still have problems in terms of effectiveness, safety or selectivity, etc., and there is still a need to study and develop new small molecule selective THR β agonists.

Disclosure of Invention

The inventors have unexpectedly found through experimental studies that compounds of the following formula (I) are effective as THR β agonists.

Wherein:

l is selected from-CH₂-、-O-、-CF₂(ii) a preferably-O-;

R¹selected from 3-4 membered cycloalkyl, wherein said cycloalkyl is optionally further substituted with one or more substituentsSubstituted with a substituent selected from hydroxy, halo, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or ═ O;

R²selected from the group consisting of hydrogen, halogen, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen or alkoxy; r²Preferably a hydrogen atom;

R³selected from hydrogen atoms or alkyl groups, wherein said alkyl groups are optionally further substituted by one or more substituents selected from hydroxy, halogen or alkoxy; r³Preferably a hydrogen atom;

or, R¹And R²Together with the carbon atoms to which they are attached form a 4-10 membered cycloalkyl group or a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group contains one or more of N, O, S or S (O)_mAnd cycloalkyl or heterocyclyl is optionally further substituted by one or more R^cSubstituted;

R^cselected from alkyl, hydroxy, halogen, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R⁶、-OC(O)R⁶、-NR⁷R⁸、-C(O)NR⁷R⁸、-NR⁷C(O)R⁸or-S (O)_mNR⁷R⁸Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy, halogen or alkoxy;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, hydroxy, alkyl, halo, and alkoxy, wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, and alkoxy; r⁴And R⁵Preferably selected from F, Cl, Br or methyl;

R⁶、R⁷and R⁸Each independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl isOptionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R⁹、-OC(O)R⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹、-NR¹⁰C(O)R¹¹or-S (O)_mNR¹⁰R¹¹Substituted with the substituent(s);

or, R⁷And R⁸Together with the N atom to which they are attached form a 4-8 membered heterocyclic group containing one or more of N, O, S or S (O)_mAnd optionally further substituted on the 4-to 8-membered heterocycle with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R⁹、-OC(O)R⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹、-NR¹⁰C(O)R¹¹or-S (O)_mNR¹⁰R¹¹Substituted with the substituent(s);

R⁹、R¹⁰and R¹¹Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;

m is selected from 1 or 2.

Preferably, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein:

R^aselected from hydrogen atoms or alkyl groups, preferably hydrogen atoms or methyl groups;

R^bis selected fromHydroxy, halo, cyano, alkyl, alkoxy or ═ O, wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halo, hydroxy or alkoxy;

n is selected from 0 or 1;

p is selected from 0, 1,2, 3 or 4;

L，R²～R⁵the definition of (A) is described in the general formula (I).

Preferably, the compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein:

the ring A is selected from 4-10 membered cycloalkyl or 4-10 heterocyclic group; preferably 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclic group, 7-10 membered spirocycloalkyl or 7-10 membered spiroheterocyclic group;

R^cselected from alkyl, hydroxy, halogen, cyano or alkoxy, wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy or alkoxy;

q is selected from 0, 1,2, 3 or 4;

L，R³～R⁵the definition of (A) is described in the general formula (I).

Preferably, the compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein:

R^cselected from alkyl, hydroxy, halogen, cyano or alkoxy, wherein said alkyl or alkoxy is optionally further substituted by oneOr substituted by a plurality of substituents selected from halogen, hydroxyl or alkoxy;

r is selected from 0, 1 or 2;

s is selected from 0, 1 or 2;

r and s are not 0 at the same time;

q is selected from 0, 1,2, 3 or 4;

L，R³～R⁸the definition of (A) is described in the general formula (I).

Typical compounds of the invention include, but are not limited to:

the above typical compounds include stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

The present invention provides a process for the preparation of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which process comprises:

reacting a compound of formula (IA) with a compound of formula (IB) in the presence of concentrated hydrochloric acid and nitrite under basic conditions to give a compound of formula (IC);

carrying out condensation reaction on the compound with the general formula (IC) to obtain a compound with a general formula (I);

wherein:

R^dselected from alkyl groups;

L，R¹～R⁵the definition of (A) is described in the general formula (I).

A compound of formula (IA) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

wherein L, R¹～R⁵The definition of (A) is shown in the general formula (I).

Typical compounds of formula (IA) include, but are not limited to:

The invention provides a pharmaceutical composition, which comprises an effective dose of a compound shown in a general formula (I), (II), (III) or (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, an excipient or a combination of the pharmaceutically acceptable carrier and the excipient.

The invention provides an application of a compound shown in a general formula (I), (II), (III) or (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament of a thyroid hormone receptor stimulant.

The invention provides application of a compound shown in a general formula (I), (II), (III) or (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating diseases related to thyroid hormone disorder, wherein the diseases are preferably metabolic diseases, atherosclerosis, cardiovascular diseases, hypothyroidism or thyroid cancer, and the metabolic diseases are preferably obesity, hyperlipidemia, hypercholesterolemia, diabetes or nonalcoholic fatty liver disease.

The invention provides application of a compound shown in a general formula (I), (II), (III) or (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating metabolic diseases, atherosclerosis, cardiovascular diseases, hypothyroidism or thyroid cancer, wherein the metabolic diseases are preferably obesity, hyperlipidemia, hypercholesterolemia, diabetes or nonalcoholic fatty liver disease.

Detailed description of the invention

Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:

"alkyl" refers to a saturated aliphatic hydrocarbon group comprising a saturated straight or branched chain monovalent hydrocarbon group of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, wherein the alkyl group may independently be optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be optionally substituted or unsubstituted.

"alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one C-C is sp²Double bonds, wherein the alkenyl groups may independently be optionally substituted with 1 or more substituents described herein, specific examples of which include, but are not limited to, vinyl, allyl, and alkenyl butyl, and the like. The alkenyl group may be optionally substituted or unsubstituted.

"alkynyl" refers to a monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, straight or branched, wherein at least one C-C is a sp triple bond, wherein the alkynyl group may independently be optionally substituted with one or more substituents described herein, specific examples including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. The alkynyl group may be optionally substituted or unsubstituted.

"cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be optionally substituted or unsubstituted.

"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures with single rings sharing a single carbon atom (called the spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spiro, di-spiro, or multi-spiro cycloalkyl groups, preferably mono-spiro and di-spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to:

"fused cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of "fused ring alkyl" include, but are not limited to:

"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclyl groups containing 3 to 12 ring atoms in which at least one ring atom is a heteroatom such as oxygen, nitrogen, sulfur, and the like. Preferably having a 5 to 7 membered monocyclic ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl. The heterocyclic group may be optionally substituted or unsubstituted.

"Spiroheterocyclyl" refers to 5 to 18 membered, two or more cyclic structures with a single ring between themPolycyclic radicals which share an atom with one another and contain 1 or more double bonds in the ring, but no ring has a completely conjugated pi-electron aromatic system, in which one or more ring atoms are selected from nitrogen, oxygen, sulfur or S (O)_mThe remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to:

"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more ring structures which share a pair of atoms with each other, one or more of which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur, or S (O)_mThe remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to:

"bridged heterocyclyl" means a 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S (O)_mThe remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. According to a groupThe number of ring formation may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to:

"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably aryl is C₆-C₁₀Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to:

"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 9-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, and benzisoxazolyl. Heteroaryl groups may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples include, but are not limited to:

"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C₁-C₆Alkoxy groups of (4) are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"haloalkyl" refers to an alkyl group having one or more halo substituents, wherein the alkyl group has the meaning as described herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1-dichloroethyl, 1, 2-dichloropropyl, and the like.

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

"amino" means-NH₂。

"cyano" means-CN.

"nitro" means-NO₂。

"benzyl" means-CH₂-phenyl.

"carboxy" refers to-C (O) OH.

"acetyl" means-C (O) CH₃Or Ac.

"carboxylate" refers to-C (O) O (alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

As used herein, "substituted" or "substituted", unless otherwise specified, refers to the groupThe groups may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, ═ O, -c (O) R⁶、-OC(O)R⁶、-NR⁷R⁸、-C(O)NR⁷R⁸、-NR⁷C(O)R⁸or-S (O)_mNR⁷R⁸Wherein, m, R⁶、R⁷And R⁸The definition of (A) is described in the general formula (I).

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents:

the Compounds of the present invention may contain asymmetric or chiral centers and thus different stereoisomers, all stereoisomeric forms of the Compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, which form part of the present invention, diastereomers may be separated into individual diastereomers on the basis of their physical Chemical differences, by chromatographic, crystallographic, distillative or sublimatic methods, enantiomers may be separated, such that mixtures of enantiomers are converted into diastereomeric mixtures, which are, for example, mixtures of diastereomers, chiral mixtures, which are, for example, optically active Compounds (e.g., racemic mixtures, chiral mixtures, or mixtures of enantiomers), which are, for example, mixtures of diastereomers which are, optically active Compounds (e.g., chiral mixtures of enantiomers, chiral Compounds which are, for example, racemic mixtures of enantiomers, chiral Compounds, chiral mixtures of enantiomers, racemic mixtures, mixtures of enantiomers, chiral mixtures of enantiomers, mixtures of enantiomers, chiral Compounds, mixtures of enantiomers, chiral Compounds, mixtures of enantiomers, chiral Compounds, mixtures of enantiomers, chiral Compounds.

"tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons. Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are intended to be within the scope of the present invention.

Synthesis of the Compounds of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

the invention relates to a preparation method of a compound shown in a general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which comprises the following steps:

under the ice bath condition, the compound of the general formula (IA) reacts with the compound of the general formula (IB) in the presence of concentrated hydrochloric acid and nitrite under the alkaline condition to obtain a compound of the general formula (IC); carrying out condensation reaction on the compound of the general formula (IC) in the presence of acetate and acetic acid to obtain a compound of a general formula (I);

wherein:

R^dselected from alkyl groups;

L，R¹～R⁵the definition of (A) is described in the general formula (I).

In the above preparation method, the basic condition is provided by an organic base or an inorganic base, the organic base is selected from diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine and 4-dimethylaminopyridine, and pyridine is preferred; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and potassium hydride.

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Examples

The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention.¹The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.¹Method for H NMR expression: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.

Mass spectra were obtained using an L C/MS instrument with ionization modes of ESI or APCI.

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by the thin layer chromatography (T L C) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification, unless otherwise indicated, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Sciadopsis Tech, and the like.

CD₃OD: deuterated methanol

CDCl₃: deuterated chloroform

DMSO-d₆: deuterated dimethyl sulfoxide

The argon atmosphere means that the reaction flask is connected with an argon balloon of about 1L volume.

In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.

Purifying the compound by silica gel column chromatography and thin layer chromatography, wherein the eluent or developing agent system is selected from: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.

Example 1

2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

2- (3, 5-dichloro-4- ((5-cyclopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 1

First step of

3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)aniline

3, 5-dichloro-4- ((6-chloro-5-cyclopropylpyridazin-3-yl) oxy) aniline 1b

3, 6-dichloro-4-cyclopropylpyridazine 1a (6.44g,34mmol, prepared as disclosed in patent application "WO 2013045519"), 2, 5-dichloro-4-aminophenol (6.13g,34mmol) and cesium carbonate (11.22g,34mmol) were added to 130m L N, N-diethylacetamide and the reaction was warmed to 90 ℃ for 16 hours, the reaction was cooled to room temperature, 400m L water was added, extraction was performed with ethyl acetate (200m L× 3), washing was performed with a saturated sodium chloride solution (250m L), drying was performed with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to give the title product 3, 5-dichloro-4- ((6-chloro-5-cyclopropylpyridazin-3-yl) oxy) aniline 1b (4.39g, grey solid) in 38.6% yield.

MS m/z(ESI):331.9[M+1]

Second step of

6-(4-amino-2,6-dichlorophenoxy)-4-cyclopropylpyridazin-3-yl acetate

6- (4-amino-2, 6-dichlorophenoxy) -4-cyclopropylpyridazin-3-ylacetic acid ester 1c

3, 5-dichloro-4- ((6-chloro-5-cyclopropylpyridazin-3-yl) oxy) aniline 1b (4.39g,14mmol) and sodium acetate (3.84g,28mmol) were added to 45M L acetic acid, the reaction mixture was warmed to 90 ℃ and reacted for 16 hours, the reaction mixture was cooled to room temperature, a 2N sodium hydroxide solution was added to adjust the pH to 8, extraction was performed with ethyl acetate (50M L× 3), washing was performed with a saturated sodium chloride solution (50M L), drying was performed with anhydrous sodium sulfate, filtration was performed, concentration was performed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to give the title product 6- (4-amino-2, 6-dichlorophenoxy) -4-cyclopropylpyridazin-3-yl acetate 1c (3g, yellow solid) in 63% yield MS M/z (ESI) 355.1[ M +1]

The third step

6-(4-amino-2,6-dichlorophenoxy)-4-cyclopropylpyridazin-3(2H)-one

6- (4-amino-2, 6-dichlorophenoxy) -4-cyclopropylpyridazin-3 (2H) -one 1d

6- (4-amino-2, 6-dichlorophenoxy) -4-cyclopropylpyridazin-3-ylacetic acid ester 1c (1g,2.8mmol) was added to 10m L of methanol, 5m L10% sodium hydroxide solution was added, reaction was carried out at room temperature for 16 hours, methanol was dried, 30m L of water was added, extraction was carried out with ethyl acetate (20m L× 3), washing was carried out with saturated sodium chloride solution (20m L), drying was carried out over anhydrous sodium sulfate, filtration and concentration under reduced pressure were carried out, and the residue was recrystallized from ethyl acetate to give the title product 6- (4-amino-2, 6-dichlorophenoxy) -4-cyclopropylpyridazin-3 (2H) -one 1d (469mg, pale yellow solid) in 53% yield.

MS m/z(ESI)：313[M+1]

The fourth step

ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate

(E) - (2-cyano-2- (2- (3, 5-dichloro-4- ((5-cyclopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) hydrazinylidene) acetyl) carbamic acid ethyl ester 1e

6- (4-amino-2, 6-dichlorophenoxy) -4-cyclopropylpyridazin-3 (2H) -one 1d (500mg,1.6mmol) was added to 10m L concentrated hydrochloric acid, the temperature was lowered to-5 ℃ and sodium nitrite (144mg,2.1mmol) was added, and stirring was carried out at low temperature for 30 minutes to obtain solution A, (2-cyanoacetyl) carbamic acid ethyl ester (263mg,1.6mmol) was added to 10m L pyridine, the temperature was lowered to-5 ℃ and solution A was slowly dropped at a temperature of not more than 0 ℃ after completion of the dropwise addition reaction at-5 ℃ for 30 minutes, the reaction solution was filtered, a solid was collected and purified by silica gel column chromatography (eluent: A system) to obtain the title product (E) - (2-cyano-2- (2- (3, 5-dichloro-4- ((5-cyclopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) hydrazinoylidene) acetyl) carbamic acid ethyl ester 1E (236mg, pale yellow solid, in a yield of 30.7%.

MS m/z(ESI)：480.1[M+1]

The fifth step

Ethyl (E) - (2-cyano-2- (2- (3, 5-dichloro-4- ((5-cyclopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) hydrazinylidene) acetyl) carbamate 1E (236mg,0.48mmol), sodium acetate (338mg,2.4mmol) were added to 15m L acetic acid and the reaction was allowed to warm to 120 ℃ for 2 hours the reaction was cooled to room temperature, 40m L water was added, extracted with ethyl acetate (40m L× 2), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (40m L), saturated sodium chloride solution (20m L), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give the title product 2- (3, 5-dichloro-4- ((5-cyclopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine (1, 6-triazine) as a pale yellow solid in yield (63 mg, 230-triazine).

MS m/z(ESI):434.3[M+1]

¹H NMR(400MHz,DMSO)12.17(s,1H),7.68(s,2H),7.50(s,1H),3.70-3.46(m,1H),2.19-2.08(m,2H),2.06-1.94(m,2H)

Example 2

2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2

2- (3, 5-dichloro-4- ((5-cyclobutyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 2

Using the synthetic route of example 1, starting material 1a was replaced with starting material 2a to give the title product 2- (3, 5-dichloro-4- ((5-cyclobutyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 2(20mg, orange solid).

MS(m/z):447(M+H)

¹H NMR(400MHz,DMSO)12.19(s,1H),7.78(s,2H),7.50(s,1H),3.70-3.46(m,1H),2.27(ddd,J＝16.7,11.3,5.6Hz,1H),2.19-2.08(m,1H),2.06-1.94(m,1H),1.82(dd,J＝18.3,9.0Hz,1H)

Example 3

2-(3,5-dichloro-4-((1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 3

2- (3, 5-dichloro-4- ((1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ d ] pyridazin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 3

Using the synthetic route of example 1, substituting starting material 1a for starting material 3a, the title product, 2- (3, 5-dichloro-4- ((1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ d ] pyridazin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 3(8mg, white solid) was obtained.

MS m/z(ESI):435[M+H]

¹H NMR(400MHz,DMSO)13.19(br,1H),12.05(s,1H),7.68(s,2H),3.08-2.79(m,2H),2.41-2.39(m,2H),1.76-1.37(m,2H)

Example 4

2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

2- (3, 5-dichloro-4- ((7-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ d ] pyridazin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 4

First step of

1,4-dichloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyridazine

1, 4-dichloro-5-methyl-6, 7-dihydro-5H-cyclopenta [ d ] pyridazine 4b

Trimethyl ((5-methylcyclopent-1-en-1-yl) oxy) silane 4a (10g,58.8mmol), 3, 6-dichloro-1, 2,4, 5-tetrazine (10.5g, 70.5mmol) was dissolved in 100m L toluene, heated to 120 ℃, reacted for 2 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A) to give the title product 1, 4-dichloro-5-methyl-6, 7-dihydro-5H-cyclopenta [ d ] pyridazine 4b (4.6g, red solid) in 54.3% yield.

MS m/z(ESI):203.0[M+1]

The second to the sixth step

Using the synthetic route of example 1, substituting starting material 1a for starting material 4b, the title product, 2- (3, 5-dichloro-4- ((7-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ d ] pyridazin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 4(78mg, white solid) was obtained.

MS m/z(ESI):447.0[M+1]

¹H NMR(400MHz,DMSO)13.29(br,1H),12.11(s,1H),7.78(s,2H),3.07-2.89(m,2H),2.41-2.36(m,1H),1.76-1.71(m,1H),1.37(d,J＝7.2Hz,1H),1.25(t,J＝7.2Hz,3H)

Example 5

(R)-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5

(R) -2- (3, 5-dichloro-4- ((7-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ d ] pyridazin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 5

(S)-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 6

(S) -2- (3, 5-dichloro-4- ((7-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ d ] pyridazin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 6

2- (3, 5-dichloro-4- ((7-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ d ] pyridazin-4-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 4(78mg,0.17mmol) was further resolved by high performance liquid preparative chromatography and chiral column using Supercritical Fluid Chromatography (SFC) to give (R) -2- (3, 5-dichloro-4- ((7-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ d ] pyridazin-4-yl) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-carbonitrile (78mg,0.17mmol) using a high performance liquid preparative chromatography and a chiral column.

5MS m/z(ESI):447.0[M+1]

6MS m/z(ESI):447.0[M+1]

Biological evaluation

Test example 1THR β in vitro enzyme Activity test

1. Experimental Material

Name of reagent	Concentration of	Suppliers of goods	Goods number
				H6-THR-β	6.3mg/ml(221μM)	viva
RXRa	3mg/ml(115μM)	viva
				Bio-GRIP1	0.2mM	GL Biochem	673025
EU-anti-6his AB	500μg/ml(3.125μM)	PerkinElmer	AD0110
				APC-streptavidin	1mg/ml	PerkinElmer	AD0201
T3	5mM	Sigma	T2877

2 experiment buffer solution

2.1 protein binding buffer

50mM Hepes PH7.0
	1mM DTT
0.05％NP-40
	0.2mg/mL BSA

2.2 detection buffer

50mM Tris PH7.4
	100mM Nacl
0.2mg/mL BSA

3 course of the experiment

(1) Compound was diluted in DMSO at 3X gradient with 10mM maximum concentration, 10 dilutions, and DMSO group was set as negative control;

(2)1: 100 dilution of the formulated compound in DMSO gradient in protein binding buffer;

(3) diluting 20nM (4X final concentration) of THR β protein in protein binding buffer;

(4) diluting 20nM (4X final concentration) of RARa protein in protein binding buffer;

(5) add 5. mu.l of compound, 5. mu.l of THR β, 5. mu.l of RARa to 384 well plates and incubate for 30 min at 37 ℃;

(6) 40nM (4X final concentration) Biotin-GRIP1 was diluted in protein binding buffer;

(7) adding 5 microliter Biotin-GRIP1 into the reaction plate, and incubating for 30 minutes at 37 ℃;

(8) diluting 12nM (6X) EU-anti-6his AB in detection buffer;

(9) diluting 30nM (6X) APC-streptavidin in assay buffer;

(10) adding 5 microliters of EU-anti-6his AB and 5 microliters of APC-streptavidin into a reaction plate, and incubating overnight at 4 ℃;

(11) the reaction signal was read with Envision.

4. Data analysis

Dose Effect (EC) on Compounds with prism software₅₀) Performing an analysis

TABLE 1 inhibition of THR β enzymatic Activity EC by the Compounds of the invention₅₀

Compound numbering	Maximal signal	THRβEC₅₀(nM)
			1	2.76	308.8
2	2.65	240.7
			4	2.57	415.3

The conclusion is that the compound has obvious agonistic effect on THR β.

Claims

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein:

l is selected from-CH₂-、-O-、-CF₂(ii) a preferably-O-;

R¹is selected from 3-4 membered cycloalkyl, wherein said cycloalkyl is optionally further substituted with one or more substituents selected from hydroxy, halo, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or ═ O;

R⁶、R⁷and R⁸Each independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R⁹、-OC(O)R⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹、-NR¹⁰C(O)R¹¹or-S (O)_mNR¹⁰R¹¹Substituted with the substituent(s);

or, R⁷And R⁸Together with the N atom to which they are attached form a 4-8 membered heterocyclic group containing one or more of N, O, S or S (O)_mAnd the 4-to 8-membered heterocycle is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R⁹、-OC(O)R⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹、-NR¹⁰C(O)R¹¹or-S (O)_mNR¹⁰R¹¹Substituted with the substituent(s);

m is selected from 1 or 2.

2. The compound according to claim 1, which is a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein:

R^bselected from hydroxy, halo, cyano, alkyl, alkoxy or ═ O, wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halo, hydroxy or alkoxy;

n is selected from 0 or 1;

p is selected from 0, 1,2, 3 or 4;

L，R²～R⁵is as defined in claim 1.

3. The compound according to claim 1, which is a compound represented by the general formula (III):

wherein:

q is selected from 0, 1,2, 3 or 4;

L，R³～R⁵is as defined in claim 1.

4. The compound according to claim 3, which is a compound represented by the general formula (IV) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein:

r is selected from 0, 1 or 2;

s is selected from 0, 1 or 2;

r and s are not 0 at the same time;

q is selected from 0, 1,2, 3 or 4;

L，R³～R⁸is as defined in claim 1.

5. A compound according to claims 1-4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound comprises:

6. a process for the preparation of a compound of general formula (I) according to claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:

reacting a compound of formula (IA) with a compound of formula (IB) in the presence of hydrochloric acid and nitrite under basic conditions to give a compound of formula (IC);

wherein:

R^dselected from alkyl groups;

L，R¹～R⁵is as defined in claim 1.

7. A compound of formula (IA) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

wherein L, R¹～R⁵Is as defined in claim 1.

8. The compound of claim 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound comprises:

9. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

10. Use of a compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the preparation of a medicament for a thyroid hormone receptor agonist.

11. Use of a compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of a disease associated with thyroid hormone disorders, preferably metabolic disorders, atherosclerosis, cardiovascular diseases, hypothyroidism or thyroid cancer, wherein the metabolic disorders are preferably obesity, hyperlipidemia, hypercholesterolemia, diabetes or nonalcoholic fatty liver disease.

12. Use of a compound according to any one of claims 1 to 5 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of a metabolic disorder, preferably obesity, hyperlipidemia, hypercholesterolemia, diabetes or nonalcoholic steatohepatitis, atherosclerosis, cardiovascular diseases, hypothyroidism or thyroid cancer.