CN112300211B

CN112300211B - Compound serving as thyroid hormone beta receptor agonist and application thereof

Info

Publication number: CN112300211B
Application number: CN202010720170.2A
Authority: CN
Inventors: 顾峥; 黎健豪; 李峥; 邓新山; 刘建余
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2019-07-26
Filing date: 2020-07-24
Publication date: 2023-12-08
Anticipated expiration: 2040-07-24
Also published as: CN112300211A

Abstract

The present invention relates to a compound as thyroid hormone beta receptor agonist and uses thereof, and further relates to a pharmaceutical composition comprising the compound. The compound or the pharmaceutical composition can be used for preparing medicines for preventing, treating or relieving the regulation of thyroid hormone beta receptor agonists, and particularly for preparing medicines for treating nonalcoholic fatty liver diseases.

Description

Compound serving as thyroid hormone beta receptor agonist and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a compound serving as a thyroid hormone beta receptor agonist and application thereof, and further relates to a pharmaceutical composition containing the compound. The invention further relates to the use of said compounds and pharmaceutical compositions for the preparation of a medicament for the prevention, treatment or alleviation of modulation by thyroid hormone beta receptor agonists, in particular for the treatment of non-alcoholic fatty liver disease.

Background

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

The physiological effects of TH are mainly carried out by thyroid hormone receptors (thyroid hormone receptor, TR). TR is a member of the nuclear receptor superfamily, a ligand T3-induced transcription factor, and is at the heart in mediating the action of T3.TR is located mainly in the nucleus and forms heterodimers with retinoic acid X receptor (retinoid X receptor, RXR) and other nuclear receptors to bind to thyroid hormone response elements (thyroid hormoneresponse element, TRE) in the target gene promoter region, thereby regulating gene transcription. There are two subtypes of TR: TR alpha and TR beta. TR alpha can be further divided into TR alpha 1 and TR alpha 2, and TR beta can be further divided into TR beta 1 and TR beta 2. Wherein only trα1, trβ1 and trβ2 are capable of binding to ligand T3.Trα mainly regulates heart rate, trβ plays a key role in controlling liver cholesterol metabolism and inhibiting Thyroid Stimulating Hormone (TSH) release, which may be associated with high expression of trβ in the liver and pituitary gland.

Thyroid hormone has certain therapeutic benefits if side effects can be minimized or eliminated (Paul M.Yen Physiological Reviews, vol.81 (3): pp.1097-1126 (2001); paul Webb Expert Opin. Invest. Drugs, vol.13 (5): pp.489-500 (2004)). For example, thyroid hormones may increase metabolic rate, oxygen consumption, and caloric production, thereby reducing body weight. Reducing body weight will improve co-morbidity associated with obesity with beneficial effects in obese patients, and may also have beneficial effects on glycemic control in obese patients with type 2 diabetes.

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

In addition, nonalcoholic fatty liver disease (NAFLD) is also closely related to thyroid hormone. On the one hand, NAFLD patients have influence on the functions of converting, inactivating and the like of thyroid hormone, and can lead to the reduction of serum thyroid hormone level; on the other hand, the decrease of thyroid hormone level further causes lipid metabolism disorder and glucose metabolism disorder, and participates in NAFLD. Studies have shown that fatty liver formation in rats is induced by choline-methionine deficiency and reversal of fatty liver is observed after T3 re-feeding (Perra A, et al Faseb,2008,22 (8): 2981).

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

Disclosure of Invention

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

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

wherein, the rings A, Y, L, R ^3a ，R ^3b ，R ^3c ，R ^3d ，R ¹ And R is ² Has the meaning as described in the present invention.

In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, optionally, further comprising any one of or any combination of pharmaceutically acceptable carriers, excipients, adjuvants, vehicles.

In one aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for agonizing a thyroid hormone receptor, or for preventing, treating or alleviating a disorder modulated by a thyroid hormone receptor agonist.

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

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

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

The foregoing merely outlines certain aspects of the invention and is not limited to these aspects. These and other aspects will be described more fully below.

Detailed Description

The invention provides a compound with better thyroid hormone beta receptor agonism, a preparation method thereof, a pharmaceutical composition thereof and application thereof. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the scope of the present invention.

Definitions and general terms

Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The application is in no way limited to the methods and materials described herein, but rather is intended to be limited to the specific embodiments shown and described herein, in the event that one or more of such incorporated references, patents, and similar materials differ or conflict with the present application, including but not limited to the terms defined, the application of the terms, the techniques described, etc.

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

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

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999 and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.

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

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. It will be appreciated that the term "optionally substituted" may be used interchangeably with the term "unsubstituted or substituted with … …". The terms "optionally," "optional," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, an optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to, H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ -SH, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl-alkylene, heterocyclyl-alkylene, carbocyclyl, heterocyclyl, aryl-alkylene, heteroaryl-alkylene, and the like.

In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … … is independently "and" … … is independently "and" … … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 Alkyl "means in particular independently disclosed C ₁ Alkyl (methyl), C ₂ Alkyl (ethyl), C ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl and C ₆ An alkyl group; "3-6-atom-composed heterocyclic group" means a 3-atom-composed heterocyclic group, a 4-atom-composed heterocyclic group, a 5-atom-composed heterocyclic group and a 6-ring-atom-composed heterocyclic group.

In the various parts of the present specification, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" refers to a saturated, straight or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms; in some embodiments, the alkyl group contains 1 to 8 carbon atoms, i.e., C _1-8 An alkyl group; in some embodiments, the alkyl group contains 1 to 6 carbon atoms, i.e., C _1-6 An alkyl group; in some embodiments, the alkyl group contains 1 to 4 carbon atoms, i.e., C _1-4 An alkyl group; in some embodiments, the alkyl groups contain 1 to 2 carbon atomsC, i.e _1-2 An alkyl group.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ) Ethyl (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) Isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) Sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-butyl (t-Bu, -C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) N-heptyl, n-octyl, and the like.

The term "alkenyl" denotes a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one unsaturated site is carbon-carbon sp ² A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In some embodiments, the alkenyl group comprises 2 to 8 carbon atoms; in some embodiments, the alkenyl group contains 2 to 6 carbon atoms, i.e., C _2-6 Alkenyl groups; in some embodiments, the alkenyl group contains 2 to 4 carbon atoms, i.e., C _2-4 Alkenyl groups.

Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch) ₂ ) Allyl (-CH) ₂ CH＝CH ₂ ) Propenyl (-ch=chch) ₃ ) Butenyl (-ch=chch) ₂ CH ₃ 、-CH ₂ CH＝CHCH ₃ 、-CH ₂ CH ₂ CH＝CH ₂ 、-CH＝C(CH ₃ ) ₂ 、-CH＝C(CH ₃ ) ₂ 、-CH ₂ C(CH ₃ )＝CH ₂ ) Etc.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation is a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. At the position ofIn some embodiments, alkynyl groups contain 2 to 8 carbon atoms; in some embodiments, alkynyl groups contain 2 to 6 carbon atoms, i.e., C _2-6 Alkynyl; in some embodiments, alkynyl groups contain 2 to 4 carbon atoms, i.e., C _2-4 Alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.CH-CH) ₃ ) Propargyl (-CH) ₂ C≡ch), and the like.

The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, i.e., alkyl-O-, wherein the alkyl group has the meaning as described herein, wherein the alkoxy group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms; in some embodiments, the alkoxy group contains 1 to 6 carbon atoms, i.e., C _1-6 An alkoxy group; in some embodiments, the alkoxy group contains 1 to 4 carbon atoms, i.e., C _1-4 An alkoxy group.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) ₃ ) Ethoxy (EtO, -OCH) ₂ CH ₃ ) N-propyloxy (n-PrO, n-propoxy, -OCH) ₂ CH ₂ CH ₃ ) Isopropoxy (i-PrO, i-propoxy, -OCH (CH) ₃ ) ₂ ) 1-butoxy (n-BuO, n-butoxy, -OCH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) ₂ CH(CH ₃ ) ₂ ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) ₃ )CH ₂ CH ₃ ) 2-methyl-isopropoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ) Etc.

The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" and denotes that the amino groups are each independently substituted with one or two alkyl groups having the definition set forth herein. Wherein the alkylamino group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkylamino group is one or two C _1-6 Alkylamino groups having alkyl groups bound to nitrogen atomsRadicals, i.e. C _1-6 An alkylamino group; in some embodiments, the alkylamino group is one or two C _1-4 An alkylamino group having an alkyl radical bound to a nitrogen atom, i.e. C _1-4 An alkylamino group. Examples of alkylamino groups include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), N, N-dimethylamino, N, N-diethylamino, N-propylamino (N-N-propylamino), isopropylamino (N-isopropylamino), t-butylamino (N-t-butylamino), and the like.

The term "alkylthio" means that the alkyl group is attached to the remainder of the molecule through a sulfur atom, i.e., alkyl-S-, wherein the alkyl group has the meaning as described herein, wherein the alkylthio group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkylthio group contains 1 to 20 carbon atoms; in some embodiments, the alkylthio group contains 1 to 6 carbon atoms, i.e., C _1-6 Alkylthio; in some embodiments, the alkylthio group contains 1 to 4 carbon atoms, i.e., C _1-4 Alkylthio groups. Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, and the like.

The term "haloalkyl" refers to an alkyl group having one or more halo substituents, wherein the haloalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, haloalkyl groups contain 1 to 10 carbon atoms; in some embodiments, the haloalkyl group contains 1 to 6 carbon atoms, i.e., C _1-6 A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 4 carbon atoms, i.e., C _1-4 A haloalkyl group. Examples of haloalkyl groups include, but are not limited to, fluoromethyl (-CH) ₂ F) Difluoromethyl (-CHF) ₂ ) Trifluoromethyl (-CF) ₃ ) Fluoroethyl (-CHFCH) ₃ ,-CH ₂ CH ₂ F) Difluoroethyl (-CF) ₂ CH ₃ ,-CFHCFH ₂ ,-CH ₂ CHF ₂ ) Perfluoroethyl, fluoropropyl (-CHFCH) ₂ CH ₃ ,-CH ₂ CHFCH ₃ ,-CH ₂ CH ₂ CH ₂ F) Difluoropropyl (-CF) ₂ CH ₂ CH ₃ ,-CFHCFHCH ₃ ,-CH ₂ CH ₂ CHF ₂ ,-CH ₂ CF ₂ CH ₃ ,-CH ₂ CHFCH ₂ F) Trifluoropropyl, 1-dichloropropyl, 1, 2-dichloropropyl, and the like.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halo substituents, wherein the haloalkoxy group may be optionally substituted with one or more substituents described herein. In some embodiments, haloalkoxy groups contain 1 to 10 carbon atoms; in some embodiments, the haloalkoxy group contains 1 to 6 carbon atoms, i.e., C _1-6 Haloalkoxy groups; in some embodiments, the haloalkoxy group contains 1 to 4 carbon atoms, i.e., C _1-4 Haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like.

The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring carbon atoms, wherein said cycloalkyl group is optionally substituted with substituents described herein, having one or more points of attachment to the remainder of the molecule. In some embodiments, cycloalkyl is a ring system containing 3 to 10 ring carbon atoms, i.e., C _3-10 Cycloalkyl; in some embodiments, cycloalkyl is a ring system containing 3 to 8 ring carbon atoms, i.e., C _3-8 Cycloalkyl; in some embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms, i.e., C _3-6 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, oxygen and phosphorus atoms, wherein said heterocyclyl is non-aromatic and free of any aromatic rings, and wherein said ring system has one or more points of attachment to the remainder of the molecule. Wherein the heterocyclyl group may optionally be substituted with one or more substituents described hereinAnd (3) substitution. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclyl groups include bridged bicyclic heterocyclyl groups, fused bicyclic heterocyclyl groups, and spiro bicyclic heterocyclyl groups. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. Unless otherwise indicated, heterocyclyl may be carbon or nitrogen, and-CH ₂ The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. The phosphorus atom of the ring may optionally be oxidized to a P-oxygen compound. In some embodiments, the heterocyclyl is a ring system consisting of 3 to 10 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 5 to 8 atoms; in some embodiments, a heterocyclyl is a ring system consisting of 5-6 atoms, i.e., a heterocyclyl consisting of 5-6 atoms; in some embodiments, a heterocyclyl is a ring system consisting of 3-6 atoms, i.e., a heterocyclyl consisting of 3-6 atoms; in some embodiments, heterocyclyl is a system of 3 ring atoms; in some embodiments, the heterocyclyl is a ring system of 4 atoms; in other embodiments, the heterocyclyl is a ring system of 5 atoms; in other embodiments, the heterocyclyl is a ring system of 6 atoms.

Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazanyl, homopiperazinyl, homopiperidinyl, oxaheptanyl, thietanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, Etc. In heterocyclic groups-CH ₂ Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane groups and 1, 1-dioxothiomorpholinyl groups. Bridged heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.2.1]Octyl, and the like.

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

The term "aryl" means a monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein each ring contains 3 to 7 ring atoms, and one or more attachment points are attached to the remainder of the molecule. Wherein the aryl group may be optionally substituted with one or more substituents described herein. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, and anthracenyl, among others.

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

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

The term "carbocyclyl" refers to a non-aromatic carbocyclic ring system of 3 to 14 ring carbon atoms that is saturated or contains one or more unsaturated units. The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein. In some embodiments, the number of ring carbon atoms of the carbocyclic ring is 3-12; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is 3 to 6, i.e. C _3-6 Carbocyclyl; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is 5 to 6, i.e. C _5-6 Carbocyclyl. "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbocycle may be fused to one or more non-aromatic carbocycles or one or more aromatic rings or combinations thereof, wherein the attached radicals or points are on the carbocycle. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl, and spiro bicyclic carbocyclyl, the "fused" bicyclic ring system comprising two rings sharing 2 adjacent ring atoms. The bridge Lian Shuanghuan group includes two rings sharing 3 or 4 adjacent ring atoms. The spiro ring system shares 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexanedienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridged carbocyclyl groups include, but are not limited to, bicyclo [2.2.2 ]Octyl, bicyclo [2.2.1]Heptyl, bicyclo [3.3.1]Nonyl, bicyclo [3.2.3]Nonyl, and the like.

The term "cycloalkyl-alkylene" means that the cycloalkyl group is attached to the remainder of the molecule through an alkyl group, wherein cycloalkyl and alkyl have the meanings described herein. The cycloalkyl-alkylene groups may be optionally substituted with one or more substituents described herein. The invention is described as "C _3-6 cycloalkyl-C _1-4 Alkylene "means C _3-6 Cycloalkyl through C _1-4 The alkyl group is attached to the remainder of the molecule. The book is provided withThe invention is described as "C _3-6 cycloalkyl-C _1-2 Alkylene "means C _3-6 Cycloalkyl through C _1-2 The alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, cyclopropyl-CH ₂ -, cyclopropyl-CH ₂ CH ₂ -, cyclobutyl-CH ₂ -, cyclobutyl-CH ₂ CH ₂ -, cyclopentyl-CH ₂ -, cyclopentyl-CH ₂ CH ₂ -, cyclohexyl-CH ₂ -, cyclohexyl-CH ₂ CH ₂ -and the like.

The term "heterocyclyl-alkylene" means that the heterocyclyl group is attached to the remainder of the molecule through an alkyl group, wherein heterocyclyl and alkyl have the meanings described herein. The heterocyclyl-alkylene groups may be optionally substituted with one or more substituents described herein. (heterocyclic group consisting of 5 to 6 atoms) -C as described in the present invention _1-4 Alkylene "means a heterocyclic group consisting of 5 to 6 atoms through C _1-4 The alkyl group is attached to the remainder of the molecule. (heterocyclic group consisting of 5 to 6 atoms) -C as described in the present invention _1-2 Alkylene "means a heterocyclic group consisting of 5 to 6 atoms through C _1-2 The alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, tetrahydropyranyl-CH ₂ -, tetrahydropyranyl-CH ₂ CH ₂ -, tetrahydrofuranyl-CH ₂ -, tetrahydrofuranyl-CH ₂ CH ₂ -, pyrrolidinyl-CH ₂ -, piperidinyl-CH ₂ -, piperidinyl-CH ₂ CH ₂ -, morpholinyl-CH ₂ -, morpholinyl-CH ₂ CH ₂ -and so on.

The term "aryl-alkylene" means that the aryl group is attached to the remainder of the molecule through an alkyl group, wherein aryl and alkyl have the meanings described herein. The aryl-alkylene groups may be optionally substituted with one or more substituents described herein. For example, "C" as described herein _6-10 aryl-C _1-4 Alkylene "means C _6-10 Aryl through C _1-4 The alkyl group is attached to the remainder of the molecule. "C" as described in the present invention _6-10 aryl-C _1-2 Alkylene group"means C _6-10 Aryl through C _1-2 The alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, phenyl-CH ₂ -, phenyl-CH ₂ CH ₂ -, naphthyl-CH ₂ -and the like.

The term "heteroaryl-alkylene" means that the heteroaryl group is attached to the remainder of the molecule through an alkyl group, wherein heteroaryl and alkyl have the meanings described herein. The heteroaryl-alkylene group may be optionally substituted with one or more substituents described herein. (heteroaryl) C consisting of 5 to 6 atoms as described in the present invention _1-4 Alkylene "means heteroaryl of 5 to 6 atoms through C _1-4 The alkyl group is attached to the remainder of the molecule. (heteroaryl) C consisting of 5 to 6 atoms as described in the present invention _1-2 Alkylene "means heteroaryl of 5 to 6 atoms through C _1-2 The alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, pyridinyl-CH ₂ -, pyrrolyl-CH ₂ CH ₂ -, quinolinyl-CH ₂ -, thienyl-CH ₂ -, furyl-CH ₂ -, pyrimidinyl-CH ₂ -, pyridinyl-CH ₂ -and the like.

The term "heteroatom" refers to O, S, N, P and Si, including any oxidized forms of S, N and P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom of the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R is a substituent on N).

The term "halogen" refers to F, cl, br or I.

The term "carboxylic acid" or "carboxyl" refers to-C (=o) OH.

The term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", means- (c=o) -.

The term "deuterium" refers to deuteration, i.e. D or ² H。

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

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

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

The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers, and the like, as well as additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, anti-atherosclerosis agents, or lipid lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

The term "prodrug" as used in the present invention", represents the in vivo conversion of a compound to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi et al, pro-drugs as Novel Delivery Systems, vol.14, A.C.S. symposium Series; roche et al Bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987; rautio et al, prodrugs Design and Clinical Applications, nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al, prodrugs of Phosphates and Phosphonates, J.Med. Chem.,2008,51,2328-2345.

The term "metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

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

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

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

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

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

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

Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Pressure Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis (e.g., jacques et al, enantiomers, racemates and Resolutions (Wiley Interscience, new York, 1981), principles of Asymmetric Synthesis (2) ^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972))。

The invention also includes isotopically-labelled compounds of the invention which are identical to those recited in the invention except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H， ³ H， ¹³ C， ¹⁴ C， ¹⁵ N， ¹⁶ O， ¹⁷ O， ³¹ P， ³² P， ³⁶ S， ¹⁸ F and F ³⁷ Cl。

The compounds of the invention containing the aforementioned isotopes and/or other isotopes of other atoms, and pharmaceutically acceptable salts of such compounds, are included within the scope of the invention. Isotopically-labelled compounds of the invention, e.g. radioactive isotopes, e.g ³ H and ¹⁴ c incorporation into the compounds of the present invention may be useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ h, and carbon-14, i.e ¹⁴ C, isotope specialAnd is not preferable. Furthermore, with heavy isotopes, e.g. deuterium, i.e ² H substitution may provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.

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

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

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attospimers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

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

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

The term "geometric isomer" is also referred to as "cis-trans isomer" as an isomer resulting from the inability of a double bond (including olefinic double bonds, c=n double bonds, and n=n double bonds) or a single bond of a ring carbon atom to rotate freely.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject is also a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.

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

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

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

Description of the Compounds of the invention

The invention provides a compound which has better effect of exciting thyroid hormone beta receptor, which is used for preparing medicines for treating nonalcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolic disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer. The invention also provides methods of preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds and compositions to prepare medicaments for treating the aforementioned disorders in mammals, particularly humans. Compared with the existing similar compounds, the compound not only has good pharmacological activity and selectivity, but also has excellent in-vivo metabolic dynamics property and in-vivo pharmacodynamics property. The preparation method of the compound is simple and feasible, and the process method is stable, thereby being suitable for industrial production. Therefore, the compound provided by the invention has better patentability than the existing similar compounds.

Specifically: in one aspect, the present invention relates to a compound which is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of a compound of formula (I),

wherein the ring A, Y, L, R ¹ 、R ² 、R ^3a 、R ^3b 、R ^3c And R is ^3d With the definition according to the invention.

In some embodiments, Y is-O-, -NH-, -CH ₂ -or-S-.

In some embodiments, L is-O-, -CH ₂ -, -CH=CH-, -NHC (=O) -, -C (=O) NH-, -NH-, or-S-.

In some embodiments, R ^3a 、R ^3b 、R ^3c And R is ^3d Each independently is H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ 、-SH、C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Alkylamino, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy C _1-6 Alkyl, amino C _1-6 Alkyl or cyano C _1-6 An alkyl group.

In some embodiments, R ¹ And R is ² Each independently is H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ 、-SH、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylamino, C _1-6 Haloalkyl or C _1-6 Haloalkoxy, wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylamino, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups are each independently unsubstituted or substituted with 1, 2 or 3R ^x Substituted; the R is ^x Having the definition according to the invention.

In some embodiments, R ¹ 、R ² And together with the phosphorus atom to which they are attached form a heterocyclic ring of 5 to 6 atoms, wherein the heterocyclic ring of 5 to 6 atoms is unsubstituted or substituted with 1, 2 or 3R ^x Substituted; the R is ^x Having the definition according to the invention.

In some embodiments, each R ^x Independently H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ 、-SH、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, heterocyclic ring of 5-6 atoms, C _6-10 Aryl or heteroaryl of 5-6 atoms, wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, heterocyclic ring of 5-6 atoms, C _6-10 Aryl and heteroaryl consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl or C _1-6 The substituent of the haloalkoxy group is substituted.

In some embodiments, ring a isThe E is ¹ 、E ² 、E ³ 、R ⁴ X and R ^y Having the definition of the invention, wherein at least one E ₁ 、E ₂ Or E is ₃ is-C (=o) -.

In some embodiments, X is N or CH.

In some embodiments, E ₁ Is- (CR) ^a R ^b ) _q -、-C(＝O)-、-O-、-S-、-S(＝O)-、-S(＝O) ₂ -or-NR ^g -, said R ^a 、R ^b 、R ^g And q has the definition according to the invention.

In some embodiments, E ₂ is-CR ^c R ^d -、-C(＝O)-、-O-、-S-、-S(＝O)-、-S(＝O) ₂ -or-NR ^g -, said R ^c 、R ^d And R is ^g Having the definition according to the invention.

In some embodiments, E ₃ is-CR ^e R ^f -、-C(＝O)-、-O-、-S-、-S(＝O)-、-S(＝O) ₂ -or-NR ^g -, said R ^e 、R ^f And R is ^g Having the definition according to the invention.

In some embodiments, each R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R is ^f Independently H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ 、-SH、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylamino, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-4 Alkylene, C _6-10 Aryl, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C _1-4 Alkylene group, wherein the C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylamino, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-4 Alkylene, C _6-10 Aryl, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C _1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, any two R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f Together with the carbon atoms to which they are attached form C _3-6 Carbocycle or heterocycle of 5-6 atoms wherein said C _3-6 Carbocycles and heterocycles consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, R ^a 、R ^b Together with the carbon atoms to which they are attached form C _3-6 Carbocycle or heterocycle of 5-6 atoms wherein said C _3-6 Carbocycles and heterocycles consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, R ^c 、R ^d Together with the carbon atoms to which they are attached form C _3-6 Carbocycle or heterocycle of 5-6 atoms wherein said C _3-6 Carbocycles and heterocycles consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, R ^e 、R ^f Together with the carbon atoms to which they are attached form C _3-6 Carbocycle or heterocycle of 5-6 atoms wherein said C _3-6 Carbocycles and heterocycles consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, each R ⁴ And R is ^g Independently H, deuterium, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-4 Alkylene, C _6-10 Aryl, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C _1-4 Alkylene group, wherein the C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-4 Alkylene, C _6-10 Aryl, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C _1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted by substituents.

In some embodiments, R ^a And R is ^c Together form a single bond; namely, R ^a 、R ^c And together with the carbon atoms to which they are each attached form-c=c-.

In some embodiments, R ^c And R is ^e Together form a single bond; namely, R ^c 、R ^e And together with the carbon atoms to which they are each attached form-c=c-.

In some embodiments, R ⁴ And R is ^e Together form a single bond; namely, R ⁴ 、R ^e And together with the atoms to which they are each attached form-n=c-.

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

In some embodiments, each R ^y Independently deuterium, F, cl, br, I, CN, OH, NH ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Alkoxy or C _1-6 An alkylamino group.

In some embodiments, R ^3a 、R ^3b 、R ^3c And R is ^3d Each independently is H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ 、-SH、C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Alkylthio, C _1-4 Alkylamino, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, hydroxy C _1-4 Alkyl, amino C _1-4 Alkyl or cyano C _1-4 An alkyl group.

In some embodiments, R ^3a 、R ^3b 、R ^3c And R is ^3d Each independently is H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ Trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl or cyanomethyl.

In some embodiments, R ¹ And R is ² Each independently is H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ 、-SH、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _1-4 Alkylamino, C _1-4 Haloalkyl or C _1-4 Haloalkoxy, wherein said C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _1-4 Alkylamino, C _1-4 Haloalkyl and C _1-4 Haloalkoxy groups are each independently unsubstituted or substituted with 1, 2 or 3R ^x Substituted, the R ^x Having the definition according to the invention.

In some embodiments, R ¹ And R is ² Each independently is H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ -SH, methyl, ethyl, n-propyl, isopropyl, -ch=ch ₂ -C≡CH, methoxy, ethoxy, methylamino, ethylamino, -CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ Or trifluoromethoxy, wherein the methyl, ethyl, n-propyl, isopropyl, -ch=ch ₂ (C.ident.) CH, methoxy, ethoxy, methylamino, ethylamino, -CHF ₂ 、-CH ₂ F and-CH ₂ CF ₃ Each independently is unsubstituted or substituted with 1, 2 or 3R ^x Substituted, the R ^x Having the definition according to the invention.

In some embodiments, R ¹ 、R ² And together with the phosphorus atom to which they are attached form Wherein said-> Each independently is unsubstituted or substituted with 1, 2 or 3R ^x Substituted, the R ^x Having the definition according to the invention.

In some embodiments, each R ^x Independently HDeuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ 、-SH、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, heterocyclic ring of 5-6 atoms, C _6-10 Aryl or heteroaryl of 5-6 atoms, wherein said C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, heterocyclic ring of 5-6 atoms, C _6-10 Aryl and heteroaryl consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Haloalkyl or C _1-4 The substituent of the haloalkoxy group is substituted.

In some embodiments, each R ^x Independently H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ -SH, methyl, ethyl, n-propyl, isopropyl, -ch=ch ₂ 、-CH ₂ CH＝CH ₂ 、-CH＝CHCH ₃ -c≡ch, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a heterocycle of 5-6 atoms, phenyl or a heteroaryl of 5-6 atoms, wherein the methyl, ethyl, n-propyl, isopropyl, -ch=ch ₂ 、-CH ₂ CH＝CH ₂ 、-CH＝CHCH ₃ -c≡ch, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a heterocycle of 5 to 6 atoms, phenyl and a heteroaryl of 5 to 6 atoms each independently being unsubstituted or substituted with 1, 2 or 3 groups independently selected from deuterium, F, cl, br, I, CN, NO ₂ 、OH、NH ₂ Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF ₃ Or a substituent of trifluoromethoxy group.

In some embodiments, each R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R is ^f Independently H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ 、-SH、C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _1-4 Alkylamino, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-2 Alkylene, C _6-10 Aryl, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C _1-2 Alkylene group, wherein the C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _1-4 Alkylamino, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-2 Alkylene, C _6-10 Aryl, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C _1-2 Alkylene groups are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, each R ^a 、R ^b 、R ^c 、R ^d 、R ^e And R is ^f Independently H, deuterium, F, cl, br, I, CN, NO ₂ 、-COOH、OH、NH ₂ -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -ch=ch ₂ 、-CH ₂ CH＝CH ₂ 、-CH＝CHCH ₃ -C≡CH, methoxy, ethoxy, methylamino, -CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ 、-CH ₂ CHF ₂ Trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH ₂ -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C _1-2 Alkylene, phenyl-CH ₂ -, phenyl-CH ₂ CH ₂ -, furyl, thienyl, imidazolesA radical, pyrimidinyl, pyridinyl, pyrrolyl, furyl-CH ₂ -, thienyl-CH ₂ -, imidazolyl-CH ₂ -, pyrimidinyl-CH ₂ -, pyridinyl-CH ₂ -or pyrrolyl-CH ₂ -, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -ch=ch ₂ 、-CH ₂ CH＝CH ₂ 、-CH＝CHCH ₃ -C≡CH, methoxy, ethoxy, methylamino, -CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ 、-CH ₂ CHF ₂ Difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH ₂ -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C _1-2 Alkylene, phenyl-CH ₂ -, phenyl-CH ₂ CH ₂ -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, furyl-CH ₂ -, thienyl-CH ₂ -, imidazolyl-CH ₂ -, pyrimidinyl-CH ₂ -, pyridinyl-CH ₂ -and pyrrolyl-CH ₂ -each independently is unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, any two R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f And the carbon atoms to which they are attached form together a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a heterocyclic ring of 5 to 6 atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the heterocyclic ring of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, R ^a 、R ^b Together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a heterocyclic ring of 5 to 6 atoms, where the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and heterocyclic ring of 5 to 6 atoms are each independently unsubstituted orIs covered by 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, R ^c 、R ^d And the carbon atoms to which they are attached form together a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a heterocyclic ring of 5 to 6 atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the heterocyclic ring of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, R ^e 、R ^f And the carbon atoms to which they are attached form together a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a heterocyclic ring of 5 to 6 atoms, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the heterocyclic ring of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted, the R ^y Having the definition according to the invention.

In some embodiments, each R ⁴ And R is ^g Independently H, deuterium, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-2 Alkylene, C _6-10 Aryl, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C _1-2 Alkylene group, wherein the C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-2 Alkylene, C _6-10 Aryl, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C _1-2 Alkylene groups are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted by a substituent, said R ^y With the inventionThe definitions are stated.

In some embodiments, each R ⁴ And R is ^g Independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, -ch=ch ₂ 、-CH ₂ CH＝CH ₂ 、-CH＝CHCH ₃ 、-C≡CH、-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-2 Alkylene, phenyl-C _1-2 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C _1-2 Alkylene, wherein the methyl, ethyl, n-propyl, isopropyl, -ch=ch ₂ 、-CH ₂ CH＝CH ₂ 、-CH＝CHCH ₃ 、-C≡CH、-CHF ₂ 、-CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C _1-2 Alkylene, phenyl-C _1-2 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C _1-2 Alkylene groups are each independently unsubstituted or substituted with 1, 2 or 3R ^y Substituted by a substituent, said R ^y Having the definition according to the invention.

In some embodiments, each R ^y Independently deuterium, F, cl, br, I, CN, OH, NH ₂ 、C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy or C _1-4 An alkylamino group.

In some embodiments, each R ^y Independently deuterium, F, cl, br, I, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl, -CF ₃ 、-CHF ₂ Trifluoromethoxy, difluoromethoxy, methoxy, ethoxy or methylamino.

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

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

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

In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the preparation of a medicament for agonizing a thyroid hormone receptor, or for preventing, treating or alleviating a disorder modulated by a thyroid hormone receptor agonist.

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

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for agonizing a thyroid hormone receptor, or for preventing, treating or alleviating a disorder modulated by a thyroid hormone receptor agonist.

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

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

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

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

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

Any formulae given herein are also intended to represent unlabeled as well as isotopically-labeled forms of these compounds. Isotopically-labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H， ³ H， ¹¹ C， ¹³ C， ¹⁴ C， ¹⁵ N， ¹⁸ F， ³¹ P， ³² P， ³⁶ S， ³⁷ Cl or ¹²⁵ I。

Compositions, formulations and administration of the compounds of the invention

The present invention relates to a pharmaceutical composition comprising a compound of the structure shown in the compounds or examples of the present invention, or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound of the invention and at least one pharmaceutically acceptable carrier, excipient, adjuvant, or vehicle. The amount of the compound in the pharmaceutical composition of the invention is effective to detectably agonize the thyroid hormone beta receptor in a biological sample or patient.

The pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or have no other adverse effects or side effects when administered to a patient. Standard pharmaceutical techniques may be employed.

The pharmaceutical or pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle as described herein, including any solvents, diluents, liquid vehicles, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like, as used herein, suitable for the particular dosage form of interest. Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York discloses various carriers for use in formulating pharmaceutically acceptable compositions and methods of making same as are well known. In addition to conventional carrier vehicles that are incompatible with the compounds of the present invention, for example, may produce adverse biological effects or may interact deleteriously with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and use thereof is also contemplated by the present invention.

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

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

The effective amount of the compounds, pharmaceutical compositions or medicaments of the present invention can be readily determined by routine experimentation, and the most effective and convenient route of administration and most suitable formulation can also be determined by routine experimentation.

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

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, and in addition to inert diluents, the oral compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

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

For example, injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by the addition of sterilizing agents which are in the form of sterile solid compositions which are soluble or dispersible in sterile water or other sterile injectable medium prior to use.

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

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

Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or swelling agents such as starch, lactose, mannitol and silicic acid, b) binders such as carboxy methyl cellulose, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar-agar, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

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

The active compounds may also be in microencapsulated form with one or more of the above-described excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical arts. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. In general, such dosage forms may also contain additional substances other than inert diluents, such as tabletting lubricants and other tabletting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.

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

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

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

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

Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing the agent with a non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Use of the compounds and compositions of the invention

The compound or the pharmaceutical composition provided by the invention can be used for preparing medicines for exciting thyroid hormone receptors or preparing medicines for preventing, treating or relieving diseases regulated by thyroid hormone receptor agonists.

The compounds or pharmaceutical compositions provided herein are useful for agonizing a thyroid hormone receptor, or for preventing, treating, or alleviating a disorder modulated by a thyroid hormone receptor agonist.

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

The thyroid hormone receptor is a thyroid hormone beta receptor.

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

In addition to being beneficial for human treatment, the compounds of the present invention are also useful in veterinary treatment of pets, introduced species of animals and farm animals, including mammals, rodents and the like. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

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

General synthetic and detection methods

For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.

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

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

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

The structure of the compound is that nuclear magnetic resonance is adopted ¹ H-NMR、 ¹³ C-NMR or/and ¹⁹ F-NMR). ¹ H-NMR、 ¹³ C-NMR、 ¹⁹ The F-NMR chemical shifts (δ) are given in parts per million (ppm). ¹ H-NMR、 ¹³ C-NMR、 ¹⁹ The F-NMR was performed using Bruker Ultrashield-400 NMR spectrometer and Bruker Avance III HD 600 NMR spectrometer, with deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD or MeOH-d ₄ ) Or deuterated dimethyl sulfoxide (DMSO-d) ₆ ). TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard. When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet) M (multiplet ), br (broadside), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet), td (triplet of doublets, triplet), brs (broadened singlet, broad singlet). Coupling constant J, in units of hertz (Hz).

Purification or resolution is typically performed using a Novasep pump 250 high performance liquid chromatograph.

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

Column chromatography generally uses 300-400 mesh silica gel of Qingdao ocean chemical industry as a carrier.

The starting materials for the present invention are known and commercially available from Shanghai remote Company (Shanghai Accela Company), an Naiji Company (Energy Company), the well-known Company (J & K), the Tianjin Alfa Company (Alfa Company), and the like, or may be synthesized using or according to methods known in the art.

The examples are not specifically described, and the reactions are all carried out under nitrogen atmosphere;

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

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

unless otherwise specified, in the examples, the solution means an aqueous solution; the reaction temperature is room temperature; the room temperature is 20-40 ℃.

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

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

HPLC refers to high performance liquid chromatography; HPLC was performed using Agilent 1260 high pressure liquid chromatograph (column: agilent ZORBAX Eclipse Plus C, 4.6 mm. Times.150 mm,3.5 μm);

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

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

the mobile phase gradient is shown in table a:

table A

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

The LC/MS system for analysis in the biological test consisted of an Agilent 1200 series vacuum degassing furnace, a binary syringe pump, an orifice plate autosampler, a column oven, an Agilent G6430 tertiary quadrupole mass spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed in MRM mode, and parameters of MRM transitions are shown in table B:

table B

Full scan	50→1400
		Fracture voltage	230V
Capillary voltage	55V
		Dryer temperature	350℃
Atomizer	0.28MPa
		Dryer flow rate	10L/min

Analysis Using an Agilent XDB-C18, 2.1X130 mm, 3.5. Mu.M column, 5. Mu.L of sample was injected. Analysis conditions: the mobile phase was 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4mL/min. The mobile phase gradient is shown in table C:

table C

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

Also for analysis was an Agilent 6330 series LC/MS spectrometer equipped with a G1312A binary syringe pump, a G1367A autosampler and a G1314C UV detector; LC/MS spectrometers employ ESI radiation sources. The appropriate cation model treatment and MRM transformations were performed for each analyte using standard solutions for optimal analysis. Capcell MP-C18 column was used during the analysis, with the following specifications: 100X 4.6mm I.D., 5. Mu.M (Phenomenex, torrance, california, USA). The mobile phase was 5mM ammonium acetate, 0.1% aqueous methanol (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70/30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; 20. Mu.L of sample was injected.

The following abbreviations are used throughout the present invention:

DMSO-d ₆ :	deuterated dimethyl sulfoxide;	Boc:	t-butoxycarbonyl;
				DCC:	dicyclohexylcarbodiimide;	DMSO:	dimethyl sulfoxide;
CDCl ₃ :	deuterated chloroform;	％wt,mass％：	weight percent;
				CD ₃ OD:	deuterated methanol;	mL:	milliliters;
μL：	microlitres of;	mol/L:	moles per liter;
				mol:	moles;	mmol:	millimoles;
g:	g;	h:	hours;
				H ₂ ：	hydrogen gas;	N ₂ :	nitrogen gas;
min:	minutes;	MPa:	megapascals;
				Et:	an ethyl group;	TIPS:	triisopropyl silicon base.

General synthetic method

Typical synthetic procedures for preparing the disclosed compounds are shown in the synthetic schemes below. Unless otherwise indicated, each E ₁ 、E ₂ 、R ^3a And R is ^3d With the definition according to the invention.

Synthesis scheme 1:

compounds having the structure shown in formula (I-A) may be prepared by the general synthetic method depicted in synthetic scheme 1, wherein R ⁰ Is C _1-6 Alkyl, PG is a phenolic hydroxyl protecting group. First, the compound (I-a) is reacted with the compound (I-b) under the action of a metal-organic reagent such as n-butyllithium,obtaining a compound (I-c); removing hydroxyl groups of the compound (I-c) through reduction to obtain a compound (I-d); removing phenolic hydroxyl protecting groups from the compound (I-d) to obtain a compound (I-e); reacting the compound (I-e) with phosphate under the action of alkali (such as sodium hydride, cesium carbonate and the like) to obtain a compound (I-f); the ester of the compound (I-f) is hydrolyzed to obtain the target compound shown in the general formula (I-A).

Synthesis scheme 2:

the compounds having the structure shown in the general formula (I-B) can be prepared by a general synthetic method described in synthetic scheme 2. The compound (I-A) and (I-g) are subjected to condensation reaction under the action of a condensing agent (such as DCC) to obtain the compound (I-B).

Preparation example

Example 1[3, 5-dimethyl-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) methyl ] phenoxy ] methylphosphonic acid

Step 1) 6- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -hydroxy-methyl]-3, 4-dihydro-1H-quinol Lin-2-one 1b

N-hexane solution of n-butyllithium (0.45 mL,1.1mmol,2.5 mol/L) was added dropwise to a tetrahydrofuran (5 mL) solution of 6-bromo-3, 4-dihydro-1H-quinolin-2-one 1a (0.10 g,0.44 mmol) at-78℃under nitrogen, stirred for 10 minutes, tetrahydrofuran (1 mL) solution of 2, 6-dimethyl-4-triisopropylsiloxy-benzaldehyde (0.14 g,0.46 mmol) was added dropwise, and the reaction mixture was reacted at-78℃for 16 hours. To the reaction solution was added saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), and the organic phase was washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by preparative TLC plate [ petroleum ether/ethyl acetate (v/v) =2/1 ] to give the title compound 1b (61 mg, yield 30%) as a white solid.

MS(ESI,poi.ion)m/z:436.1[M-OH] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.93(s,1H),7.29(d,J＝9.4Hz,1H),7.02(d,J＝8.4Hz,1H),6.70-6.61(m,1H),6.56(s,2H),6.21(s,1H),2.92(dd,J＝15.8,8.1Hz,2H),2.63(dd,J＝7.9,3.8Hz,2H),2.20(s,3H),2.17(s,1H),1.62(s,3H),1.30-1.24(m,3H),1.11(d,J＝7.3Hz,18H)。

Step 2) 6- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -methyl]-3, 4-dihydro-1H-quinoline-2- Ketone 1c

Boron trifluoride etherate (0.10 mL,0.37mmol,47 mass%) was added dropwise to a solution of 6- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -hydroxy-methyl ] -3, 4-dihydro-1H-quinolin-2-one 1b (61 mg,0.13 mmol) in dichloromethane (2 mL), followed by triethylsilane (0.05 mL,0.3 mmol) and reacted at room temperature for 15 hours. The reaction was quenched with water (10 mL), extracted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by preparative TLC plate [ petroleum ether/ethyl acetate (v/v) =2/1 ] to give the title compound 1c (15 mg, yield 99%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.23(s,1H),6.79(d,J＝8.0Hz,1H),6.74(s,1H),6.64(d,J＝8.0Hz,1H),6.60(s,2H),3.90(s,2H),2.86(t,J＝7.5Hz,2H),2.59(t,J＝7.5Hz,2H),2.16(s,6H),1.28-1.23(m,3H),1.11(d,J＝7.2Hz,18H)。

Step 3) 6- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl]-3, 4-dihydro-1H-quinolin-2-one 1d

Tetrabutylammonium fluoride in tetrahydrofuran (0.10 mL,0.10mmol,1 mol/L) was added to a solution of 6- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -methyl ] -3, 4-dihydro-1H-quinolin-2-one 1c (15 mg,0.034 mmol) in tetrahydrofuran (2 mL) and reacted at room temperature for 1 hour. To the reaction solution was added ethyl acetate (10 mL), which was then washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 1d (9.6 mg, yield 99%) as a white solid.

MS(ESI,poi.ion)m/z:282.1[M+H] ⁺ 。

Step 4) 6- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ]]Methyl group]3, 4-dihydro-1H-) Quinolin-2-one 1e

Cesium carbonate (0.46 g,1.4 mmol) was added to a solution of 6- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl ] -3, 4-dihydro-1H-quinolin-2-one 1d (0.26 g,0.92 mmol) and (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate (0.36 g,1.1 mmol) in N, N-dimethylformamide (5 mL) and reacted at room temperature for 24 hours. To the reaction solution was added water (10 mL), extracted with ethyl acetate (10 ml×3), and the combined organic phases were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =1/1 ] to give the title compound 1e (0.16 g, yield 40%) as a colorless liquid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.03(s,1H),6.72-6.66(m,3H),6.61(s,2H),4.26-4.13(m,6H),3.83(s,2H),2.77(t,J＝7.6Hz,2H),2.49(t,J＝7.2Hz,2H),2.13(s,6H),1.30(t,J＝7.1Hz,6H)。

Step 5) [3, 5-dimethyl-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) methyl]Phenoxy group]Methyl phosphorus Acid example 1

Trimethylbromosilane (0.75 mL,5.6 mmol) was added to a solution of 6- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ] methyl ] -3, 4-dihydro-1H-quinolin-2-one 1e (0.16 g,0.37 mmol) in dichloromethane (5 mL) and reacted at room temperature for 16 hours. The reaction solution was concentrated to give the title compound 1 (0.14 g, yield 99%) as a yellow solid.

MS(ESI,neg.ion)m/z:374.0[M-H] ^- ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.95(s,1H),6.74(d,J＝12.0Hz,3H),6.70(s,2H),4.04(d,J＝10.2Hz,2H),3.84(s,2H),2.76(t,J＝7.5Hz,2H),2.42-2.35(t,J＝7.5Hz,2H),2.16(s,6H)。

Example 2[3, 5-dimethyl-4- [ (7-oxo-6, 8-dihydro-5H-1, 8-naphthyridin-3-yl) methyl ] phenoxy ] methylphosphonic acid

Step 1) 6- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -hydroxy-methyl]-3, 4-dihydro-1H-naphthalene Pyridin-2-one 2b

3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one 2a (0.20 g,0.88 mmol) was dissolved in tetrahydrofuran (5 mL), a n-hexane solution of n-butyllithium (0.74 mL,1.9mmol,2.5 mol/L) was added dropwise at-78℃under nitrogen protection, the reaction was carried out for 10 minutes, and then a tetrahydrofuran (1 mL) solution of 2, 6-dimethyl-4-triisopropylsiloxy-benzaldehyde (0.27 g,0.88 mmol) was added dropwise thereto, the reaction was carried out for 10 minutes, and then the reaction was carried out at-60℃for 8 hours. The reaction was quenched by dropwise addition of saturated aqueous sodium chloride (5 mL), room temperature was restored, water (15 mL) was added, extracted with ethyl acetate (20 ml×3), the combined organic phases were washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =3/1 ] to give the title compound 2b (50 mg, yield 12%) as a yellow solid.

MS(ESI,poi.ion)m/z:436.1[M+H] ⁺ 。

Step 2) 6- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -methyl]-3, 4-dihydro-1H-naphthyridine-2- Ketone 2c

Boron trifluoride diethyl etherate (0.037 mL,0.29 mmol) was added dropwise to a solution of 6- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -hydroxy-methyl ] -3, 4-dihydro-1H-naphthyridin-2-one 2b (0.11 g,0.24 mmol) in dichloromethane (5 mL) and triethylsilane (0.078 mL,0.48 mmol) was added and reacted at room temperature for 4 hours. The reaction was quenched with water (10 mL) at 0 ℃ and extracted with dichloromethane (20 ml×3), the combined organic phases were washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =3/2 ] to give the title compound 2c (0.10 g, yield 94%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.47(s,1H),8.04(s,1H),6.98(s,1H),6.63(s,2H),3.92(s,2H),2.85(t,J＝7.5Hz,2H),2.64(t,J＝7.6Hz,2H),2.20(s,6H),1.27(dd,J＝14.8,7.2Hz,3H),1.13(d,J＝7.2Hz,18H)。

Step 3) 6- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl]-3, 4-dihydro-1H-naphthyridin-2-one 2d

6- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -methyl ] -3, 4-dihydro-1H-naphthyridin-2-one 2c (0.10 g,0.23 mmol) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.27 mL,0.27mmol,1 mol/L) was added dropwise to react at room temperature for 1 hour. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated by suction, and the resulting residue was purified by silica gel column chromatography [100% ethyl acetate ] to give the title compound 2d (56 mg, yield 87%) as a yellow solid.

MS(ESI,poi.ion)m/z:283.1[M+H] ⁺ 。

Step 4) 6- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ]]Methyl group]3, 4-dihydro-1H-) Naphthyridin-2-one 2e

Sodium hydride (8 mg,0.20mmol,60 mass%) was added to N, N-dimethylformamide (3 mL), 6- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl ] -3, 4-dihydro-1H-naphthyridin-2-one 2d (50 mg,0.18 mmol) and (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate (69 mg,0.21 mmol) were added and reacted at room temperature for 4 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and the resulting residue was purified by silica gel column chromatography [100% ethyl acetate ] to give the title compound 2e (11 mg, yield 14%) as a white solid.

MS(ESI,poi.ion)m/z:433.2[M+H] ⁺ 。

Step 5) [3, 5-dimethyl-4- [ (7-oxo-6, 8-dihydro-5H-1, 8-naphthyridin-3-yl) methyl ]]Phenoxy group]Nail armor Example 2 based phosphoric acid

6- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ] methyl ] -3, 4-dihydro-1H-naphthyridin-2-one 2e (14 mg,0.032 mmol) was dissolved in dichloromethane (5 mL), and trimethylbromosilane (0.065 mL,0.48 mmol) was added and reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound 2 (12 mg, yield 98%, HPLC purity: 93.35%) as a yellow oil.

MS(ESI,neg.ion)m/z:375.0[M-H] ^- ；

¹ H NMR(400MHz,CD ₃ OD)δ(ppm)7.90(s,1H),7.67(s,1H),6.81(s,2H),4.85(s,2H),4.10(s,2H),3.12(s,2H),2.76(t,J＝7.4Hz,2H),2.26(s,6H)。

Example 3[3, 5-dimethyl-4- [ (2-oxospiro [ cyclopropan-1, 3-indoline ] -5-yl) methyl ] phenoxy ] methylphosphonic acid

Step 1) 5-bromospiro [ cyclopropyl-1, 3-indoline]-2-one 3b

A solution of n-butyllithium in n-hexane (6.0 mL,15mmol,2.5 mol/L) was added dropwise to a white suspension of 5-bromoindolin-2-one 3a (1.0 g,4.7 mmol) in tetrahydrofuran (15 mL) under nitrogen at-30℃and the reaction mixture was allowed to react under ice for 0.5 hours, followed by dropwise addition of a solution of 1, 2-dibromoethane (1.2 mL,14 mmol) in tetrahydrofuran (2 mL) and subsequent reaction at room temperature for 18 hours. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), and the combined organic phases were washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated by suction, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =2/1 ] to give the title compound 3b (0.54 g, yield 48%) as a red solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.17(s,1H),7.30(dd,J＝8.2,1.8Hz,1H),6.93(d,J＝1.7Hz,1H),6.85(d,J＝8.2Hz,1H),1.79(dd,J＝7.9,4.1Hz,2H),1.55(dd,J＝8.0,4.2Hz,2H)。

Step 2) 5- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -hydroxy-methyl]Spiro [ cyclopropyl-1, 3 ] Indoline]-2-one 3c

N-hexane solution of n-butyllithium (1.8 mL,4.5mmol,2.5 mmol/L) was added dropwise to tetrahydrofuran (10 mL) solution of 5-bromospiro [ cyclopropyl-1, 3-indoline ] -2-one 3b (0.50 g,2.1 mmol) at-78deg.C under nitrogen protection, reacted for 10 min, then tetrahydrofuran (2 mL) solution of 2, 6-dimethyl-4-triisopropylsiloxy-benzaldehyde (0.65 g,2.1 mmol) was added dropwise, and the reaction was continued for 16 h. The reaction was quenched by addition of saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =1/1 ] to give the title compound 3c (0.69 g, yield 71%) as a yellow oil.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.18(s,1H),6.96(d,J＝8.1Hz,1H),6.84(d,J＝8.6Hz,2H),6.56(s,2H),6.22(s,1H),2.19(s,6H),1.78-1.71(m,2H),1.56-1.46(m,2H),1.26-1.21(m,3H),1.11(d,J＝7.2Hz,18H)。

Step 3) 5- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) methyl]Spiro [ cyclopropyl-1, 3-indoles A process for the preparation of a liquid crystal display device]-2-one 3d

To a solution of 5- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -hydroxy-methyl ] spiro [ cyclopropyl-1, 3-indolin ] -2-one 3c (0.69 g,1.5 mmol) in dichloromethane (10 mL) was added dropwise a solution of boron trifluoride in diethyl ether (0.50 mL,1.9 mmol), triethylsilane (0.60 mL,3.7 mmol) was added and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by the addition of water (10 mL), and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction to give the title compound 3d (0.67 g, 99% yield) as a yellow liquid.

Step 4) 5- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl]Spiro [ cyclopropyl-1, 3-indolines]-2-one 3e

A tetrahydrofuran solution (6.0 mL,6.0mmol,1 mol/L) of tetrabutylammonium fluoride was added dropwise to 5- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) methyl ] spiro [ cyclopropyl-1, 3-indolin ] -2-one 3d (1.34 g,2.98 mmol) of tetrahydrofuran (15 mL), and the mixture was reacted at room temperature for 0.5 hours. The reaction solution was concentrated, and the residue was dissolved with ethyl acetate (20 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) in this order, dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =1/1 ] to give the title compound 3e (0.52 g, yield 59%) as a brown solid.

MS(ESI,poi.ion)m/z:294.1[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.26(s,1H),8.17(s,1H),7.47(d,J＝1.6Hz,1H),7.38(dd,J＝8.3,1.8Hz,1H),6.76(d,J＝8.0Hz,1H),6.56(s,2H),3.92(s,2H),2.16(s,6H),1.72(dd,J＝7.7,4.0Hz,2H),1.46(dd,J＝7.8,4.0Hz,2H)。

Step 5) 5- [ [4- (diethyloxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ]]Methyl group]Spiro [ cyclopropyl-1, 3 ] Indoline]-2-one 3f

Cesium carbonate (1.2 g,3.6 mmol) was added to a solution of 5- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl ] spiro [ cyclopropyl-1, 3-indolin ] -2-one 3e (0.52 g,1.8 mmol) and (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate (0.64 g,1.9 mmol) in N, N-dimethylformamide (5 mL) and reacted at room temperature for 36 hours. To the reaction solution was added water (20 mL), and the combined organic phases were washed with ethyl acetate (10 ml×3), saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =1/2 ] to give the title compound 3f (0.26 g, yield 33%) as a yellow liquid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)6.97(d,J＝8.1Hz,1H),6.79(d,J＝7.8Hz,1H),6.67(s,2H),6.48(s,1H),4.28-4.23(m,4H),4.15(d,J＝3.4Hz,2H),3.94(s,2H),2.19(s,6H),1.71(dd,J＝7.9,4.2Hz,2H),1.45(dd,J＝7.8,4.1Hz,2H),1.37(t,J＝7.1Hz,6H)。

Step 6) [3, 5-dimethyl-4- [ (2-oxospiro [ cyclopropane-1, 3-indoline ]]-5-yl) methyl]Phenoxy group]Nail armor Example 3 of the base phosphoric acid

Trimethylbromosilane (1.2 mL,8.9 mmol) was added dropwise to a solution of 5- [ [4- (diethylphosphorylmethoxy) -2, 6-dimethyl-phenyl ] methyl ] spiro [ cyclopropyl-1, 3-indolin ] -2-one 3f (0.26 g,0.59 mmol) in dichloromethane (5 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound 3 (0.23 g, yield 99%, HPLC purity: 90.44%) as a yellow solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.03(s,1H),6.97(d,J＝8.1Hz,1H),6.77(d,J＝8.0Hz,1H),6.71(s,2H),4.04(d,J＝10.2Hz,2H),3.91(s,2H),3.87(d,J＝10.6Hz,2H),2.31-2.23(m,2H),2.17(s,6H)。

Example 4[4- [ (3, 3-dimethyl-2-oxo-indolin-5-yl) methyl ] -3, 5-dimethyl-phenoxy ] methylphosphoric acid

Step 1) 5-bromo-2-oxo-indoline-1-carbonate tert-butyl ester 4a

Di-tert-butyl dicarbonate (5.5 mL,24 mmol) was added to a white suspension of 5-bromoindolin-2-one 3a (2.0 g,9.4 mmol), sodium bicarbonate (7.2 g,85 mmol) in tetrahydrofuran (100 mL) and reacted at 70℃for 5 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =4/1 ] to give the title compound 4a (2.54 g, yield 86%) as a white solid.

MS(ESI,poi.ion)m/z:336.1[M+Na] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.69(d,J＝8.7Hz,1H),7.42(d,J＝9.5Hz,1H),7.37(s,1H),3.64(s,2H),1.63(s,9H)。

Step 2) 5-bromo-3, 3-dimethyl-2-oxo-indoline-1-carbonate tert-butyl ester 4b

Sodium hydride (0.14 g,3.5mmol,60 mass%) was added to a solution of 5-bromo-2-oxo-indoline-1-carbonate tert-butyl ester 4a (0.50 g,1.6 mmol) in tetrahydrofuran (5 mL,62 mmol) at 0deg.C, followed by methyl iodide (0.30 mL,4.7 mmol) and the reaction was allowed to spontaneously recover at room temperature for 16 hours. The reaction was quenched with water (15 mL), extracted with ethyl acetate (15 mL), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =8/1 ] to give the title compound 4b (0.38 g, yield 70%) as a red liquid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.75(d,J＝8.7Hz,1H),7.39(dd,J＝8.7,2.0Hz,1H),7.31(d,J＝2.0Hz,1H),1.63(s,9H),1.41(s,6H)。

Step 3) 5-bromo-3, 3-dimethyl-indolin-2-one 4c

To 5-bromo-3, 3-dimethyl-2-oxo-indoline-1-carbonate tert-butyl ester 4b (0.36 g,1.1 mmol) was added ethyl acetate solution of hydrogen chloride (4 mL,16mmol,4 mol/L), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to give the title compound 4c (0.25 g, yield 98%) as a gray solid.

Step 4) 5- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -hydroxymethyl]-3, 3-dimethyl-indole Lin-2-one 4d

N-butyllithium (0.80 mL,2.0mmol,2.5 mol/L) was added dropwise to a solution of 5-bromo-3, 3-dimethyl-indolin-2-one 4c (0.21 g,0.87 mmol) in tetrahydrofuran (10 mL) under nitrogen protection at-78deg.C, reacted for 10 min, then a solution of 2, 6-dimethyl-4-triisopropylsiloxy-benzaldehyde (0.29 g,0.95 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction was continued for 16 h. The reaction was quenched by addition of saturated ammonium chloride solution (20 mL) at-78 ℃, extracted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =4/1 ] to give the title compound 4d (0.11 g, yield 27%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.74(s,1H),7.19(s,1H),6.96(d,J＝8.1Hz,1H),6.78(d,J＝8.0Hz,1H),6.57(s,2H),6.25(s,1H),2.20(s,6H),2.16(s,1H),1.29-1.22(m,3H),1.11(d,J＝7.2Hz,18H)。

Step 5) 5- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -methyl ]3, 3-dimethyl-indoline- 2-Ketone 4e

A solution of boron tribromide in diethyl ether (0.65 mL,2.4mmol,47 mass%) was added dropwise to a solution of 5- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -hydroxymethyl ] -3, 3-dimethyl-indolin-2-one 4d (0.95 g,2.0 mmol) in dichloromethane (10 mL), triethylsilane (0.70 mL,4.3 mmol) was added dropwise and reacted at room temperature for 2 hours. The reaction was quenched with water (10 mL), separated, and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction to give the title compound 4e (0.86 g, 99% yield) as a pink solid.

Step 6) 5- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl]-3, 3-dimethyl-indolin-2-one 4f

Tetrabutylammonium fluoride tetrahydrofuran (3.8 mL,3.8mmol,1 mol/L) was added to 5- [ (2, 6-dimethyl-4-triisopropylsiloxy-phenyl) -methyl ] -3, 3-dimethyl-indolin-2-one 4e (0.86 g,1.9 mmol) tetrahydrofuran (10 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was diluted with ethyl acetate (10 mL), washed with water (10 ml×2) and saturated sodium chloride solution (10 mL) in this order, dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =2/1 ] to give the title compound 4f (0.52 g, yield 92%) as a white solid.

MS(ESI,poi.ion)m/z:296.2[M+H] ⁺ 。

Step 7) 5- [ [4- (diethyloxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ]]Methyl group]-3, 3-dimethyl-indole Indolin-2-one 4g

Cesium carbonate (1.2 g,3.6 mmol) was added to a solution of 5- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl ] -3, 3-dimethyl-indolin-2-one 4f (0.52 g,1.8 mmol) and (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate (0.67 g,2.0 mmol) in N, N-dimethylformamide (5 mL) and reacted at room temperature for 12 hours. The reaction was quenched with water (25 mL), extracted with ethyl acetate (25 mL. Times.3), and the combined organic phases were washed with saturated sodium chloride solution (25 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\2] to give 4g (0.22 g, yield 28%) of the title compound as a colorless liquid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.30(dd,J＝8.3,1.8Hz,1H),7.24(d,J＝1.8Hz,1H),7.15(dd,J＝15.9,7.5Hz,1H),7.00(d,J＝7.7Hz,1H),6.90(d,J＝8.3Hz,1H),4.08-4.03(m,8H),1.31(d,J＝1.5Hz,12H),1.19(t,6H)。

Step 8) [4- [ (3, 3-dimethyl-2-oxo-indolin-5-yl) methyl ]]-3, 5-dimethyl-phenoxy]Methyl group Phosphoric acid example 4

Trimethylbromosilane (1.0 mL,7.4 mmol) was added to a solution of 5- [ [4- (diethylphosphorylmethoxy) -2, 6-dimethyl-phenyl ] methyl ] -3, 3-dimethyl-indolin-2-one 4g (0.22 g,0.49 mmol) in dichloromethane (5 mL) and reacted at room temperature for 8 hours. The reaction solution was concentrated, and purified by preparation to give the title compound 4 (93 mg, yield 48%) as a white solid.

MS(ESI,neg.ion)m/z:388.1[M-H] ^- ；

¹ H NMR(400MHz,CD ₃ OD)δ(ppm)6.93(s,1H),6.78(dd,J＝16.9,8.9Hz,2H),6.73(s,2H),4.02(d,J＝10.3Hz,2H),3.97(s,2H),2.18(s,6H),2.13(s,1H),1.28(s,6H)。

Example 5[ [3, 5-dimethyl-4- [ [ 2-oxospiro [ cyclopentane-1, 3-indoline ] -5-yl ] methyl ] phenoxy ] methylphosphonic acid

Step 1) 5-bromopro [ cyclopentane-1, 3-indoline]-2-Ketone 5a

A solution of n-butyllithium in n-hexane (58 mL,150mmol,2.5 mol/L) was added dropwise to a white suspension of 5-bromoindolin-2-one 3a (10.0 g,47.2 mmol) in tetrahydrofuran (50 mL) at-30℃under nitrogen, the reaction mixture was moved to an ice-water bath for 0.5 hours, then a solution of 1, 4-dibromobutane (17.24 mL,141.5 mmol) in tetrahydrofuran (5 mL) was added dropwise slowly, followed by reaction at room temperature for 18 hours. The reaction was quenched by addition of saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 ml×3), the combined organic phases were washed with saturated sodium chloride solution (45 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 4\1] to give the title compound 5a (8.53 g, yield 68%) as a pale red solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.76(s,1H),7.32(dt,J＝11.9,5.7Hz,2H),6.82(d,J＝8.1Hz,1H),2.26-2.15(m,2H),2.15-2.05(m,2H),2.04-1.94(m,2H),1.94-1.84(m,2H).

Step 2) 5- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) -hydroxy-methyl]Spiro [ cyclopentane-1, a compound selected from the group consisting of, 3-indoline]-2-one 5b

A solution of n-butyllithium in n-hexane (13.0 mL,33.0mmol,2.5 mmol/L) was slowly added dropwise to a solution of 5-bromospiro [ cyclopentane-1, 3-indoline ] -2-one 5a (3.50 g,13.15 mmol) in tetrahydrofuran (30 mL) at-78deg.C under nitrogen, reacted for 2 hours, then a solution of 2, 6-dimethyl-4-triisopropylsiloxy-benzaldehyde (5.24 g,17.1 mmol) in tetrahydrofuran (4 mL) was added dropwise, and the reaction was continued under nitrogen at-78deg.C for 18 hours. The reaction was quenched by addition of saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 ml×3), the combined organic phases were washed with saturated sodium chloride solution (30 ml×3), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 4\1] to give the title compound 5b (2.23 g, yield 34.3%) as a yellow oil.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.23(s,1H),7.16(s,1H),6.95(d,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,1H),6.57(s,2H),6.24(s,1H),2.39(s,1H),2.20(s,6H),2.18-2.09(m,2H),2.07-1.96(m,2H),1.95-1.77(m,4H),1.25(dd,J＝14.8,7.2Hz,3H),1.11(d,J＝7.2Hz,18H).

Step 3) 5- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) methyl]Spiro [ cyclopentane-1, 3-indole A process for the preparation of a liquid crystal display device]-2-one 5c

To a solution of 5- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) -hydroxy-methyl ] spiro [ cyclopentane-1, 3-indoline ] -2-one 5b (2.10 g,4.25 mmol) in dichloromethane (25 mL) was added dropwise a solution of boron trifluoride in diethyl ether (1.33 mL,5.10 mmol), triethylsilane (1.52 mL,9.33 mmol) was added and the reaction was carried out at room temperature for 2.5 hours. The reaction was quenched with water (25 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phase was washed with saturated sodium chloride solution (25 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated by suction to give the title compound 5c (2.01 g, 98.9%) as a yellow liquid.

Step 4) 5- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl]Spiro [ cyclopentane-1, 3-indoline]-2-one 5d

A solution of tetrabutylammonium fluoride in tetrahydrofuran (11.0 mL,11.0mmol,1.0 mol/L) was slowly added dropwise to a solution of 5- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) methyl ] spiro [ cyclopentane-1, 3-indoline ] -2-one 5c (2.30 g,4.81 mmol) in tetrahydrofuran (25 mL) at 0℃and reacted at room temperature for 3.5 hours. The reaction solution was concentrated, the residue was dissolved with ethyl acetate (25 mL), washed with water (15 mL) and saturated sodium chloride solution (20 mL) in this order, the organic phase was dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\1] to give the title compound 5d (1.26 g, yield 81.4%) as a yellow liquid.

MS(ESI,neg.Scan)m/z:320.3[M-H] ^- 。

Step 5) 5- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ]]Methyl group]Spiro [ cyclopentane-1, a compound selected from the group consisting of, 3-indoline]-2-one 5e

Sodium hydride (0.166g,4.15mmol,60mass%in oil) was added in portions to a solution of 5- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl ] spiro [ cyclopentane-1, 3-indolin ] -2-one 5d (0.95 g,2.96 mmol) in N, N-dimethylformamide (20 mL) at 0℃and reacted at room temperature for 1 hour, followed by a solution of (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate (1.01 mL,3.83 mmol) in N, N-dimethylformamide (2 mL) at 0℃and reacted at room temperature for 20 hours. The reaction was quenched with water (25 mL), extracted with ethyl acetate (25 ml×3), the combined organic phases were washed with saturated sodium chloride solution (25 ml×3), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\2] to give the title compound 5e (0.93 g, yield 67%) as a yellow liquid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.54(s,1H),6.92(s,1H),6.69(dd,J＝8.8,5.5Hz,4H),4.31-3.97(m,6H),3.97(s,2H),2.23(s,6H),2.22-2.13(m,2H),2.11-2.01(m,2H),1.94(dd,J＝14.3,7.6Hz,2H),1.88-1.79(m,2H),1.40(t,J＝7.1Hz,6H)。

Step 6) [ [3, 5-dimethyl-4- [ [ 2-oxospiro [ cyclopentane-1, 3-indoline ]]-5-yl]Methyl group]Phenoxy group] Methyl phosphoric acid example 5

5- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ] methyl ] spiro [ cyclopentane-1, 3-indolin ] -2-one 5e (0.625 g,1.33 mmol) was dissolved in dichloromethane (20 mL), and trimethylbromosilane (2.32 mL,17.2 mmol) was added dropwise at 0deg.C, followed by reaction at room temperature for 2 hours. The reaction solution was concentrated and dried in vacuo to give the title compound 5 (0.52 g, yield 94.4%, HPLC purity: 89.42%) as a gray solid.

MS(ESI,neg.Scan)m/z:414.6[M-H] ^- ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.16(s,1H),6.98(s,1H),6.70(s,2H),6.67(d,J＝7.9Hz,1H),6.59(d,J＝7.9Hz,1H),4.04(d,J＝10.2Hz,2H),3.88(s,2H),2.17(s,6H),1.96-1.83(m,6H),1.73-1.64(m,2H)。

Example 6[3, 5-dimethyl-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) methyl ] phenoxy ] methylphosphoric acid

Step 1) 7-bromo-4H-1, 4-benzoxazin-3-one 6b

2-amino-5-bromophenol 6a (5.64 g,30.0 mmol) was dissolved in acetonitrile (80 mL), potassium carbonate (12.6 g,90.3 mmol) was added, and 2-chloroacetyl chloride (2.86 mL,35.9 mmol) was slowly added dropwise and reacted at room temperature for 18 hours. Concentrated under reduced pressure, water (50 mL) was added, extracted with ethyl acetate (30 ml×3), and the combined organic phases were washed with saturated aqueous sodium chloride (30 ml×3), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was recrystallized [ petroleum ether/ethyl acetate (v/v) =20/1, 100mL ], to give the title compound 6b (6.5 g, yield 95%) as a brown solid.

GC-MS:Exact Mass:226.958,found:227.0。

Step 2) 7- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) -hydroxy-methyl]-4H-1, 4-benzo Oxazin-3-one 6c

A solution of n-butyllithium in n-hexane (5.1 mL,13mmol,2.5 mol/L) was added dropwise to a solution of 7-bromo-4H-1, 4-benzoxazin-3-one 6b (1.15 g,5.13 mmol) in tetrahydrofuran (10 mL) under nitrogen at-78deg.C, reacted for 50 minutes, then a solution of 2, 6-dimethyl-4-triisopropylsilyloxy-benzaldehyde (2.04 g,6.67 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction was continued for 16 hours. The reaction was quenched by addition of saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 ml×3), the organic phase was washed with saturated sodium chloride solution (20 ml×3), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 3\1] to give the title compound 6c (0.71 g, yield 30%) as a brown solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.19(s,1H),6.90(s,1H),6.85(d,J＝8.1Hz,1H),6.72(d,J＝8.1Hz,1H),6.55(s,2H),6.18(s,1H),4.59(s,2H),2.20(s,6H),2.13(s,1H),1.30(s,1H),1.21(d,J＝6.6Hz,2H),1.11(d,J＝7.2Hz,18H).

Step 3) 7- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) methyl]4H-1, 4-benzoxazine-3- Ketone 6d

A solution of boron trifluoride in diethyl etherate (0.53 mL,0.94 mmol) was added dropwise to a solution of 7- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) -hydroxy-methyl ] -4H-1, 4-benzoxazin-3-one 6c (0.63 g,1.38 mmol) in dichloromethane (10 mL) under nitrogen, triethylsilane (0.563 mL,3.45 mmol) was added dropwise slowly and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by the addition of water (10 mL), and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction to give the title compound 6d (0.60 g, 98.5% yield) as a brown solid.

Step 4) 7- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl]-4H-1, 4-benzoxazin-3-one 6e

A solution of tetrabutylammonium fluoride in tetrahydrofuran (3.0 mL,3.0mmol,1 mol/L) was slowly added dropwise to a solution of 7- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) methyl ] -4H-1, 4-benzoxazin-3-one 6d (0.60 g,1.36 mmol) in tetrahydrofuran (10 mL) at 0deg.C and reacted at room temperature for 3 hours. The reaction solution was concentrated, the residue was dissolved with ethyl acetate (20 mL), washed with water (20 mL) and saturated sodium chloride solution (25 mL) in this order, dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\1] to give the title compound 6e (0.30 g, yield 78%) as a pale yellow solid.

MS(ESI,neg.ion)m/z:282.2[M-H] ^- ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.58(s,1H),9.03(s,1H),6.77(d,J＝8.0Hz,1H),6.57(d,J＝8.0Hz,1H),6.47(d,J＝9.3Hz,3H),4.50(s,2H),3.79(s,2H),2.09(s,6H)。

Step 5) 7- [ [4- (diethoxyphosphorylmethoxy) 2, 6-dimethyl-phenyl ]]Methyl group]-4H-1, 4-benzoxazole Oxazin-3-one 6f

Sodium hydride (42.4 mg,1.06mmol,60 mass%) was slowly added to a solution of 7- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl ] -4H-1, 4-benzoxazin-3-one 6e (0.250 g,0.882 mmol) in N, N-dimethylformamide (10 mL) at 0deg.C, reacted for 1 hour at room temperature, followed by a solution of ethoxyphosphorylmethyl 4-methylbenzenesulfonate (0.295 mL,1.15 mmol) in N, N-dimethylformamide (2 mL) at 0deg.C, and then reacted for 21 hours at room temperature. To the reaction solution was added water (20 mL), and the combined organic phases were washed with ethyl acetate (20 ml×3), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\2] to give the title compound 6f (0.32 g, yield 84%) as a white needle-like solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.10(s,1H),6.69(d,J＝7.1Hz,3H),6.65-6.58(m,2H),4.58(s,2H),4.33-4.22(m,6H),3.92(s,2H),2.22(s,6H),1.39(t,J＝7.1Hz,6H)。

Step 6) [3, 5-dimethyl-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) methyl ]]Phenoxy group]Methyl phosphorus Acid example 6

Trimethylbromosilane (1.51 mL,11.1 mmol) was added dropwise to a solution of 7- [ [4- (diethoxyphosphorylmethoxy) 2, 6-dimethyl-phenyl ] methyl ] -4H-1, 4-benzoxazin-3-one 6f (0.32 g,0.738 mmol) in dichloromethane (8 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound 6 (0.265 g, yield 95%, HPLC purity: 96.27%) as a gray solid.

MS(ESI,neg.Scan)m/z:376.2[M-H] ^- ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.58(s,1H),6.77(d,J＝8.0Hz,1H),6.92-6.64(m,5H),6.71(s,2H),6.56(d,J＝7.8Hz,1H),6.48(s,1H),4.49(s,2H),4.05(d,J＝10.2Hz,2H),3.84(s,2H),2.15(s,6H)。

Example 7[3, 5-dimethyl-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) methyl ] phenoxy ] methylphosphonic acid

Step 1) (2-amino-5-bromo-phenyl) methanol 7b

2-amino-5-bromo-benzoic acid 7a (6.48 g,30.0 mmol) was dissolved in tetrahydrofuran (50 mL) and lithium aluminum hydride (2.35 g,60.0 mmol) was added in portions at 0deg.C, after which the reaction was transferred to room temperature for 3 hours. The reaction was quenched by the addition of water (15 mL) and 5% sodium hydroxide solution (35 mL), stirred for 10 min, filtered, the filter cake rinsed with ethyl acetate (20 ml×3), the filtrate was collected and concentrated, and the resulting residue recrystallized (petroleum ether/ethyl acetate=10/1, 70 mL) to give the title compound 7b (5.9 g, 97% yield) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.25-7.17(m,2H),6.59(d,J＝8.4Hz,1H),4.62(s,2H),3.96(s,2H),2.05(s,1H)。

Step 2) 6-bromo-1, 4-dihydro-3, 1-benzoxazin-2-one 7c

(2-amino-5-bromo-phenyl) methanol 7b (4.04 g,20.0 mmol) was dissolved in tetrahydrofuran (50 mL) under nitrogen, and triphosgene (6.06 g,20.0 mmol) was added thereto and reacted at room temperature for 20 minutes. To the reaction solution was slowly added dropwise water (30 mL) for quenching, extraction was performed with ethyl acetate (20 ml×3), and the combined organic layers were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 7c (4.20 g, yield 92%) as a white solid.

GC-MSLRMS(EI)m/z:227.0。

Step 36- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) -hydroxy-methyl]1, 4-dihydro-3, 1- Benzoxazin-2-one 7d

A solution of n-butyllithium in n-hexane (5.9 mL,15mmol,2.5 mol/L) was slowly added dropwise to a solution of 6-bromo-1, 4-dihydro-3, 1-benzoxazin-2-one 7c (1.4 g,6.14 mmol) in tetrahydrofuran (10 mL) under nitrogen at-78deg.C, reacted for 50 minutes, then a solution of 2, 6-dimethyl-4-triisopropylsiloxy-benzaldehyde (2.45 g,7.98 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction was continued for 18 hours. The reaction was quenched by addition of saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 ml×3), and the combined organic phases were washed with saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\1] to give the title compound 7d (1.2 g, yield 43%) as a pale yellow solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.90(s,1H),7.14(d,J＝8.2Hz,1H),7.05(s,1H),6.75(d,J＝8.2Hz,1H),6.58(s,2H),6.22(s,1H),5.28(s,2H),2.20(s,6H),2.17(s,1H),1.32-1.29(m,2H),1.25(d,J＝6.9Hz,2H),1.13(d,J＝7.2Hz,18H).

Step 4) 6- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) methyl]-1, 4-dihydro-3, 1-benzo Oxazin-2-one 7e

To a solution of 6- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) -hydroxy-methyl ] -1, 4-dihydro-3, 1-benzoxazin-2-one 7d (1.10 g,2.4 mmol) in methylene chloride (25 mL) was added dropwise a solution of boron trifluoride in diethyl ether (0.75 mL,3.0mmol,2.5 mmol), triethylsilane (0.87 mL,5.3 mmol) was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 7e (1.03 g, 97% yield) as a yellow solid.

Step 5) 6- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl]-1, 4-dihydro-3, 1-benzoxazin-2-one 7f

A solution of tetrabutylammonium fluoride in tetrahydrofuran (5.17 mL,5.17mmol,1 mol/L) was slowly added dropwise under nitrogen at 0deg.C to a solution of 6- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) methyl ] -1, 4-dihydro-3, 1-benzoxazin-2-one 7e (1.033 g,2.35 mmol) in tetrahydrofuran (15 mL) and then transferred to room temperature for reaction for 3 hours. The reaction solution was concentrated, the residue was dissolved with ethyl acetate (20 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) in this order, dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\2] to give the title compound 7f (0.52 g, yield 78.1%) as a pale yellow solid.

MS(ESI,neg.Scan)m/z:282.1[M-H] ^- ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.03(s,1H),9.02(s,1H),6.88(d,J＝8.2Hz,1H),6.77(d,J＝7.7Hz,2H),6.46(s,2H),5.19(s,2H),3.82(s,2H),2.09(s,6H)。

Step 6) 6- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ]]Methyl group]-1, 4-dihydro-3, 1-Benzoxazin-2-one 7g

Sodium hydride (99mg,2.5mmol,60mass%in oil) was added portionwise to a solution of 6- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl ] -1, 4-dihydro-3, 1-benzoxazin-2-one 7f (0.5.1 g,1.77 mmol) in N, N-dimethylformamide (10 mL) at 0deg.C, reacted at room temperature for 1 hour, followed by addition of a solution of N, N-dimethylformamide (2 mL) in (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate (0.292 mL,1.8 mmol) at 0deg.C, and reacted at room temperature for 20 hours. The reaction solution was quenched by addition of water (20 mL), extracted with ethyl acetate (20 ml×3), and the combined organic phases were washed with saturated sodium chloride solution (20 ml×3), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\2] to give 7g (0.345 g, yield 45%) of the title compound as a white solid.

¹ H NMR(600MHz,CDCl ₃ )δ(ppm)7.51(s,1H),6.93(d,J＝8.4Hz,1H),6.70(d,J＝9.8Hz,4H),5.24(s,2H),4.34-4.21(m,6H),3.95(s,2H),2.21(s,6H),1.40(t,J＝7.1Hz,6H)。

Step 7) [3, 5-dimethyl-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) methyl ]]Phenoxy group] Methyl phosphoric acid example 7

7g (0.38 g,0.88 mmol) of 6- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ] methyl ] -1, 4-dihydro-3, 1-benzoxazin-2-one (15 mL) was dissolved in methylene chloride, and trimethylbromosilane (1.77 mL,13.1 mmol) was added dropwise at 0deg.C and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the title compound 7 (0.32 g, yield 97%, HPLC purity: 99.69%) as a pale yellow solid.

MS(ESI,pos.Scan)m/z:378.1[M+H] ⁺ ；MS(ESI,neg.Scan)m/z:376.1[M-H] ^- ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.04(s,1H),6.87(d,J＝8.8Hz,1H),6.77(d,J＝8.3Hz,2H),6.71(s,2H),5.18(s,2H),4.57(s,2H),4.04(d,J＝10.2Hz,2H),3.86(s,2H),2.16(s,6H)。

Example 8[3, 5-dimethyl-4- [ (2-oxospiro [ cyclobutane-1, 3-indoline ] -5-yl) methyl ] phenoxy ] methylphosphonic acid

Step 1) 5-bromospiro [ cyclobutane-1, 3-indoline]-2-Ketone 8a

A solution of n-butyllithium in n-hexane (24 mL,60mmol,2.5 mol/L) was added dropwise to a suspension of 5-bromoindol-2-one 3a (4.24 g,20 mmol) in tetrahydrofuran (30 mL) at-30℃under nitrogen, and the reaction was carried out at 0℃for 30 minutes, followed by dropwise addition of a solution of 1, 3-dibromopropane (6.09 mL,60 mmol) in tetrahydrofuran (5 mL) and reaction at room temperature for 18 hours. To the reaction solution was added a saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 ml×3), the combined organic phases were washed with a saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 2\1] to give the title compound 8b (3.5 g, yield 69%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.91(s,1H),7.59(d,J＝1.7Hz,1H),7.32(dd,J＝8.2,1.9Hz,1H),6.79(d,J＝8.2Hz,1H),2.73-2.63(m,2H),2.41-2.31(m,3H),2.29-2.19(m,1H)。

Step 2) 5- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) -hydroxy-methyl]Spiro [ cyclobutane-1, a compound which is, 3-indoline]-2-Ketone 8b

A solution of n-butyllithium in n-hexane (2.9 mL,7.16mmol,2.5 mol/L) was slowly added dropwise to a solution of 5-bromospiro [ cyclobutane-1, 3-indoline ] -2-one 8a (0.82 g,3.25 mmol) in tetrahydrofuran (15 mL) under nitrogen protection at-78deg.C, reacted for 50 minutes, then a solution of 2, 6-dimethyl-4-triisopropylsiloxy-benzaldehyde (1.20 g,3.90 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction was continued for 18 hours. The reaction was quenched by addition of saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 ml×3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 4\1] to give the title compound 8b (0.95 g, yield 61%) as a yellow oil.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.53(s,1H),7.50(s,1H),6.98(d,J＝8.0Hz,1H),6.78(d,J＝8.0Hz,1H),6.60(s,2H),6.31(s,1H),2.70-2.59(m,3H),2.34(dd,J＝10.8,6.7Hz,2H),2.24(s,6H),2.17(dd,J＝14.4,7.3Hz,1H),2.06(s,1H),1.27(dd,J＝7.3,4.2Hz,3H),1.13(d,J＝7.2Hz,18H)。

Step 3) 5- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) methyl]Spiro [ cyclobutane-1, 3-indoles A process for the preparation of a liquid crystal display device]-2-one 8c

A solution of boron trifluoride in diethyl etherate (0.69 mL,2.12 mmol) was added dropwise to a solution of 5- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) -hydroxy-methyl ] spiro [ cyclobutane-1, 3-indoline ] -2-one 8b (0.82 g,1.7 mmol) in dichloromethane (10 mL), triethylsilane (0.61 mL,2.04 mmol) was added and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by the addition of water (10 mL), and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction to give the title compound 8c (0.78 g, 98% yield) as a yellow liquid.

Step 4) 5- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl]Spiro [ cyclobutane-1, 3-indoline]-2-one 8d

A solution of tetrabutylammonium fluoride in tetrahydrofuran (3.14 mL,3.14mmol,1 mol/L) was slowly added dropwise to a solution of 5- [ (2, 6-dimethyl-4-triisopropylsilyloxy-phenyl) methyl ] spiro [ cyclobutane-1, 3-indoline ] -2-one 8c (0.73 g,1.57 mmol) in tetrahydrofuran (10 mL) at 0deg.C and reacted at room temperature for 3 hours. The reaction solution was concentrated, the residue was dissolved with ethyl acetate (20 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) in this order, dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\1] to give the title compound 8d (0.39 g, yield 81%) as a white solid.

MS(ESI,neg.Scan)m/z:306.3[M-H] ^- ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.11(s,1H),9.02(s,1H),7.27(s,1H),6.64(t,J＝5.2Hz,2H),6.48(s,2H),3.87(s,2H),3.37(s,6H),2.39(t,J＝8.5Hz,2H),2.21(ddd,J＝12.3,8.4,3.6Hz,4H)。

Step 5) 5- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ]]Methyl group]Spiro [ cyclobutane-1, a compound which is, 3-indoline]-2-one 8e

Sodium hydride (58.1mg,1.45mmol,60mass%in oil) was slowly added to 5- [ (4-hydroxy-2, 6-dimethyl-phenyl) methyl ] spiro [ cyclobutane-1, 3-indoline ] -2-one e (0.37 g,1.21 mmol) of N, N-dimethylformamide (8 mL) at 0℃and reacted at room temperature for 1 hour, and a solution of (diethoxyphosphoryl) methyl-4-methylbenzenesulfonate (0.37 mL,1.45 mmol) of N, N-dimethylformamide (2 mL) was added at 0℃and reacted at room temperature for 20 hours after the completion of the dropwise addition. To the reaction solution was added water (20 mL), extracted with ethyl acetate (20 ml×3), the combined organic phases were washed with saturated sodium chloride solution (20 ml×3), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) = 1\2] to give the title compound 8e (0.23 g, yield 42%) as a pale yellow liquid.

¹ H NMR(600MHz,CDCl ₃ )δ(ppm)7.61(s,1H),7.19(s,1H),6.68(dd,J＝13.9,9.1Hz,4H),4.30-4.21(m,6H),3.99(s,2H),2.63(dt,J＝15.5,7.5Hz,2H),2.36-2.28(m,3H),2.23(s,6H),2.19-2.13(m,1H),1.38(t,J＝7.1Hz,6H)。

Step 6) [3, 5-dimethyl-4- [ (2-oxospiro [ cyclobutane-1, 3-indoline ]]-5-yl) methyl]Phenoxy group]Nail armor Example 8 of the base phosphoric acid

5- [ [4- (diethoxyphosphorylmethoxy) -2, 6-dimethyl-phenyl ] methyl ] spiro [ cyclobutane-1, 3-indoline ] -2-one 8e (0.10 g,0.22 mmol) was dissolved in dichloromethane (3 mL), and trimethylbromosilane (0.44 mL,3.2 mmol) was slowly added dropwise at 0deg.C and reacted at room temperature for 2 hours. The reaction solution was concentrated, water (10 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 8 (86 mg, yield 98%, HPLC purity: 96.06%) as a gray solid.

MS(ESI,pos.Scan)m/z:402.1[M+H] ⁺ ；MS(ESI,neg.Scan)m/z:400.1[M-H] ^- ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.11(s,1H),7.29(s,1H),6.72(s,2H),6.64(d,J＝7.9Hz,1H),6.59(d,J＝7.9Hz,1H),4.05(d,J＝9.8Hz,2H),3.92(s,2H),2.39(dd,J＝15.7,10.0Hz,2H),2.29-2.20(m,3H),2.19(s,6H),2.15-2.06(m,1H)。

Test examples of Activity

1. Method for detecting TR alpha or TR beta agonistic activity of compound in double-luciferase reporter gene experiment

Test materials:

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

fugene HD transfection reaagent from Promega, cat No. E231A;

DMEM, available from Gibco, cat No.11995;

FBS, available from Biosera, cat No. FB-1280/500;

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

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

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

The test method comprises the following steps:

HEK293 cells were cultured in 10% fbs+dmem whole medium. pBind-TR. Alpha. Or pBind-TR. Beta. (100 ng/. Mu.l), pG5Luc (100 ng/. Mu.l), fuGENE HD and Opti-MEM were thoroughly mixed and incubated at room temperature for 15min, HEK293 cells were digested with 0.25% Trypsin-EDTA, resuspended in whole medium, the cell density was calculated, the cell density was adjusted to 500,000cells/ml, and then the transcriptional mix was added to the cell suspension and plated in 96-well plates (100. Mu.L/well) and incubated at 37℃for 24h. After 24 hours of the time period, the mixture was stirred,test compounds were dissolved in DMSO and 3-fold diluted, 10 total concentrations,the compound was then diluted with DMEM to a 10% DMSO in compound solution, 5 μl of compound was plated in 96-well plates with a final compound DMSO concentration of 0.5% and the compound was co-cultured with the cells for 18h. After 18h, the firefly fluorescence signal and the Renilla fluorescence signal were detected with Dual-Luciferase Reporter Assay System. Dividing the firefly fluorescence signal by the Renilla fluorescence signal to calculate the F/R ratio, plotting a curve using Graph Pad Prism software and calculating the EC ₅₀ Values. The compound has good activity of exciting TR beta.

Specifically, the compounds of the invention have an EC for agonistic activity on TR beta ₅₀ The value is less than 0.1. Mu.M. Meanwhile, the compound has good selectivity to TR beta, in particular, the compound agonizes EC of TR alpha ₅₀ EC of value and agonism TR beta ₅₀ The ratio of values is greater than 10.

Compounds of formula (I)	Selectivity TR alpha/TR beta (fold)
		VK-2809 mother medicine	7
Example 5	250

The test results show that: the compounds of the invention have a pronounced selectivity for trβ.

The synthesis of the parent compound VK-2809 is described in example 7 of the patent application WO 2005051298.

2. Method for detecting in vitro binding activity of compound on TR alpha or TR beta

Test materials:

LanthaScreen TR-FRET Thyroid Receptor beta Coactivator Assay kit is purchased from Invitrogen, cat. No. PV4686;

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

The test method comprises the following steps:

the method was performed using a LanthaScreen TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit. Test compounds were dissolved in DMSO and 3-fold diluted, 10 total concentrations, followed by dilution with TR-FRET Coregulator Buffer C in the kit to a compound solution containing 2% DMSO. mu.L of a compound solution containing 2% DMSO was taken into 384-well plates, then 5. Mu.L of 4 XTR. Alpha. -LBD or TR. Beta. -LBD, 5. Mu.L of a mixture containing 0.4. Mu.M fluorescein-SRC2-2 and 8nM Tb anti-GST anti-ibody were added to each well, and after thoroughly mixing, incubated at room temperature in the dark for 1h. After 1h, the fluorescence values were read using a PHERAstar FSX microplate reader of BMG LABECH at excitation 520nm and emission 495nm (RFU). The TR-FRET ratio is calculated by dividing the emission signal at 520nm by the emission signal at 495 nm. Curve was drawn and EC was calculated using Graph Pad Prism 5 software ₅₀ Values.

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

3. Pharmacokinetic assay of the compounds of the invention

Measurement purposes the following methods were used to determine the pharmacokinetics of the compounds of the invention.

Test materials:

experimental reagent and test article used: propranolol (internal standard), methanol, ammonium acetate, K ₂ EDTA (potassium ethylenediamine tetraacetate), formic acid, acetonitrile, MTBE (methyl tert-butyl ether), kolliphorHS15 (polyethylene glycol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available;

SD rats: male, 180-220g,7-8 week old, purchased from Hunan Style laboratory animal Co.

The test method comprises the following steps:

1. test sample preparation

The test solutions were prepared in 5% dmso+5% kolliphorhs15+90% physiological saline, specifically adjusted according to the dissolution of each compound, so that the compound was completely dissolved.

2. Design of animal experiment

3. Animal administration dosage scale

Group of	Sex (sex)	Number of animals	Dosage for administration	Concentration of drug administration	Administration volume
						I.v. intravenous.	Male male	3	1mg/kg	1mg/mL	1mL/kg
P.O it is administered orally.	Male male	3	5mg/kg	1mg/mL	5mL/kg

4. Solution preparation

(1) Preparation of sample stock solution: precisely weighing a proper amount of test sample, dissolving with DMSO, diluting with acetonitrile to 1mg/mL, and shaking. And (5) placing the mixture at the temperature of minus 20 ℃ for standby.

(2) Preparing an internal standard substance solution: a quantity of 1mg/mL Propranolol stock was pipetted precisely and diluted with water to 100ng/mL.

5. Sample analysis

The method comprises the steps of treating a sample by adopting a liquid-liquid extraction method, carrying out chromatographic separation, carrying out quantitative analysis by adopting a multiple reaction ion monitoring (MRM) mode on a triple quadrupole tandem mass spectrometer, and carrying out concentration calculation on the result by using instrument quantitative software.

6. Plasma sample pretreatment

30. Mu.L of plasma sample was precisely aspirated, 250. Mu.L of internal standard was added and vortexed well. Extracting with 1mL MTBE once, centrifuging at 13000rpm at 4deg.C for 2min, sucking 800 μl of supernatant, volatilizing in a 96-well nitrogen blower, redissolving the residue with 150 μl methanol/water=50/50, mixing by vortex, and sampling with a sample injection amount of 8 μl.

7. Preparation of a Standard sample

Accurately absorbing a proper amount of compound stock solution, and adding acetonitrile to dilute the stock solution to prepare a standard series of solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, mixing uniformly by vortex, preparing plasma samples with the plasma concentrations of 3, 5, 10, 30, 100, 300, 1000, 3000, 5000 and 10000ng/mL, carrying out double-sample analysis according to the operation of pretreatment of the plasma samples, and establishing a standard curve.

8. Analysis method

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

9. Data processing

And calculating pharmacokinetic parameters by adopting WinNonlin 6.1 software and a non-atrioventricular model method.

The test results show that the compounds of the present invention exhibit excellent pharmacokinetic properties when administered intravenously or orally.

4. Pharmacodynamic evaluation of the Compounds of the invention

Test materials:

western diet: purchased from Research set, cat: D12079B;

MCD diet: purchased from south Tong Talaofe feed technologies Co., ltd., product number: TP3006R;

ALT, AST, ALP, TG, CHO, HDL, LDL and GLU: purchased from Roche, goods number was: 20764957322 20764949322, 03333701190, 20767107322, 03039773190, 04399803190, 03038866322 and 04404483190;

male OB/OB mice at 8 weeks of age: purchased from Jiangsu Jizhikang biotechnology Co., ltd;

male db/db mice at 8 weeks of age: purchased from Jiangsu Jizhikang biotechnology Co.

A. Compound non-alcoholic steatohepatitis (NASH) model in Western diet induced OB/OB mice Pharmacodynamic evaluation of (C)

The OB/OB mice are leptin gene deletion mice, and the Western diet induced NASH model of the OB/OB mice is a commonly used in vivo drug efficacy evaluation model of NASH. The experiment was started after 1 week of acclimatization. OB/OB mice were fed with Western diet, the diet was changed three times per week (Monday, three, five), and the mice were dosed orally once a day for 6 weeks starting at the fifth week after feeding, for a total experimental period of 10 weeks. The animals were monitored daily for baseline conditions during the experiment and mice weights were recorded weekly. After the experiment was completed, the mice were fasted overnight, and after anesthesia, the mice were subjected to orbital blood collection to collect whole blood, and centrifuged at 4℃and 4000rpm for 10min to obtain serum, which was stored at-80 ℃. Serum was used for ALT, AST, ALP, TG, CHO, HDL, LDL and GLU detection. Mice were dissected, lived and weighed. The middle lobe of the liver was stored in EP tube at-80℃for determination of TG and CHO contents in the liver. After left lobe of liver was fixed in 10% formalin, HE staining was performed and NAS scoring was performed.

B. Drug efficacy of compounds in MCD diet-induced db/db mice non-alcoholic steatohepatitis (NASH) model Evaluation of study

The db/db mice are leptin receptor gene deletion mice, and the NASH model of the db/db mice induced by MCD diet is a commonly used in vivo drug effect evaluation model of NASH. The experiment was started after 1 week of acclimatization. db/db mice were fed with MCD feed and the feed was changed three times per week (monday, wednesday, friday) and the mice were tested by mode of administration with molding, once a day for 8 weeks with a total test period of 8 weeks. The animals were monitored daily for baseline conditions during the experiment and mice weights were recorded weekly. After the experiment was completed, the mice were fasted overnight, and after anesthesia, the whole blood was collected by orbital blood collection, and centrifuged at 4℃and 4000rpm for 10min to obtain serum, which was stored at-80 ℃. Serum was used for ALT, AST, ALP, TG, CHO, HDL, LDL and GLU detection. Mice were dissected, lived and weighed. The middle lobe of the liver was stored in EP tube at-80℃for determination of TG and CHO contents in the liver. After left lobe of liver was fixed in 10% formalin, HE staining was performed and NAS scoring was performed.

The test result shows that the compound can effectively reduce fat accumulation in liver, reduce inflammation and improve liver fibrosis.

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

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. A compound having the structure of one of:

Or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound of claim 1, optionally, further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or any combination thereof.

3. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 2 in the manufacture of a medicament for agonizing a thyroid hormone receptor, or for preventing, treating or alleviating a disease mediated by a thyroid hormone receptor agonist, wherein the thyroid hormone receptor is a thyroid hormone beta receptor.

4. The use according to claim 3, wherein the disorder modulated by a thyroid hormone receptor agonist is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, a metabolic disorder, a lipid metabolic disorder, a glycogen storage disease type 1A, hypothyroidism or thyroid cancer;

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