HK40049241A - A ring fused thr-beta receptor agonist compound and a preparation method and use thereof - Google Patents

Description

Fused-ring THR beta receptor agonist compound and preparation method and application thereof

The present application claims priority rights of the invention patent application with application number 201910763932.4, entitled "a fused ring THR β receptor agonist compound and its preparation method and use" filed by 2019 on 8/19 to the chinese patent office, which is incorporated herein by reference.

Technical Field

The invention relates to the field of drug synthesis, in particular to a compound serving as a novel agonist of THR beta receptor, and a preparation method and application thereof.

Background

Thyroid Hormone (TH) is synthesized in the thyroid gland in response to Thyroid Stimulating Hormone (TSH) secreted by the pituitary. Thyroxine plays a very important role in regulating body growth, development, metabolism, and matrix balance. There are two major thyroid hormones, 3,5, 3' -triiodo-L-thyroxine (T3) and thyroxine (T4). The human body secretes mainly T4, and in peripheral organs, T4 is converted by deiodinase to more active T3. Thyroid production of T3 and T4 is under negative feedback control, and Thyroid Stimulating Hormone (TSH) is responsible for normal thyroid function and thyroid hormone secretion. Thyroid stimulating hormone is synthesized in the anterior lobe of the pituitary gland, and its secretion is controlled by Thyroid Releasing Hormone (TRH) synthesized in the hypothalamus.

Thyroid hormones function by binding to Thyroid Hormone Receptors (THR). Thyroid hormone receptors belong to a large family of nuclear receptors and regulate the expression of target genes. There are two distinct subtypes of thyroid hormone receptors, THR α and THR β. THR alpha is mainly distributed in heart tissues and plays an important role in regulating and controlling the functions of the heart. The THR β subtype is mainly expressed in the liver and pituitary, regulates cholesterol metabolism, and regulates thyroid stimulating hormone secretion.

At normal levels, the thyroid hormone THs maintains body weight, metabolic rate, body temperature, mood and regulates serum cholesterol. The use of thyroid hormones to regulate serum cholesterol has been attempted. However, administration of natural thyroid hormones has adverse effects on the heart (such as tachycardia and arrhythmia, heart failure, and the cause of thyroid axis function, muscle metabolism and osteoporosis), making it unusable for the treatment of high cholesterol and obesity. Animal studies of selective knockdown of the THR gene, as well as the results of some selective THR ligands, have shown that these cardiac side effects caused by thyroid hormones can be attributed to THR α.

Thyroid hormone receptor pathways regulate lipid metabolism, including cholesterol, triglycerides, and lipoproteins. It has been shown clinically that lowering low-density cholesterol will reduce the incidence of cardiovascular and cerebrovascular diseases.

Non-alcoholic fatty liver disease (NAFLD), also a type of metabolic disorder caused by excessive accumulation of triglycerides in the liver, further can cause damage to liver cells and cause inflammation, resulting in non-alcoholic fatty liver disease (NASH). NASH patients are also commonly associated with type ii diabetes, high cholesterol, high blood lipids, and obesity. NASH patients have a high probability of developing into cirrhosis, liver failure, and eventually liver cancer. There is currently a lack of effective drugs for treating NASH. Thyroid hormones regulate the function of lipid metabolism, making the thyroid receptor pathway a potential target for treatment of NASH and NAFLD. In animals, thyroid hormone analogues have been shown to significantly reduce the degree of liver fat in animals.

The selective THR beta agonist can be used for avoiding the cardiac side effect caused by the conventional THR receptor agonist, selectively activates the THR beta only, improves the metabolism of cell lipid and plays the roles of reducing cholesterol and blood fat. However, selective THR β agonists may also inhibit the thyroid axis, resulting in depression, fatigue, osteoporosis, and other side effects. It is therefore desirable to develop a selective THR β agonist that activates THR β but reduces inhibition of the thyroid axis, thereby circumventing the side effects associated with thyroid axis inhibition.

Patents WO03094845, WO2007009913, WO2010122980, WO2011038207, etc., disclose THR receptor agonists whose structures are almost all designed and developed based on the natural ligand T3 of the THR receptor. Based on these backgrounds, there is still a need to develop selective THR β receptor agonists that have both the beneficial effects of thyroid hormones but avoid the adverse side effects of the heart.

WO2005051298 also discloses certain THR receptor agonists, of which the preferred compound (MB07444) is of the structure:

WO2006128058 also discloses certain THR receptor agonists in which several naphtholic fused ring compounds are of the following structure. However, this patent does not disclose any other structures or embodiments similar to the compounds of the present invention.

The invention is based on the structural modification of THR receptor natural ligand T3, and the inventor unexpectedly discovers that after the structural modification of naphthol part, some compounds unpredictably improve THR beta receptor agonistic activity (compared with compound No. 7/MB07444 in WO2005051298 patent); almost all fused ring compounds improved selectivity to THR α (compared to MB 07444). Meanwhile, after being modified by prodrugs, some compounds of the invention can be highly enriched in liver target organs, and further reduce the distribution in heart organs, thereby potentially reducing clinical side effects.

Disclosure of Invention

In order to solve the technical problems, the invention adopts the following technical scheme:

according to one aspect of the present invention, there is provided a compound represented by the following formula (I) and isomers thereof or pharmaceutically acceptable salts thereof,

wherein the content of the first and second substances,

R₁and R₂Each independently selected from halogen atoms or C_1-6An alkyl group;

R₃and R₄Each independently selected from hydrogen, C_1-6Alkyl, unsubstituted phenyl, substituted by one or more radicals selected from halogen atoms, trifluoromethyl, C_1-6Alkyl radical, C_1-6Phenyl substituted with at least one substituent selected from the group consisting of alkoxy and cyano, unsubstituted naphthyl, substituted with at least one substituent selected from the group consisting of halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6Naphthyl substituted with a substituent of at least one of alkoxy and cyano,or R₃、R₄Together with adjacentTogether form a six-membered ringWherein V is an unsubstituted five-to ten-membered aryl group consisting of a halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6A five-to ten-membered aryl group substituted with at least one substituent selected from the group consisting of alkoxy and cyano, containing 1 or 2 hetero atoms selected from the group consisting of N, S and OUnsubstituted five-to ten-membered heteroaryl of an atom consisting of a group selected from halogen atoms, trifluoromethyl, C_1-6Alkyl radical, C_1-6A five-to ten-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, S and O, substituted with at least one substituent of alkoxy and cyano;

R₅is selected from H or C_1-6An alkyl group;

R₆、R₇、R₈each independently selected from C_1-6An alkyl group;

x is selected from-O-or-CH₂-；

Y is selected from-O-or-CH₂-；

Z, Z' are each independently selected from-O-or-NH-;

l is selected from-O-, -S-or-CH₂-

n is 1,2 or 3;

the halogen atom is selected from F, Cl or Br.

According to another aspect of the present invention, preferably, in the structure represented by formula (I), R₁And R₂Each independently selected from F, Cl, Br or-CH₃。

Further preferably, R₁And R₂Are all Cl.

Or preferably R₁And R₂Are all-CH₃。

According to another aspect of the present invention, preferably, in the structure represented by formula (I), R₅Is selected from H or-CH₃；

According to another aspect of the present invention, preferably, in the structure represented by formula (I), n is 1 or 2; further preferably, n is 1;

according to another aspect of the present invention, preferably, in the structure represented by formula (I), X is-CH₂-；

According to another aspect of the present invention, preferably, in the structure represented by formula (I), Y is-O-;

preferably, in the structure represented by formula (I), V is an unsubstituted phenyl group consisting of a halogen atom, trifluoromethyl, C_1-3Alkyl and C_1-3At least one of the alkoxy groups being a hetero atomPhenyl substituted by substituents, unsubstituted five-to six-membered monocyclic heteroaryl containing 1 or 2 heteroatoms selected from N, S and O, substituted by substituents selected from halogen atoms, trifluoromethyl, C_1-3Alkyl and C_1-3A five to six membered monocyclic heteroaryl group containing 1 or 2 heteroatoms selected from N, S and O substituted with at least one substituent of alkoxy.

According to another aspect of the present invention, preferably, the compound represented by formula (I) and isomers thereof or pharmaceutically acceptable salts thereof have a structure as shown in the following formula (II):

wherein the content of the first and second substances,

R₁、R₂、R₅x, Y, n are as defined above for formula (I);

further preferably, in the structure represented by the formula (II),

R₁and R₂Are all-CH₃；

R₅Is selected from-CH₃；

X is-CH₂-；

Y is-O-;

l is-CH₂-；

n is 1 or 2.

According to another aspect of the present invention, preferably, the compound represented by formula (I) and isomers thereof or pharmaceutically acceptable salts thereof have a structure as shown in the following formula (III):

wherein the content of the first and second substances,

R₁、R₂、R₅x, Y, L, n, V are as defined above for formula (I);

further preferably, in the structure represented by the formula (II),

R₁and R₂Are all-CH₃；

R₅Is selected from-CH₃；

X is-CH₂-；

Y is-O-;

l is-CH₂-；

n is 1 or 2;

preferably, V is an unsubstituted phenyl radical, consisting of a group selected from halogen atoms, trifluoromethyl, C_1-3Alkyl and C_1-3Phenyl substituted by at least one substituent selected from the group consisting of alkoxy, pyridyl consisting of a halogen atom, trifluoromethyl, C_1-3Alkyl and C_1-3Pyridyl substituted with at least one substituent of alkoxy.

Even more preferably, V is m-chlorophenyl.

According to another aspect of the present invention, preferably, the compound represented by formula (I) and isomers thereof or pharmaceutically acceptable salts thereof have a structure as shown in the following formula (IV):

wherein the content of the first and second substances,

R₁、R₂、R₅x, Y, L, n are as defined above for formula (I);

R₃and R₄Each independently is C_1-6Alkyl, phenyl, substituted by radicals selected from halogen atoms, trifluoromethyl, C_1-6Alkyl radical, C_1-6Phenyl substituted with at least one substituent selected from the group consisting of alkoxy and cyano, naphthyl, substituted with at least one substituent selected from the group consisting of halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6Naphthyl substituted with at least one substituent of alkoxy and cyano,

wherein R is₆Is selected from C_1-6An alkyl group;

further preferably, in the structure shown in formula (IV),

R₁and R₂Are all-CH₃；

R₅Is selected from-CH₃；

X is-CH₂-；

Y is-O-;

l is-CH₂-；

n is 1 or 2;

R₃and R₄Are all thatWherein R is₆Is C_1-6An alkyl group;

even more preferably, R₃And R₄Are all that

According to another aspect of the present invention, preferably, the compound represented by formula (I) and isomers thereof or pharmaceutically acceptable salts thereof have a structure represented by the following formula (V):

wherein the content of the first and second substances,

R₁、R₂、R₅x, Y, L, n are as defined above for formula (I);

R₄is selected from C_1-6Alkyl, phenyl, substituted by radicals selected from halogen atoms, trifluoromethyl, C_1-6Alkyl radical, C_1-6Phenyl substituted with at least one substituent selected from the group consisting of alkoxy and cyano, naphthyl, substituted with at least one substituent selected from the group consisting of halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6Naphthyl substituted with a substituent of at least one of alkoxy and cyano,

R₇、R₈each independently selected from C_1-6An alkyl group;

further preferably, in the structure represented by formula (V),

R₁and R₂Are all-CH₃；

R₅Is selected from-CH₃；

X is-CH₂-；

Y is-O-;

l is-CH₂-；

n is 1 or 2;

R₄is phenyl or naphthyl;

R₇is methyl;

R₈is ethyl or isopropyl;

according to another aspect of the present invention, preferably, the compound and pharmaceutically acceptable salts and prodrugs thereof is one of the following compounds:

according to another aspect of the present invention, there is provided a process for the preparation of the compound, the process comprising the steps of:

1) adding paraformaldehyde and potassium carbonate into isopropanol, heating to 50 ℃, slowly dropwise adding diisopropyl phosphite, and stirring for 2 hours at 50 ℃. Post-treating to obtain a compound of general formula 1-b;

2) and respectively adding the compound 1-b and triethylamine into dichloromethane, and cooling the system by using an ice bath to 4 ℃. Under stirring, the solution of p-toluenesulfonyl chloride was slowly dropped into the reaction solution through a dropping funnel, and after dropping, stirring was continued for 2 hours while maintaining the ice bath. After the reaction is finished, carrying out post-treatment to obtain active ester 1-c;

3) adding the compound 1-c into a mixture of dimethyl sulfoxide, the compound 1-d and cesium carbonate, heating to 55 ℃ under the atmosphere of nitrogen, and stirring for 6 hours to react to obtain a compound of a general formula 1-e;

4) adding the compound 1-e into a dichloromethane solution of the compound 1-f, cooling the system to 4 ℃ by using an ice bath, and dropwise adding trifluoroacetic acid for catalytic reaction. After post-treatment, a compound of general formula 1-g is obtained;

5) adding dropwise trimethylchlorosilane into acetonitrile solution of 1-g of the compound and potassium iodide, heating to 50 ℃, and stirring for reacting for 2 hours. Removing alkyl to obtain a phosphate compound II;

6) the phosphoric acid compound II and 1- (3-chlorophenyl) propane-1, 3-diol were dissolved in pyridine and DMF, and the condensation reagent DCC was added at room temperature. Heating to 70 ℃, stirring for 4h, and carrying out post-treatment to obtain the prodrug compound III of II.

7) Alternatively, diisopropylethylamine was added to a solution of the phosphate compound II in acetonitrile at room temperature. After heating to 40 ℃ and stirring for half an hour, the mixture is added with iodide and stirred overnight. Diester reaction occurs to produce the phosphate ester prodrug IV.

8) Alternatively, the phosphoric acid compound II is reacted with phenol or naphthol R₄The reaction of-OH under the promotion of condensation reagent DCC, then sulfonyl chloride to generate acyl chloride intermediate, and then reacting with amino acid ester to obtain prodrug compound V of II.

Each substituent R in the above reaction scheme₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈X, Y, L, n, V are as defined above for formula (I).

According to another aspect of the invention, the invention provides the use of the compound in the manufacture of a medicament for the treatment of a metabolic-related disorder or a fibrosis-related disorder.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the compound according to the present invention and pharmaceutically acceptable salts thereof as an active ingredient, and pharmaceutically acceptable excipients.

Preferably, the metabolic-related disease is selected from: obesity, hyperlipidemia, hypercholesterolemia, diabetes, and nonalcoholic fatty liver disease (NASH), hepatic steatosis, atherosclerosis, hypothyroidism and thyroid cancer, hepatic fibrosis, pulmonary fibrosis; preferably, the metabolic-related disease is selected from: nonalcoholic fatty liver disease (NASH), hypothyroidism, thyroid cancer, hepatic fibrosis, and pulmonary fibrosis.

According to another aspect of the present invention, there is provided a method for treating metabolic-related diseases, the method comprising administering to a subject an effective amount of the compound according to the present invention or a pharmaceutical composition comprising the compound and pharmaceutically acceptable salts thereof as an active ingredient.

Preferably, according to the method of treating a metabolic-related disorder, the metabolic-related disorder is selected from the group consisting of: obesity, hyperlipidemia, hypercholesterolemia, diabetes, as well as nonalcoholic fatty liver disease (NASH), hepatic steatosis, atherosclerosis, hypothyroidism, and thyroid cancer; preferably, the metabolic-related disease is selected from: nonalcoholic fatty liver disease (NASH), hypothyroidism, and thyroid cancer.

Preferably, according to another aspect of the present invention, there is provided a method for treating a metabolic-related disease or a fibrosis-related disease, the method comprising administering to a subject an effective amount of the compound according to the present invention or a pharmaceutical composition comprising the compound and its isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

Detailed Description

Hereinafter, the present invention will be described in detail. Before the description is made, it should be understood that the terms used in the present specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the invention, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the invention.

In accordance with the present invention, all terms referred to herein have the same meaning as those skilled in the art to understand the present invention, unless otherwise specified.

The term "salt" as used herein refers to a cation and anion containing compound that can be produced by protonation of an acceptable proton site and/or deprotonation of an available proton site. Notably, protonation of the acceptable proton sites results in the formation of cationic species whose charge is balanced by the presence of physiological anions, while deprotonation of the available proton sites results in the formation of anionic species whose charge is balanced by the presence of physiological cations.

The term "pharmaceutically acceptable salt" means that the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-p-toluenesulfonic acid, camphoric acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, cis-hexadiene diacid, and the like; or (2) a base addition salt, and a conjugate base of any of the above inorganic acids, wherein the conjugate base comprises a compound selected from Na⁺、K⁺、Mg²⁺、Ca²⁺、NH_xR_4-x ⁺The cationic component of (1), wherein NH_xR_4-x ⁺(R is C_1-4Alkyl, subscript x is an integer selected from 0, 1,2, 3, or 4) represents a cation in the quaternary ammonium salt. It is to be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein of the same acid addition salt.

The term "C_1-MAlkyl "refers to an alkyl group containing from 1 to M carbon atoms, for example where M is an integer having the following value: 2. 3, 4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28. 29 or 30. For example, the term "C_1-6Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

The term "aryl" refers to an aromatic system, which may be a single ring or multiple aromatic rings that are otherwise fused or linked together such that at least a portion of the fused or linked rings form a conjugated aromatic system. Aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl. Aryl groups may be optionally substituted, such as aryl or heterocyclic which may be substituted with 1 to 4 groups selected from: halogen, -CN, -OH, -NO₂Amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio.

The term "substituted" means that the reference group may be substituted with one or more additional groups individually and independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic hydrocarbon, hydroxy, alkoxy, alkylthio, arylthio, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, arylsulfonyl, cyano, halo, carbonyl, thiocarbonyl, nitro, haloalkyl, fluoroalkyl and amino, including mono-and di-substituted amino groups and protected derivatives thereof.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound provided by the present invention may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be present in a suitable solid or liquid carrier or diluent, as well as in a suitable sterile device for injection or instillation.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. For example, a unit dose of the formulation thereof may contain from 0.05 to 200mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably a unit dose of the formulation may contain from 0.1mg to 100mg of a compound of formula (I).

The compounds and pharmaceutical compositions of the present invention represented by general formula (I) can be administered to mammals clinically, including humans and animals, via oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Most preferably oral. The optimal daily dosage is 0.01-200mg/kg body weight, and can be administered in one time or 0.01-100mg/kg body weight in several times. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.

In the present invention, the term "effective amount" may refer to an effective amount in a dosage and for a period of time required to achieve a desired effect. This effective amount may vary depending on factors such as the type of disease or the condition of the disease being treated, the particular target organ being administered, the size of the individual patient, or the severity of the disease or symptoms. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation.

Typical formulations are prepared by mixing a compound of the invention of formula (I) with a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The particular carrier, diluent or excipient employed will depend upon the mode of use and the purpose of the compound of the invention. The solvent is generally selected based on the solvent that one of skill in the art would consider safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water, as well as other non-toxic solvents that are soluble or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents or other known additives to make or use the drug in an acceptable form.

When the compound of formula (I) according to the present invention is used in combination with at least one other drug, the two drugs or more may be used separately or in combination, preferably in the form of a pharmaceutical composition. The compounds or pharmaceutical compositions of the invention according to formula (I) can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, other topical or systemic administration form.

These pharmaceutical compositions may also contain one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents or other known additives to allow the pharmaceutical composition to be manufactured or used in an acceptable form.

The route of oral administration is preferred for the medicaments of the invention. Solid dosage forms for oral administration may include capsules, tablets, powders or granules. In solid dosage forms, the compounds or pharmaceutical compositions of the present invention are mixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starches, lactose, sucrose, mannitol, silicic acid and the like; binders such as carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; humectants such as glycerin, etc.; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicate, sodium carbonate, etc.; solution retarding agents such as paraffin, etc.; absorption accelerators such as quaternary ammonium compounds and the like; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the like. In the case of capsules and tablets, the dosage form may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose and high molecular weight polyethylene glycols and the like as excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds of the present invention or pharmaceutical compositions thereof, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide; oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or mixtures of several of these substances, and the like.

In addition to these inert diluents, the compositions can also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, and perfuming agents.

The suspension may further contain a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, or a mixture of several of these substances, in addition to the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

The compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the same can be administered by other topical administration dosage forms, including ointments, powders, sprays and inhalants. The medicament may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier, and any preservatives, buffers or propellants which may be required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be within the scope of the present invention.

In addition, kits (e.g., pharmaceutical packages) are also contemplated by the present disclosure. The provided kits can comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampoule, bottle, syringe, and/or split-pack or other suitable container). In some embodiments, the provided kits may optionally further comprise a second container comprising a pharmaceutically acceptable excipient for diluting or suspending a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical compositions or compounds described herein disposed in the first and second containers are combined to form one unit dosage form.

In certain embodiments, the kits described herein further comprise instructions for using the compounds or pharmaceutical compositions contained in the kit. The kits described herein may also include information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kits and instructions provide for the treatment and/or prevention of a proliferative disease in a subject in need thereof. The kits described herein may comprise one or more additional pharmaceutical agents as separate compositions.

The present invention is described in further detail below with reference to specific examples, but the present invention is not limited to the following examples, which are intended to better illustrate certain embodiments of the present invention and should not be construed as limiting the scope of the present invention in any way. Conditions not noted in the examples are conventional conditions. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.

The structures of the compounds in the following examples were determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethylsulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) and Tetramethylsilane (TMS) as an internal standard.

MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

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

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

In the examples, the reaction temperature is, unless otherwise specified, room temperature and is 20 ℃ to 30 ℃.

The reaction progress in the examples was checked by Thin Layer Chromatography (TLC), the developing solvent system used, and the elution system for column chromatography used for purifying the compounds included: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone and petroleum ether system, the volume ratio of the solvent is adjusted according to the polarity of the compound.

Abbreviations used in the experiments: DCC, dicyclohexylcarbodiimide; TMSI, iodotrimethylsilane; EA, ethyl acetate; DCM, dichloromethane; h, hours; DMF, N-dimethylamide.

With reference to example a: preparation of ((4- ((4-hydroxynaphthyl-1-yl) methyl) -3, 5-dimethylphenoxy) methyl) phosphoric acid

The first step is as follows: synthesis of 4-hydroxymethyl-3, 5-dimethylphenol A-2:

compound A-1(91.5g,750mmol), water (525ml), 50% by mass NaOH solution (30ml) were mixed and stirred for 1h until completely clear. The system was cooled to 4 ℃ with an ice-water bath and formaldehyde solution (50g, 618mmol) was added in one portion. After stirring for 6 hours while maintaining the ice bath, the temperature was naturally raised to room temperature, and the mixture was stirred for 12 hours. The reaction solution was poured into a mixed solution of dichloromethane (200ml) and ethyl acetate (200ml), concentrated HCl (56ml) was added dropwise to pH 5, and stirred for 6 hours, and the precipitated solid was collected by filtration. The filter cake was washed with water (50ml), and dichloromethane (75ml), and dried to give A-2(40g) as a white solid.

¹H NMR(400MHz,CD3OH):6.47(s,2H),4.60(s,2H),2.34(s,6H).

The second step is that: synthesis of diisopropyl hydroxymethyl phosphate A-4:

paraformaldehyde (9g, 326mmol) and potassium carbonate were added to isopropanol (90ml), and after warming to 50 ℃, diisopropyl phosphite (45.2g, 272mmol) was slowly added dropwise and stirred at 50 ℃ for 2 hours. The temperature of the system is reduced to 35 ℃, the filtration is carried out, the filter cake is washed twice by isopropanol, and the filtrates are combined and concentrated under reduced pressure. To the residue was added dichloromethane (180ml), followed by 1N hydrochloric acid (27ml) and saturated NaHCO₃(45ml) was washed, dried and concentrated under reduced pressure to give colorless liquid A-4(53.2 g).

¹H NMR(400MHz,CDCl3):6.53(m,J＝28.0Hz,2H),4.60(m,J＝32.0Hz,2H),3.64(m,J＝12.0Hz,2H),1.24(d,J＝8.0Hz,12H).

The third step: synthesis of (diisopropoxyphosphate) methyl-4-methylbenzenesulfonate A-5:

compound A-4(49g, 250mmol) and triethylamine (69.5ml, 500mmol) were added to dichloromethane (150ml) respectively and the system was cooled to 4 ℃ with an ice bath. While stirring, a solution of p-toluenesulfonyl chloride (50g, 263mmol) in dichloromethane (350ml) was slowly added dropwise to the reaction solution (temperature controlled below 10 ℃) via a dropping funnel, and after completion of the addition, stirring was continued for 2 hours while maintaining the ice bath. The reaction mixture was washed with 1M hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate (300ml), respectively, dried, and the organic phase was concentrated under reduced pressure and purified by column chromatography to give colorless liquid A-5(78 g).

¹H NMR(400MHz,CDCl3):7.80(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),4.78(m,J＝48.0Hz,2H),4.17(m,J＝46.0Hz,3H),2.30(s,1H),1.32(m,J＝24Hz,12H).

The fourth step: synthesis of diisopropyl ((4- (hydroxymethyl) -3, 5-dimethylphenoxy) methyl) phosphate A-6:

compound A-5(35g, 100mmol) was added to a mixture of dimethyl sulfoxide (85ml), compound A-2(18g, 120mmol) and cesium carbonate (52g, 160mmol), warmed to 55 degrees Celsius under a nitrogen atmosphere, stirred for 6 hours, and cooled. Ethyl acetate (100ml) and a 1% by mass aqueous solution (200ml) of sodium chloride were added to the system, followed by liquid separation, and the organic phase was washed with saturated brine and concentrated under reduced pressure to give brown oil A-6(45 g).

¹H NMR(400MHz,CDCl3):6.62(s,2H),4.85(m,J＝32Hz,2H),4.66(s,2H),4.16(d,J＝8.0Hz,2H),2.39(s,6H),1.37(m,J＝16.0Hz,12H).

The fifth step: synthesis of diisopropyl ((4- ((4-hydroxynaphthalen-1-yl) methyl) -3, 5-dimethylphenoxy) methyl) phosphate A-8:

compound A-7(275mg, 1.91mmol) was added to a solution of Compound A-6(315mg, 0.95mmol) in dichloromethane (3ml), the system was cooled to 4 ℃ with an ice bath, trifluoroacetic acid (326mg, 2.86mmol) was added dropwise, and the TLC spot plate followed the disappearance of starting material A-6. Water (5ml) was added, the layers were separated and the organic phase was washed with water (5ml) and concentrated under reduced pressure to give a brown oil, diethyl ether (5ml) was added and the ambient temperature was-18 ℃ and after 5 minutes stirring was allowed to occur at room temperature for 1h to precipitate A-8 as a white solid (100 mg).

¹H NMR(400MHz,CDCl3):8.32(d,J＝8.0Hz,1H),8.18(d,J＝8.0Hz,1H),7.63(t,J＝12.0Hz,1H),7.56(t,J＝16.0Hz,1H),6.71(s,2H),6.43(d,J＝8.0Hz,2H),4.91(m,J＝44.0Hz,2H),4.26(m,J＝12.0Hz,4H),2.15(s,6H),1.40(m,J＝12.0Hz,12H).

And a sixth step: synthesis of ((4- ((4-hydroxynaphthyl-1-yl) methyl) -3, 5-dimethylphenoxy) methyl) phosphoric acid A

Trimethylchlorosilane (76mg, 0.7mmol) was added dropwise to a mixture of Compound A-8(100mg, 0.22mmol) and potassium iodide (116mg, 0.70mmol) in acetonitrile (1ml), the temperature was raised to 50 ℃ and the reaction was stirred for 2 hours. Ethyl acetate (20ml) and water (20ml) were added to the residue, and the mixture was separated, the organic phase was washed with saturated brine (20ml) for 1 time, and the solvent was concentrated under reduced pressure to give a black solid. Water (12ml) was added, the temperature was raised to 35 to 40 ℃, stirred for 30 minutes, filtered and dried to obtain a brown solid, reference Compound A (35 mg).

¹H NMR(400MHz,CDCl3):8.26(d,J＝8.0Hz,1H),8.18(d,J＝8.0Hz,1H),7.58(t,J＝16.0Hz,1H),7.48(t,J＝20.0Hz,1H),6.81(m,J＝16.0Hz,2H),6.57(d,J＝8.0Hz,1H),6.36(d,J＝8.0Hz,1H),4.26(s,2H),4.23(d,J＝9.0Hz,2H),2.16(s,6H).

MS m/z(ESI):371.1[M-1].

With reference to example B: preparation of ((4- ((4-hydroxy-5, 6,7, 8-tetrahydronaphthalen-1-yl) methyl) -3, 5-dimethylphenoxy) methyl) phosphoric acid.

Using the synthetic route of reference example A, reference compound B was obtained by replacing 1-naphthol (A-7) as the starting material synthesized in the fifth step with tetrahydronaphthol.

¹H NMR(400MHz,CD₃OH):6.72(s,2H),6.35(d,J＝8.0Hz,1H),6.04(d,J＝8.0Hz，1H),4.18(d,J＝12.0Hz,2H),3.68(s,2H),2.74(t,J＝4.0Hz,2H),2.67(t,J＝12.0Hz,2H),2.11(s,6H),1.86(m,J＝64.0Hz，4H).

MS m/z(ESI):375.1[M-1].

Example 1: preparation of ((4- ((7-hydroxy-1, 1-dimethyl-2, 3-dihydro-1H-indene-4-position) methyl) -3, 5-dimethylphenoxy) methyl) phosphoric acid (Compound 1).

Compound 1 can be obtained in the following synthetic manner using the synthetic route of reference example a.

The first step is as follows: synthesis of Compounds 1-2:

dissolving the compound 1-1(1.94g, 1.0eq) in 20ml THF, replacing the reaction system with nitrogen, then cooling to about 0 ℃, starting to slowly dropwise add 3M methyl magnesium bromide, controlling the temperature below 5 ℃, keeping the temperature and stirring for 0.5 hour after dropwise addition. After the reaction, a saturated ammonium chloride solution was added dropwise to the reaction mixture to quench the reaction, EA (50 ml. times.3) was extracted, the EA phase was washed with water (50 ml. times.2), saturated brine (100ml) was washed, dried over anhydrous sodium sulfate, and concentrated to give 1-2, 2.0g of an intermediate compound.

¹H NMR(400MHz,CDCl₃):7.26-7.17(m,1H),6.81-6.72(m,2H),3.79(s,3H),2.70-2.66(m,2H),1.81-1.77(m,2H),1.28(s,6H).

The second step is that: synthesis of Compounds 1-3:

polyphosphoric Acid (PPA) (2.9g) was added to the reaction flask followed by starting stirring, compound 1-2(582mg) was slowly added, and the reaction was stirred at room temperature for 2 hours. Quenching the reaction with ice water (100ml), extracting with EA (100 ml. times.3), mixing the EA phases, washing with water (50 ml. times.2), drying with saturated brine (100ml), drying over anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain compound intermediate compound 1-3, 50 mg.

¹H NMR(400MHz,CDCl₃):7.14-7.10(m,1H),6.80(d,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),3.82(s,3H),2.89-2.85(m,2H),1.91-1.88(m,2H),1.36(s,6H).

The third step: synthesis of Compounds 1-4:

dissolving compound 1-3(349mg, 2mmol) in DCM (20ml), cooling to 0 deg.C, and adding BBr dropwise₃(2 ml). Stirring and reacting for 1h at 0 ℃ after the dropwise addition. After the reaction is finished, 10ml of water is added, EA is extracted to obtain an organic phase, the organic phase is washed by 10ml of salt solution, dried, concentrated and subjected to column chromatography to obtain compound intermediates 1-4 and 230mg, and the compound intermediates are directly put into the next reaction without purification.

The fourth step: synthesis of Compounds 1-5:

compound 1-4(220mg, 1.4mmol) and A-6(2.0mmol) were dissolved in DCM (5ml), cooled to-1 deg.C, added TFA (307. mu.l, 4.1mmol) dropwise, and stirred for 1 h. After the reaction, 20ml of DCM and 10ml of water were added, EA extraction and liquid separation were carried out to obtain an organic phase, and the organic phase was washed with 10ml of water and 10ml of brine, respectively. Drying, concentrating, and performing column chromatography (PE: EA: 1) to obtain compound 1-5(110mg, pale yellow oil).

The fifth step: synthesis of Compound 1:

compound 1-5(105mg, 2.2mmol), KI (118mg, 0.71mmol) and TMSCl (77mg, 0.71mmol) were dissolved in acetonitrile (1ml), the temperature was raised to 50 ℃ and the reaction was stirred for 2 h. After the reaction was completed, 10ml of water and 10ml of EA were added and extracted to obtain an organic phase, and 10ml of EA was added to an aqueous phase and extracted, and the organic phases were combined, dried, concentrated, and prepared on a thin layer silica gel plate (DCM: MeOH. RTM.8: 1) to obtain Compound 1(20 mg).

¹H NMR(400MHz,DMSO-d₆):6.71(s,2H),6.32(d,J＝8.0Hz,1H),6.09(d,J＝8.0Hz,1H),4.03(d,J＝12.0Hz,2H),3.73(s,2H),2.88-2.85(m,2H),1.94-1.91(m,2H),1.37(s,6H).

MS m/z(ESI):389.1[M-1].

Example 2: preparation of ((4- ((7-hydroxy-1-methyl-2, 3-dihydro-1H-indene-4-position) methyl) -3, 5-dimethylphenoxy) methyl) phosphoric acid (Compound 2).

Compound 2 can be obtained by replacing intermediates 1-4 of the fourth synthesis step with 3-methyl-2, 3-dihydro-1H-inden-4-ol using the synthetic route of example 1.

MS m/z(ESI):375.1[M-1].

Example 3: preparation of ((4- ((4-hydroxy-5, 5-dimethyl-5, 6,7, 8-tetrahydronaphthalen-1-yl) methyl) -3, 5-dimethylphenoxy) methyl) phosphoric acid (compound 3).

Compound 3 can be obtained using the synthetic route of example 1, wherein intermediates 3-4 are synthesized as follows.

The first step is as follows: synthesis of Compound 3-2:

mg powder (1.56g, 65.1mmol) was immersed in anhydrous ether (10ml) and 1 pellet I was added₂. Firstly, slowly dripping 1/3 raw material compound 3-1(10g, 46.5mmol) aether (10ml) solution to initiate reaction, then slowly dripping the rest raw material compound 3-1, and continuing to slightly reflux for 0.5 h. Adding CuI (0.66g, 3.5mmol) and THF (10ml) into another reaction flask, cooling to-20 deg.C, adding dropwise prepared Grignard reagent, adding dropwise dimethyl ethylene oxide (5ml, 55.8mmol) after completion of dropwise addition, and stirring for 2 h. Reaction junctionAfter that, 20ml of water was added to quench the reaction, 30ml of EA was added to extract the organic phase, and the organic phase was dried, concentrated and subjected to column chromatography (PE: EA 10:1 to 1:1) to obtain intermediate compound 3-2(4.2g, pale yellow liquid).

The second step is that: synthesis of Compounds 3-3:

slowly dripping the compound 3-1(2.2g, 10.6mmol) into PPA (10g), controlling the temperature to be 15-25 ℃, and stirring for 2 hours at normal temperature after finishing dripping. After the reaction, 10ml of water and 10ml of ether were added and the aqueous phase was extracted with ether 2 times. The combined organic phases were dried, concentrated, and column chromatographed (PE) to give compound 3-3(230mg, pale yellow oil).

The third step: synthesis of Compounds 3-3:

dissolve compound 3-2(230mg, 1.2mmol) in DCM (10ml), cool to 0 deg.C and add BBr dropwise₃(1ml), the reaction was stirred at 0 ℃ for 1 h. Adding 10ml of water to quench and react, adding 10ml of DCM to extract an organic phase, drying, concentrating, and carrying out column chromatography (PE: EA is 10:1) to obtain a compound 3-4(100mg, light yellow oily substance).

The fourth and fifth reactions were carried out according to the synthetic route of example 1 to obtain compound 3.

¹H NMR(400MHz,DMSO-d₆):6.71(s,2H),6.32(d,J＝8.0Hz,1H),6.02(d,J＝12.0Hz,1H),4.04(d,J＝12.0Hz，2H),3.67(s,2H),2.73-2.70(m,2H),2.10(s,6H),1.85-1.78(m,2H),1.67-1.63(m,2H),1.42(s,6H).

MS m/z(ESI):403.1[M-1].

Example 4: preparation of ((4- ((4-hydroxy-5, 5-dimethyl-6, 7,8, 9-tetrahydro-5H-benzo [7] annulen-1-yl) methyl) -3, 5-dimethylphenoxy) methyl) phosphoric acid (Compound 4).

Compound 4 can be obtained using the synthetic route of example 1, wherein intermediates 4-7 are synthesized as follows.

One step: synthesis of Compound 4-2

Adding the compound 4-1(4.4g) into a reaction bottle, adding chloroform (30ml), stirring, cooling to 0 ℃, then starting to dropwise add liquid bromine (3.5g/30ml chloroform), and stirring at room temperature for 0.5h after dropwise addition. Sodium sulfite solution (20ml) was quenched, EA extracted (100ml x 3), washed with water (50ml x 2), washed with saturated brine (50ml) and dried over anhydrous sodium sulfate to give 5.3g of product.

¹H NMR(400MHz,CDCl₃):7.40(d,J＝8.0Hz,1H),6.76(d,J＝4.0Hz,1H),6.63-6.60(m,1H),3.77(s,3H),3.67(s,3H),2.71-2.67(m,2H),2.38-2.34(m,2H),1.74-1.63(m,4H).

The second step is that: synthesis of Compound 4-3

Compound 4-2(5.7g, 1.0eq) was dissolved in THF (30ml), water (30ml) was added, lithium hydroxide monohydrate (3.9g, 5.0eq) was added with stirring, pH was adjusted to 2 with 4N hydrochloric acid after stirring overnight, EA (100ml) was extracted, washed with water (100ml × 2), washed with saturated brine (100ml), dried over anhydrous sodium sulfate, and concentrated to give compound 4-3:5.3 g.

The third step: synthesis of Compound 4-4

To PPA (240g) was added dropwise compound 4-3(3.6g), and the reaction was stirred at 55 ℃ for 4 hours. Quenching with ice water (400ml), EA (150ml × 3), washing with water (100ml × 2), washing with saturated brine (100ml), drying over anhydrous sodium sulfate, and concentrating to give oily compound 4-4: 2.4 g.

¹H NMR(400MHz,CDCl₃):7.54(d,J＝8.0Hz,1H),6.73(d,J＝8.0Hz,1H),3.79(s,3H),2.93-2.90(m,2H),2.61-2.60(m,2H),1.76(m,4H).

The fourth step: synthesis of Compounds 4-5

The compound 4-4(1.61g, 1.0eq) and sodium acetate (0.5g,1.0eq) were charged in a reaction flask, and methanol (8ml), dioxane (16ml) and Pd/c (160mg), H were added₂The reaction mixture was stirred at room temperature under hydrogen atmosphere overnight. Filtration and concentration, dissolution of the residue EA (200ml), washing with water (50ml × 2), washing with saturated brine (50ml), drying over anhydrous sodium sulfate, concentration to give yellow oily compound 4-5: 1.2 g.

¹H NMR(400MHz,CDCl₃):7.29-7.25(m,1H),6.83(d,J＝8.0Hz,1H),6.74(d,J＝8.0Hz,1H),3.81(s,3H),2.75-2.72(m,2H),2.65-2.63(m,2H),1.82-1.80(m,4H).

The fifth step: synthesis of Compounds 4-6

Mixing TiCl₄(7.8g, 6.8mmol) was dissolved in DCM (15ml), cooled to-50 ℃ and (CH) was added₃)₂Zn (41ml, 0.1M in toluene) was stirred for 0.5h, 4-5(1.3g in 40ml DCM) was added dropwise, and stirring was carried out overnight with natural warming. After the reaction, 50ml of water was added to quench the reaction, 50ml of DCM was extracted 3 times, the combined organic phases were washed with 50ml of brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography gave 4-6(1g of colorless liquid).

And a sixth step: synthesis of Compounds 4-7

Dissolve compound 4-6(1g, 4.9mmol) in DCM (50ml), cool to 0 deg.C, add BBr₃(5ml), stirred at ambient temperature for 1 h. After the reaction, 50ml of water was added to quench the reaction, and the DCM phase was obtained by extraction and washed with 50ml of brine. Dried over anhydrous sodium sulfate, concentrated, and passed through a column (PE: EA: 100:1 to 10:1) to give compound 4-7(335mg, colorless oil).

¹H NMR(400MHz,CD₃OD):6.80-6.76(m,1H),6.56(d,J＝12.0Hz,1H),6.48(d,J＝8.0Hz,1H),2.84(brs,2H),1.86-1.75(m,6H),1.46(s,6H).

Compound 4 can be prepared following the synthetic route of example 1 using intermediates 4-7.

¹H NMR(400MHz,CD₃OD):9.29(s,1H),6.63-6.21(m,2H),6.38(d,J＝12.0Hz,1H),6.12(d,J＝12.0Hz,1H),4.42-4.32(m,1H),3.76-3.69(m,4H),2.61-2.55(m,2H),2.05(s,6H),1.65-1.53(m,6H),1.11(d,J＝8.0Hz,6H).

MS m/z(ESI):417.1[M-1].

Example 5: preparation of ((4- ((7-hydroxy-1, 1-dimethyl-2, 3-dihydro-1H-indene-4-position) oxy) -3, 5-dimethylphenoxy) methyl) phosphoric acid (Compound 5).

Using a synthetic route analogous to example 1, Compound 5 can be obtained.

MS m/z(ESI):391.1[M-1].

Example 6: preparation of ((3, 5-dichloro-4- ((7-hydroxy-1, 1-dimethyl-2, 3-dihydro-1H-indene-4-position) methyl) phenoxy) methyl) phosphate (Compound 6).

Using a synthetic route analogous to example 1, Compound 6 can be obtained.

¹H NMR(400MHz,CD₃OD):7.08(s,2H),6.35(d,J＝8.4Hz,1H),6.19(d,J＝8.4Hz,1H),4.66-4.51(m,2H),4.07-4.02(m,4H),2.90(t,J＝14.7Hz,2H),1.93(t,J＝14.7Hz,2H),1.37(m,6H).

MS m/z(ESI):429.5[M-1].

Example 7: preparation of 4- (3-chlorophenyl) -2- ((4- ((7-hydroxy-1, 1-dimethyl-2, 3-dihydro-1H-indene-4-position) methyl) -3, 5-dimethylphenoxy) methyl) -1,3, 2-dioxaphosphorinane 2-oxo (Compound 7).

The following synthetic route is adopted:

compound 1(211mg,0.54mmol) and 1- (3-chlorophenyl) propane-1, 3-diol (302mg,1.62mmol) were dissolved in pyridine (1ml) and DMF (5ml), and DCC (334mg,1.62mmol) was added at room temperature. Heated to 70 ℃ and stirred for 4 h. After cooling to room temperature, filtration, concentration and column chromatography gave racemic compound 7(100 mg).

MS m/z(ESI):541.1[M+1].

Example 8: preparation of ((4- ((7-hydroxy-1, 1-dimethyl-2, 3-dihydro-1H-indene-4-position) methyl) -3, 5-dimethylphenoxy) methyl) phosphoryl) bis (oxy)) bis (methylene) bispentanoyl (compound 8).

The following synthetic route is adopted:

diisopropylethylamine (140mg,1.08mmol) was added to a solution of compound 1(211mg,0.54mmol) in acetonitrile (10ml) at room temperature. After heating to 40 ℃ and stirring for half an hour, the mixture was stirred overnight with the addition of iodo-8-1 (261mg,1.08 mmol). Then, iodo (8-1) (261mg,1.08mmol) and diisopropylethylamine (140mg,1.08mmol) were added further and the reaction was continued at this temperature for 6 h. The reaction was quenched with 50ml of water and extracted to obtain EA phase, which was washed with 50ml of brine. Dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give racemic compound 7(150 mg).

MS m/z(ESI):619.2[M+1].

Examples 9 and 11: preparation of compounds 9 and 11.

The following synthetic route is adopted:

first step, synthesis of intermediate 9-1:

to a mixture of compound 1(780mg, 2mmol), phenol (376mg,4mmol), DCC (1.24g, 6mmol), and DMAP (244mg, 2mmol), DMF (20mL) and pyridine (4mL) were added in this order, and after the addition, the temperature was raised to 80 ℃ and the reaction was stirred for 15 hours. After cooling, the solvent was directly concentrated under reduced pressure and column chromatography was carried out to give intermediate 9-1(200 mg).

MS m/z(ESI):465.1[M+1].

Second step, synthesis of compounds 9 and 11:

to a solution of compound 9-1(200mg, 0.43mmol) and DMF (32mg, 0.43mmol) in dichloromethane (2mL) was slowly added thionyl chloride (1.72mmol) dropwise under ice-cooling. After the completion of the dropwise addition, the reaction system was heated to reflux and stirred for 3 hours. After cooling to room temperature, L-alanine isopropyl ester hydrochloride (287mg, 1.72mmol) and diisopropylethylamine (222mg, 1.72mmol) were added to the reaction system, and stirring was performed at room temperature for 15 hours. The reaction was quenched by the addition of water (50ml) and extracted 1 time with ethyl acetate (50 ml). The organic phase was concentrated under reduced pressure and resolved to give compounds 9 and 11.

Structural characterization of compound 9:

MS m/z(ESI):580.1[M+1].

¹H NMR(400MHz,DMSO-d6):8.79(s,1H),7.38-7.34(m,2H),7.23-7.15(m,3H),6.70(m,2H),6.35(d,J＝8.0Hz,1H),6.01-5.99(m,1H),5.90-5.84(m,1H),4.78-4.70(m,1H),4.32(d,J＝9.6Hz,2H),4.00-3.93(m,1H),3.66(s,2H),2.84-2.80(m,2H),2.09(s,6H),1.87-1.83(m,2H),1.30(s,6H),1.19(d,J＝6.8Hz,3H),1.10-1.08(m,6H).

example 10: preparation of Compound 10

Using a synthetic route analogous to example 7, Compound 10 can be obtained.

To a mixture of compound 1(780mg, 2mmol), compound 10-1(1.16g, 6mmol) and DCC (1.24g, 6mmol) were added DMF (20mL), and pyridine (4mL) in that order. After the addition, the temperature was raised to 70 ℃ and the mixture was stirred for 18 hours. The solvent was concentrated under reduced pressure, and the compound 10(150mg) was obtained by resolution.

MS m/z(ESI):541.1[M+1].

¹H NMR(400MHz,DMSO-d6):8.81(s,1H),7.48(s,1H),7.43-7.41(m,3H),6.74(s,2H),6.35(d,J＝7.6Hz,1H),6.02(d,J＝7.6Hz,1H),5.82(m,1H),4.62-4.38(m,4H),3.66(s,2H),2.86-2.77(m,2H),2.29-2.18(m,2H),2.09(s,6H),1.90-1.80(m,2H),1.30(s,6H).

The following compounds can be prepared by following the synthetic routes of example 7-example 11 using compound 2 as a starting material.

Test example 1: compound binding to TR α assay:

1. main experimental materials and instruments:

an Envision 2104 microplate reader,

Biotin-SRC 2-2 coactivator peptide was purchased from Biotechnology engineering (Shanghai) Ltd

TR α LBD, GST Purchase Saimei Feishale (Cat number PV4762)

Europium-binding anti-glutathione antibodies were purchased from Cisbio (cat # 61GSTKLB)

streptavidin-D2 was purchased from Cisbio (cat # 610SADAB)

2. Preparation and treatment of compounds

2.1 preparation of stock solutions of Compound dimethyl sulfoxide

All compounds 1 to 6 were dissolved in dimethyl sulfoxide and prepared as 10 mmol stock solutions.

2.2 storage of Compounds

After the compounds 1 to 6 were dissolved in dimethyl sulfoxide, they were stored in a desiccator at room temperature for three months. And storing for a long time in a refrigerator at the temperature of minus 20 ℃.

3. Experimental procedure

3.1 preparation of 1 Xreaction buffer

3.2 screening of Compounds:

a) the positive drug, triiodothyronine (T3), was diluted 1:3 from 10 millimoles (100X) or the test compound from 1 millimole (100X) in 100% dimethylsulfoxide at 10 concentrations.

b) Compounds diluted 4x over a concentration gradient were prepared with 1x reaction buffer.

c) Add 5 μ l of 4x concentration gradient diluted compound to 384 well assay plate.

d) 4X TR α LBD and 4X RXR α were prepared with 1 × reaction buffer.

e) Add 5 microliters of 4X TR α LBD and 4X RXR α to 384 well assay plates.

f) 2 XBiotin-SRC 2-2,2 Xeuropium-binding anti-glutathione antibodies and 2X streptavidin-d 2 were prepared in 1 Xreaction buffer.

g) Add 10. mu.l of 2 Xmix (cf. step f) to 384 well assay plates.

h) The 384 well assay plates were centrifuged for 1 minute at 1000 rpm in a centrifuge.

i) Incubate for 1 hour at room temperature in the dark.

j) The Envision 2104 microplate reader records the fluorescence signal values at 665nm and 615nm wavelength of each well of the 384-well test plate, and calculates the 665nm/615nm fluorescence ratio.

4. Data analysis

4.1 calculate the relative ratio per well (ratio)_665nm/615nm-ratio of_{Blank space})

4.2 percent Activity is calculated as follows:

average of relative ratio of compound wells of examples

Average of relative ratio of all positive control wells.

Average of relative ratio of all negative control wells.

4.3 plotting of the curves and calculation of EC 50:

EC50 was calculated by fitting the relationship between activity (%) and log concentration of compound using Graphpad 5.0 by non-linear regression.

Y ═ bottom + (top-bottom)/(1 +10^ ((LogEC50-X) × slope))

X compound logarithmic concentration Y percent specific activity

Specific test data are shown in table 1 below.

Test example 2: compound TR beta binding assay

1. Main experimental materials and instruments:

an Envision 2104 microplate reader,

Biotin-SRC 2-2 coactivator peptide was purchased from Biotechnology engineering (Shanghai) Ltd

TR β LBD, GST purchase Saimei Feishale (Cat number PV4762)

Europium-binding anti-glutathione antibodies were purchased from Cisbio (cat # 61GSTKLB)

streptavidin-D2 was purchased from Cisbio (cat # 610SADAB)

2. Preparation and treatment of compounds

2.1 preparation of stock solutions of Compound dimethyl sulfoxide

All compounds 1 to 6 were dissolved in dimethyl sulfoxide and prepared as 10 mmol stock solutions.

2.2 storage of Compounds

After the compound is dissolved in dimethyl sulfoxide, the compound can be stored in a dryer at room temperature for three months. And storing for a long time in a refrigerator at the temperature of minus 20 ℃.

3. Experimental procedure

3.1 preparation of 1 Xreaction buffer

3.2 screening of Compounds:

a) the positive drug, triiodothyronine (T3), was diluted 1:3 from 10 micromoles (100X) or the test compound from 1 millimole (100X) in 100% dimethylsulfoxide at 10 concentrations.

b) Compounds diluted 4x over a concentration gradient were prepared with 1x reaction buffer.

c) Add 5 μ l of 4x concentration gradient diluted compound to 384 well assay plate.

d) 4X TR β LBD and 4X RXR β were prepared with 1 × reaction buffer.

e) Add 5 microliters of 4X TR β LBD and 4X RXR β to 384 well assay plates.

f) 2 XBiotin-SRC 2-2,2 Xeuropium-binding anti-glutathione antibodies and 2X streptavidin-d 2 were prepared in 1 Xreaction buffer.

g) Add 10. mu.l of 2 Xmix (cf. step f) to 384 well assay plates.

h) The 384 well assay plates were centrifuged for 1 minute at 1000 rpm in a centrifuge.

i) Incubate for 1 hour at room temperature in the dark.

j) The Envision 2104 microplate reader recorded the 665nm and 615nm fluorescence signal values for each well of the 384-well plate and calculated Ratio 665nm/615 nm.

4. Data analysis

4.1 calculate the relative ratio per well (ratio)_665nm/615nm-ratio of_{Blank space})

4.2 percent Activity is calculated as follows:

average of relative ratio of compound wells of examples

Average of relative ratio of all positive control wells.

Average of relative ratio of all negative control wells.

4.3 plotting of the curves and calculation of EC 50:

EC50 was calculated by fitting the relationship between activity (%) and log concentration of compound using Graphpad 5.0 by non-linear regression.

Y ═ bottom + (top-bottom)/(1 +10^ ((LogEC50-X) × slope))

X compound logarithmic concentration Y percent specific activity

Specific test data are shown in table 1 below. The selection algorithm was calculated according to the literature (A Pharmacology Primer Techniques for More efficient and robust Drug Discovery, 4th Edition, Page 220) after normalization with T3.

The binding activity of the compounds of table 1 for the thyroxine receptor β is as follows:

and (4) conclusion: most of the compounds of the present invention unexpectedly show a very high selectivity compared to the disclosed comparative compound MB 07444; while the THR beta activity of compound 1 is much better than that of the comparative compound MB 07444. The compounds of the invention still have higher activity and selectivity even compared to the naphthol reference compound a.

And (3) testing: drug metabolism assay of prodrugs in SD rats

Two groups of 12 SD male rats with similar body weight were selected for the experiment, and the compound 9, the compound 10 and the control drug VK2809 (a prodrug of MB07444, the structure of which is shown below) were orally administered at a dose of 3mg/kg respectively, and blood and liver were collected at different time points by single administration.

Preparation of test article

Compound 9/compound 10 and VK2809 were each prepared to a final concentration of 0.6mg/mL in PEG400 with pure water 50:50 (v/v).

Group and dose

No random grouping is performed. Animal body weights were measured prior to dosing and healthy animals of similar body weights were selected for inclusion in the experiment. The dose administered orally was 3 mg/kg.

Sample collection

At least 0.2mL of tail vein or jugular vein blood is collected, and the volume of anticoagulant: heparin sodium.

Time of acquisition

15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration.

Sample processing

Blood sample is placed in a marked ice water bath centrifugal tube after being collected, and plasma is rapidly separated by centrifugation, wherein the centrifugation conditions are as follows:

3500 rpm, 10 min, 4 ℃, and storing the plasma below-40 ℃ for testing.

After the liver sample is collected, the surface of the liver sample is cleaned by normal saline, and the liver sample is placed in a marked small self-sealing bag after being wiped by medical gauze and is stored to be tested under the condition of-40 ℃.

Sample analysis

Conditions of liquid phase-mass spectrometry

Liquid phase analysis conditions:

HPLC：LC-20AD_XR,SHIMADZU

liquid phase pump: LC-20AD_XR

Column oven: CTO-20A

Automatic sample injector: SIL-20AC_XR

A controller: CBM-20A

A degasser: DGU-20A_3RA chromatographic column: ZORBAX Eclipse Plus C182.1 x 50mm,3.5 μm, Agilent

Pre-column: guard column C184 x 2.0mm, Phenomenex

Mobile phase: a: 2mM ammonium acetate in water;

b: acetonitrile;

automatic injector needle wash: 80% acetonitrile in water

Auto injector needle wash procedure: a flushing mode: before and after suction

Flushing volume of 200 μ L

Washing speed 35 μ L/sec

Gradient of mobile phase:

flow rate: 0.75mL/min

Autosampler temperature: 4 deg.C

Sample introduction volume: 2 μ L

Operating time: 2.50min

Mass spectrometry conditions:

q TRAP6500 mass spectrum with ESI source, scanned with negative ion MRM. And (3) detecting the contents of the compound 9, the compound 10 and the active metabolite 1 thereof, the VK2809 and the active metabolite MB07444 in the blood plasma and the liver by adopting an LC-MS/MS analysis method. The plasma concentration data were statistically analyzed using the pharmacokinetic data analysis software WinNonlin 7.0, and the pharmacokinetic parameters were calculated using the non-compartmental model (NCA).

Results and analysis:

the main pharmacokinetic parameters in SD rat plasma are shown in table 2 below:

TABLE 2

And (4) conclusion: prodrug compounds 9, 10 were rapidly converted to the active parent compound 1 after oral administration in rats as the control drug VK 2809. Meanwhile, the concentration of the two in plasma is not high.

The concentration parameters in the liver of SD rats and the comparison with the concentration in plasma are shown in table 3 below:

TABLE 3

And (4) conclusion: the prodrug compound 10 prepared by the invention has much better conversion capability to the active metabolism drug 1 in the liver than VK 2809. Under the same prodrug dosage, the absolute concentration of the active metabolic compound 1 in the liver is at least 3 times of that of the active metabolic drug MB07444 of the control drug VK2809, and the liver-blood ratio is obviously better than that of the control drug. Similarly, prodrug compound 9 was rapidly metabolized in the liver to active metabolite compound 1, also at higher absolute concentrations than the control drug VK 2809. The data show that the compound and the prodrug thereof are more drugs with liver targeting characteristics and have incomparable drug property.

The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (28)

1. A compound represented by the following formula (I) and isomers thereof or pharmaceutically acceptable salts thereof,

wherein the content of the first and second substances,

R₁and R₂Each independently selected from halogen atoms or C_1-6An alkyl group;

R₃and R₄Each independently selected from hydrogen, C_1-6Alkyl, unsubstituted phenyl, substituted by one or more radicals selected from halogen atoms, trifluoromethyl, C_1-6Alkyl radical, C_1-6Phenyl substituted with at least one substituent selected from the group consisting of alkoxy and cyano, unsubstituted naphthyl, substituted with at least one substituent selected from the group consisting of halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6Naphthyl substituted with a substituent of at least one of alkoxy and cyano,or R₃、R₄Together with adjacentAre combined togetherA six-membered ring constructed asWherein V is an unsubstituted five-to ten-membered aryl group consisting of a halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6A five-to ten-membered aryl group substituted with at least one substituent selected from the group consisting of alkoxy and cyano, an unsubstituted five-to ten-membered heteroaryl group containing 1 or 2 heteroatoms selected from the group consisting of N, S and O, a five-to ten-membered heteroaryl group substituted with at least one substituent selected from the group consisting of halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6A five-to ten-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, S and O, substituted with at least one substituent of alkoxy and cyano

R₅Is selected from H or C_1-6An alkyl group;

R₆、R₇、R₈each independently selected from C_1-6An alkyl group;

x is selected from-O-or-CH₂-；

Y is selected from-O-or-CH₂-；

Z, Z' are each independently selected from-O-or-NH-;

l is selected from-O-, -S-or-CH₂-

n is 1,2 or 3;

the halogen atom is selected from F, Cl or Br.

2. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₁And R₂Each independently selected from F, Cl, Br or-CH₃。

3. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 2, wherein R is₁And R₂Are all Cl.

4. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 2, wherein R is₁And R₂Are all-CH₃。

5. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₅Is selected from H or-CH₃。

6. The compound of claim 1, wherein n is 1 or 2, and isomers or pharmaceutically acceptable salts thereof.

7. The compound of claim 6, wherein n is 1, and isomers or pharmaceutically acceptable salts thereof.

8. The compound of claim 1, and pharmaceutically acceptable salts and prodrugs thereof, wherein X is-CH₂-。

9. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 1, wherein Y is-O-.

10. The compound according to claim 1, wherein V is an unsubstituted phenyl group consisting of a halogen atom, trifluoromethyl, C_1-3Alkyl and C_1-3Phenyl substituted by at least one substituent of alkoxy, unsubstituted five-to six-membered monocyclic heteroaryl containing 1 or 2 heteroatoms selected from N, S and O, substituted by a group consisting of halogen atom, trifluoromethyl, C_1-3Alkyl and C_1-3A five to six membered monocyclic heteroaryl group containing 1 or 2 heteroatoms selected from N, S and O substituted with at least one substituent of alkoxy.

11. The compound of claim 1, and isomers or pharmaceutically acceptable salts thereof, wherein the compound has the structure shown in formula (II):

wherein the content of the first and second substances,

R₁、R₂、R₅x, Y, L, n are as defined in claim 1.

12. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 11,

R₁and R₂Are all-CH₃；

R₅Is selected from-CH₃；

X is-CH₂-；

Y is-O-;

l is-CH₂-；

n is 1 or 2.

13. The compound of claim 1, and isomers or pharmaceutically acceptable salts thereof, wherein the compound has the structure shown in formula (III):

wherein the content of the first and second substances,

R₁、R₂、R₅x, Y, L, n and V are defined as in claim 1.

14. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 13,

R₁and R₂Are all-CH₃；

R₅Is selected from-CH₃；

X is-CH₂-；

Y is-O-;

l is-CH₂-；

n is 1 or 2;

v is unsubstituted phenyl, consisting of a group selected from halogen atoms, trifluoroMethyl, C_1-3Alkyl and C_1-3Phenyl substituted by at least one substituent selected from the group consisting of alkoxy, pyridyl consisting of a halogen atom, trifluoromethyl, C_1-3Alkyl and C_1-3Pyridyl substituted with at least one substituent of alkoxy.

15. A compound as claimed in claim 14 wherein V is m-chlorophenyl, and isomers or pharmaceutically acceptable salts thereof.

16. The compound of claim 1, wherein the compound has the structure of formula (IV):

wherein the content of the first and second substances,

R₁、R₂、R₅x, Y, L, n are as defined in claim 1;

R₃and R₄Each independently C_1-6Alkyl, phenyl, substituted by radicals selected from halogen atoms, trifluoromethyl, C_1-6Alkyl radical, C_1-6Phenyl substituted with at least one substituent selected from the group consisting of alkoxy and cyano, naphthyl, substituted with at least one substituent selected from the group consisting of halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6Naphthyl substituted with at least one substituent of alkoxy and cyano,wherein R is₆Is selected from C_1-6An alkyl group.

17. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 16,

R₁and R₂Are all-CH₃；

R₅Is selected from-CH₃；

X is-CH₂-；

Y is-O-;

l is-CH₂-；

n is 1 or 2;

R₃and R₄Are all thatWherein R is₆Is C_1-6An alkyl group.

18. A compound and isomers or pharmaceutically acceptable salts thereof as claimed in claim 17, wherein R is₃And R₄Are all that

19. The compound of claim 1, and isomers or pharmaceutically acceptable salts thereof, wherein the compound has the structure shown in formula (V):

wherein the content of the first and second substances,

R₁、R₂、R₅x, Y, L, n are as defined in claim 1;

R₄is selected from C_1-6Alkyl, phenyl, substituted by radicals selected from halogen atoms, trifluoromethyl, C_1-6Alkyl radical, C_1-6Phenyl substituted with at least one substituent selected from the group consisting of alkoxy and cyano, naphthyl, substituted with at least one substituent selected from the group consisting of halogen atom, trifluoromethyl, C_1-6Alkyl radical, C_1-6Naphthyl substituted with a substituent of at least one of alkoxy and cyano,

R₇、R₈each independently selected from C_1-6An alkyl group.

20. The compound and isomers or pharmaceutically acceptable salts thereof according to claim 19,

R₁and R₂Are all-CH₃；

R₅Is selected from-CH₃；

X is-CH₂-；

Y is-O-;

l is-CH₂-；

n is 1 or 2;

R₄is phenyl or naphthyl;

R₇is methyl;

R₈is ethyl or isopropyl.

21. The compound and isomers or pharmaceutically acceptable salts thereof according to any one of claims 1 to 20, wherein the compound and pharmaceutically acceptable salts and prodrugs thereof are one of the following compounds:

22. use of a compound according to claims 1-21 and isomers thereof or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of metabolic-related or fibrosis-related disorders.

23. Use of a compound according to claim 22, and isomers or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of metabolic-related disorders selected from: obesity, hyperlipidemia, hypercholesterolemia, diabetes, and nonalcoholic fatty liver disease (NASH), hepatic steatosis, atherosclerosis, hypothyroidism and thyroid cancer, hepatic fibrosis, and pulmonary fibrosis.

24. Use of a compound according to claim 23 and isomers thereof or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of metabolic-related disorders selected from: nonalcoholic fatty liver disease (NASH), hypothyroidism, thyroid cancer, hepatic fibrosis, and pulmonary fibrosis.

25. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 21 and isomers or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

26. A method for treating a metabolic-related disease, comprising administering to a subject an effective amount of the compound according to any one of claims 1 to 21 or a pharmaceutical composition comprising the compound and its isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

27. The method of treating a metabolic-related disorder according to claim 26, wherein said metabolic-related disorder or fibrosis-related disorder is selected from the group consisting of: obesity, hyperlipidemia, hypercholesterolemia, diabetes, and nonalcoholic fatty liver disease (NASH), hepatic steatosis, atherosclerosis, hypothyroidism and thyroid cancer, hepatic fibrosis, and pulmonary fibrosis.

28. A method of treating a metabolic-related disorder according to claim 27, selected from the group consisting of: nonalcoholic fatty liver disease (NASH), hypothyroidism, thyroid cancer, hepatic fibrosis, and pulmonary fibrosis.