Triazinediones as thyroid hormone receptor agonists, their synthesis, use

Abstract

The application discloses a triazine dione compound as a thyroid hormone receptor agonist, and synthesis and application thereof, and belongs to the field of medicines. The application provides a triazine dione compound as shown in a structure of formula (I) or a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate compound, a crystal form, a stereoisomer or an isotopic variant thereof. The compound of the application is a THR-beta agonist, and can be used for treating and / or preventing diseases regulated by thyroid hormone analogues.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to a class of triazine dione compounds that act as thyroid hormone receptor agonists, as well as their synthesis and uses. Background Technology

[0002] Thyroid hormones (TH) are produced by the thyroid gland and secreted into the circulatory system (hypothalamic / pituitary / thyroid system) in two different forms: 3,5,3',5'-tetraiodo-L-thyroxine (T4) and 3,5,3'-triiodo-L-thyroxine (T3). Although T4 is the predominant form secreted by the thyroid gland, T3 is the physiologically more active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues, but primarily in the liver and kidneys.

[0003] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs). TRs are encoded by different genes expressing α and β on human chromosomes 17 and 3, respectively. Different protein isoforms are generated through selective splicing of the primary transcript; each gene produces two isoforms: TRα1, TRα2, TRβ1, and TRβ2. TRβ1 and TRβ2 are derived from promoter differential expression, differing only at the N-terminus. TRα1 and TRα2 are derived from differential splicing of precursor mRNA, differing primarily at the C-terminus. TRα1, TRβ1, and TRβ2 can bind thyroid hormones. It has been shown that thyroid hormone receptor isoforms can differ in their contribution to specific physiological responses. TRβ1 plays an important role in regulating thyroid-stimulating hormone (TSH) and thyroid hormones in the liver. TRβ2 plays a major role in regulating thyroid-stimulating hormone (TSH).

[0004] Thyroid hormones have the effect of lowering serum low-density lipoprotein (LDL). Hyperthyroidism is associated with low total serum cholesterol, which is attributed to thyroid hormones increasing the expression of hepatic LDL receptors and stimulating the metabolism of cholesterol into bile acids. Hypothyroidism is associated with hypercholesterolemia, and thyroid hormone replacement therapy is known to lower total cholesterol. Thyroid hormones can also reduce the risk of atherosclerosis and other cardiovascular diseases. The incidence of atherosclerotic vascular disease is directly related to LDL cholesterol levels. Thyroid hormones have beneficial effects on obese patients by increasing metabolic rate, oxygen consumption, and heat release, thereby reducing body weight and improving obesity-related comorbidities. They can also have beneficial effects on glycemic control in obese patients with type 2 diabetes.

[0005] Thyroid hormones are essential for normal growth and development, as well as for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly regulated through feedback mechanisms in the hypothalamic / pituitary / thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates the profound impact of thyroid hormones on heart function, weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle mass, and behavior.

[0006] Synthetic thyroid hormone beta receptor agonists can selectively act on thyroid hormone beta receptors. Preclinical animal studies have shown that they can significantly reduce weight, regulate lipids, and enhance insulin sensitivity, while having fewer side effects such as tachycardia and skeletal muscle loss compared to natural thyroid hormones. Therefore, they hold promise as a next-generation treatment for inflammatory and metabolic diseases such as non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, and cirrhosis.

[0007] Currently, companies such as Madrigal and Viking are developing specific agonists targeting the β receptor of thyroid hormones, such as MGL-3196 (Martha J. Kelly, Sherrie Pietranico-Cole, J. Douglas Larigan et al., J. Med. Chem. 2014, 57:3912-3923), which is in early clinical stages. The structural formula of MGL-3196 is shown below:

[0008]

[0009] Poor absorption, distribution, metabolism, and / or excretion (ADME) properties are known to be a major cause of clinical trial failures for many drug candidates. Many currently marketed drugs also have limited applicability due to their poor ADME properties. Rapid drug metabolism can render many potentially highly effective treatments ineffective due to their rapid elimination from the body. While frequent or high-dose administration may address the issue of rapid drug clearance, this approach can lead to problems such as poor patient compliance, side effects from high doses, and increased treatment costs. Furthermore, rapidly metabolized drugs may expose patients to adverse toxic or reactive metabolites.

[0010] While MGL-3196, as a THR-β agonist, is effective in treating a variety of diseases, discovering novel compounds that possess the beneficial effects of thyroid hormones while avoiding adverse effects, have good oral bioavailability, and are druggable remains a challenging task. Therefore, the field continues to discover and develop THR-β agonists with better specificity, efficacy, and pharmacokinetic properties for the treatment of diseases related to thyroid hormone receptors. Summary of the Invention

[0011] To address the above technical problems, this invention discloses a novel triazine dione compound and its composition.

[0012] Its uses include fewer side effects and better pharmacodynamic / pharmacokinetic properties, and it can be used as a THR-β agonist to treat and / or prevent related diseases regulated by thyroid hormone analogs.

[0013] As used herein, the term "compound of the invention" refers to a compound of formula (I). The term also includes pharmaceutically acceptable salts, prodrugs, hydrates or solvents, crystal forms, stereoisomers or isotopic variants of compounds of formula (I).

[0014] To address this, the present invention adopts the following technical solution:

[0015] In a first aspect, the present invention provides a compound of formula (I) or its stereoisomers, tautomers, enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, and crystal forms thereof:

[0016]

[0017] in:

[0018] R1 and R2 are independently selected from hydrogen, halogen atoms, substituted or unsubstituted C1-6 alkyl groups, methyl groups substituted with 1-3 deuterium atoms, substituted or unsubstituted C3-6 cycloalkyl groups, and substituted or unsubstituted C1-6 alkoxy groups; the substituents are selected from halogen atoms, hydroxyl groups, C1-6 alkyl groups, and C1-6 epoxy groups.

[0019] Ring A is selected from:

[0020]

[0021] in:

[0022] R3, R3', R4, R4', and R5 are each independently selected from hydrogen, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted 3-10 heterocyclic alkyl, substituted or unsubstituted C6-10 aryl, and substituted or unsubstituted 5-10 heteroaryl; the substituted substituents are selected from halogen atoms, hydroxyl groups, C1-6 alkoxy groups, C1-6 alkyl groups, C3-10 cycloalkyl groups, C6-10 aryl groups, halo-C6-10 aryl groups, C1-10 alkyl-substituted C6-10 aryl groups, C1-10 alkoxy-substituted C6-10 aryl groups, 5-10 heteroaryl groups, C1-10 alkyl-substituted 5-10 heteroaryl groups, halo-5-10 heteroaryl groups, and 3-10 heterocyclic alkyl groups;

[0023] R6 and R7 are each independently selected from hydrogen, substituted or unsubstituted C1-10 alkyl groups; the substituted substituents are selected from halogen atoms, hydroxyl groups, C1-6 alkyl groups and C1-6 epoxy groups;

[0024] X is selected from N, CH; Y is selected from NH, CH2, O or S.

[0025] In a preferred embodiment, the compound is a compound of formula (1a):

[0026]

[0027] In this configuration, R1 and R2 are both methyl groups, R1 and R2 are both chlorine groups, and R3 is isopropyl.

[0028] In another preferred embodiment, the compound is a compound of formula (1b):

[0029]

[0030] Among them, R1 and R2 are both chlorine, and R3 is isopropyl;

[0031] X is selected from CH, Y is selected from N; or, X is selected from CH, Y is selected from O; or, X is selected from CH, Y is selected from S; or, X is selected from N, Y is selected from NH; or, X is selected from N, Y is selected from O; or, X is selected from N, Y is selected from S.

[0032] In another preferred embodiment, the compound is a compound of formula (1c):

[0033]

[0034] In this configuration, R1 and R2 are both methyl or chlorine, R4 is H or methyl, and R5 is 2-hydroxyisopropyl.

[0035] In this invention, the further preferred compounds of general formula (I) are specifically selected from:

[0036]

[0037] The present invention relates to compounds of general formula (I) or pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salt is an inorganic or organic salt, the inorganic salt including hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, and salicylate.

[0038] In a second aspect, the present invention provides a pharmaceutical composition and a method of administration.

[0039] The pharmaceutical composition provided by the present invention comprises the above-described compound of general formula (I) or its stereoisomers, tautomers, enantiomers, diastereomers, resonance bodies, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof, as well as pharmaceutically acceptable carriers, excipients, or diluents.

[0040] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compound of general formula (I) of the present invention is mixed as the active ingredient with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate. Or it may be mixed with the following components: (1) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silica; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) slowing agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, such as kaolin; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium dodecyl sulfate, etc., or mixtures thereof. Buffers may also be included in capsules, tablets and pills.

[0041] The solid dosage forms, such as tablets, sugar pills, capsules, pellets, and granules, can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They may contain opaque agents, and the release of the active ingredient from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0042] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compound of general formula (I) or its pharmaceutically acceptable salt as the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc., or mixtures thereof. In addition to these inert diluents, the liquid dosage forms of the present invention may also include conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0043] The suspending agent includes, for example, ethoxylated octadecyl alcohol, polyoxyethylene sorbitol, and dehydrated sorbitol, microcrystalline cellulose, agar, or mixtures thereof.

[0044] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, and excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0045] The compounds of this invention or pharmaceutically acceptable salts thereof can be formulated into dosage forms for topical administration, including ointments, powders, suppositories, drops, sprays, and inhalers. The compounds of general formula (I) of this invention or pharmaceutically acceptable salts thereof, as active ingredients, are mixed under sterile conditions with a physiologically acceptable carrier and optionally with preservatives, buffers, and propellants, if necessary.

[0046] The pharmaceutical compositions of the present invention comprise a compound of general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient, and diluent. In preparing the pharmaceutical compositions, the compound of general formula (I) or a pharmaceutically acceptable salt thereof is typically mixed with a pharmaceutically acceptable carrier, excipient, or diluent. The content of the compound of general formula (I) or a pharmaceutically acceptable salt thereof can be 0.01-1000 mg, for example 0.05-800 mg, 0.1-500 mg, 0.01-300 mg, 0.01-200 mg, 0.05-150 mg, 0.05-50 mg, etc.

[0047] Another object of the present invention is to provide the use of the above-mentioned compound in the preparation of a medicament for a therapeutic indication:

[0048] The novel compounds of this invention are thyroid hormone analogs. Therefore, the compounds of this invention can be used to treat and / or prevent diseases regulated by thyroid hormone analogs, particularly metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, and diabetes, and can also be used for other diseases such as NASH (non-alcoholic fatty liver disease), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, and related conditions and diseases. Obese patients are defined as those with a body mass index (BMI) of 25 or higher.

[0049] In another preferred embodiment, the present invention relates to a method for treating and / or preventing diseases regulated by thyroid hormone analogs, particularly metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, and diabetes, as well as NASH (non-alcoholic fatty liver disease), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, and related conditions and diseases, the method comprising administering a compound as defined above to a human or animal. Preferably, the amount of the compound administered is from about 0.01 mg / kg to about 50 mg / kg daily, more preferably from about 0.3 mg / kg to about 10 mg / kg daily, and even more preferably from about 0.70 mg / kg to about 3.5 mg / kg daily.

[0050] The present invention also includes the use of compounds as defined above for the treatment and / or preventive treatment of diseases regulated by thyroid hormone analogs, particularly metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, as well as NASH (non-alcoholic fatty liver disease), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases.

[0051] The present invention also relates to the use of the compounds described above in the preparation of medicaments for the treatment and / or preventive treatment of diseases regulated by thyroid hormone analogs, particularly metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, as well as NASH (non-alcoholic fatty liver disease), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases.

[0052] Beneficial effects:

[0053] The compounds of this invention can be used as thyroid hormone receptor β subtype agonists, exhibiting significantly improved activity or selectivity compared to the positive control (MGL-3196), and can be used for the treatment and / or prevention of diseases regulated by thyroid hormone analogs. Furthermore, the compounds of this invention possess superior pharmacokinetic properties compared to MGL-3196, and such inhibitors are expected to have good therapeutic effects and show promising development prospects. Detailed Implementation

[0054] The technical solution of the present invention will be described in detail below with reference to the embodiments.

[0055] In this invention, "C1-C6 alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, and 2-methyl-2-propyl.

[0056] In this invention, "C3-C6 cycloalkyl" refers to cycloalkyl groups with 3 to 6 carbon atoms respectively.

[0057] In this invention, "heteroaryl" refers to, unless otherwise stated, an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, or an unsubstituted or substituted 9- or 10-membered benzo[a]-fused heteroaromatic ring system, or a bicyclic heteroaromatic ring system, which consists of a carbon atom and 1-4 heteroatoms selected from N, O, or S, wherein the nitrogen or sulfur heteroatoms are selectively oxidized and the nitrogen heteroatoms are selectively quaternized.

[0058] In this invention, "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents.

[0059] In this invention, “administering” or “giving” an individual compound means providing the compound of this invention to an individual in need of treatment.

[0060] The term "pharmaceutically acceptable salt" refers to a salt that, within reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0061] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions.

[0062] Example 1: 2-(4-(4-(2-hydroxypropyl-2-yl)-1H-indol-1-yl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 1)

[0063]

[0064] Step 1: Preparation of intermediate 3a

[0065] 2-(1H-indol-4-yl)prop-2-ol (1a, 5 g, 26.0 mmol) and 2-fluoro-1,3-dimethyl-5-nitrobenzene 2a (4.47 g, 26.4 mmol) were dissolved in DMF (100 mL), and potassium carbonate (7.28 g, 52.8 mmol) was added. The mixture was heated to 80 °C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, poured into water (200 mL), and extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 3a (8 g, 98%), a brown solid. This was used directly in the next step without purification.

[0066] ESI-MS m / z: 325.1 [M+H]+

[0067] Step 2: Preparation of intermediate 4a

[0068] Intermediate 3a (8 g, 23.0 mmol) was dissolved in ethanol (150 mL), followed by the addition of ammonium chloride (6.3 g, 118 mmol), iron powder (6.6 g, 118 mmol), and water (50 mL). The reaction mixture was then refluxed for 3 hours. After the reaction was complete, the mixture was hot-filtered and washed with solid ethanol. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL) and water (200 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Column purification yielded intermediate 4a (5.5 g, 75%), a brown solid. ESI-MS m / z: 294.1 [M+H] +

[0069] Step 3: Preparation of 2-(4-(4-(2-hydroxypropyl-2-yl)-1H-indol-1-yl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (compound 1)

[0070] Dissolve tert-butyl nitrite (200 mg, 1.94 mmol) in acetic acid (2 mL) and cool to 0 °C. Slowly add this solution to a solution of intermediate 4a (500 mg, 1.62 mmol) in acetic acid (20 mL) and acetonitrile (10 mL). React at 0 °C for 30 minutes. Then, slowly add N-cyanoaceturane (379 mg, 2.43 mmol) in acetonitrile (5 mL). After the addition is complete, react for 3 hours. After the reaction is complete, pour the reaction solution into a saturated sodium bicarbonate aqueous solution (200 mL). The solid precipitates out, is washed with water and petroleum ether, and dried. N,N-dimethylacetamide (5 mL) and potassium acetate (190 mg, 1.94 mmol) were added to the obtained solid, and the mixture was heated to 120 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, and 100 mL of water was added. The mixture was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative oxidation (ACN / H₂O (0.1% TFA)) to give 2-(4-(4-isopropyl-5-methoxy-1H-indol-1-yl)-3,5-dimethylphenyl)-3,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile (compound 1) (120 mg, 17.2%), a white solid. ESI-MS m / z: 416.2 [M+H] +

[0071] 1H NMR(400MHz,Chloroform-d)δ7.62(dd,J=6.0,1.4Hz,1H),7.47(d,J=4.8Hz,1H),7.41(s,2H),7.26( dd,J=7.5,1.4Hz,1H),7.17(dd,J=7.5,6.1Hz,1H),6.87(d,J=4.8Hz,1H),2.18(s,6H),1.26(s,6H).

[0072] Example 2: 2-(3,5-dichloro-4-(4-(2-hydroxypropane-2-yl)-1H-indol-1-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 2)

[0073]

[0074] The synthesis of intermediate 5b follows the preparation of compound 1, wherein 1b replaces 1a and 2b replaces 2a; it is a white solid. ESI-MS m / z: 456.1 [M+H] +

[0075] 1 H NMR(400MHz,Chloroform-d)δ7.82(s,1H),7.78(s,2H),7.70(d,J=5.0Hz,1H),7.4 5(s,1H),7.11(d,J=2.2Hz,1H),6.80(dd,J=4.9,2.2Hz,1H),1.21(d,J=6.9Hz,6H).

[0076] By replacing the intermediates in Example 1 or 2 with the appropriate intermediates, Examples 3-5 (see Table 1) were synthesized following a similar procedure to Example 2, thereby obtaining the desired products.

[0077] Table 1

[0078]

[0079] Example 6: 2-(3,5-dichloro-4-(7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-3-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 6)

[0080]

[0081] Step 1: Preparation of 7-oxide of 3-bromothiopheno[2,3-b]pyridine (intermediate 2c)

[0082] 3-Bromothiophene[2,3-b]pyridine 1c (3 g, 14.0 mmol) was dissolved in dichloromethane (50 mL), and 70% m-CPBA (4.14 g, 16.8 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, and the pH was adjusted to 8.5 with a saturated sodium carbonate aqueous solution. The organic phase was washed with water, then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then slurried with methyl tert-butyl ether to obtain intermediate 2c (1.53 g, 74.5%), a pale yellow solid.

[0083] Step 2: Preparation of 3-bromothiopheno[2,3-b]pyridine-6(7H)-one (intermediate 3c)

[0084] Intermediate 2c (1.5 g, 6.52 mmol) was dissolved in DMF (30 mL). Trifluoroacetic anhydride (2.7 mL, 19.56 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 3 hours. After the reaction was complete, 80 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography to obtain 3-bromothieno[2,3-b]pyridin-6(7H)-one (intermediate 3c) (810 mg, 54.0%), a pale yellow solid.

[0085] Step 3: Preparation of 3-bromo-7-isopropylthiopheno[2,3-b]pyridine-6(7H)-one (intermediate 4c)

[0086] Intermediate 3c (800 mg, 3.48 mmol) was dissolved in DMF (20 mL). 60% sodium hydroxide (167 mg, 4.17 mmol) was added in portions under ice bath conditions, and the mixture was stirred at room temperature for half an hour. Then, 2-iodopropane (709 mg, 4.17 mmol) was slowly added under ice bath conditions, and the mixture was stirred overnight at room temperature. After the reaction was complete, 50 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. After washing with water and saturated sodium chloride, the mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Column purification yielded 3-bromo-7-isopropylthiopheno[2,3-b]pyridin-6(7H)-one (intermediate 4c) (520 mg, 55.0%), a pale yellow solid. ESI-MS m / z: 272.10 [M+H] +

[0087] Step 4: Preparation of 3-(4-amino-2,6-dichlorophenyl)-7-isopropylthiopheno[2,3-b]pyridine-6(7H)-one (intermediate 6c)

[0088] Intermediate 4C (500 mg, 1.84 mmol) and 3,5-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)aniline 5C (636 mg, 2.21 mmol) were dissolved in dioxane (15 mL) and water (3 mL). Sodium carbonate (390 mg, 3.68 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol) were added. The reaction was carried out under nitrogen protection. The solution was heated to 80℃ and reacted for 5 hours. After the reaction was completed, it was cooled to room temperature, and 20 mL of water was added. The mixture was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column purification yielded 3-(4-amino-2,6-dichlorophenyl)-7-isopropylthiopheno[2,3-b]pyridin-6(7H)-one (intermediate 6c) (300 mg, 46.2%), a pale yellow solid. ESI-MS m / z: 353.10 [M+H] +

[0089] Step 5: Preparation of 2-(3,5-dichloro-4-(7-isopropyl-6-oxo-6,7-dihydrothiopheno[2,3-b]pyridin-3-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (compound 6)

[0090] Dissolve tert-butyl nitrite (69 mg, 0.67 mmol) in acetic acid (1 mL) and cool to 0 °C. Slowly add this solution to a solution of intermediate 6c (200 mg, 0.56 mmol) in acetic acid (10 mL) and acetonitrile (5 mL). React at 0 °C for 30 minutes. Then slowly add N-cyanoaceturane (131 mg, 0.84 mmol) in acetonitrile (1 mL). After the addition is complete, react for 3 hours. After the reaction is complete, pour the reaction solution into a saturated sodium bicarbonate aqueous solution (50 mL). The solid precipitates out, is washed with water and petroleum ether, and dried. N,N-dimethylacetamide (5 mL) and potassium acetate (66 mg, 0.67 mmol) were added to the obtained solid, and the mixture was heated to 120 °C and reacted for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, and 50 mL of water was added. The mixture was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparation (ACN / H2O (0.1% TFA)) to give 2-(3,5-dichloro-4-(7-isopropyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-3-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile (compound 6) (40 mg, 15%), a white solid.

[0091] ESI-MS m / z: 474.00 [M+H]+

[0092] 1 H NMR (400MHz, Chloroform-d) δ7.91(d,J=9.2Hz,1H),7.70(s,2H),7.27(s,1H),6.52(d,J=9.2Hz,1H),4.92(p,J=6.1Hz,1H),1.43(d,J=6.0Hz,6H).

[0093] By replacing the intermediate in Example 6 with the corresponding intermediate, Examples 7-9 were synthesized according to a similar operation to Example 6 (see Table 2) to obtain the desired product.

[0094] Table 2

[0095]

[0096]

[0097] Example 10: 2-(3,5-dichloro-4-(7-isopropyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 10)

[0098]

[0099] Step 1: Preparation of 3-bromo-1-toluenesulfonyl-1H-pyrazolo[3,4-b]pyridine (intermediate 2d)

[0100] 1d (5 g, 25.2 mmol) of 3-bromo-1H-pyrazolo[3,4-b]pyridine was dissolved in 50 mL of tetrahydrofuran. Triethylamine (3.5 mL, 25.2 mmol) and DMAP (307 mg, 2.52 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, 100 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Column purification yielded 3-bromo-1-toluenesulfonyl-1H-pyrazolo[3,4-b]pyridine (intermediate 2d) (6.5 g, 73%), a white solid. ESI-MS m / z: 352.10 [M+H] +

[0101] Steps two through six can be synthesized using the same method as compound 6. The result was 2-(3,5-dichloro-4-(7-isopropyl-6-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (intermediate 7d) (500 mg, gray solid), ESI-MS m / z: 612.10 [M+H] +

[0102] Step 7: Preparation of 2-(3,5-dichloro-4-(7-isopropyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (compound 10)

[0103] Intermediate 7d (200 mg, 0.33 mmol) was dissolved in methanol (5 mL), potassium carbonate (91 mg, 0.66 mmol) was added, and the mixture was heated to 50 °C and reacted overnight. After the reaction was completed, the mixture was concentrated under reduced pressure, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparation (ACN / H2O (0.1% FA)) to give 2-(3,5-dichloro-4-(7-isopropyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile (compound 10) (57 mg, 38%), a white solid.

[0104] ESI-MS m / z: 458.10 [M+H] +

[0105] 1 H NMR (400MHz, Chloroform-d) δ7.85 (s, 2H), 7.59 (d, J = 10.1Hz, 1H), 6.50 (d, J = 10.1Hz, 1H), 4.94 (p, J = 6.6Hz, 1H), 1.43 (d, J = 6.6Hz, 6H).

[0106] Example 11: 1-(3,5-dichloro-4-(7-isopropyl-6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-nitrile (Compound 11)

[0107]

[0108] The synthesis method is the same as that used in the preparation of compound 10, wherein 3-bromo-1H-pyrazolo[3,4-b]pyridine 1d is replaced by 3-bromo-1H-pyrrolo[2,3-b]pyridine 1e. (27 mg, 32%), white solid.

[0109] ESI-MS m / z: 456.10 [M+H] +

[0110] 1 H NMR(400MHz,Chloroform-d)δ8.70(s,1H),7.84(s,2H),7.69(d,J=7.1Hz,1H),7.65( d,J=9.7Hz,1H),6.53(d,J=9.7Hz,1H),4.87(p,J=6.6Hz,1H),1.43(d,J=6.6Hz,6H).

[0111] Example 12: 2-(3,5-dichloro-4-(4-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 12)

[0112]

[0113] Step 1: Preparation of tert-butyl 2-formyl-3-nitro-1H-pyrrole-1-carboxylic acid (intermediate 2f)

[0114] 1f of 3-nitro-1H-pyrrole-2-carboxaldehyde (10 g, 71.4 mmol) was dissolved in methanol (100 mL), and DMAP (8.71 g, 71.4 mmol) was added. The mixture was reacted overnight at room temperature. After the reaction was completed, the solution was concentrated under reduced pressure, and 50 mL of water was added. The solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give tert-butyl 2-formyl-3-nitro-1H-pyrrole-1-carboxylic acid (intermediate 2f) (15 g, 88%), a white solid. ESI-MS m / z: 241.10 [M+H] +

[0115] Step 2: Preparation of (E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)-3-nitro-1H-pyrrole-1-carboxylic acid tert-butyl ester (intermediate 3f)

[0116] Intermediate 2f (12 g, 50 mmol) and monomethyl malonate (5.9 g, 50 mmol) were dissolved in pyridine (100 mL), and piperidine (10 mL) was added. The reaction mixture was heated to 100 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to 3-4 with dilute hydrochloric acid. A solid precipitated out, which was filtered, washed with water, and dried to obtain (E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)-3-nitro-1H-pyrrole-1-carboxylic acid tert-butyl ester (intermediate 3f) (11.5 g, 77%), a white solid. ESI-MS m / z: 297.10 [M+H] +

[0117] Step 3: Preparation of 5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (intermediate 4f)

[0118] Intermediate 3f (10 g, 33.8 mmol) was dissolved in methanol (100 mL), and 10% palladium on carbon (1 g) was added. The mixture was stirred overnight at room temperature, then stirred at 50 °C for 4 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give 5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (intermediate 4f) (5.3 g, 66%), a white solid. ESI-MS m / z: 237.10 [M+H] +

[0119] Step 4: Preparation of tert-butyl 4-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid (intermediate 5f)

[0120] Intermediate 4f (5 g, 21.2 mmol) was dissolved in DMF (50 mL). Under ice bath conditions, 60% sodium hydroxide (1.27 g, 31.8 mmol) was added in portions, and the mixture was stirred at room temperature for half an hour. Then, under ice bath conditions, 2-iodopropane (5.4 g, 31.8 mmol) was slowly added, and the mixture was stirred overnight at room temperature. After the reaction was complete, 200 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column purification yielded 4-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (intermediate 5f) (3.2 g, 54.4%), a pale yellow solid. ESI-MS m / z: 279.10 [M+H] +

[0121] Step 5: Preparation of 4-isopropyl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 6f)

[0122] Intermediate 5f (3 g, 10.8 mmol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH was adjusted to 7-8 with sodium bicarbonate, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column purification yielded 4-isopropyl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 6f) (1.2 g, 62.5%), a pale yellow solid. ESI-MS m / z: 179.10 [M+H] +

[0123] The procedures for steps 6 and 7 are the same as those for the synthesis of compound 1.

[0124] The final product was prepared and separated by reverse phase to give 2-(3,5-dichloro-4-(4-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile (compound 12) (31 mg, 22%), a white solid.

[0125] ESI-MS m / z: 459.10 [M+H] +

[0126] 1 H NMR(400MHz,Chloroform-d)δ7.76(s,2H),7.63(d,J=5.5Hz,1H),5.94(d,J=5.5Hz,1H),4.69(p,J=7.1Hz,1H),3.13(dd,J=8 .1,5.3Hz,1H),3.05(dd,J=8.2,5.3Hz,1H),2.68(dd,J=8.2,5.3Hz,1H),2.64(dd,J=8.1,5.3Hz,1H),1.37(d,J=7.1Hz,6H).

[0127] Example 13: 2-(4-(4-isopropyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-dimethylphenyl)-3,5-2-oxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 13)

[0128]

[0129] The synthesis of compound 13 was performed following the same procedure as compound 12. 3,5-dichloro-4-fluoronitrobenzene 2b was replaced with 2-fluoro-1,3-dimethyl-5-nitrobenzene 2a. White solid, ESI-MS m / z: 419.20 [M+H] +

[0130] 1 H NMR(400MHz,Chloroform-d)δ7.70(d,J=5.5Hz,1H),7.38(s,2H),5.89(d,J=5.7Hz,1H),4.69(hept,J=7.1Hz,1H),3.14(dd,J=8.1,5. 3Hz, 1H), 3.05 (dd, J=8.1, 5.3Hz, 1H), 2.68 (dd, J=8.2, 5.3Hz, 1H), 2.64 (dd, J=8.1, 5.3Hz, 1H), 2.18 (s, 6H), 1.37 (s, 3H), 1.36 (s, 3H).

[0131] Example 14 Bioactivity Assay

[0132] THR reporter gene assay for detecting the agonistic activity of compounds on THRα and THRβ

[0133] Huh7 cells were cultured in DMEM medium containing 10% FBS. Cells were seeded into 10cm cell culture dishes and allowed to proliferate to approximately 90%. They were then co-transfected with a human THRα eukaryotic expression plasmid or a human eukaryotic expression plasmid and a reporter gene plasmid containing a THR response sequence driven by PGL 4.26-DR4-Luc using Lipofectamine 2000. The procedure was performed according to the Lipofectamine 2000 manufacturer's instructions. The day after transfection, cells were seeded into 96-well cell culture plates with phenol red-free DMEM medium (containing 5% activated charcoal-treated FBS) at a density of 20,000 cells per well and a volume of 135 μL per well. Six hours after seeding, cells adhered. The compound dissolved in DMSO was diluted 20-fold to 10-fold with phenol red-free DMEM medium (containing 5% activated charcoal-treated FBS) and added to each well at a final concentration of 15 μL, thus achieving a final concentration after a further 10-fold dilution. The positive control was set as triiodothyronine (T3) (100 nM), and the blank control was 0.5% DMSO. After drug addition, the cells were cultured overnight (16 hours) at 37°C in a 5% CO2 incubator. After incubation, the culture medium was discarded, and 35 μL of serum-free and phenol red-free DMEM culture medium and 35 μL of Steady-Glo were added to each well. After shaking at room temperature in the dark for 10 minutes, the chemiluminescence value of the samples was detected.

[0134] The agonistic activity of a compound is calculated as follows: Effect % = (Compound - Blank Control) / (Positive Control - Blank Control) * 100%. The EC50 of the compound... 50 EC was obtained by fitting the agonistic activity of the compound to the logarithm of the compound concentration using GraphPad Prism. 50 The lower the value, the better the activity.

[0135] EC50 of the compound’s agonistic activity against THRα and THRβ 50 The values ​​were first calculated using the EC50 values ​​of T3 on the agonistic activity of THRα and THRβ in the same experiment. 50 After value correction, the fold increase, i.e., receptor selectivity, is calculated based on the obtained value. The specific calculation method is as follows: Selectivity = (compound THRαEC) / (receptor selectivity) * (receptor selectivity ... 50 / T3 THRαEC 50 ) / (compound THRβEC 50 / T3 THRβEC 50 The higher the value, the higher the selectivity of the compound for the THRβ receptor.

[0136] The results are shown in Table 3.

[0137] Table 3. Agonistaltic activity and selectivity of compounds for THRα and THRβ

[0138]

[0139] The results showed that the compound of the present invention had significantly improved activity or selectivity compared with the positive control (MGL-3196).

[0140] For compounds of general formula (I), the linking and substituent groups have a significant impact on the pharmacodynamic properties of the compound. Although the invention has been described through specific embodiments above, it should not be construed as limiting; rather, the invention covers the general aspects previously disclosed. Various modifications and embodiments are possible without departing from the spirit and scope of the invention.

[0141] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined in the claims of this invention.

Claims

1. Triazine diones or pharmaceutically acceptable salts thereof, as shown in general formula (I): The triazine dione compounds are selected from: 。 2. The triazine dione compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, The pharmaceutically acceptable salt is an inorganic or organic salt; wherein, the inorganic salt is selected from sodium salts, potassium salts, calcium salts, magnesium salts, iron salts, hydrochloride salts, hydrobromide salts, hydroiodide salts, sulfate salts, hydrogen sulfate salts, nitrate salts, phosphate salts, and acid phosphate salts; and the organic salt is selected from acetate salts, trifluoroacetate salts, propionate salts, pyruvate salts, glycolate salts, oxalate salts, malonate salts, fumarate salts, maleate salts, lactate salts, malate salts, citrate salts, tartrate salts, methanesulfonate salts, ethanesulfonate salts, benzenesulfonate salts, and salicylates.

3. A pharmaceutical composition, characterized in that, This includes the triazine dione compounds of any one of claims 1-2 or pharmaceutically acceptable salts thereof, as well as pharmaceutically acceptable carriers, excipients, or diluents.

4. A drug for treating non-alcoholic steatohepatitis, characterized in that, Contains a triazine dione compound as described in any one of claims 1-2 or a pharmaceutically acceptable salt thereof.

5. Use of the triazine dione compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing diseases regulated by thyroid hormone analogs.

6. The use according to claim 5, characterized in that, The diseases mentioned are selected from obesity, hyperlipidemia, diabetes, non-alcoholic steatohepatitis, cardiovascular disease, hypothyroidism, and thyroid cancer.

7. The use according to claim 5, characterized in that, The disease in question is hypercholesterolemia.

8. The use according to claim 5, characterized in that, The disease in question is atherosclerosis.

9. The use according to claim 5, characterized in that, The dosage form of the drug is selected from solid dosage forms for oral administration, liquid dosage forms for oral administration, and parenteral injection dosage forms.

10. The use according to claim 5, characterized in that, The dosage form of the drug is a topical dosage form, selected from ointments, powders, suppositories, drops, sprays, or inhalers.

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