Substituted aza-uracil compound, pharmaceutical composition and application of substituted aza-uracil compound

Abstract

The invention relates to a substituted aza-uracil compound as shown in a formula (I), and an isotope form, a stereoisomer, a tautomer, a cis-trans-isomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, a prodrug and a polymorphic substance of the substituted aza-uracil compound. The compound has a good agonistic effect and high selectivity, so that the compound has a good application prospect in the aspect of preparing medicines for preventing and / or treating THR-beta activity mediated diseases.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a substituted aza-uracil compound, a pharmaceutical composition and uses thereof. Background Art

[0002] Non-alcoholic steatohepatitis (NASH) is a serious chronic liver disease characterized by hepatocyte fatty degeneration, inflammation, and fibrosis, which can progress to cirrhosis, liver failure, and even liver cancer. Currently, the number of NASH patients worldwide is increasing dramatically. Existing treatments primarily rely on lifestyle interventions and adjunctive medications targeting metabolic syndrome (such as insulin sensitizers and antioxidants), but these have limited efficacy and are unable to reverse the disease progression.

[0003] Thyroid hormones (THs) are essential regulatory molecules for normal growth and development, as well as for maintaining metabolic homeostasis. By binding to thyroid hormone receptors (THRs), THs promote growth and metabolism, enhance nervous system excitability, accelerate heart rate, and increase heat production. THs are involved in the development and maintenance of brain function, influencing various activities such as neuronal and glial cell differentiation, myelination, and neurogenesis. In the liver, THs regulate hepatic lipid metabolism through multiple pathways, profoundly affecting energy expenditure, fat oxidation, and cholesterol metabolism. THRs are primarily composed of two isoforms, THR-α and THR-β. THR-α is abundant in the brain and heart, while THR-β is expressed at higher levels in the liver, regulating lipid metabolism, mitochondrial function, and inflammatory responses. Studies have shown that THR-β plays an important role in regulating triglycerides and cholesterol, improving insulin sensitivity, promoting liver regeneration, and reducing apoptosis. THR-β not only regulates the high-density lipoprotein (HDL) pathway and promotes the liver's absorption of HDL particles, but also enhances the ability of LDL to enter the liver through interaction with the low-density lipoprotein receptor (LDLR), promotes the conversion of cholesterol to bile acids by upregulating cytochrome P450 enzyme 7A1 (CYP7A1), and inhibits triglyceride synthesis by downregulating the transcription factor sterol regulatory element binding protein 1 (SREBP1). Therefore, activation of THR-β can significantly promote liver fat clearance, inhibit fibrosis, and improve metabolic disorders, making it an important target for the treatment of NASH. However, first-generation thyroid hormone analogs (such as T3 or T4) cannot be used clinically due to side effects on the heart (mediated by THR-α) (such as tachycardia and arrhythmias).

[0004] Based on this, the development of a highly active and selective THR-β agonist can provide a more comprehensive and effective treatment strategy for the prevention and treatment of NASH. Summary of the Invention

[0005] To solve the above problems, the present invention provides a substituted aza-uracil compound, a pharmaceutical composition and its use. This type of compound can selectively activate THR-β, has good agonistic effects and high selectivity, and thus has good application prospects in the preparation of drugs for preventing and / or treating diseases mediated by THR-β activity.

[0006] Specifically, the present invention provides the following technical solutions:

[0007] The first aspect of the present invention provides a substituted azauracil compound represented by formula (I) or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph.

[0008]

[0009] in,

[0010] R1 is selected from a linear or branched C 1-10 Alkyl, more preferably a linear or branched C 1-5 alkyl;

[0011] X is H or N;

[0012] R2 and R3 are each independently selected from halogen, linear or branched C 1-10 Alkyl, including but not limited to F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.;

[0013] R4 is selected from cyano, amino, aminomethyl, carbamoyl, hydroxymethyl, methoxymethyl, methylamino, dimethylamino, and cyanomethyl.

[0014] Furthermore, the pharmaceutically acceptable salt is an inorganic salt or an organic salt; wherein the inorganic salt includes one of hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; and the organic salt includes one of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

[0015] More preferably, the pharmaceutically acceptable salt is hydrochloride, sulfate, succinate or methanesulfonate.

[0016] Furthermore, the substituted azauracil compound is a compound represented by structural formula I-1 to I-15:

[0017]

[0018] Furthermore, R1 is

[0019] Furthermore, R2 and R3 are both chlorine or methyl.

[0020] Furthermore, R4 is cyano.

[0021] The second aspect of the present invention provides a pharmaceutical composition comprising a substituted aza-uracil compound represented by formula (I) according to the first aspect or one or more of its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs.

[0022] Furthermore, in the pharmaceutical composition, the substituted aza-uracil compound represented by any one of the above formula (I) or its isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs are used in combination with other drugs, such as other NASH therapeutic drugs.

[0023] The third aspect of the present invention provides a substituted azauracil compound represented by formula (I) according to the first aspect or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph or the pharmaceutical composition according to the second aspect in the preparation of a THR-β agonist.

[0024] The fourth aspect of the present invention provides a substituted aza-uracil compound represented by formula (I) according to the first aspect or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph or the pharmaceutical composition according to the second aspect in the preparation of a drug for treating and / or preventing diseases mediated by THR-β activity.

[0025] Furthermore, the disease includes non-alcoholic steatohepatitis, obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism and thyroid cancer.

[0026] Furthermore, the drug further comprises one or more of a pharmaceutically acceptable carrier, an excipient, and a diluent; preferably, the pharmaceutically acceptable carrier comprises microspheres, nanoparticles, and liposomes.

[0027] Furthermore, the dosage form of the drug includes but is not limited to injection, lyophilized powder for injection, suspension, implant I, embolic agent, capsule, tablet, pill and oral solution.

[0028] Furthermore, when the dosage form of the drug is a solid dosage form for oral administration (such as capsules, tablets, pills, powders, granules, etc.), the substituted aza-uracil compound represented by formula (I) or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph or the pharmaceutical composition as an active ingredient can be mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate; and / or, mixed with one or more of the following ingredients: (1) fillers or solubilizers, such as starch, lactose, Sucrose, glucose, mannitol and silicic acid, etc.; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrants, such as agar, calcium carbonate, potato starch, tapioca starch, alginic acid, silicate, sodium carbonate, etc.; (5) dispersants, such as paraffin, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate, etc.; (8) adsorbents, such as kaolin, etc.; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc.

[0029] Furthermore, when the solid dosage form is a tablet, pill, capsule, or granule, it may be coated or microencapsulated with an enteric coating material and / or other materials known in the art. The release of the active ingredient in such a solid dosage form can be delayed in a certain portion of the digestive tract. Materials that can be used to encapsulate the components include polymeric substances and waxes. If desired, the active ingredient may also be microencapsulated with one or more of the above-mentioned excipients.

[0030] Furthermore, when the dosage form of the drug is a liquid dosage form for oral administration (e.g., emulsion, solution, suspension, syrup, tincture, etc.), in addition to the active ingredient (the substituted azauracil compound represented by formula (I) or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph or the pharmaceutical composition), the liquid dosage form may also contain an inert diluent conventionally used in the art, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular one or more of cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil. In addition to these inert diluents, the liquid dosage form of the present invention may also include conventional adjuvants, such as pharmaceutically acceptable wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents and fragrances.

[0031] Furthermore, the suspending agent includes one or more of ethoxylated stearyl alcohol, polyoxyethylene sorbitol, dehydrated sorbitol, microcrystalline cellulose, and agar.

[0032] Furthermore, the dosage form of the drug can also be a dosage form for parenteral injection, including but not limited to sterile aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, sterile powders for reconstitution into sterile injectable solutions and dispersions, etc.

[0033] Furthermore, the dosage form of the drug may be a dosage form for topical administration, including but not limited to ointments, powders, suppositories, drops, sprays, inhalants, etc. In addition to the active ingredient, the dosage form for topical administration may further comprise a pharmaceutically acceptable carrier, preservative, buffer, etc., and may contain a propellant if necessary.

[0034] Further, the substituted azauracil compound of formula (I) or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph or pharmaceutical composition is administered to a mammal in a unit dose of 0.01-2000 mg / kg (e.g., 2.5-1000 mg / kg, or 5-500 mg / kg), and this should provide an effective dose. However, the daily dose will necessarily vary depending on the host being treated, the specific route of administration, and the severity of the disease being treated. Therefore, the optimal dose can be determined by the practitioner treating any particular patient.

[0035] As used herein, the following definitions and terms shall apply unless otherwise indicated.

[0036] The term C used here i-j It means that the part has ij carbon atoms. For example, "C 1-10 "Alkyl" means an alkyl unit having any number of carbon atoms between 1 and 10.

[0037] As used herein, "alkyl" refers to a fully saturated straight chain or branched chain alkane group. 1-5 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, pentyl, and the like.

[0038] In this article Indicates the point from which a substituent is attached.

[0039] As used herein, "pharmaceutically acceptable" refers to compositions that are suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., within a reasonable medical range and at a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" refer to salts that are pharmaceutically considered safe and effective, and that, upon administration to a recipient, are capable of providing, directly or indirectly, a compound or prodrug of a compound of the present invention.

[0040] As used herein, "agonist" refers to a compound or agent that has the ability to agonize the biological function of a targeted protein or polypeptide, for example, by agonizing the activity or expression of the protein or polypeptide.

[0041] As used herein, "disease mediated by THR-β activity" refers to any disease or other deleterious condition in which THR-β or its mutants are known to play a role; the term "disease" refers to any condition or disorder that damages or interferes with the normal function of a cell, organ or tissue.

[0042] The term "effective therapeutic amount" herein refers to an amount of the compound or pharmaceutical composition described herein that is sufficient to achieve the intended effect, including but not limited to treating a disease.

[0043] By means of the above technical solution, the present invention has at least the following advantages:

[0044] The present invention provides a class of substituted aza-uracil compounds that exhibit high agonist activity and high selectivity for THR-β protein, can effectively reduce triglycerides and cholesterol in tissue cells, and have good application prospects in terms of being used as THR-β agonists and in the preparation of drugs for preventing and / or treating diseases mediated by THR-β activity (such as NASH, etc.). DETAILED DESCRIPTION

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0046] The present invention will be further described below with reference to specific examples so that those skilled in the art may better understand and implement the present invention, but the examples are not intended to limit the present invention. Unless otherwise indicated, all reagents used were purchased from commercial suppliers and used without further purification. The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as MS, NMR, etc. The abbreviations used are those conventional in the art.

[0047] In the following examples of this application, the synthesis method of the reaction intermediates used is as follows:

[0048] Intermediate A: 4-chloro-7-methylpyrrolo[2,3-d]pyrimidine, the structure is shown below:

[0049]

[0050] The specific preparation process is as follows:

[0051] 4-Chloropyrrolopyrimidine (5.0 g, 65.1 mmol) and anhydrous potassium carbonate (27.0 g, 193.3 mmol) were dissolved in DMF (150 mL). Methyl iodide (27.7 g, 195.3 mmol) was slowly added in portions under a nitrogen atmosphere. The reaction was stirred at room temperature under a nitrogen atmosphere for 24 hours. TLC detected that the reaction was complete [PE:EA=10:1 (v / v)]. The reaction solution was added to water and extracted with EA (100 mL×3). The organic layers were combined, washed with water (100 mL×2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography [PE:EA=20:1 (v / v)] to obtain white solid intermediate A (3.4 g, 63.1%). HRMS (ESI) m / z:168.0338 [M+H] + (Theoretical value: 168.0329).

[0052] Intermediate B: 4-chloro-7-ethylpyrrolo[2,3-d]pyrimidine, the structure is shown below:

[0053]

[0054] Using 4-chloropyrrolopyrimidine and iodoethane as starting materials, the synthesis and purification steps of intermediate A were followed to obtain intermediate B (5.1 g, 68.5%) as a white solid. HRMS (ESI) m / z: 182.0496 [M+H] + (Theoretical value: 182.0485).

[0055] Intermediate C: 4-chloro-7-isopropylpyrrolo[2,3-d]pyrimidine, the structure is shown below:

[0056]

[0057] Using 4-chloropyrrolopyrimidine and 2-bromopropane as starting materials, the synthesis and purification steps of Intermediate A were followed to obtain Intermediate C (6.8 g, 63.2%) as a white solid. HRMS (ESI) m / z: 196.0653 [M+H] + (Theoretical value: 196.0641).

[0058] Intermediate D: 4-chloro-7-(pentan-3-yl)pyrrolo[2,3-d]pyrimidine, the structure of which is shown below:

[0059]

[0060] Using 4-chloropyrrolopyrimidine and 2-bromobutane as starting materials, the synthesis and purification steps of Intermediate A were followed to obtain Intermediate D (5.8 g, 65.7%) as a white solid. HRMS (ESI) m / z: 210.0812 [M+H] + (Theoretical value: 210.0798).

[0061] Intermediate E: 4-chloro-7-(pentan-3-yl)pyrrolo[2,3-d]pyrimidine, the structure of which is shown below:

[0062]

[0063] Starting from 4-chloropyrrolopyrimidine and 3-bromopentane, intermediate E (6.7 g, 65.9%) was obtained as a white solid, following the synthesis and purification procedures of intermediate A. HRMS (ESI) m / z: 224.0969 [M+H]+ (theoretical value: 224.0954).

[0064] Intermediate F: 6-chloro-9-ethyl-9H-purine, the structure is shown below:

[0065]

[0066] Using 6-chloropurine and iodoethane as starting materials, the synthesis and purification steps of Intermediate A were followed to obtain Intermediate F (3.7 g, 66.8%) as a white solid. HRMS (ESI) m / z: 183.0448 [M+H] + (Theoretical value: 183.0437).

[0067] Intermediate G: 6-chloro-9-sec-butyl-9H-purine, the structure is shown below:

[0068]

[0069] Starting from 6-chloropurine and 2-bromobutane, the synthesis and purification steps of intermediate A were referred to obtain white solid intermediate G (3.6 g, 62.7%). HRMS (ESI) m / z: 211.0764 [M+H] + (Theoretical value: 211.0750).

[0070] Intermediate H: 6-chloro-9-(pentan-3-yl)-9H-purine, the structure is shown below:

[0071]

[0072] Starting from 6-chloropurine and 3-bromopentane, the synthesis and purification steps of intermediate A were referred to obtain white solid intermediate H (3.2 g, 64.6%). HRMS (ESI) m / z: 225.0921 [M+H] + (Theoretical value: 225.0907).

[0073] Intermediate I: tert-butyl (3,5-dichloro-4-hydroxyphenyl)carbamate, the structure is shown below:

[0074]

[0075] The specific preparation process is as follows:

[0076] The compound 2,6-dichloro-4-aminophenol (20.0 g, 112.3 mmol) was dissolved in THF (300 mL), and di-tert-butyl dicarbonate (29.4 g, 134.8 mmol) was added portionwise. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 10 hours. TLC confirmed the reaction was complete [PE:EA = 10:1 (v / v)]. The resulting mixture was concentrated under reduced pressure and added to water, extracted with EA (100 mL × 3). The organic layers were combined, washed with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography (PE:EA = 30:1 (v / v)) to obtain Intermediate I (24.6 g, 78.7%) as a white solid. 1 H NMR (400MHz, CCl3D) δ7.34(s,2H),6.34(s,1H),5.61(s,1H),1.51(s,9H).

[0077] Example 1

[0078] This embodiment relates to the preparation of a substituted azauracil compound I-1, the structure of which is shown below:

[0079]

[0080] The specific preparation process is as follows:

[0081] (1) Intermediate E (1.2 g, 5.4 mmol) was dissolved in DMF (10 mL), potassium carbonate (3.4 g, 24.3 mmol) and intermediate I (1.7 g, 6.1 mmol) were added, and the resulting mixture was stirred at 90°C under nitrogen atmosphere for 12 hours. TLC showed that the reaction was complete [PE:EA=5:1 (v / v)]. The reaction solution was added to water and extracted with EA (50 mL×3). The organic layers were combined, washed with water (50 mL×2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography [PE:EA=5:1 (v / v)] to obtain tert-butyl (3,5-dichloro-4-((7-(pentan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)carbamate (2.1 g, 83.6%) as a white solid.

[0082] (2) The white solid tert-butyl (3,5-dichloro-4-((7-(pentan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)carbamate (2.1 g, 4.5 mmol) prepared in step (1) was dissolved in a DCM:TFA=4:1 (v / v) solution (20 mL) and reacted at room temperature for 1 h. The reaction was detected by TLC to be complete [PE:EA=1:1 (v / v)]. The resulting mixture was adjusted to pH 7-8 with saturated sodium bicarbonate and extracted with DCM (50 mL×3). The combined organic layer was washed with water (50 mL×2), then with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain a pale yellow solid of 3,5-dichloro-4-((7-(pentan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (1.6 g, 99.8%). The product was used directly in the next reaction without purification.

[0083] (3) The light yellow solid 3,5-dichloro-4-((7-(pentane-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (1.6 g, 4.5 mmol) prepared in step (2) was dissolved in a mixed solution of HOAc (60 mL) and HCl (20 mL), and an aqueous solution of sodium nitrite (0.7 g, 10.1 mmol) was added in batches under a nitrogen atmosphere. The mixture was stirred at 0°C under a nitrogen atmosphere for 0.5 h. The reaction solution was then quickly poured into a second reaction flask containing N-cyanoacetylurea (1.22 g, 7.8 mmol), water (60 mL) and pyridine (20 mL) at 0°C. The mixture was stirred at 0°C under a nitrogen atmosphere for 0.5 h. The reaction was detected by TLC to be complete [PE:EA=1:1 (v / v)]. The precipitated solid was filtered, collected, and washed with water (100 mL × 3). The filter cake was dried to obtain ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((7-(pentan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (2.0 g, 85.8%) as an orange solid. The product was used directly in the next reaction without purification.

[0084] (4) The orange solid ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((7-(pentan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (2.0 g, 4.4 mmol) prepared in step (3) was dissolved in DMF (20 mL), potassium acetate (801.2 mg, 8.8 mmol) was added, and the resulting mixture was reacted at 110° C. for 4 h under a nitrogen atmosphere. The reaction was detected by TLC [DCM:MeOH=15:1 (v / v)]. The reaction solution was poured into a beaker filled with ice water, and the precipitated solid was filtered. After the filter cake was dried, it was slurried with ethanol and filtered and dried to obtain an orange solid. The orange solid product was characterized, and the results are as follows:

[0085] HRMS(ESI)m / z:486.0882[M+H] + (Theoretical value: 486.0876);

[0086] 1 HNMR(400MHz,DMSO-d6)δ8.37(s,1H),7.87(s,2H),7.76(d,J=3.6Hz,1H),6.85(d, J=3.6Hz,1H),4.64(p,J=7.3Hz,1H),1.95(p,J=7.4Hz,4H),0.71(t,J=7.3Hz,6H);

[0087] 13C NMR(101MHz,DMSO-d6)δ159.86,156.69,153.76,150.03,148.71,145.51,138.3 7,129.03,127.08,126.85,123.30,113.18,104.18,98.23,58.95,27.88,11.09.

[0088] Example 2

[0089] This embodiment relates to the preparation of a substituted azauracil compound I-2, the structure of which is shown below:

[0090]

[0091] The specific preparation process differs from that of Example 1 only in that an equimolar amount of intermediate D is used to replace intermediate E. Other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0092] HRMS(ESI)m / z:472.0640[M+H] + (Theoretical value: 472.0648);

[0093] 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.16(s,1H),7.87–7.73(m,2H),6.89–6.76(m,1H),4.89 (q, J=7.1Hz, 1H), 1.97 (dh, J=15.2, 7.2Hz, 2H), 1.56 (d, J=6.8Hz, 3H), 0.79 (t, J=7.3Hz, 3H).

[0094] Example 3

[0095] This embodiment relates to the preparation of a substituted azauracil compound I-3, the structure of which is shown below:

[0096]

[0097] The specific preparation process differs from that of Example 1 only in that an equimolar amount of intermediate F is used to replace intermediate E. Other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0098] HRMS (ESI) m / z: 445.0356 [M+H] + (Theoretical value: 445.0356);

[0099] 1H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H), 8.54 (s, 1H), 7.88 (s, 2H), 4.37 (q, J = 7.3Hz, 2H), 1.51 (t, J = 7.3Hz, 3H).

[0100] Example 4

[0101] This example relates to the preparation of a substituted azauracil compound I-4, the structure of which is shown below:

[0102]

[0103] The specific preparation process differs from that of Example 1 only in that an equimolar amount of intermediate G is used to replace intermediate E. Other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0104] HRMS(ESI)m / z:473.0687[M+H] + (Theoretical value: 473.0644);

[0105] 1 H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H), 8.54 (s, 1H), 7.88 (s, 2H), 4.37 (q, J = 7.3Hz, 2H), 1.51 (t, J = 7.3Hz, 3H).

[0106] Example 5

[0107] This example relates to the preparation of a substituted azauracil compound I-5, the structure of which is shown below:

[0108]

[0109] The specific preparation process differs from that of Example 1 only in that an equimolar amount of intermediate H is used to replace intermediate E. Other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0110] HRMS(ESI)m / z:487.0843[M+H] + (Theoretical value: 487.0827);

[0111] 1 H NMR (400MHz, DMSO-d6) δ 8.76 (s, 1H), 8.53 (s, 1H), 7.89 (s, 2H), 4.50 (dt, J = 9.3, 4.4Hz, 1H), 2.12–1.99 (m, 4H), 0.76 (t, J = 7.3Hz, 6H).

[0112] Example 6

[0113] This example relates to the preparation of a substituted azauracil compound I-6, the structure of which is shown below:

[0114]

[0115] The specific preparation process is as follows:

[0116] (1) Using intermediate C and 2,6-dimethyl-4-nitrophenol as raw materials, the synthesis and purification steps of step (1) in Example 1 were referred to to prepare 4-(2,6-dimethyl-4-nitrophenoxy)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (2.1 g, 83.1%) as a white solid.

[0117] (2) Ammonium chloride (1.5 g, 28.4 mmol) was added to a solution of EtOH:H2O=2:1 (v / v), and iron powder (1.1 g, 20.3 mmol) was added in batches. After heating and reflux for 1 h, the white solid compound 4-(2,6-dimethyl-4-nitrophenoxy)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (2.1 g, 6.4 mmol) prepared in step (2) was added in batches. Under a nitrogen atmosphere, the reaction was refluxed for 3 h. TLC detection showed that the reaction was complete [PE:EA=3:1 (v / v)]. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure. The pH was adjusted to 7-8 with saturated sodium bicarbonate and extracted with EA (50 mL×3). The combined organic layer was washed with water (50 mL×2), then with saturated brine (50 mL×1), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the obtained solid was purified by silica gel column chromatography [PE:EA=5:1 (v / v)] to give 4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylaniline (1.6 g, 83.7%) as a white solid.

[0118] (3) Using the white solid 4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylaniline prepared in step (2) as raw material, referring to the synthesis and purification steps of step (3) in Example 1, an orange solid ethyl (Z)-(2-cyano-2-(2-(4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)hydrazono)acetyl)carbamate (2.0 g, 85.6%) was prepared.

[0119] (5) Using the orange solid ethyl (Z)-(2-cyano-2-(2-(4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)hydrazono)acetyl)carbamate prepared in step (3) as a raw material, the synthesis and purification steps of step (4) in Example 1 were referred to to prepare orange solid 2-(4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (1.7 g, 94.4%). The orange solid product was characterized, and the results were as follows:

[0120] HRMS(ESI)m / z:418.1634[M+H] + (Theoretical value: 418.1628);

[0121] 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 1H), 7.62 (d, J = 3.6Hz, 1H), 7.20 (s, 2H), 6.56 ( d,J=3.6Hz,1H),4.96(hept,J=6.7Hz,1H),2.00(s,6H),1.42(d,J=6.8Hz,6H).

[0122] Example 7

[0123] This example relates to the preparation of a substituted azauracil compound I-7, the structure of which is shown below:

[0124]

[0125] The specific preparation process differs from that of Example 6 only in that an equimolar amount of intermediate B is used to replace intermediate C. Other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0126] HRMS(ESI)m / z:404.1464[M+H] + (Theoretical value: 404.1466);

[0127] 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 1H), 7.62 (d, J = 3.6Hz, 1H), 7.20 (s, 2H), 6.56 ( d,J=3.6Hz,1H),4.96(hept,J=6.7Hz,1H),2.00(s,6H),1.42(d,J=6.8Hz,6H).

[0128] Example 8

[0129] This example relates to the preparation of a substituted azauracil compound I-8, the structure of which is shown below:

[0130]

[0131] The specific preparation process differs from that of Example 6 only in that an equimolar amount of intermediate E is used to replace intermediate C. Other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0132] HRMS(ESI)m / z:446.2016[M+H] + (Theoretical value: 446.1941);

[0133] 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),7.66(d,J=3.6Hz,1H),7.28(s,2H),6.67(d,J=3.6H z,1H),4.59(p,J=7.3Hz,1H),2.09(s,6H),1.91(p,J=7.3Hz,4H),0.68(t,J=7.3Hz,6H).

[0134] Example 9

[0135] This example relates to the preparation of a substituted azauracil compound I-9, the structure of which is shown below:

[0136]

[0137] The specific preparation process differs from that of Example 6 only in that an equimolar amount of intermediate D is used to replace intermediate C. Other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0138] HRMS(ESI)m / z:432.1791[M+H] + (Theoretical value: 432.1784);

[0139] 1 H NMR (400MHz, DMSO-d6) δ13.07(s,1H),8.29(s,1H),7.70(d,J=3.6Hz,1H),7.30(s,2H),6.67(d,J=3.6Hz,1H),4.8 1(dt,J=8.2,6.3Hz,1H),2.09(s,6H),1.89(dh,J=13.9,7.1Hz,2H),1.49(d,J=6.8Hz,3H),0.72(t,J=7.3Hz,3H).

[0140] Example 10

[0141] This example relates to the preparation of a substituted azauracil compound I-10, the structure of which is shown below:

[0142]

[0143] The specific preparation process differs from that of Example 6 only in that an equimolar amount of intermediate A is used to replace intermediate C. Other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0144] HRMS (ESI) m / z: 390.1362 [M+H] + (Theoretical value: 390.1315);

[0145] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.55(d,J=3.5Hz,1H),7.31(s,2H),6.63(d,J=3.4Hz,1H),3.84(s,3H),2.07(s,6H).

[0146] Intermediate J

[0147]

[0148] The specific preparation process of Intermediate J differs from that of Example 1 only in that an equimolar amount of Intermediate C is used to replace Intermediate E. All other operations are the same to prepare a solid product. HRMS (ESI) m / z: 458.0572 [M+H] + (Theoretical value: 458.0562); 1 H NMR (400MHz, DMSO-d6) δ 8.35 (s, 1H), 7.82 (s, 2H), 7.79 (d, J = 3.7Hz, 1H), 6.78 (d, J = 3.6Hz, 1H), 5.06 (hept, J = 6.7Hz, 1H), 1.52 (d, J = 6.8Hz, 6H).

[0149] Intermediate K

[0150]

[0151] The specific preparation process of Intermediate K differs from that of Example 1 only in that an equimolar amount of Intermediate A is used to replace Intermediate E. Other operations are the same to prepare a solid product. HRMS (ESI) m / z: 430.0169 [M+H] + (Theoretical value: 430.0217);1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.83(s,2H),7.63(d,J=3.5Hz,1H),6.76(d,J=3.5Hz,1H),3.87(s,3H)

[0152] Example 11

[0153] This embodiment relates to the preparation of a substituted azauracil compound I-11, the structure of which is shown below:

[0154]

[0155] The specific preparation process is as follows:

[0156] (1) Intermediate J (1.0 g, 2.1 mmol) was dissolved in a mixed solution of HCl (10 mL) and HOAc (2 mL) and refluxed at 100°C for 10 h under a nitrogen atmosphere. The reaction was complete by TLC. The reaction solution was added to water and stirred for 1 h. The precipitated solid was filtered and washed with water. The filter cake was dried to obtain yellow-white solid 2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (709.3 mg, 67.3%) without purification. HRMS (ESI) m / z: 477.0489 [M+H] + (Theoretical value: 477.0481); 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.37(s,1H),7.87(s,2H),7.80(d,J=3. 6Hz, 1H), 6.81 (d, J = 3.7Hz, 1H), 5.07 (p, J = 6.7Hz, 1H), 1.52 (d, J = 6.8Hz, 6H).

[0157] (2) The yellow-white solid dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (400.0 mg, 0.8 mmol) prepared in step (1) was added to tert-butanol (10 mL), and DPPA (692.0 mg, 2.5 mmol) and triethylamine (339.0 mg, 3.3 mmol) were added in batches. The mixture was refluxed at 85° C. under a nitrogen atmosphere for 24 h. The reaction mixture was detected by TLC. The reaction was observed to be complete, quenched with saturated sodium bicarbonate, extracted with DCM (50 mL × 3), and the organic layers were combined, washed with water (50 mL × 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)carbamate (313.2 mg, 68.1%) as a pale yellow solid. The product was used directly in the next reaction without purification.

[0158] (3) The light yellow solid tert-butyl (2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)carbamate (313.2 mg, 0.6 mmol) prepared in step (2) was dissolved in a DCM:TFA=4:1 (v / v) solution (20 mL) and reacted at room temperature for 1 h. The reaction was detected by TLC to be complete. The resulting mixture was adjusted to pH 7-8 with saturated sodium bicarbonate. The reaction solution was added. Add water, extract with EA (50 mL × 3), combine the organic layers, wash with water (50 mL × 2), wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting solid is purified by silica gel column chromatography with PE:EA = 3:1 (v / v) to obtain a white solid 6-amino-2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (223.2 mg, 87.2%). The solid product was characterized, and the results are as follows:

[0159] HRMS(ESI)m / z:448.0640[M+H] + (Theoretical value: 448.0686);

[0160] 1H NMR (400MHz, DMSO-d6) δ12.22(s,1H),8.27(s,1H),7.84(s,2H),7.69(d,J=3.7Hz,1H) ,6.67(d,J=3.6Hz,1H),6.35(s,2H),4.97(hept,J=6.7Hz,1H),1.43(d,J=6.8Hz,6H);

[0161] 13 C NMR (101MHz, DMSO-d6) δ160.11,155.80,152.26,150.05,149.28,145.17,142.67,140.07,128.23,126.49,124.76,104.55,97.93,46.94,22.78.

[0162] Example 12

[0163] This example relates to the preparation of a substituted azauracil compound I-12, the structure of which is shown below:

[0164]

[0165] The specific preparation process differed from that of Example 11 only in that an equimolar amount of the product prepared in Example 2 was used to replace the raw material intermediate J. All other operations were the same to prepare a solid product. The solid product was characterized, and the results were as follows:

[0166] HRMS(ESI)m / z:462.0841[M+H] + (Theoretical value: 462.0843);

[0167] 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.34(s,1H),7.90(s,2H),7.73(d,J=3.6Hz,1H),6.77(d,J=3.6Hz,1H), 6.56 (s, 2H), 4.82 (h, J = 6.9Hz, 1H), 1.89 (dq, J = 18.0, 7.1Hz, 2H), 1.49 (d, J = 6.7Hz, 3H), 0.71 (t, J = 7.3Hz, 3H).

[0168] Example 13

[0169] This example relates to the preparation of a substituted azauracil compound I-13, the structure of which is shown below:

[0170]

[0171] The specific preparation process differs from that of Example 11 only in that an equimolar amount of intermediate K is used to replace the raw material intermediate J. All other operations are the same to prepare a solid product. The solid product was characterized, and the results are as follows:

[0172] HRMS(ESI)m / z:420.0370[M+H] + (Theoretical value: 420.0373);

[0173] 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.37(s,1H),7.89(s,2H),7.62(s,1H),6.77–6.68(m,1H),6.55(s,2H),3.87(s,3H).

[0174] Example 14

[0175] This example relates to the preparation of a substituted azauracil compound I-14, the structure of which is shown below:

[0176]

[0177] The specific preparation process differed from that of Example 11 only in that an equimolar amount of the product prepared in Example 10 was used to replace the raw material intermediate J. All other operations were the same to prepare a solid product. The solid product was characterized, and the results were as follows:

[0178] HRMS(ESI)m / z:380.1421[M+H] + (Theoretical value: 380.1466);

[0179] 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.32(s,1H),7.52(d,J=3.5Hz,1H),7.30(s,2H),6.54(d,J=3.5Hz,1H),6.35(s,2H),3.83(s,3H),2.04(s,6H).

[0180] Example 15

[0181] This example relates to the preparation of a substituted azauracil compound I-15, the structure of which is shown below:

[0182]

[0183] The specific preparation process differed from that of Example 11 only in that an equimolar amount of the product prepared in Example 6 was used to replace the raw material intermediate J. All other operations were the same to prepare a solid product. The solid product was characterized, and the results were as follows:

[0184] HRMS(ESI)m / z:408.1822[M+H] + (Theoretical value: 408.1784);

[0185] 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.31(s,1H),7.69(d,J=3.6Hz,1H),7.31(s,2H),6.60 (d,J=3.6Hz,1H),6.37(s,2H),5.03(hept,J=6.7Hz,1H),2.05(s,6H),1.49(d,J=6.8Hz,6H).

[0186] Test Example 1

[0187] The compounds prepared in the above examples were evaluated for their agonistic activity on THR-α and β proteins using the HTRF assay. ) was used as the reference compound, and the agonist rate of the target compound on THR-β protein at 5 μM was determined. The compound with better agonist rate was selected to determine the EC50 of THR-β and THR-α.

[0188] The specific testing process is as follows:

[0189] (1) Preparation of compound dose gradient solution

[0190] Agonism Assay: Compounds were prepared in DMSO to a stock concentration of 10 mM. Each compound was then diluted from the stock concentration to a working concentration (5 mM) in DMSO. Using an Echo pipetting system, 20 nL of the diluted compound solution was transferred to a 384-well assay plate (Corning-4512) at a 100% DMSO concentration. Positive control wells were treated with 20 nL of the highest concentration of triiodothyronine, while negative control wells were treated with 20 nL of DMSO. The final 20 μL DMSO concentration was diluted to 0.1%.

[0191] EC50 Assay: Compounds were prepared in DMSO to a stock concentration of 30 mM. Control compounds were diluted in DMSO from the stock concentration to the working concentration. 10 μL of compound was added to column 1 of a 384-well LDV plate, and 10 μL of DMSO was added to columns 2 through 10 to prepare compound dilution solutions in the 384-well LDV plate. Compounds were diluted 3-fold using a Bravo liquid handling system. 5 μL of compound was transferred from column 1 to column 2 and mixed. 5 μL of compound was then transferred from column 2 to column 3 and mixed. This was followed by dilutions to column 10. According to the experimental design, 20 nL of these diluted compound solutions were transferred to a 384-well assay plate (Corning-4512) using an Echo pipetting system. The DMSO concentration was 100%. 20 nL of the highest concentration of triiodothyronine was added to the positive control wells, and 20 nL of DMSO was added to the negative control wells. The final 20 μL solution was diluted to 0.1% DMSO.

[0192] (2) Preparation of 4×THR-β working solution

[0193] Dilute the THR-β protein to 4× the working concentration in buffer, resulting in a protein concentration of 4 nM. According to the experimental design, add 5 μL of the protein solution to the corresponding wells of the assay plate containing 20 nL of compound. Add 5 μL of blank buffer to the negative control wells. The THR-β protein concentration is 4 nM, and the DMSO content is 0.4%. Centrifuge at 1000 rpm for 1 minute.

[0194] (3) Preparation of 4×SRCs (steroid receptor coactivator) working solution

[0195] Dilute SRCs to a 4x working concentration in buffer, now a concentration of 400 nM. Add 5 μL of the prepared SRCs solution to the corresponding wells of the assay plate containing 20 nL of the test compound and 5 μL of THRs protein (test compound diluted 500-fold, DMSO content 0.2%). Centrifuge at 1000 rpm for 1 minute, seal the membrane, and incubate at 25°C for 30 minutes.

[0196] (4) Preparation of detection reagents

[0197] Dilute mAb Antibody GST-Eu cryptate and Streptavidin-XL665 in buffer to a 2× working mixture. Add 10 μL of this 2× working mixture to the corresponding wells of the assay plate (Streptavidin-XL665 to SRCs concentration ratio of 1:16) with a final DMSO content of 0.1%. Centrifuge at 1000 rpm for 1 minute. Read continuously for 30 minutes using an Envision microplate reader using the following detection program: Homogeneous TRF Laser 384665 nm / 620 nm.

[0198] (5) Result analysis

[0199] The percent activation (%) of the compound at each concentration was calculated relative to the luminescent signal in the positive and negative control wells included in each assay plate. The high control wells contained 1 μM triiodothyronine, which was used as 100% activation, and the low control wells contained 0.1% DMSO, which was used as 0% activation. Using XL-fit, the four-parameter logistic dose-response equation was used to determine whether the data from each run met the experimental criteria, and the compound concentration required for 50% activation (EC50) was calculated.

[0200] The test results are shown in Table 1 below:

[0201] Table 1 Activity determination data of different substituted aza-uracil compounds and reference compounds

[0202]

[0203]

[0204] As shown in Table 1, the substituted azauracil compounds provided by the present invention all exhibited high agonist activity against THR-β protein. Compounds I-1, I-5, and I-8 not only exhibited high agonist activity against THR-β protein but also exhibited high selectivity. Compound I-1, in particular, exhibited comparable agonist activity against THR-β protein to that of MGL-3196, exhibiting superior selectivity and, therefore, greater safety.

[0205] Test Example 2

[0206] The triglyceride (TG) and cholesterol (TC) content were determined using an enzymatic assay kit. MGL-3196 was used as a reference compound to determine the TG and TC content in HepG2 cells after the target compound acted on them.

[0207] The determination of TG and TC content specifically includes the following steps:

[0208] (1) Tissue cell lysis: digest with trypsin, collect cells by centrifugation and then lyse. 6 Add 0.1 mL of lysis buffer to each cell, mix well, and let stand at room temperature for 10 minutes.

[0209] (2) Lysate treatment: Transfer an appropriate amount of supernatant to a 1.5 mL centrifuge tube, heat at 70°C for 10 minutes, and centrifuge at 2000 rpm for 5 minutes at room temperature. The supernatant is used for enzymatic assay.

[0210] (3) Preparation of working solution: Mix 4 mL of reagent R1 and 1 mL of reagent R2 in a ratio of 4:1.

[0211] (4) Standard dilution: Use distilled water, physiological saline, or a liquid consistent with the sample buffer to dilute the 4 mM glycerol standard to 1000, 500, 250, 125, and 62.5 μmol / L, and set up a 0 concentration control reaction tube.

[0212] The 5 mM cholesterol standard was diluted with anhydrous ethanol to 2500, 1250, 625, 312.5, 156.2, and 562.5 μmol / L, and a 0 concentration control reaction tube was set up.

[0213] (5) Determination of TG and TC concentrations: After adding the sample, incubate at 25°C for 15 minutes. Zero the tubes with distilled water and a working solution. Measure the OD value of each tube, plot a standard curve, and calculate the TG and TC concentrations.

[0214] The test results are shown in Table 2 below:

[0215] Table 2 Effects of different substituted aza-uracil compounds and reference compounds on TG and TC contents in HepG2 cells

[0216] Compound <![CDATA[TG value (μmol / L) a > <![CDATA[TC value (μmol / L) a > I-1 331.3±4.0 550.0±8.7 I-5 324.3±4.0 530.0±8.7 I-8 349.0±8.9 578.3±10.4 I-12 423.3±5.1 698.3±7.6 I-15 390.3±7.5 560.0±5.0 MGL-3196 322.0±10.0 493.3±12.6 Control(blank) 429.3±6.1 706.3±5.5

[0217] In the table, a represents the standard deviation of three experiments.

[0218] As shown in Table 2, compared with the blank control experiment, compounds I-1, I-5, I-8, and I-15 can significantly reduce the TG and TC levels in HepG2 cells after acting on them. Among them, the improvement effects of compounds I-1 and I-5 on TG and TC are comparable to those of MGL-3196.

[0219] In summary, the substituted aza-uracil compounds provided by the present invention have agonist activity on THR-β protein, and some compounds have agonist activity on THR-β protein comparable to that of MGL-3196, or even exhibit higher selectivity, and can effectively reduce triglycerides and cholesterol in tissue cells. They have good application prospects as THR-β agonists and in the preparation of drugs for the prevention and / or treatment of diseases mediated by THR-β activity (such as NASH, etc.).

[0220] The above embodiments are merely preferred embodiments for the purpose of fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are within the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

Claims

1. A substituted azauracil compound represented by formula (I) or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, in, R1 is selected from a linear or branched C 1-10 alkyl; X is H or N; R2 and R3 are each independently selected from halogen, linear or branched C 1-10 alkyl; R4 is selected from cyano, amino, aminomethyl, carbamoyl, hydroxymethyl, methoxymethyl, methylamino, dimethylamino, and cyanomethyl.

2. The substituted azauracil compound of formula (I) according to claim 1 or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, characterized in that: The pharmaceutically acceptable salt is an inorganic salt or an organic salt; The inorganic salt includes one of hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; The organic salt includes one of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

3. The substituted azauracil compound of formula (I) according to claim 1 or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, characterized in that: The substituted azauracil compounds are compounds represented by the following structural formulas I-1 to I-15:

4. The substituted azauracil compound of formula (I) according to claim 1 or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, characterized in that: R1 is 5. The substituted azauracil compound of formula (I) according to claim 1 or 4, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, characterized in that: R2 and R3 are both chlorine or methyl.

6. The substituted azauracil compound of formula (I) according to claim 5 or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph, wherein: R4 is cyano.

7. A pharmaceutical composition, characterized in that Comprising a substituted azauracil compound represented by formula (I) according to any one of claims 1 to 6 or one or more of its isotopic forms, stereoisomers, tautomers, cis-trans isomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs.

8. Use of a substituted azauracil compound of formula (I) according to any one of claims 1 to 6, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph, or the pharmaceutical composition according to claim 7 in the preparation of a THR-β agonist.

9. Use of a substituted azauracil compound of formula (I) according to any one of claims 1 to 6, or its isotopic form, stereoisomer, tautomer, cis-trans isomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, polymorph, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and / or preventing diseases mediated by THR-β activity.

10. The use according to claim 9, characterized in that Such conditions include nonalcoholic steatohepatitis, obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

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