Methylene bisphenol-based phosphorus ligand derivatives, their preparation and therapeutic use

Abstract

The present invention relates to methylenediphosphine derivatives, their preparation and therapeutic use, said methylenediphosphine derivatives being represented by the general formula I, which can be used as therapeutic agents for non-alcoholic steatohepatitis (NASH).

Description

Technical Field

[0001] This invention relates to a methylenebisphenol phosphorus ligand derivative, its preparation method, and its use in the treatment of NASH disease. Background Technology

[0002] With the prevalence of obesity, diabetes, and metabolic syndrome, the prevalence of non-alcoholic steatohepatitis (NASH) in ordinary adults is as high as 3%–6%, and the age of onset is also trending younger (Greenfield V, Cheung O, Sanyal AJ. CurrOpin Gastroenterol 2008; 24:320-327.). It has become an increasingly important cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. 15%–20% of NASH patients may progress to cirrhosis within 10–20 years.

[0003] In NASH disease, insulin resistance, lipotoxicity, oxidative stress, immune or cytokine or mitochondrial dysfunction, and apoptosis are all pathogenic pathways involved in its occurrence and development. Therefore, targeted interventions against these pathogenesis mechanisms are currently a hot research topic. The exploration of these therapeutic targets is at different stages of research. Future research will focus on combined interventions with multiple drugs targeting different aspects of NASH pathogenesis, and the therapeutic targets need to address the prevention and treatment of hepatic steatosis, inflammation, hepatocellular damage, and fibrosis.

[0004] The development of NASH-specific therapeutics is progressing rapidly, involving multiple targets and mechanisms. This invention aims to target the thyroid hormone β receptor (THR-β). Thyroid hormone (TH) is synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland. Thyroid hormones function by binding to the thyroid hormone receptor (THR). THR belongs to the nuclear receptor family and regulates the expression of target genes. There are two different subtypes of the thyroid hormone receptor, THR-α and THR-β. The THR-β subtype is highly expressed in the liver (Bookout AL, Jeong Y, Downes M, et al. Cell, 2006, 126:789-799.), and is an important regulator of lipid metabolism, increasing LDL receptor expression, increasing CYP7A1 enzyme expression, and decreasing sterol regulator-binding protein-1 expression. THR-β agonists in the liver reduce lipotoxicity and improve liver function by promoting fatty acid breakdown and stimulating mitochondrial biogeneration, thereby reducing liver fat. They have been shown to reduce low-density lipoprotein, triglycerides and hepatic steatosis in humans, which may alleviate lipotoxicity and improve NASH. They have potential therapeutic benefits for NASH patients and patients with elevated low-density lipoprotein cholesterol (LDL-C), and do not cause thyrotoxicosis (THR-α effect).

[0005] THR-β agonists are effective in treating a variety of diseases, but there are currently no approved drugs for NASH. Therefore, this invention provides a series of compounds with novel structures to develop THR-β agonists with better specificity, efficacy, and pharmacokinetic properties, providing a basis for new drugs for the clinical treatment of NASH. Summary of the Invention

[0006] On the one hand, the present invention provides a methylenebisphenol phosphorus ligand derivative as shown in Formula I, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] X is C 0-1 alkyl;

[0010] R1 and R2 are each independently selected from methyl, ethyl, isopropyl, and halogen;

[0011] R3 is selected from -OH, methoxy, ethoxy, isopropoxy, phenoxy, or benzyloxy.

[0012] R4 is selected from -OH or the following structures:

[0013]

[0014] Preferably, the methylenebisphenol phosphorus ligand derivative or its pharmaceutically acceptable salt described in this invention has the following general formula:

[0015]

[0016]

[0017] in,

[0018] R1 and R2 are each independently selected from methyl and isopropyl groups;

[0019] R3 is selected from methoxy, ethoxy, phenoxy, or benzyloxy.

[0020] R4 is selected from the following structure:

[0021]

[0022] More preferably, the methylenebisphenol phosphorus ligand derivatives or pharmaceutically acceptable salts thereof described in this invention are selected from the following compounds:

[0023]

[0024] The present invention further includes methylene bisphenol phosphorus ligand derivatives of general formula I or pharmaceutically acceptable salts thereof, solvates, metabolite prodrugs, etc.

[0025] The present invention also includes the use of the methylenebisphenol phosphorus ligand derivatives thereof, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for treating diseases associated with NASH.

[0026] The present invention relates to a methylenebisphenol phosphorus ligand derivative or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a salt formed by the methylenebisphenol phosphorus ligand derivative with the following acids: hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, or trifluoroacetic acid. Preferably, it is a salt formed by the methylenebisphenol phosphorus ligand derivative with the following acids: toluenesulfonic acid, hydrochloric acid, tartaric acid, or trifluoroacetic acid.

[0027] The present invention also includes pharmaceutical compositions comprising the methylenebisphenol phosphorus ligand derivatives or pharmaceutically acceptable salts thereof described herein. The pharmaceutical compositions of the present invention further comprise at least one other therapeutic agent for treating NASH.

[0028] The pharmaceutical compositions of the present invention are preferably in the form of a unit dose pharmaceutical formulation. When formulated into a pharmaceutical formulation, they can be prepared into any pharmaceutically acceptable dosage form, selected from: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, suspensions, solutions, injections, suppositories, ointments, plasters, creams, sprays, and patches. Oral formulations are preferred, with tablets and capsules being the most preferred.

[0029] This pharmaceutical formulation can be prepared using conventional pharmaceutical techniques, such as mixing the imine compound of the present invention, or its solvate, or a pharmaceutically acceptable salt of the imine compound, or a pharmaceutically acceptable salt of its solvate, with a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier includes, but is not limited to: mannitol, sorbitol, sorbic acid or its potassium salt, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine ​​hydrochloride, thioglycolic acid, methionine, vitamin A, vitamin C, vitamin E, vitamin D, azone, disodium EDTA, sodium calcium EDTA, carbonates, acetates, phosphates of monovalent alkali metals or their aqueous solutions, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, and dextrorotatory glucose. Glycosides, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerol, propylene glycol, ethanol, Tween 60-80, Span-80, beeswax, lanolin, liquid paraffin, cetyl alcohol, gallate esters, agar, triethanolamine, basic amino acids, urea, allantoin, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, β-cyclodextrin, phospholipids, kaolin, talc, calcium stearate, magnesium stearate, etc.

[0030] The pharmaceutical compositions of the present invention, when formulated into a pharmaceutical preparation, may contain 0.1-1000 mg of the active pharmaceutical ingredient of the present invention per unit dose, with the remainder being a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be 0.1-99.9% by weight of the total weight of the preparation.

[0031] The compound described in this invention can be prepared using the following methods:

[0032] Option 1:

[0033]

[0034] In Scheme 1, compound A-1 reacts with pentafluorophenol phosphorus ligand under Grignard reagent conditions to obtain compound A-2. Compound A-2 can be deprotected by acid to obtain compound A-3.

[0035] Option 2:

[0036]

[0037] In Scheme 2, compound A-1 reacts with p-toluenesulfonic acid phosphorus ligand under alkaline conditions to obtain compound A-4, and then compound A-4 is deprotected under acidic conditions to obtain compound A-5.

[0038] Option 3:

[0039]

[0040] In Scheme 3, compound A-1 reacts with p-toluenesulfonic acid phosphorus ligand under alkaline conditions to obtain compound A-6. Then, compound A-6 selectively removes one of the R3 groups under alkaline conditions to obtain compound A-7. Compound A-7 undergoes a condensation reaction to obtain compound A-8. Compound A-8 is deprotected to obtain compound A-9. Attached image description:

[0041] Figure 1. Compound 1 1 H-NMR spectrum

[0042] Figure 2. Compound 1 31 P-NMR spectrum

[0043] Figure 3 Compound 2 1 H-NMR spectrum

[0044] Figure 4. Compound 2 31 P-NMR spectrum

[0045] Figure 5. Compound 3 1 H-NMR spectrum

[0046] Figure 6. Compound 3 31 P-NMR spectrum

[0047] Figure 7. Compound 4 1 H-NMR spectrum

[0048] Figure 8. Compound 4 31 P-NMR spectrum

[0049] Figure 9. Compound 5 1 H-NMR spectrum

[0050] Figure 10. Compound 5 31 P-NMR spectrum

[0051] Figure 11 Compound 6 1 H-NMR spectrum

[0052] Figure 12 Compound 6 31 P-NMR spectrum Detailed implementation method:

[0053] The present invention will be further described below with reference to specific embodiments.

[0054] Example 1: Synthesis of Compound 1

[0055] a. Synthesis of compounds 1-3

[0056]

[0057] Compound 1-1 (300 mg, 0.9541 mmol, 1.0 eq) was added to tetrahydrofuran (6 mL). Under nitrogen protection, tert-butylmagnesium chloride (1N) (1.717 mL, 1.7174 mmol, 1.8 eq) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 1 h. Then, a tetrahydrofuran solution of 1-2 (624.2 mg, 1.3358 mmol, 1.4 eq) was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 4 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (EA:PE = 1:10 - 1:3) to obtain 360 mg of a colorless oily liquid, which was compound 1-3. Yield: 63.1%. MS (ESI): m / z = 598.23 [M+1] + .

[0058] b. Synthesis of Compound 1

[0059]

[0060] Compounds 1-3 (320 mg, 0.5354 mmol, 1.0 eq) were added to anhydrous methanol (32 mL), followed by p-toluenesulfonic acid (305.6 mg, 1.6062 mmol, 3.0 eq). The reaction was carried out at 50 °C for 2 h. Water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (EA:PE = 1:6-1:3) to obtain 227 mg of a colorless oily liquid, which was compound 1. Yield: 68.1%. MS (ESI): m / z = 554.04 [M+1] + , 1 H NMR (400MHz, CDCl3) δ7.36-7.22(m,5H),6.90-6.74(m,3H),6.52(d,J=8.1Hz ,1H),6.41-6.38(m,1H),5.40(s,1H),5.12-4.99(m,2H),4.92(dd,J=12.7,6 .3Hz,1H),3.90(s,1H),3.81(s,2H),3.50(d,J=10.8Hz,1H),3.23-3.00(m,1 H),2.08(d,J=1.9Hz,6H),1.26(dd,J=17.8,7.0Hz,3H),1.20-1.09(m,12H). 31P NMR (162MHz, CDCl3) δ2.48,2.36.

[0061] Example 2: Synthesis of Compound 2

[0062] a. Synthesis of compound 2-2

[0063]

[0064] 1-1 (200 mg, 0.6361 mmol, 1.0 eq) was added to tetrahydrofuran (4 mL), and tert-butylmagnesium chloride (1N) (1.145 mL, 1.1450 mmol, 1.8 eq) was added dropwise at 0 °C under nitrogen protection. The reaction was carried out at 0 °C for 1 h. Then, 2 mL of tetrahydrofuran solution (400 mg, 0.8905 mmol, 1.4 eq) of 2-1 was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 2 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography was performed. EA:PE = 1:10 - 1:3, yielding 310 mg of a colorless oily liquid, which was compound 2-2. Yield: 83.5%. MS (ESI): m / z = 584.22 [M+1] + .

[0065] b. Synthesis of Compound 2

[0066]

[0067] Compound 2 (260 mg, 0.4455 mmol, 1.0 eq) was added to anhydrous methanol (26 mL), followed by p-toluenesulfonic acid (254.2 mg, 1.3364 mmol, 3.0 eq). The reaction was carried out at 50 °C for 1.5 h. Water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (EA:PE = 1:8-1:3) to obtain 170 mg of a colorless oily liquid, which was compound 2. Yield: 70.7%. MS (ESI): m / z = 540.05 [M+1] + , 1H NMR (400MHz, CDCl3) δ7.25 (dd, J=11.3, 4.5Hz, 2H), 7.17 (dd, J=7.7, 1.0Hz, 2H), 7.13 -7.00(m,1H),6.84(dd,J=9.3,5.0Hz,3H),6.50(d,J=8.1Hz,1H),6.40(dd,J=8.2,2.2 Hz,1H),5.02-4.84(m,1H),4.16-3.92(m,1H),3.82(s,2H),3.69(dd,J=11.7,9.5Hz, 1H),3.22-2.94(m,1H),2.24-1.98(m,6H),1.30(d,J=7.0Hz,3H),1.21-1.07(m,12H). 31 P NMR (162MHz, CDCl3) δ-2.77,-2.83.

[0068] Example 3: Synthesis of Compound 3

[0069] a. Synthesis of compound 3-2

[0070]

[0071] Sodium hydride (76 mg, 1.9083 mmol, 1.2 eq) was added to DMF (5 mL). Under nitrogen protection, 1-1 (500 mg, 1.5902 mmol, 1.0 eq) of DMF (2 mL) solution was added at 0 °C, and the reaction was carried out at rest for 1 h. Then, 3-1 (896 mg, 1.9083 mmol, 1.2 eq) of DMF (2 mL) solution was added at 0 °C, and the reaction was carried out at rest for 16 h. The reaction was quenched with methanol, and the mixture was extracted with water (50 mL) and ethyl acetate (50 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (EA:PE = 1:10 - 1:5) to obtain 708 mg of a colorless oily liquid, which was compound 3-2. Yield: 72.8%. MS (ESI): m / z = 612.28 [M+1] + .

[0072] b. Synthesis of Compound 3

[0073]

[0074] Compound 3-2 (730 mg, 1.1934 mmol, 1.0 eq) was added to anhydrous methanol (73 mL), followed by p-toluenesulfonic acid (681.0 mg, 3.5801 mmol, 3.0 eq). The reaction was carried out at 50 °C for 2.5 h. The mixture was concentrated under vacuum, then extracted with water (50 mL) and dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (EA:PE = 1:6-1:2) to obtain 263 mg of a colorless oily liquid, which was compound 3, yield: 38.8%. MS (ESI): m / z = 568.08 [M+1] + , 1 H NMR (400MHz, CDCl3) δ7.36-7.22(m,5H),6.84(d,J=1.9Hz,1H),6.79(s,2H),6.52(d,J=8.1Hz,1H),6.38(dd,J=8.1,1.8Hz,1H),5.75(s,1H),5.18 -5.00(m,2H),5.01-4.84(m,1H),3.80(s,2H),3.31(dd,J=7.0,3.4Hz,1H ),3.24-3.05(m,2H),2.99-2.90(m,1H),2.06(s,6H),1.22-1.11(m,15H). 31 P NMR (162MHz, CDCl3) δ22.57,22.55.

[0075] Example 4: Synthesis of Compound 4

[0076] a. Synthesis of compound 4-2

[0077]

[0078] Compound 4-1 (2.3 g, 7.1360 mmol, 1.0 eq) was added to tetrahydrofuran (27.6 mL) and H₂O (9.2 mL), followed by the addition of NaOH (2.85 g, 71.3599 mmol, 10.0 eq). The reaction was carried out at rest for 2 days. The mixture was concentrated under vacuum and then subjected to column chromatography (DCM:MeOH = 10:1-4:1) to give 1.8 g of a colorless oily liquid, which was compound 4-2, yield: 85.8%. MS (ESI): m / z = 295.01 [M+1] + .

[0079] b. Synthesis of compound 4-3

[0080]

[0081] Add 4-2 (4 g, 13.5934 mmol, 1.0 eq) to DCM (160 mL), then add a catalytic amount of DMF, and add dropwise a solution of oxaloyl chloride (5.18 g, 40.7803 mmol, 3.0 eq) in DCM (160 mL) at rest. React for 1 h at rest. Concentrate under reduced pressure, then add DCM (160 mL), phenol (2.56 g, 27.1868 mmol, 2.0 eq), and add dropwise a solution of triethylamine (5.5 g, 54.3737 mmol, 4.0 eq) in DCM (80 mL) at rest. React for 2 h at rest. Add water (100 mL), extract with dichloromethane (100 mL * 2), combine the organic phases, dry to anhydrous sodium sulfate, and perform column chromatography (EA:PE = 1:10 - 1:2) to obtain 3.95 g of colorless oily liquid, which is compound 4-3, yield: 78.4%. MS(ESI): m / z = 371.04 [M+1] + .

[0082] c. Synthesis of compound 4-4

[0083]

[0084] Compound 4-3 (3.35 g, 9.0453 mmol, 1.0 eq) was added to DCM (35 mL), and TMSBr (4.15 g, 27.1358 mmol, 3.0 eq) was added dropwise at 0 °C. The reaction was carried out at rt for 16 h. The mixture was concentrated under vacuum and subjected to column chromatography (DCM:MeOH = 20:1-8:1) to give 2.62 g of a yellow oily liquid, which was compound 4-4, yield: 84.6%. MS (ESI): m / z = 343.02 [M+1] + .

[0085] d. Synthesis of compounds 4-5

[0086]

[0087] Add 4-4 (3.37 g, 9.8452 mmol, 1.0 eq) to DCM (130 mL), then add a catalytic amount of DMF, and add dropwise a solution of oxaloyl chloride (3.75 g, 29.5355 mmol, 3.0 eq) in DCM (130 mL) at rest, and react for 1 h at rest. Concentrate under reduced pressure, then add DCM (130 mL), L-alanine isopropyl hydrochloride (3.3 g, 19.6903 mmol, 2.0 eq), and add dropwise a solution of triethylamine (5.98 g, 59.0710 mmol, 6.0 eq) in DCM (65 mL) at rest, and react for 2 h at rest. Add water (100 mL), extract with dichloromethane (100 mL * 2), combine the organic phases, dry to anhydrous sodium sulfate, and column chromatography (EA:PE = 1:6-1:2) to obtain 3.11 g of yellow oily liquid, which is compound 4-5, yield: 69.4%. MS(ESI): m / z = 456.01 [M+1] + .

[0088] e. Synthesis of compounds 4-6

[0089]

[0090] Sodium hydride (213.7 mg, 5.3432 mmol, 1.2 eq) was added to DMF (14 mL), and 1-1 (1.4 g, 4.4526 mmol, 1.0 eq) of DMF (5.6 mL) solution was added dropwise at 0 °C. The reaction was carried out at rest for 1 h. Then, 4-5 (2.43 g, 5.3432 mmol, 1.2 eq) of DMF (5.6 mL) solution was added dropwise at 0 °C, and the reaction was carried out at rest for 16 h. Water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography was performed. EA:PE = 1:15-1:5 to give 1.34 g of a pale yellow oily liquid, which was compound 4-6, yield: 50.4%. MS (ESI): m / z = 598.21 [M+1] + .

[0091] f. Synthesis of Compound 4

[0092]

[0093] Compound 4-6 (1.2 g, 2.0078 mmol, 1.0 eq) was added to anhydrous methanol (120 mL), followed by p-toluenesulfonic acid (1.15 g, 6.0233 mmol, 3.0 eq). The reaction was carried out at 50 °C for 2 h. The mixture was concentrated under vacuum, and extracted with water (150 mL) and dichloromethane (150 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (EA:PE = 1:10-1:4) to obtain 460 mg of a colorless oily liquid, which was compound 4, yield: 41.4%. MS (ESI): m / z = 554.29 [M+1] + , 1 H NMR (400MHz, CDCl3) δ7.31-7.06(m,5H),6.83(d,J=2.6Hz,3H),6.47(d,J=8.1Hz,1H),6.37(dd,J=8.1,2.1Hz,1H),5.42(s,1H),5.02-4.95(m, 1H),3.81(s,2H),3.47-3.30(m,2H),3.23-2.99(m,2H),2.08(s,6H),1. 26(d,J=7.0Hz,3H),1.17(dd,J=6.2,3.5Hz,6H),1.12(d,J=6.9Hz,6H). 31 P NMR (162MHz, CDCl3) δ 18.58.

[0094] Example 5: Synthesis of Compound 5

[0095] a. Synthesis of compound 5-1

[0096]

[0097] Sodium hydride (610.6 mg, 15.2662 mmol, 1.2 eq) was added to DMF (40 mL). A solution of 1-1 (4 g, 12.7218 mmol, 1.0 eq) in DMF (16 mL) was added dropwise at 0 °C, and the reaction was carried out at rest for 1 h. Then, a solution of 4-1 (4.92 g, 15.2662 mmol, 1.2 eq) in DMF (16 mL) was added dropwise at 0 °C, and the reaction was carried out at rest for 2 h. Water (150 mL) was then added, and the mixture was extracted with ethyl acetate (150 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (EA:PE = 1:8 - 1:2) to obtain 4.75 g of a pale yellow oily liquid, which was compound 5-1, yield: 80.4%. MS (ESI): m / z = 465.13 [M+1] + .

[0098] b. Synthesis of compound 5-2

[0099]

[0100] Compound 5-1 (4.75 g, 10.2254 mmol, 1.0 eq) was added to THF (55 mL) and H₂O (18 mL), followed by NaOH (4.09 g, 102.2539 mmol, 10.0 eq). The reaction was carried out at rest for 3 days. The mixture was extracted with saturated brine (150 mL) and ethyl acetate (150 mL x 2), washed with 1 N HCl aq., dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4 g of a pale yellow oily liquid, which was compound 5-2. Yield: 89.7%. MS (ESI): m / z = 437.01 [M+1] + .

[0101] c. Synthesis of compound 5-3

[0102]

[0103] Add 5-2 (500 mg, 1.1455 mmol, 1.0 eq) to DCM (20 mL), then add the catalytic amount of DMF, and add oxalyl chloride (436.2 mg, 3.4366 mmol, 3.0 eq) in DCM (20 mL) dropwise at rest. React for 1 h at rest. Concentrate under reduced pressure, then add DCM (20 mL), Y-27632 dihydrochloride (733.1 mg, 2.2911 mmol, 2.0 eq), and DMAP (70.0 mg, 0.5728 mmol, 0.5 eq). Add triethylamine (927.3 mg, 9.1642 mmol, 8.0 eq) in DCM (10 mL) dropwise at rest. React for 2 h at rest. Water (100 mL) was added, followed by extraction with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM:MeOH = 50:1-20:1) to give 379 mg of a pale yellow solid, which was compound 5-3. Yield: 49.7%. MS (ESI): m / z = 666.46 [M+1] + .

[0104] d. Synthesis of compound 5

[0105]

[0106] Compound 5-3 (150 mg, 0.2253 mmol, 1.0 eq) was added to anhydrous methanol (15 mL), followed by p-toluenesulfonic acid (128.6 mg, 0.6759 mmol, 3.0 eq). The reaction was carried out at 50 °C for 16 h. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM:MeOH = 40:1-10:1) to give 75 mg of a white solid, which was compound 5. Yield: 53.6%. MS (ESI): m / z = 622.23 [M+1] + . 1 H NMR(400MHz,CD3OD)δ8.41(s,2H),7.72(s,2H),6.78(dt,J=19.8,9.9Hz,1H),6.70(s,2H), 6.56(d,J=2.8Hz,2H),4.73-4.52(m,1H),4.26-4.10(m,4H),3.87(d,J=3.0Hz,2H),3.24-3. 13(m,3H),2.41-2.23(m,1H),2.20(s,6H),2.15-2.01(m,1H),1.93(dd,J=31.2,14.4Hz,3H) ,1.52(dt,J=23.8,7.6Hz,2H),1.41-1.27(m,7H),1.21-1.17(m,3H),1.11(t,J=6.4Hz,6H). 31 P NMR (162MHz, CD3OD) δ26.00, 25.98, 25.93, 25.90.

[0107] Example 6: Synthesis of Compound 6

[0108] a. Synthesis of compound 6-1

[0109]

[0110] Compound 6-1 (4 g, 12.4104 mmol, 1.0 eq) was added to acetonitrile (120 mL), and TMSBr (5.70 g, 37.2312 mmol, 3.0 eq) was added at 0 °C. The reaction was carried out at rest for 4 h. The mixture was concentrated under vacuum and subjected to column chromatography with DCM:MeOH ratios of 25:1–10:1 to obtain 3 g of a yellow oily liquid, which was compound 6-1, yield: 90.1%. MS (ESI): m / z = 267.02 [M+1] + .

[0111] b. Synthesis of compound 6-2

[0112]

[0113] Add 6-1 (3 g, 11.2693 mmol, 1.0 eq) to DCM (120 mL), then add a catalytic amount of DMF, and dropwise add oxalyl chloride (7.15 g, 56.3465 mmol, 5.0 eq) in DCM (120 mL) at rest, reacting for 1 h at rest. Concentrate under reduced pressure, then add DCM (120 mL), BnOH (4.87 g, 45.0772 mmol, 4.0 eq), and dropwise add triethylamine (9.12 g, 90.1544 mmol, 8.0 eq) in DCM (60 mL) at rest, reacting for 2 h at rest. Add water (150 mL), extract with dichloromethane (150 mL * 2), combine the organic phases, dry to anhydrous sodium sulfate, and column chromatography (EA:PE = 1:8-1:3) to give 3.03 g of pale yellow solid, which is compound 6-2, yield: 60.2%. MS(ESI): m / z = 447.05 [M+1] + .

[0114] c. Synthesis of compound 6-3

[0115]

[0116] Sodium hydride (175.6 mg, 4.3890 mmol, 1.2 eq) was added to DMF (11.5 mL). A solution of 1-1 (1.15 g, 3.6575 mmol, 1.0 eq) in DMF (4.3 mL) was added dropwise at 0 °C, and the reaction was carried out at rest for 1 h. Then, a solution of 6-2 (1.96 g, 4.3890 mmol, 1.2 eq) in DMF (4.3 mL) was added dropwise at 0 °C, and the reaction was carried out at rest for 2 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography (EA:PE = 1:8-1:4) yielded 1.1 g of a colorless oily liquid, which was compound 6-3, yield: 72.3%. MS (ESI): m / z = 589.03 [M+1] + .

[0117] d. Synthesis of compound 6-4

[0118]

[0119] Compound 6-3 (500 mg, 0.8494 mmol, 1.0 eq) was added to THF (4.2 mL), followed by 1 N NaOH (4.2 mL, 4.2469 mmol, 5.0 eq), and the reaction was carried out at rest for 16 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM:MeOH = 30:1-10:1) to obtain 310 mg of a white solid, which was compound 6-4, yield: 73.2%. MS (ESI): m / z = 499.03 [M+1] + .

[0120] e. Synthesis of compounds 6-5

[0121]

[0122] Add 6-4 (300 mg, 0.6017 mmol, 1.0 eq) to DCM (12 mL), then add the catalytic amount of DMF, and add oxalyl chloride (229.1 mg, 1.8052 mmol, 3.0 eq) in DCM (12 mL) dropwise at rest, and react for 1 h at rest. Concentrate under reduced pressure, then add DCM (12 mL), Y-27632 dihydrochloride (385.1 mg, 1.2035 mmol, 2.0 eq), DMAP (36.8 mg, 0.3009 mmol, 0.5 eq), and add triethylamine (487.1 mg, 4.8140 mmol, 8.0 eq) in DCM (6 mL) dropwise at rest, and react for 2 h at rest. Water (50 mL) was added, followed by extraction with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM:MeOH = 50:1-15:1) to give 185 mg of a pale yellow solid, which was compound 6-5. Yield: 42.2%. MS (ESI): m / z = 728.33 [M+1] + .

[0123] f. Synthesis of Compound 6

[0124]

[0125] Compound 6-5 (125 mg, 0.1717 mmol, 1.0 eq) was added to anhydrous methanol (12.5 mL), followed by p-toluenesulfonic acid (98.0 mg, 0.5152 mmol, 3.0 eq). The reaction was carried out at 50 °C for 4 h. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to column chromatography (DCM:MeOH = 40:1-8:1) to give 62 mg of a white solid, which was compound 6. Yield: 52.8%. MS (ESI): m / z = 684.34 [M+1] + .1 H NMR(400MHz,CD3OD)δ8.42(s,2H),7.74(s,2H),7.48-7.26(m,5H),6.81(s,1 H),6.70(s,2H),6.65-6.49(m,2H),5.13(t,J=8.3Hz,2H),4.35-4.24(m,2H), 3.87(s,2H),3.29-3.13(m,2H),2.34(d,J=8.1Hz,1H),2.20(s,6H),2.05(d,J =11.5Hz,1H),2.01-1.82(m,3H),1.51(d,J=12.1Hz,2H),1.26-1.03(m,12H). 31 P NMR (162MHz, CD3OD) δ26.57,26.46.

[0126] Example 7: Experimental study on the agonistic activity of the compound against THR-β

[0127] Experimental methods:

[0128] Prepare a 100X reference compound or compound using DMSO and perform a 1:3 serial dilution. Dilute the 100X reference compound or compound to 4X using 1X reaction buffer and add it to the experimental plate. Prepare a mixed solution of 4X TRα-LBD or TRβ-LBD and 4X RXRα using 1X reaction buffer and add it to the experimental plate. Prepare a mixed solution of 2X biotin-SRC2-2, 2X Eu-anti-GST, and 2X streptavidin-d2 using 1X reaction buffer and add it to the experimental plate. Centrifuge at 1000 rpm for 1 min and incubate at room temperature and in the dark for 4 hours. Read the fluorescence signal values ​​at 665 nm and 615 nm using an Envision 2104 plate reader and calculate the Ratio. 665nm / 615nm The experimental results are shown in Table 1, where A represents EC. 50 ≤200nM, B represents EC 50 The range is 200-500 nM, where C represents EC. 50 The range is 500-1000 nM, where D represents EC. 50 >1000nM.

[0129] Table 1: Agonistaltic activity of selected compounds against THR-β

[0130] compound <![CDATA[EC 50 (nM)]]> Compound 1 D Compound 2 D Compound 3 C Compound 4 D Compound 5 D Compound 6 C

Claims

1. A methylenebisphenol phosphorus ligand derivative or a pharmaceutically acceptable salt thereof, as shown below: 。 2. The methylenebisphenol phosphorus ligand derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a salt formed by the methylenebisphenol phosphorus ligand derivative and the following acids: hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, or trifluoroacetic acid.

3. The methylenebisphenol phosphorus ligand derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein the pharmaceutically acceptable salt is a salt formed by the methylenebisphenol phosphorus ligand derivative and the following acids: toluenesulfonic acid, hydrochloric acid, tartaric acid or trifluoroacetic acid.

4. The use of the methylenebisphenol phosphorus ligand derivative of claim 1 or a pharmaceutically acceptable salt thereof as a THR-β agonist in the preparation of a medicament for treating non-alcoholic steatohepatitis.

5. A pharmaceutical composition comprising the methylenebisphenol phosphorus ligand derivative of claim 1 or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 5 further comprises at least one other therapeutic agent for treating NASH.

7. The pharmaceutical composition according to claim 5, selected from tablets or capsules.

Images