Butyric acid aryl ether derivatives and their medical use

Abstract

The present application relates to the formula I shown with peroxide body proliferation of aryl ether derivatives of butyric acid PPARδ agonist, its racemic or optical isomer, its solvate, or its pharmaceutically acceptable salt, and its use in the preparation of the treatment of metabolic syndrome or obesity drugs and the use of the pharmaceutical composition containing them. Wherein n1 is selected from 1, 2; n2 is selected from 1, 3; R3 is selected from benzopentacyclic ring (pyrrole, thiophene, furan, 1, 3- thiazolidine, imidazole) or benzohexacyclic ring (pyridine), or naphthalene ring, or benzene substituted with one or two heteroatom containing five-membered ring (thiophene, furan, 1, 3- thiazolidine, 1, 3- thiazolidine) or benzene ring. The benzene ring of R3 can be independently substituted by hydrogen, chlorine, bromine, methyl and trifluoromethyl.

Description

Technical Field

[0001] This invention relates to butyrate aryl ether derivatives having peroxisome proliferator-activated receptor PPARδ agonist activity, and their use in the preparation of medicaments for treating metabolic syndrome and pharmaceutical compositions containing them. Background Technology

[0002] Metabolic syndrome refers to a group of co-occurring medical conditions, including abdominal obesity, hyperglycemia due to insulin resistance, atherosclerotic dyslipidemia, and hypertension. It increases the risk of various diseases, thus necessitating the discovery of novel and effective drugs targeting relevant receptors to treat the resulting illnesses. PPARs, or peroxisome proliferator-activated receptors, comprise three subtypes in nature: PPARα, PPARβ / δ, and PPARγ, which control many intracellular metabolic processes. PPARδ is widely expressed in most tissues and is the most abundant of the three PPAR subtypes. Pharmacological effects of activated PPARδ include reducing weight gain, improving skeletal muscle endurance, improving insulin resistance, inhibiting atherosclerotic inflammation, and treating muscle and demyelinating diseases such as multiple sclerosis. Therefore, targeting PPARδ could improve various diseases caused by altered fatty acid metabolism; currently, there are no clinically available PPARδ agonists. Summary of the Invention

[0003] The technical problem solved by this invention is to provide a compound of formula I that has an agonistic effect on PPARδ protein, its stereoisomer, its prodrug and pharmaceutically active metabolite, its pharmaceutically acceptable salt, solvate, and hydrate, and to provide its use in the preparation of medicaments for treating metabolic-related diseases.

[0004]

[0005] in,

[0006] n1 is selected from 1 and 2;

[0007] n2 is selected from 1 and 3;

[0008] R3 is selected from a benzo5-membered ring (pyrrole, thiophene, furan, 1,3-thiazazacyclopentane, imidazole) or a benzo6-membered ring (pyridine), or a naphthalene ring, or a benzene-substituted benzo5-membered ring containing one or two heteroatoms (thiophene, furan, 1,3-thiazazacyclopentane, 1,3-thiazazacyclopentane) or a benzene ring. The benzene ring moiety of R3 can be independently substituted with hydrogen, chlorine, bromine, methyl, and trifluoromethyl.

[0009] In a preferred embodiment of the present invention, the compound represented by Formula I, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, are selected from the following compounds:

[0010] {[4-({[(5-chloro-1H-indole-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 1)

[0011] [(4-{[(1-benzofuran-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid (compound 2)

[0012] [(4-{[(benzo[b]thiophene-2-ylcarbonyl)amino]methyl]phenyl)oxy]acetic acid (compound 3)

[0013] [(4-{[(benzo[d][1,3]thiazacyclopentan-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid (compound 4)

[0014] {[4-({[(6-bromonaphthyl-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 5)

[0015] {[4-({[(5-methyl-1H-indole-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 6)

[0016] 4-[(4-{2-[(benzo[b]thiophene-2-ylcarbonyl)amino]ethyl}phenyl)oxy]butyric acid (compound 7)

[0017] {[4-({[(4-phenylphenyl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 8)

[0018] {[4-({[(5-phenylthiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 9)

[0019] 4-[(4-{2-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}phenyl)oxy]butyric acid (compound 10)

[0020] {[4-({[(5-bromo-1-benzofuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 11)

[0021] {[4-({[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 12)

[0022] [(4-{[(1H-indol-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid (compound 13)

[0023] {[4-({[(5-bromobenzo[b]thiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 14)

[0024] {[4-({[(6-methylbenzo[b]thiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 15)

[0025] [(4-{[(1H-benzo[d]imidazol-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid (compound 16)

[0026] {[4-({[(5-bromo-1H-benzo[d]imidazol-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 17)

[0027] [(4-{[(quinoline-3-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid (compound 18)

[0028] {[4-(2-{[(5-phenylthiophen-2-yl)carbonyl]amino}ethyl)phenyl]oxy}acetic acid (compound 19)

[0029] {[4-({[(2-phenyl-1,3-thiazacyclopentan-5-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 20)

[0030] {[4-({[(2-phenyl-1,3-oxazacyclopentan-5-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 21)

[0031] {[4-({[(5-phenylfuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid (compound 22)

[0032] [(4-{[({5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)amino]methyl}phenyl)oxy]acetic acid (compound 23) Detailed Implementation

[0033] The technical solution of the present invention is described in detail below with reference to the specific examples. However, it should be understood that the present invention is not limited to the specific examples described below. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). All solvents used in the reactions, unless otherwise specified, were standardized and pretreated.

[0034] Preparation of intermediates

[0035] Preparation of Intermediate 1: Methyl 5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate

[0036]

[0037] [4-(trifluoromethyl)phenyl]borondiol (1 g, 5.3 mmol), methyl 5-bromothiophene-2-carboxylate (1.16 g, 5.3 mmol), tetra(triphenylphosphine)palladium (0.3 g, 0.26 mmol), and cesium carbonate (5.14 g, 15.8 mmol) were placed in a round-bottom flask. Approximately 60 mL of solvent (1,4-dioxane = 15:1) was added. After reflux, the mixture was evacuated to ensure an oxygen-free environment and stirred at 110 °C overnight. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product. The crude product was then separated by column chromatography in a petroleum ether:ethyl acetate ratio of 10:1 to obtain 1.17 g of pure product. The yield was 77.2%.

[0038] 1H NMR (600MHz, DMSO) δ 8.01-7.97 (m, 2H), 7.86 (d, J=3.9Hz, 1H), 7.84-7.80 (m, 2H), 7.78 (d, J=4.0Hz, 1H), 3.86 (s, 3H).

[0039] Preparation of Intermediate 2: 5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid

[0040]

[0041] The intermediate (0.5 g, 1.75 mmol) and lithium hydroxide (1 g, 41.67 mmol) were placed in a round-bottom flask and stirred at room temperature for 12 hours. After the reaction was complete, water was added to quench the reaction, and a white solid precipitated. The precipitate was filtered and dried to give 0.46 g of a white solid, with a yield of 96.6%.

[0042] 1H NMR (600MHz, DMSO) δ7.96 (d, J=8.1Hz, 2H), 7.81 (d, J=8.2Hz, 2H), 7.77-7.71 (m, 2H). ESI-MS (m / z): 271[MH] -

[0043]

[0044] Example 1: {[4-({[(5-chloro-1H-indol-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0045] 5-Chloro-1H-indole-2-carboxylic acid (0.5 g, 2.6 mmol), 4-(aminomethyl)phenol (0.38 g, 3.0 mmol), HOBT (0.52 g, 3.8 mmol), and EDCI (1.47 g, 7.67 mmol) were placed in a round-bottom flask. 10-15 ml of DMF solution was added to dissolve the starting materials. The mixture was stirred and reacted at room temperature for 6-12 hours. After the reaction was monitored for completeness using a petroleum ether:ethyl acetate ratio of 3:1, the reaction was quenched with water, resulting in the precipitation of a yellow solid. The precipitate was filtered, dried, and the insoluble yellow solid was weighed to obtain 0.55 g of the yellow solid, yielding a yield of 70%.

[0046] Potassium carbonate (0.92 g, 6.67 mmol) was placed in a round-bottom flask, and anhydrous DMF was added. The mixture was stirred at room temperature, and the reaction apparatus was kept in the absence of air. The crude product from the previous step (0.5 g, 1.67 mmol) was weighed and slowly added to the flask. After reacting at room temperature for 3–6 hours, ethyl bromoacetate (1 g, 6 mmol) was added, and the temperature was raised to 50 °C and reacted overnight. After the reaction was complete, the mixture was quenched with water, resulting in a cloudy, insoluble substance. This substance was filtered to remove some impurities from the aqueous phase. The filtered product was dissolved in ethyl acetate, concentrated under reduced pressure, and separated by column chromatography using petroleum ether:ethyl acetate (3:1 ratio). The solution was concentrated under reduced pressure and dried to give 0.42 g of a brownish-red solid. The yield was 65.2%.

[0047] The purified product obtained in the previous step (0.3 g, 0.7 mmol) was placed in a round-bottom flask, and lithium hydroxide (0.44 g, 18.5 mmol) was added in approximately 20 ml of tetrahydrofuran:water (5:1 ratio). The mixture was stirred and reacted at room temperature for 8 hours. The reaction was monitored using petroleum ether:ethyl acetate (2:1 ratio). After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to acidic by adding water. A brownish-red solid precipitated out, which was filtered and dried. 0.24 g of the brownish-red solid was obtained. The yield was 96%.

[0048] 1H NMR (600MHz, DMSO) δ12.99 (s, 1H), 11.81 (d, J = 2.2Hz, 1H), 9.06 (t, J = 6.0Hz, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.43 (d, J = 8.7Hz, 1H), 7.29-7.23 (m, 2H), 7.18 (dd, J=8.7, 2.1Hz, 1H), 7.15 (d, J=2.1Hz, 1H), 6.92-6.85 (m, 2H), 4.64 (s, 2H), 4.44 (d, J=5.9Hz, 2H). ESI-MS (m / z): 357 [MH] -

[0049] Example 2 [(4-{[(1-benzofuran-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid

[0050]

[0051] Using 1-benzofuran-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 2, a white powder.

[0052] 1H NMR (600MHz, DMSO) δ13.39-12.67 (m, 1H), 9.23 (t, J=6.0Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 7.56 (s, 1H), 7.47 (t, J=7. 7Hz, 1H), 7.34 (t, J=7.5Hz, 1H), 7.26 (d, J=8.2Hz, 2H), 6.87 (d, J=8.2Hz, 2H), 4.64 (s, 2H), 4.41 (d, J=6.1Hz, 2H). ESI-MS (m / z): 324 [MH] -

[0053] Example 3 [(4-{[(benzo[b]thiophene-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid

[0054]

[0055] Using benzo[b]thiophene-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 3, a white powder.

[0056] 1H NMR (600MHz, DMSO) δ12.98 (s, 1H), 9.26 (t, J = 6.0Hz, 1H), 8.13 (s, 1H), 8.06-7.88 (m, 2H), 7.51-7.37 (m , 2H), 7.32-7.23 (m, 2H), 6.94-6.83 (m, 2H), 4.65 (s, 2H), 4.42 (d, J=5.9Hz, 2H).ESI-MS (m / z): 340[MH] -

[0057] Example 4 [(4-{[(benzo[d][1,3]thiazacyclopentan-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid

[0058]

[0059] Using benzo[d][1,3]thiazacyclopentane-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 4, a white powder.

[0060] 1H NMR (600MHz, DMSO) δ12.99 (s, 1H), 9.69 (t, J=6.3Hz, 1H), 8.29-8.19 (m, 1H), 8.14 (dt, J=8.1, 1.0Hz, 1H), 7.64 (ddd, J=8.3, 7.1, 1.3Hz, 1H), 7.59 (ddd, J=8.2, 7.1, 1.2Hz, 1H), 7.36-7.19 (m, 2H), 6.95-6.79 (m, 2H), 4.64 (s, 2H), 4.43 (d, J=6.3Hz, 2H). ESI-MS (m / z): 341 [MH] -

[0061] Example 5 {[4-({[(6-bromonaphthyl-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0062]

[0063] Using 6-bromonaphthalene-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 5, a white solid.

[0064] 1H NMR (600MHz, DMSO) δ13.04 (s, 1H), 9.17 (t, J=5.9Hz, 1H), 8.52-8.49 (m, 1H), 8.29 (d, J=1.9Hz, 1H), 8.04-7.97 (m, 3H), 7.71 (dd, J=8.8, 2.0Hz, 1H), 7.30-7.25 (m, 2H), 6.91-6.85 (m, 2H), 4.63 (s, 2H), 4.46 (d, J=5.9Hz, 2H).

[0065] ESI-MS (m / z): 414 [MH] -

[0066] Example 6 {[4-({[(5-methyl-1H-indol-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0067]

[0068] Using 5-methyl-1H-indole-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 6, a pale yellow powder.

[0069] 1H NMR (600MHz, DMSO) δ12.93 (s, 1H), 11.37 (d, J = 2.1Hz, 1H), 8.83 (t, J = 6.0Hz, 1H), 7.30 (s, 1H), 7.24 (d, J = 8.4Hz, 1H), 7.21-7.15 (m, 2H), 6.99 ( dd, J=2.2, 0.9Hz, 1H), 6.93 (dd, J=8.4, 1.6Hz, 1H), 6.83-6.78 (m, 2H), 4.56 (s, 2H), 4.35 (d, J=6.0Hz, 2H), 2.29 (s, 3H). ESI-MS (m / z): 337 [MH] -

[0070] Example 7 4-[(4-{2-[(benzo[b]thiophene-2-ylcarbonyl)amino]ethyl}phenyl)oxy]butyric acid

[0071]

[0072] The first step used benzo[b]thiophene-2-carboxylic acid and 4-(2-aminoethyl)phenol as raw materials, and the second step used 4-bromobutyric acid as raw material. The procedure was the same as in Example 1, yielding compound 7, a white solid powder.

[0073] 1H NMR (600MHz, DMSO) δ8.92 (t, J=5.6Hz, 1H), 8.07 (s, 1H), 8.00 (dd, J=7.7, 1. 4Hz, 1H), 7.95-7.90 (m, 1H), 7.43 (pd, J=7.1, 1.4Hz, 2H), 7.15-7.10 (m, 2H), 6.86-6.80 (m, 2H), 3.90 (t, J=6.8Hz, 2H), 3.46-3.42 (m, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.02 (t, J=7.1Hz, 2H), 1.84 (p, J=7.0Hz, 2H). ESI-MS (m / z): 382[MH] -

[0074] Example 8 {[4-({[(4-phenylphenyl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0075]

[0076] Using 4-phenylbenzoic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 8, a white solid.

[0077] 1H NMR (600MHz, DMSO) δ9.04 (t, J=6.0Hz, 1H), 8.01-7.96 (m, 2H), 7.80-7.76 (m, 2H), 7.76-7.71 (m, 2H), 7.50 (t, J=7.7Hz, 2 H), 7.44-7.38 (m, 1H), 7.27-7.22 (m, 2H), 6.88-6.83 (m, 2H), 4.56 (s, 2H), 4.43 (d, J=5.9Hz, 2H). ESI-MS (m / z): 360 [MH] -

[0078] Example 9 {[4-({[(5-phenylthiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0079]

[0080] Using 5-phenylthiophene-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 9, a white solid.

[0081] 1H NMR (600MHz, DMSO) δ9.06 (t, J=5.9Hz, 1H), 7.81 (d, J=3.9Hz, 1H), 7.71 (d, J=7.7Hz, 2H), 7.53 (d, J=3.9Hz, 1H), 7.45 (t, J=7.6Hz, 2 H), 7.37 (t, J=7.4Hz, 1H), 7.18 (d, J=8.2Hz, 2H), 6.77 (d, J=8.3Hz, 2H), 4.37 (d, J=5.9Hz, 2H), 4.09 (s, 2H). ESI-MS (m / z): 366[MH] -

[0082] Example 10 4-[(4-{2-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}phenyl)oxy]butyric acid

[0083]

[0084] Using 1-benzofuran-2-carboxylic acid and 4-(2-aminoethyl)phenol as the first-step starting material, and 4-bromobutyric acid as the second-step starting material, the same procedure as in Example 1 was followed to obtain compound 10, a white solid powder.

[0085] 1H NMR (600MHz, DMSO) δ12.12 (s, 1H), 8.77 (t, J=5.7Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.65 (d, J=8 .4Hz, 1H), 7.51 (d, J=0.9Hz, 1H), 7.46 (ddd, J=8.4, 7.1, 1.3Hz, 1H), 7.33 (t, J=7.5Hz, 1H), 7 .22-7.09 (m, 2H), 6.91-6.80 (m, 2H), 3.94 (t, J=6.4Hz, 2H), 3.46 (dt, J=7.9, 6.1Hz, 2H), 2.7 9 (t, J=7.5Hz, 2H), 2.37 (t, J=7.3Hz, 2H), 1.91 (dd, J=7.6, 6.2Hz, 2H). ESI-MS (m / z): 366 [MH] -

[0086] Example 11 {[4-({[(5-bromo-1-benzofuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0087]

[0088] Using 5-bromo-1-benzofuran-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 11, a white solid.

[0089] 1H NMR (600MHz, DMSO) δ9.22 (t, J=6.1Hz, 1H), 7.93 (d, J=2.0Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 7.52 (dd, J=8.8, 2.1Hz, 1H), 7 .47 (d, J=1.0Hz, 1H), 7.17-7.09 (m, 2H), 6.77-6.71 (m, 2H), 4.31 (d, J=6.0Hz, 2H), 4.29 (s, 2H).ESI-MS (m / z): 404[MH] -

[0090] Example 12 {[4-({[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0091]

[0092] Using 5-chloro-1-benzofuran-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 12, a white solid.

[0093] 1H NMR (600MHz, DMSO) δ9.29 (t, J=6.1Hz, 1H), 7.87 (d, J=2.2Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 7.55 (s, 1H), 7.48 (dd, J= 8.8, 2.2Hz, 1H), 7.25-7.20 (m, 2H), 6.85-6.80 (m, 2H), 4.45 (s, 2H), 4.39 (d, J=6.0Hz, 2H). ESI-MS (m / z): 358[MH] -

[0094] Example 13 [(4-{[(1H-indol-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid

[0095]

[0096] Using 1H-indole-2-carboxylic acid as the first-step starting material, the same procedure as in Example 1 was followed to obtain compound 13, a white solid.

[0097] 1H NMR (600MHz, DMSO) δ13.00 (s, 1H), 11.60-11.57 (m, 1H), 8.96 (t, J=6.0Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.43 (dd, J=8.2, 1.1Hz, 1H), 7.29-7.2 4 (m, 2H), 7.21-7.13 (m, 2H), 7.03 (ddd, J=7.9, 6.9, 1.0Hz, 1H), 6.92-6.86 (m, 2H), 4.65 (s, 2H), 4.45 (d, J=6.0Hz, 2H). ESI-MS (m / z): 323 [MH] -

[0098] Example 14 {[4-({[(5-bromobenzo[b]thiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0099]

[0100] Using 5-bromobenzo[b]thiophene-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 14, a white solid.

[0101] 1H NMR (600MHz, DMSO) δ9.37 (t, J=5.9Hz, 1H), 8.18 (d, J=1.9Hz, 1H), 8.09 (s, 1H), 8.00 (d, J=8.6Hz, 1H), 7.59 (dd, J= 8.6, 2.0Hz, 1H), 7.24-7.19 (m, 2H), 6.83-6.78 (m, 2H), 4.39 (d, J=5.8Hz, 2H), 4.28 (s, 2H). ESI-MS (m / z): 419[MH] -

[0102] Example 15 {[4-({[(6-methylbenzo[b]thiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0103]

[0104] Using 6-methylbenzo[b]thiophene-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 15, a white solid.

[0105] 1H NMR (600MHz, DMSO) δ9.21 (t, J=5.9Hz, 1H), 8.07 (s, 1H), 7.82-7.78 (m, 2H), 7.25 (dd, J=8.3, 1.4Hz, 1H), 7. 23-7.19 (m, 2H), 6.85-6.79 (m, 2H), 4.39 (d, J=5.9Hz, 2H), 4.36 (s, 2H), 2.44 (s, 3H). ESI-MS (m / z): 354 [MH] -

[0106] Example 16 [(4-{[(1H-benzo[d]imidazol-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid

[0107]

[0108] Using 1H-benzo[d]imidazole-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 16, a white solid.

[0109] 1H NMR (600MHz, DMSO) δ13.17 (s, 1H), 9.28 (t, J = 6.4Hz, 1H), 9.24 (s, 1H), 7.68-7.42 (m, 2H), 7.28-7.18 (m , 2H), 7.13-7.05 (m, 2H), 6.68-6.55 (m, 2H), 4.31 (d, J=6.4Hz, 2H), 3.27 (s, 2H).ESI-MS (m / z): 324[MH]-

[0110] Example 17 {[4-({[(5-bromo-1H-benzo[d]imidazol-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0111]

[0112] Using 5-bromo-1H-benzo[d]imidazol-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 17, a white solid.

[0113] 1H NMR (600MHz, DMSO) δ13.53-13.34 (m, 1H), 12.97 (s, 1H), 9.51 (q, J=6.5Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 7.61-7 .32(m, 2H), 7.30-7.24(m, 2H), 6.90-6.83(m, 2H), 4.64(s, 2H), 4.42(d, J=6.3Hz, 2H).ESI-MS(m / z): 404[MH] -

[0114] Example 18 [(4-{[(quinolin-3-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid

[0115]

[0116] Using quinoline-3-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 18, a brown solid.

[0117] 1H NMR (600MHz, DMSO) δ9.56 (t, J=5.9Hz, 1H), 9.47 (d, J=2.1Hz, 1H), 9.20-9.16 (m, 1H), 8.25-8.22 (m, 1H), 8.22-8.20 (m, 1H), 8.00 (ddd, J=8.5, 6.9 , 1.4Hz, 1H), 7.81 (ddd, J=8.1, 6.9, 1.1Hz, 1H), 7.35-7.30 (m, 2H), 6.92-6.86 (m, 2H), 4.66 (s, 2H), 4.50 (d, J=5.8Hz, 2H). ESI-MS (m / z): 335[MH] -

[0118] Example 19 {[4-(2-{[(5-phenylthiophen-2-yl)carbonyl]amino}ethyl)phenyl]oxy}acetic acid

[0119]

[0120] Using 5-phenylthiophene-2-carboxylic acid and 4-(2-aminoethyl)phenol as the first-step raw materials, the same procedure as in Example 1 was followed to obtain compound 19, a white solid.

[0121] 1H NMR (400MHz, DMSO) δ8.68 (t, J=4.4Hz, 1H), 7.82-7.75 (m, 2H), 7.67 (d, J=6.9Hz, 1H), 7.51-7.43 (m, 3H), 7.31 (d, J=6.9Hz, 1H ), 7.18-7.12(m, 2H), 6.89-6.81(m, 2H), 4.66(s, 2H), 3.43(td, J=5.3, 4.4Hz, 2H), 2.91-2.82(m, 2H).ESI-MS(m / z): 380[MH] -

[0122] Example 20 {[4-({[(2-phenyl-1,3-thiazacyclopentan-5-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0123]

[0124] Using 2-phenyl-1,3-thiazacyclopentane-5-carboxylic acid as the first-step starting material, the same procedure as in Example 1 was followed to obtain compound 20, a white solid.

[0125] 1H NMR (600MHz, DMSO) δ13.07 (s, 1H), 9.23 (t, J = 5.9Hz, 1H), 8.49 (s, 1H), 8.02-7.96 (m, 2H), 7.53 (dd, J = 5.1, 1 .9Hz, 3H), 7.29-7.23(m, 2H), 6.91-6.86(m, 2H), 4.63(s, 2H), 4.41(d, J=5.8Hz, 2H).ESI-MS(m / z): 367[MH] -

[0126] Example 21 {[4-({[(2-phenyl-1,3-oxazacyclopentan-5-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0127]

[0128] Using 2-phenyl-1,3-oxazacyclopentane-5-carboxylic acid as the first-step starting material, the same procedure as in Example 1 was followed to obtain compound 21, a white solid.

[0129] 1H NMR (600MHz, DMSO) δ12.98 (s, 1H), 9.21 (t, J=6.1Hz, 1H), 8.16-8.10 (m, 2H), 7.89 (s, 1H), 7.62-7.58 (m, 2H), 7.5 8-7.56 (m, 1H), 7.29-7.24 (m, 2H), 6.91-6.86 (m, 2H), 4.65 (s, 2H), 4.42 (d, J=6.0Hz, 2H). ESI-MS (m / z): 351[MH] -

[0130] Example 22 {[4-({[(5-phenylfuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid

[0131]

[0132] Using 5-phenylfuran-2-carboxylic acid as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 22, a white solid.

[0133] 1H NMR (600MHz, DMSO) δ9.01 (t, J=6.1Hz, 1H), 7.94-7.89 (m, 2H), 7.46 (dd, J=8.4, 7.2Hz, 2H), 7.39-7.33 (m, 1H), 7.27-7.21 (m, 2 H), 7.19 (d, J=3.6Hz, 1H), 7.09 (d, J=3.6Hz, 1H), 6.89-6.83 (m, 2H), 4.55 (s, 2H), 4.40 (d, J=6.1Hz, 2H). ESI-MS (m / z): 350[MH] -

[0134] Example 23 [(4-{[({5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)amino]methyl}phenyl)oxy]acetic acid

[0135]

[0136] Using intermediate 2 as the first-step raw material, the same procedure as in Example 1 was followed to obtain compound 23, a white solid.

[0137] 1H NMR (600MHz, DMSO) δ9.11 (t, J=5.9Hz, 1H), 7.93 (d, J=8.1Hz, 2H), 7.85 (d, J=4.0Hz, 1H), 7.79 (d, J=8.2Hz, 2H), 7.7 0 (d, J=3.9Hz, 1H), 7.22-7.17 (m, 2H), 6.82-6.77 (m, 2H), 4.38 (d, J=5.8Hz, 2H), 4.25 (s, 2H). ESI-MS (m / z): 434[MH] -

[0138] Example 24: Activity assay of the compound against PPARδ protein

[0139] The activation rate of 23 compounds on PPARδ cells was detected using luciferase reporter gene assay (LCRA). Elafibranor (Med Chem Express Ltd.) was used as a positive control compound. The 23 compounds were screened on PPARδ cells at a concentration of 10 μM, and assays were performed in duplicate.

[0140] (1) On the first day at 5:00 PM, after digestion, resuspend stable GAL4 / PPAR δ_UAS_LUC / HEK293T (ATCC) cells in medium containing 1% FBS and 1% P / S. Seed 16,000 cells per well in a 96-well plate, with 90 μL of medium per well. (2) On the second day at 5:00 PM, dilute the compound from 20 mM to 10 mM with DMSO. Add 2 μL of the diluted compound to 198 μL of medium containing 1% FBS and 1% P / S and mix well. (3) Observe the cell plate under a microscope to ensure cell status. (4) Add 10 μL of the compound diluted in medium to the cell detection plate. (5) On the third day at 9:00 AM, equilibrate the plate and Bright-lite to room temperature. Then add 50 μL of Bright-lite to the wells. Shake for 1 minute and read the signal value. (6) Read and calculate the activation rate using Envision. The results are shown in Table 1. At 10 μM, the activation rates of compounds 7 and 10 were around 50%, while the activation rates of compounds 11, 14, and 23 were all greater than 90%, showing good activation activity.

[0141] Table 1. Initial screening results of compounds

[0142]

Claims

1. Compounds of Formula I, their stereoisomers, their prodrugs and active metabolites, their pharmaceutically acceptable salts, solvates, and hydrates. in, n1 is selected from 1 and 2; n2 is selected from 1 and 3; R3 is selected from a benzo5-membered ring (pyrrole, thiophene, furan, 1,3-thiazazacyclopentane, imidazole) or a benzo6-membered ring (pyridine), or a naphthalene ring, or a benzene-substituted benzo5-membered ring containing one or two heteroatoms (thiophene, furan, 1,3-thiazazacyclopentane, 1,3-thiazazacyclopentane) or a benzene ring. The benzene ring moiety of R3 can be independently substituted with hydrogen, chlorine, bromine, methyl, and trifluoromethyl.

2. The compounds of formula I and II as claimed in claims 1 and 2, or their stereoisomers, their prodrugs and active metabolites, their pharmaceutically acceptable salts, solvates, and hydrates, selected from the following compounds: {[4-({[(5-chloro-1H-indol-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid [(4-{[(1-benzofuran-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid [(4-{[(benzo[b]thiophene-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid [(4-{[(benzo[d][1,3]thiazacyclopentan-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid {[4-({[(6-bromonaphthyl-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid {[4-({[(5-methyl-1H-indol-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid 4-[(4-{2-[(benzo[b]thiophene-2-ylcarbonyl)amino]ethyl}phenyl)oxy]butyric acid {[4-({[(4-phenylphenyl)carbonyl]amino}methyl)phenyl]oxy}acetic acid {[4-({[(5-phenylthiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid 4-[(4-{2-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}phenyl)oxy]butyric acid {[4-({[(5-bromo-1-benzofuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid {[4-({[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid [(4-{[(1H-indol-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid {[4-({[(5-bromobenzo[b]thiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid {[4-({[(6-methylbenzo[b]thiophen-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid [(4-{[(1H-benzo[d]imidazol-2-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid {[4-({[(5-bromo-1H-benzo[d]imidazol-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid [(4-{[(quinolin-3-ylcarbonyl)amino]methyl}phenyl)oxy]acetic acid {[4-(2-{[(5-phenylthiophen-2-yl)carbonyl]amino}ethyl)phenyl]oxy}acetic acid {[4-({[(2-phenyl-1,3-thiazacyclopentan-5-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid {[4-({[(2-phenyl-1,3-oxazacyclopentan-5-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid {[4-({[(5-phenylfuran-2-yl)carbonyl]amino}methyl)phenyl]oxy}acetic acid [(4-{[({5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}carbonyl)amino]methyl}phenyl)oxy]acetic acid.

3. The use of the compound according to claims 1-2, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, in the preparation of medicaments for treating metabolic syndrome and pharmaceutical compositions containing them.

4. The metabolic syndrome described in claim 4 includes obesity, diabetes, atherosclerosis, dyslipidemia, hypertension, multiple sclerosis, etc.

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