Substituted Benzimidazole Derivative And Use Thereof

Abstract

The present invention relates to a substituted benzimidazole derivative as represented by formula (I) and a pharmaceutically acceptable salt, a polymorph, a tautomer, a stereoisomer, a hydrate, a solvate or an isotopic variant of the derivative. The compound is a PPAR α and/or PPAR δ agonist, therefore the compound can be used for treating and/or preventing diseases associated with by PPAR α and/or PPAR δ, such as non-alcoholic steatohepatitis, Duchenne muscular dystrophy syndrome, Alzheimer's disease, tumors and PBC (primary biliary cholangitis)

##STR00001##

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate or isotopic variant thereof: ##STR00076## wherein, R.sup.1 is selected from H, —CN, —NO.sub.2, —CF.sub.3, —OCF.sub.3, —CO.sub.2H, OH, halogen, amino, alkyl, alkenyl, haloalkyl, haloalkenyl, heteroalkyl, heterocycloalkyl, arylalkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxy, alkoxyalkyl, alkenyloxy, alkynyloxy, amino, alkylamino, aminoalkyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, aminosulfonyl, acyl; each of the above groups can be un-substituted or substituted with one or more substituents selected from the group consisting of halogen, —CF.sub.3, alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, alkoxy, and alkoxyalkyl; R.sup.1 can be a non-hydrogen substituent or two or more different non-hydrogen substituents; R.sup.2 is selected from H, —CN, —NO.sub.2, —CF.sub.3, —OCF.sub.3, —CO.sub.2H, OH, —CONHR.sup.5, —CSNR.sup.6, —SR.sup.7, halogen, amino, alkyl, alkenyl, haloalkyl, haloalkenyl, heteroalkyl, heterocycloalkyl, arylalkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkoxy, alkoxyalkyl, alkylamino, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, aminosulfonyl; each of the above groups may be un-substituted or substituted with one or more substituents selected from the group consisting of halogen, —CF.sub.3, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; R.sup.2 can be a non-hydrogen substituent or two or more different non-hydrogen substituents; R.sup.3 is selected from H, —CN, —NO.sub.2, —CF.sub.3, —OCF.sub.3, —CO.sub.2H, OH, —SR.sup.7, halogen, amino, alkyl, alkoxy, alkoxyalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, cycloalkyl, heterocycloarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl; each of the above groups may be un-substituted or substituted with one or more substituents selected from the group consisting of halogen, —CF.sub.3, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; R.sup.3 can be a non-hydrogen substituent or two or more different non-hydrogen substituents; R.sup.4 is selected from H, —CN, —NO.sub.2, —CF.sub.3, —OCF.sub.3, —SR.sup.7, halogen, amino, alkyl, alkoxy, alkoxyalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, cycloalkyl, heterocycloarylalkyl, heterocycloalkyl, heterocycloalkenyl, alkenyloxy, alkynyloxy, alkylamino, aminoalkyl, alkylaminocarbonyl; each of the above groups may be un-substituted or substituted with one or more substituents selected from the group consisting of halogen, —CF.sub.3, alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, and alkoxyalkyl; R.sup.4 can be a non-hydrogen substituent or two or more different non-hydrogen substituents; R.sup.5 is selected from H, alkyl, heterocycloalkyl, arylalkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloarylalkyl, heterocycloalkyl, heterocycloalkenyl; R.sup.6 is selected from H, alkyl, heterocycloalkyl, arylalkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloarylalkyl, heterocycloalkyl, heterocycloalkenyl; R.sup.7 is selected from H, alkyl, heterocycloalkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloalkyl, heterocycloalkenyl; m, n and p are each independently selected from 0-6; X, Y and Z are each independently selected from —O—, —S—, —NH—, —SO.sub.2—, —CONH— or (CH.sub.2).sub.q, wherein q is an integer ranges from 1-4.

2. A compound according to claim 1, wherein R.sup.1 is selected from H, hydroxyl, C.sub.1-14 alkyl, C.sub.1-14 alkyl, C.sub.2-14 heteroalkyl, C.sub.5-12 arylC.sub.1-14 alkyl, heteroarylC.sub.1-14 alkyl, C.sub.1-6 alkyloxyC.sub.1-14 alkyl, aminoC.sub.1-14 alkyl and C.sub.4-7 heterocycloalkyl, each of these groups can be un-substituted or substituted with one or more substituents independently selected from the group consisting of halogens, OH, C.sub.1-14 alkyl, C.sub.2-14 heteroalkyl, C.sub.3-9 cycloalkyl, C.sub.4-7 heterocycloalkyl, C.sub.1-6 alkyloxy, amino and C.sub.1-14 alkylamino.

3. A compound according to claim 1, wherein R.sup.2 is selected from H, hydroxyl, halogen, C.sub.1-14 alkyl, C.sub.2-14 heteroalkyl, C.sub.1-6 alkyloxyC.sub.1-4 alkyl, each of these groups can be un-substituted or substituted with one or more substituents independently selected from the group consisting of halogens, —CO.sub.2H, OH, C.sub.1-14 alkyl, C.sub.2-14 heteroalkyl, C.sub.3-9 cycloalkyl, C.sub.4-7 heterocycloalkyl, C.sub.1-6 alkyloxy, C.sub.5-12 aryl C.sub.1-14 alkyl.

4. A compound according to claim 1, wherein R.sup.3 is selected from H, hydroxyl, halogen, C.sub.1-14 alkyl, C.sub.2-14 heteroalkyl, C.sub.1-6 alkyloxy C.sub.1-14 alkyl, each of these groups can be un-substituted or substituted with one or more substituents independently selected from the group consisting of halogens, —CO.sub.2H, OH, C.sub.1-14 alkyl, C.sub.2-14 heteroalkyl, C.sub.3-9 cycloalkyl, C.sub.4-7 heterocycloalkyl, C.sub.1-6 alkyloxy, C.sub.5-12 aryl C.sub.1-14 alkyl.

5. A compound according to claim 1, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof: ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081##

6. A pharmaceutical composition, comprising a compound according to claim 1 and pharmaceutically acceptable diluents, excipients or carriers.

7. A method for treating and/or preventing a disease mediated by PPARα and PPARδ, comprising administering therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a composition comprising a compound according to claim 1.

8. The method according to claim 7, wherein the diseases mediated by PPARδ are hyperlipidemia, dyslipidemia, hyperchlolesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia and/or HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, disease of arterial sclerosis, disease of cardiovascular systems, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, diabetic complication, cardiac insufficiency, cardiac infarction, cardio myopathy, hypertension, fatty liver, non-alcoholic fatty hepatitis, thrombus, Alzheimer disease, neurodegenerative, demyelinating disease, multiple sclerosis, adrenal leukodystrophy, dermatitis, psoriasis, acne, skin aging, trichosis, inflammation, asthma, hyper sensitive intestine syndrome, ulcerative colitis, Crohn's disease, pancreatitis, or cancer including colon cancer, large intestine cancer, skin cancer, breast cancer, prostate cancer, ovary cancer, and lung cancer.

9. The method according to claim 7, wherein the diseases mediated by PPARδ are any kinds of dyslipidemia, metabolic syndrome, obesity, atherosclerosis or diabetes.

10. The method according to claim 7, wherein the diseases mediated by PPARδ are NASH and Duchenne muscular dystrophy syndrome.

11. The method according to claim 7, wherein the diseases mediated by PPARδ are primary biliary cirrhosis and cholangitis, including Alzheimer's disease and tumors.

12. The method according to claim 7, wherein the diseases mediated by PPARδ are increased energy and activation properties of T lymphocytes to enhance immune function, as well as transformation of tumor cells into adipose cells and reduced cancer metastasis.

13. The method according to claim 9, wherein the obesity is visceral fat type obesity.

Description

EXAMPLE 1

Preparation of 2-(4-((2-((5-bromo-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)-2-ethylphenoxy) acetic acid (1)

[0133] Compound 1 of example 1 can be prepared by the method of the above scheme 1 or the method of scheme 2. Specifically, by choosing the starting materials as needed, the compound can be synthesized by the specific route represented as follows.

##STR00014## ##STR00015##

Step 1. Synthesis of methyl 3-ethyl-4-hydroxylbenzoate (1T-1)

[0134] ##STR00016##

[0135] In a reaction flask, I-1 (40.0 g, 0.2 mol), Pd(dppf)Cl.sub.2 (14.6 g, 0.02 mol), potassium acetate (58.8 g, 0.6 mol) and methanol (200.0 mL) were added sequentially, and the air was replaced using carbon monoxide balloon for 3 times, the contents in the flask were stirred overnight in the CO atmosphere at 70° C. After the reaction was complete, the solvent was evaporated under reduced pressure. The reaction mixture was added into water (100.0 mL), then extracted with ethyl acetate (150.0 mL×3). The organic phases were washed with saturated salt water, dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column purification [eluent: petroleum ether-ethyl acetate (1:2)]. The eluant was collected. The solvent was evaporated under reduced pressure to obtain a yellow solid II-1 (18.0 g, yield:50.0%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.85 (d, J=2.0 Hz, 1H), 7.80 (dd, J=10.4, 6.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.41 (s, 1H), 3.87 (s, 3H), 2.68 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H).

Step 2. Synthesis of 2-ethyl-4-(hydroxymethyl)phenol (III-1)

[0136] ##STR00017##

[0137] In a reaction flask, II-1 (15.0 g, 83.3 mmol) and dried tetrahydrofuran (200.0 mL) were added, and stirred under nitrogen gas protection, then cooled to 0° C. in an ice bath. Lithium aluminum hydride (3.8 g, 99.9 mmol) was added slowly in batches. The temperature was kept at 0° C. After the addition was completed, the materials were stirred for 1h at 0° C. Water (15.0 mL), 15% sodium hydroxide (15.0 mL) and water (30.0 mL) were dropwise added into the reaction slowly and sequentially. The temperature was kept at 0° C. After the addition was completed, the temperature was increased to room temperature and the system was kept stirring for 1 hour, then was filtered. The filtrate was collected and dried with anhydrous sodium sulfate, then was filtered again, and the filtrate was collected. The solvent was evaporated under reduced pressure to obtain white solid III-1 (8.0 g, yield: 63.1%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.16 (d, J=2.0 Hz, 1H), 7.10 (dd, J=10.4, 6.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 4.81 (s, 1H), 4.61 (d, J=5.6 Hz, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=4.8 Hz, 3H).

Step 3. Synthesis of ethyl 2-(2-ethyl-4-(hydroxymethyl)phenoxy acetate (III-1)

[0138] ##STR00018##

[0139] In a reaction flask, III-1 (8.0 g, 52.6 mmol), ethyl bromoacetate (10.6 g, 63.2 mmol, IV-A), and cesium carbonate (25.7 g, 78.9 mmol) and acetonitrile (100.0 mL) were added sequentially, stirred overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure. Water (50.0 mL) was added, and the obtained system was extracted by ethyl acetate (100.0 mL×3). Then the organic phases were washed by saturated salt water and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column purification [eluent: petroleum ether-ethyl acetate (1:2)], then the eluant was collected and the solvent was evaporated under reduced pressure to obtain an off-white solid V-1 (7.5 g, yield:60.00%). LCMS (method B) purity: 90.75%, Rt=1.86 min; MS measurement: 238.1; MS measurement: 221.4 [M-17].

Step 4. Synthesis of ethyl 2-(4-(chloromethyl)-2-ethylphenoxy) acetate (VI-1)

[0140] ##STR00019##

[0141] In a reaction flask, V-1 (100 mg, 0.42 mmol), N,N-dimethylformamide (2 drops) and dry dichloromethane (4.0 mL) were added, then cooled to 0° C. in an ice bath under stirring. Thionyl chloride (150 mg, 1.26 mmol) was dropwise added thereto slowly. After the addition was completed, the mixture was stirred for 2 hours at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a yellow solid VI-1 (122 mg, yield:100.0%).

[0142] LCMS (method A) purity: 91.98%, Rt=0.83 min; MS measurement: 256.1; measurement: 257.2 [M+H].sup.+.

Step 5. Synthesis of 4-bromo-N-(2-methoxybenzyl)-2-nitroaniline (TX-1)

[0143] ##STR00020##

[0144] In a reaction flask, 2-methoxybenzylamine (10.0 g, 73.1 mmol), VII-1 (16.0 g, 73.1 mmol), triethylamine (14.7 g, 146.2 mmol) and tetrahydrofuran (200.0 mL) were added sequentially and stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure. Then water (100.0 mL) was added. The system was extracted with ethyl acetate (150.0 mL×3). The organic phases were washed by saturated salt water and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain yellow solid IX-1 (22.0 g, yield: 89.8%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.49 (s, 1H), 8.31 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.41-7.19 (m, 2H), 6.94-6.90 (m, 2H), 6.79 (d, J=9.2 Hz, 1H), 4.52 (d, J=6.0 Hz, 2H), 8.49 (s, 3H).

Step 6. Synthesis of 4-bromo-Ni-(2-methoxybenzyl)benzene-1,2-diamine (X-1)

[0145] ##STR00021##

[0146] In a reaction bottle, IX-1 (22.0 g, 65.5 mmol), ammonium chloride (17.7 g, 327.4 mmol), iron powder (18.3 g, 327.4 mmol) and methanol (500.0 mL) were added sequentially and heated to 70° C. and stirred for 2 hours. After the reaction was completed, the reaction mixture was filtered. The filter cake was washed by methanol. The filtrate was collected. The solvent was evaporated under reduced pressure. Then water was added (100.0 mL). The system was extracted by dichloromethane (150.0 mL×3). The organic phases were washed by saturated salt water and dried with anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure to obtain off-white solid X-1 (19.6 g, yield 98.0%). LCMS (method B) purity: 84.53%. Rt=1.99 min; MS measurement: 306.0; MS measurement: 307.0 [M+H].sup.+.

Step 7 Synthesis of N-(5-bromo 2-((2-methoxybenzyl)amino)phenyl)propionamide (XII-1)

[0147] ##STR00022##

[0148] In a reaction flask, X-1 (1.5 g, 4.9 mmol), propionic acid (0.36 g, 4.9 mmol), HATU (2.2 g, 5.9 mmol), triethylamine (0.99 g, 9.8 mmol) and N, N-dimethylformamide (30.0 mL) were added sequentially and stirred for 3 hours at room temperature. After the reaction was completed, the reaction solution was poured into water and extracted by ethyl acetate (60.0 mL×3). The organic phases were washed with water and saturated salt water sequentially, then dried with anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column purification [eluent: petroleum ether-ethyl acetate (3:1)]. The eluant was collected. The solvent was evaporated under reduced pressure to obtain a white solid XII-1 (1.5 g, yield: 84.7%). LCMS (method B) purity: 93.39%. Rt=2.18 min; MS measurement: 362.1; MS measurement: 363.2 [M+H].sup.+.

Step 8. Synthesis of 5-bromo-2-ethyl-1-(2-methoxybenzyl)-1H-benzo[d]imidazole (XIII-1)

[0149] ##STR00023##

[0150] In a reaction flask, XII-1 (1.5 g, 4.14 mmol) and glacial acetic acid (20.0 mL) were added then heated to 60° C. to react for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column purification [eluent: petroleum ether-ethyl acetate (3:1)]. Then the eluant was collected. The solvent was evaporated under reduced pressure to obtain a yellow solid XIII-1 (1.2 g, yield: 84.5%). LCMS (method B) purity: 97.21%, Rt=1.68 min; MS measurement: 344.1; MS measurement: 345.2 [M+H].sup.+.

Step 9. Synthesis of 2-((5-bromo-2-ethyl-1H-benzo[d]imidazole-1-yl)methyl)phenyl (XIV-1)

[0151] ##STR00024##

[0152] In a reaction flask, XIII-1 (1.5 g, 4.14 mmol) and glacial acetic acid (20.0 mL) were added then heated to 60° C. to react for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column purification [eluent: petroleum ether-ethyl acetate (3:1)]. Then the eluant was collected. The solvent was evaporated under reduced pressure to obtain a yellow solid XIV-1 (1.2 g, yield: 84.5%) LCMS (method B) purity: 97.21%, Rt=1.68 min; MS measurement: 344.1; MS measurement: 345.2 [M+H].sup.+.

Step 10. Synthesis of ethyl 2-(4-((2-((5-bromo-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)-phenoxy)methyl)-2-ethylphenoxy) acetate (XV-1)

[0153] ##STR00025##

[0154] In a reaction flask, XIV-1 (157 mg, 0.47 mmol), VI-1 (122 mg, 0.47 mmol), potassium carbonate (197 mg, 1.43 mmol) and N,N-dimethylformamide (5.0 mL) were added sequentially and stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into water then extracted by ethyl acetate (20.0 mL×3). The organic phases were washed with water and saturated salt water sequentially, dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column purification [eluent: petroleum ether-ethyl acetate (3:1)]. Then the eluant was collected. The solvent was evaporated under reduced pressure to obtain a colorless oily substance XV-1 (231 mg, yield: 88.2%). LCMS (Method A) purity: 93.53%. Rt=0.75 min; MS measurement: 550.2; MS measurement: 551.2 [M+H].sup.+.

Step 11. Synthesis of 2-(4-((2-((5-bromo-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)-phenoxy)methyl)-2-ethylphenoxy)acetic acid (1)

[0155] ##STR00026##

[0156] In a reaction flask, XV-1 (231 mg, 0.42 mmol), methanol (6.0 mL) and 2 M LiOH (0.63 mL, 1.26 mmol) were added sequentially and stirred for 3 hours at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, then water (6.0 mL) was added. 1M HCl was added to adjust the pH to be 5-6. The system was filtered. The filter cake was washed with water, then dried to obtain a white solid 1 (XVI-1) (100 mg, yield: 45.7%). HPLC-MS (method D) purity: 97.10%, Rt=8.36 min; MS measurement: 522.2; MS measurement: 523.2 [M+H].sup.+.

[0157] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 13.00 (brs, 1H, H9), 7.79 (d, J=1.6 Hz, 1H, H1), 7.37-7.24 (m, 3H), 7.14-7.09 (m, 2H), 7.03 (d, J=2.0 Hz, 1H, H7), 6.90-6.84 (m, 2H), 6.79 (d, J=8.4 Hz, 1H), 5.41 (s, 2H, H4), 4.99 (s, 2H, H5), 4.70 (s, 2H, H6), 2.82 (q, J=7.2 Hz, 2H, H2), 2.58 (q, J=7.6 Hz, 2H, H7), 1.17-1.08 (in, 6H, H3, H8).

Examples 2-12

[0158] A wide range of derivatives can be synthesized in accordance with the method of Example 1, as long as the starting materials are changed properly. Examples 2-12 list some of the representative examples (see Table 1).

TABLE-US-00001 TABLE 1 Examples Structure Name m/z[MH].sup.+  2 [00027] 2-(4-((2-((2-amino-5-bromo--1 H-benzo[d]imidazol-1-yl) methyl)phenoxy)methyl)-2- ethylphenoxy)acetic acid 509.10  3 [00028] 3-(4-((2-((5-Bromo-2-(2.4- dichlorophenethyl)-1H-benzo[d] imidazol-1-yl)methyl)phenoxy) methyl)-2-ethylphenyl)propanoic acid 664.09  4 [00029] 3-(4-((2-((5-Bromo-2-butyl-1H- benzo[d]imidazol-1-yl)methyl) phenoxy)methyl)-2-ethylphenyl) propanoic acid 548.17  5 [00030] 2-(4-((2-((5-Bromo-2-ethyl-1H- benzo[d]imidazol-1-yl)methyl)- 4-methoxy-phenoxy)methyl)-2- ethylphenoxy)acetic acid 552.13  6 [00031] 3-(4-((2-((5-Bromo-1H-benzo[d] imidazol-1-yl)methyl)-3-methoxy- phenoxy)methyl)-2-ethyl phenyl)propanoic acid 552.12  7 [00032] 2-(4-((2-((5-Bromo-2-ethyl-1H- benzo[d]imidazol-1-yl)methyl) phenoxy)methyl)benzyl)butanoic acid 520.14  8 [00033] 3-(4-((2-((5-Bromo-2-ethyl-1H- benzo[d]imidazol-1-yl)methyl) phenoxy)methyl)-2-methylphenyl) propanoic acid 506.12  9 [00034] 3-(2-Ethyl-4-((2-((1-(2-(pyrrolidin- 1-yl)ethyl)-1H-benzo[d] imidazol-2-yl)methyl)phenoxy) methyl)phenyl)propanoic acid 511.28 10 [00035] 3-(4-((2-((5-Bromo-1-(2-(pyrrolidin- 1-yl)ethyl)-1H-benzo[d]imidazol- 2-yl)methyl)-phenoxy)methyl)-2- ethylphenyl)propanoic acid 589.19 11 [00036] 3-(2-Ethy-4-((3-((2-ethyl-1H- benzo[d]imidazol-1-yl)methyl)-4- methoxyphenoxy)methyl)phenyl) propanoic acid 472.24 12 [00037] 2-(2-Ethyl-4-((4-((1-ethyl-1H- benzo[d]imidazol-2-yl)methyl)-3- methoxyphenoxy)methyl)phenoxy) acetic acid 474.22 13 [00038] 3-(2-Ethyl-4-((4-((1-(2-(pyrrolidin- 1-yl)ethyl)-1H-benzo[d]imidazol- 2-yl)methyl)phenoxy)methyl) phenyl)propanoic acid 511.28 14 [00039] 3-(4-((2-((5-Bromo 2-(pyrrolidin-1-yl)methyl)-1H- benzo[d]imidazol-1-yl)methyl)- phenoxy)methyl)-2ethylphenyl) propanoic acid 575.18 15 [00040] 2-(4-((2-((5-Bromo-2-(3-(pyrrolidin- 1-yl)propyl)-1H-benzo[d]imidazol- 1-yl)methyl)phenoxy)methyl)- 2-ethylphenoxy)acetic acid 605.19 16 [00041] 3-(4-((2-((5-Bromo-2-ethyl-1H- benzo[d]imidazol-1-yl)methyl)- phenoxy)methyl)-2-ethylphenyl) propanoic acid 520.14 17 [00042] 3-(4-((2-((5-Bromo-2-(3-(pyrrolidin- 1-yl)propyl)-1H-benzo[d]imidazol- 1-yl)methyl)-phenoxy)methyl)-2- ethylphenyl)propanoic acid 603.21 18 [00043] 2-(4-((2-((5-Bromo-2-ethyl-1H- benzo[d]imidazol-1-yl)methyl) phenoxy)methyl)-2-ethylphenoxy) acetic acid 522.12

[0159] Besides, by reference to the method provided by Example 1, a wide range of derivatives can be synthesized as long as the starting materials are selected properly. The compounds listed in Table 2 are some of the examples

TABLE-US-00002 TABLE 2 19 [00044]   m/z[MH].sup.+ 560.03 20 [00045]   m/z[MH].sup.+ 516.08 21 [00046]   m/z[MH].sup.+ 550.15 22 [00047]   m/z[MH].sup.+ 553.45 23 [00048]   m/z[MH].sup.+ 536.47 24 [00049]   m/z[MH].sup.+ 521.45 25 [00050]   m/z[MH].sup.+ 521.12 26 [00051]   m/z[MH].sup.+ 492.10 27 [00052]   m/z[MH].sup.+ 522.12 28 [00053]   m/z[MH].sup.+ 506.12 29 [00054]   m/z[MH].sup.+ 466.05 30 [00055]   m/z[MH].sup.+ 464.07 31 [00056]   m/z[MH].sup.+ 484.10 32 [00057]   m/z[MH].sup.+ 454.09 33 [00058]   m/z[MH].sup.+ 481.06 34 [00059]   m/z[MH].sup.+ 477.11 35 [00060]   m/z[MH].sup.+ 481.06 36 [00061]   m/z[MH].sup.+ 477.11 37 [00062]   m/z[MH].sup.+ 552.22 38 [00063]   m/z[MH].sup.+ 554.20 39 [00064]   m/z[MH].sup.+ 460.22 40 [00065]   m/z[MH].sup.+ 462.20 41 [00066]   m/z[MH].sup.+ 529.27 42 [00067]   m/z[MH].sup.+ 531.25 43 [00068]   m/z[MH].sup.+ 529.27 44 [00069]   m/z[MH].sup.+ 531.25 45 [00070]   m/z[MH].sup.+ 543.29 46 [00071]   m/z[MH].sup.+ 545.27 47 [00072]   m/z[MH].sup.+ 506.12 48 [00073]   m/z[MH].sup.+ 562.01 49 [00074]   m/z[MH].sup.+ 520.14 50 [00075]   m/z[MH].sup.+ 577.16

[0160] Pharmacological Experiment

[0161] I. Experiment Methods

[0162] The following methods were used to determine the PPAR activation effect of the tested compounds (compounds in the examples)

[0163] Receptor expression plasmid (pSG5-GAL4-hPPARα, 7 or 6 (LBD)), luciferase expression plasmid (pUC8-MH100×4-TK-Luc) and β-Galactosidase expression plasmid (pCMX-β-GAL) (Kilewer, S. A. et. al., (1992) Nature, 358: 771-774) were introduced into CV-1 cells (ATCC). After gene introduction using a lipofection reagent (Lipofectamine 2000 (Invitrogen)), the cells were cultured in the presence of the test compounds for about 40 hours. Soluble cells were used in luciferase activity and β-GAL activity determinations. β-GAL activity was used to correct luciferase activity, using the luciferase activity in cells treated with GW-590735 (PPARα selective agonist) as 100% to calculate the relative ligand activity of PPARα, and using the luciferase activity in cells treated with Rosiglitazone as 100% to calculate the relative ligand activity of PPARγ, and using the luciferase activity in cells treated with GW-501516 as 100% to calculate the relative ligand activity of PPARδ, and the EC.sub.50 values were calculated.

[0164] II. Experiment Results

[0165] The experiment results were shown in Table 3.

TABLE-US-00003 TABLE 3 PPAR activities EC.sub.50 (μM) Compounds PPARα PPARγ PPARδ  2 0.2429 5.682 1.623 (m/z[MH].sup.+ 509.10)  3 0.104 0.1857 0.0365 (m/z[MH].sup.+ 644.09)  4 0.202 2.368 0.03314 m/z[MH].sup.+ 548.17  5 0.3763 13.43 21.06 m/z[MH].sup.+ 552.13  6 0.1548 6.652 6.11 m/z[MH].sup.+ 522.12  7 0.1603 6.808 12.81 m/z[MH].sup.+ 520.14  8 0.1563 2.785 0.01419 m/z[MH].sup.+ 506.12  9 0.09364 9.195 4.77 m/z[MH].sup.+ 511.28 10 0.1229 4.373 0.6597 m/z[MH].sup.+ 589.19 11 0.0901 2.298 19.85 m/z[MH].sup.+ 472.24 12 2.101 8.771 29.78 m/z[MH].sup.+ 474.22 13 1.058 6.59 21.03 m/z[MH].sup.+ 511.28 14 3.424 0.6725 0.1418 m/z[MH].sup.+ 575.18 15 2.112 9.112 6.561 m/z[MH].sup.+ 605.19 17 3.045 15.45 41.77 m/z[MH].sup.+ 603.21 18 0.2647 4.918 0.0697 m/z[MH].sup.+ 522.12 50 3.989 2.038 0.8035 m/z[MH].sup.+ 577.16

[0166] II. Experiment Results

[0167] The experiment results were shown in Table 3.

[0168] PPAR activities: the relative values in 10.sup.−7 M of the tested compound, using the control medicine as 10000.

[0169] PPARα: GW-590735 10.sup.−6M

[0170] PPARγ: Rosiglitazone 10.sup.−5M

[0171] PPARδ: GW-501516 10.sup.−7M

[0172] From Table 3, it can be seen that the test compounds showed excellent PPARδ activator effects, especially the compound of example 5 showed strong and selective PPARδ activator effect.

[0173] Details of specific examples described in the present invention are not meant to be inferred as limiting. Various synonymous transformations and modifications can be made without departing from the nature and scope of the invention, but knowing such synonymous embodiments are parts of this invention.