CN104961645A - Phenoxyacetic acid derivatives and preparation method thereof, and application of phenoxyacetic acid derivatives as drug - Google Patents

Abstract

The present invention relates to a novel phenoxyacetic acid derivative represented by the general formula (I), a preparation method thereof and a pharmaceutical composition containing the derivative as a medicine for treating diabetes and metabolic syndrome. The phenoxyacetic acid derivatives have excellent in vivo hypoglycemic activity, and can be used to prevent or treat diabetes.

Description

Phenoxyacetic acid derivatives, their preparation method and their use as medicine

technical field

The invention relates to the field of pharmacology related to diabetes, in particular to a new phenoxyacetic acid derivative, its preparation method and the application of the pharmaceutical composition containing the derivative in the preparation of medicines for treating diabetes and metabolic syndrome. The derivative structure involved in the present invention has uniqueness and novelty in structural modification of this type of compound.

Background technique

Diabetes is a disease of energy metabolism and is divided into type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (non-insulin-dependent diabetes). At present, there are about 366 million diabetic patients in the world, accounting for 6.4% of the world's population, and type 2 diabetic patients account for about 90-95% of the total number of diabetic patients.

Diabetes can be treated with diet and exercise. When these do not relieve symptoms, medical treatment is required. Current treatments for diabetes include: biguanides such as metformin, which reduce the formation of glucose in the liver; sulfonylureas such as glibenclamide, which stimulate pancreatic beta cells to secrete more insulin; thiazolidinediones such as piglide Ketones, which enhance the biological effectiveness of insulin by activating oxisome proliferator-activated receptor gamma (PPAR-γ); α-glucosidase inhibitors such as acarbose, can inhibit the production of glucose in the gut; glucagon Peptide-like peptide-1 (GLP-1) analogs such as liraglutide can promote insulin secretion from pancreatic β cells; dipeptidyl peptidase IV (DPP-IV) inhibitors such as sitagliptin can inhibit GLP- 1 degradation. However, the currently existing methods for treating diabetes all have certain defects. Examples include insulin injections and sulfonylureas, which may cause hypoglycemia and weight gain; metformin, alpha-glucosidase inhibitors, and GLP-1 analogs may cause gastrointestinal side effects; PPAR-γ agonists may cause weight gain And side effects of edema; DPP-IV inhibitors may cause suprapharyngitis, headache and infection side effects. Research in multiple fields is underway in order to bring new, safer and more effective hypoglycemic drugs to diabetic patients.

Free fatty acid receptors (FFARs) are G protein-coupled receptors (GPCRs) that have been de-orphaned in recent years. The currently identified free fatty acid receptors include the G protein-coupled receptor 40 (GPR40) family, including GPR40 (also known as free fatty acid receptor 1, FFA1), GPR41 (also known as free fatty acid receptor 3, FFA3), GPR43 (also known as free fatty acid receptor 2, FFA2) and GPR84, GPR120 of other families. GPR40, an orphan GPCR discovered during the search for new somatotropin neuropeptide-galanin receptor (GALR) subtypes, is highly expressed in pancreatic beta cells and insulin-secreting cell lines. GPR40 can bind fatty acids in plasma such as palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid to achieve various physiological functions. For example, the combination of long-chain free fatty acids and GPR40 activates, induces an increase in intracellular calcium ion levels, and enhances glucose-stimulated insulin secretion (GSIS). GPR40 modulators exert incretin effects to promote GISI, and can also be used in combination with various diabetes drugs. Based on the above, GPR40 agonists can treat diabetes and related indications, especially type 2 diabetes, insulin resistance in obesity, glucose intolerance, and other metabolic syndrome conditions. With GPR40 as a potential therapeutic target, it is of great research value and application prospect to discover and transform compounds with GPR40 agonistic activity.

A series of patent applications for GPR40 agonists have been published, including WO2004041266, WO2005087710, WO2005051890, WO2006083781, WO2007013689, WO2008066097, WO2009054390, WO2010085525, WO2015024448, WO28, etc.

The present invention relates to a phenoxyacetic acid derivative with a novel structure, which has excellent GPR40 agonistic activity and in vivo hypoglycemic activity. Therefore, the phenoxyacetic acid derivatives and pharmaceutically acceptable salts thereof can be potentially used in the treatment or prevention of diabetes and related diseases, and have broad development prospects.

Contents of the invention

The object of the present invention is to provide a compound or pharmaceutically acceptable salt thereof shown in general formula (I):

in:

Ring A is selected from aryl or heteroaryl;

Each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, wherein the alkyl, cycloalkyl, alkoxy are optionally further replaced by _one or more Substituted by a group selected from halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl;

R and _R are each independently selected from _hydrogen , alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

Each _R4 is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O) _OR8 , -OC (O)R ₈ , -C(O)R ₈ , -NHC(O)R ₈ , -NR ₉ R ₁₀ , -OC(O)NR ₉ R ₁₀ , -NHC(O)NR ₉ R ₁₀ , or -S (O) _q R ₈ , wherein the alkyl, cycloalkyl, alkoxy, heterocyclic, aryl or heteroaryl is optionally further replaced by one or more selected from halogen, hydroxyl, cyano, nitro , alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR ₈ , -OC(O)R ₈ , -C(O)R ₈ , -NHC( O)R ₈ , -NR ₉ R ₁₀ , -OC(O)NR ₉ R ₁₀ , -NHC(O)NR ₉ R ₁₀ or -S(O) _q R ₉ are substituted;

_R and R are each independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl _;

R ₇ is selected from a hydrogen atom or an alkyl group;

R _is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein each of the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is independently any is further substituted by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylate;

R ₉ or R ₁₀ are independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Each group is optionally further substituted by one or more groups selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylate base replaced;

m is 0 or 1;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1 or 2.

A preferred version of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, preferably a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

in:

Ring A is selected from aryl or heteroaryl;

Each R is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, wherein the alkyl, alkoxy is optionally further replaced by _one or more selected from halogen, hydroxyl, cyano, nitro, alkoxy Substituted by radicals, alkoxy groups, cycloalkyl groups;

R ₂ and R ₃ are each independently selected from hydrogen, alkyl, alkoxy;

Each R is _{independently} selected from hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, Alkoxy, heterocyclyl, aryl or heteroaryl are optionally further selected from one or more of halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by groups of radicals and heteroaryls;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3, 4 or 5.

A further preferred embodiment of the present invention, a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, preferably a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

in:

R ₂ and R ₃ are each independently selected from hydrogen, alkyl, alkoxy;

Each R is _{independently} selected from hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, Alkoxy, heterocyclyl, aryl or heteroaryl are optionally further selected from one or more of halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by groups of radicals and heteroaryls;

p is 0, 1, 2, 3, 4 or 5.

Preferred compounds of general formula (III) or pharmaceutically acceptable salts thereof are:

R ₂ and R ₃ are each independently preferably selected from hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl;

Each R is _{independently} preferably selected from hydrogen, halogen, hydroxyl, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, alkoxy , heterocyclyl, aryl or heteroaryl are optionally further replaced by one or more selected from halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl groups are substituted;

p is preferably 0, 1, 2 or 3.

More preferred compounds of the invention include, but are not limited to:

2-(2-fluoro-4-(2-phenoxyacetylamino)phenoxy)acetic acid (I-1);

2-(2-fluoro-4-(2-(o-tolyloxy)acetamide)phenoxy)acetic acid (I-2);

2-(2-fluoro-4-(2-(m-tolyloxy)acetamide)phenoxy)acetic acid (I-3);

2-(2-fluoro-4-(2-(p-tolyloxy)acetamide)phenoxy)acetic acid (I-4);

2-(4-(2-(4-ethylphenoxy)acetamide)-2-fluorophenoxy)acetic acid (I-5);

2-(2-fluoro-4-(2-(3-isopropylphenoxy)acetamide)phenoxy)acetic acid (I-6);

2-(2-fluoro-4-(2-(4-isopropylphenoxy)acetamide)phenoxy)acetic acid (I-7);

2-(4-(2-(3-(tert-butyl)phenoxy)acetamide)-2-fluorophenoxy)acetic acid (I-8);

2-(4-(2-(4-(tert-butyl)phenoxy)acetamide)-2-fluorophenoxy)acetic acid (I-9);

2-(2-fluoro-4-(2-(3-methylphenoxy)acetamide)phenoxy)acetic acid (I-10);

2-(2-fluoro-4-(2-(4-methylphenoxy)acetamide)phenoxy)acetic acid (I-11);

2-(2-fluoro-4-(2-(4-(trifluoromethoxy)phenoxy)acetamide)phenoxy)acetic acid (I-12);

2-(2-fluoro-4-(2-(3-(trifluoromethyl)phenoxy)acetamide)phenoxy)acetic acid (I-13);

2-(2-fluoro-4-(2-(5-isopropyl-2-methylphenoxy)acetamide)phenoxy)acetic acid (I-14);

2-(2-fluoro-4-(2-phenoxypropionamido)phenoxy)acetic acid (I-15);

2-(4-(2-(3,4-Dimethylphenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-16);

2-(4-(2-(3,5-Dimethylphenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-17);

2-(4-(2-(2,5-Dimethylphenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-18);

2-(2-fluoro-4-(2-(5-isopropyl-2-methylphenoxy)propionamido)phenoxy)acetic acid (I-19);

2-(4-(2-(2-ethoxyphenoxy)propionamido)phenoxy)acetic acid (I-20);

2-(2-Fluoro-4-(2-(3-(trifluoromethyl)phenoxy)propionamido)phenoxy)acetic acid (I-21);

2-(4-(2-(3-(tert-butyl)phenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-22);

2-(4-(2-(4-ethoxyphenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-23);

2-(2-Fluoro-4-(2-(2-fluorophenoxy)propionamido)phenoxy)acetic acid (I-24).

The present invention relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

Compound (IA) carries out ether synthesis reaction with alcohol or phenol under basic condition, and further carries out ester hydrolysis under basic condition, obtains compound (I), and the reagent that provides basicity includes inorganic base and organic base, described Inorganic bases can be mentioned, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; alkali metal bicarbonates such as potassium bicarbonate, etc.; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, hydrogen Potassium oxide, etc.; as the organic base, there may be mentioned, for example, triethylamine, pyridine, lutidine, n-butyllithium, tert-butylpotassium, and the like.

Wherein: ring A, R ₁ ~ R ₇ , n, m and p are as defined in claim 1, R represents a substituted or unsubstituted alkyl group, X represents a leaving group, for example, Cl, Br , I, optionally halogenated C ₁ -C ₆ alkylsulfonyloxy (for example, methylsulfonyloxy, ethylsulfonyloxy, trichloromethanesulfonyl), optionally substituted C ₆ -C ₁₀ arylsulfonyloxy (for example, phenylsulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, etc.) and the like.

Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective dose of said compound or a pharmaceutically acceptable salt thereof and a suitable carrier, diluent or excipient.

The present invention also relates to the application of the compound or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of medicines for treating diabetes and metabolic syndrome.

Detailed Description of the Invention

Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 10 carbon atoms is preferred, an alkyl group containing 1 to 6 carbon atoms is more preferred, an alkyl group containing 1 to 3 carbon atoms is more preferred, and methyl is most preferred. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and Various branched chain isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, cyano , nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably a cycloalkyl ring comprising 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl alkenyl, cyclooctyl, etc.

"Heterocyclic group" can refer to, for example, a 5-10 membered (monocyclic, bicyclic or tricyclic) heterocyclic group. The atoms constituting the heterocyclic ring contain, in addition to carbon atoms, one or two kinds selected from N, S, 1 to 4 heteroatoms of O, preferably 5-10 membered non-aromatic heterocycle or 5-10 membered aromatic heterocycle, etc. Specifically, non-aromatic heterocycles such as tetrahydrofuran, tetrahydropyran, pyrrolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.; aromatic heterocycles such as thienyl, furyl , pyridyl, thiazolyl, pyrimidinyl, pyrazolyl, imidazolyl, etc.

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is the aryl ring.

Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, Halogen, Thiol, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkoxy, Cycloalkylthio, Heterocycle Alkylthio groups are substituted.

"Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. Preferably it is 5 to 10 yuan. The heteroaryl group is preferably 5-membered or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.

Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio radical, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio groups are substituted.

"Alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio radical, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio groups are substituted.

"Haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

"Pharmaceutical composition" means a mixture containing one or more compounds of the present invention or pharmaceutically acceptable salts thereof, or prodrugs thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients agent. The purpose of the pharmaceutical composition is to promote the absorption of the active ingredient by the organism, and facilitate the biological activity of the active ingredient in the organism.

The GPR40 agonistic activity and in vivo hypoglycemic activity of the compounds of the present invention can be measured by using the assay system described below.

The following biological test example descriptions illustrate the invention.

The experimental method of specific conditions in the test example of the present invention is usually according to conventional conditions or according to the conditions suggested by the commodity manufacturer. Reagents whose specific sources are not indicated are commonly used reagents purchased in the market.

Test Example 1 The agonistic activity of the compound of the present invention on hGPR40-CHO stably transfected cells

The present invention uses the following methods to measure the GPR40 agonistic activity of the compounds of the present invention:

hGPR40-CHO stably transfected cells were seeded into a 96-well plate at a density of 3×10 ⁴ /well, and cultured overnight in a cell culture incubator at 37°C and 5% CO ₂ ; the culture medium was discarded, and 100ul HBSS was added to each well for washing. Add 100ul of Probenecid-containing Fluo-4 dye solution and incubate at 37°C for 90min; after the incubation, aspirate the Fluo-4 dye solution, add 100ul of HBSS buffer to wash away the dye; add 100ul of Probenecid-containing HBSS to each well, and incubate at 37°C for 10min; Drugs of different concentrations were added to each well of the 96-well plate, and read by FLIPR (Molecular Devices) according to the parameter setting table. Analyze the experimental results. Agonistic activity = (fluorescence value of compound well - fluorescence value of blank control well) / (fluorescence value of linoleic acid well - fluorescence value of blank control well) × 100%. The results are shown in Table 1.

Table 1: hGPR40 receptor agonistic activity

Conclusion: All the compounds of the present invention have obvious agonistic activity on GPR40, among which I-3, I-6, I-15, I-16 and I-24 have strong GPR40 agonistic activity.

Test Example 2 The in vivo hypoglycemic activity of the compounds of the present invention can be determined by using the assay system described below:

Oral glucose tolerance test (OGTT) in normal mice: 10 weeks old Kunming kind of clean level mice, body weight 18 ~ 22g, male, were randomly divided into 7 groups, blank control group (blank vehicle: 0.5% sodium carboxymethyl cellulose solution), the positive drug control group (TAK-875: 20mg/kg), the test compound group (20mg/kg), 8 mice in each group, and the mice were fasted for 12 hours before the experiment, and each group was given oral gavage Drugs were taken, blood was taken from the tail, and the blood sugar value was measured (recorded as -30min). Then the blank vehicle, TAK-875 and the test compound were given by intragastric administration respectively, and the blood glucose value was measured as 0min after 30min, and then the glucose solution with a concentration of 2g/10ml was given by intragastric administration immediately after 10ml/kg, and at 15, 30, and 60 , 120min to measure the blood glucose value. The results are shown in Table 2.

Table 2: The effect of preferred compounds on oral glucose tolerance in normal mice ( n=8)

Note: *P≤0.05 is the result of Student’s t test relative to the blank control group.

The oral glucose tolerance test of normal mice showed that: I-3, I-6, I-15, I-16 and I-24 can significantly improve the oral glucose tolerance of normal mice in vivo, showing better hypoglycemic effect.

Detailed ways

The present invention will be further described below in conjunction with embodiment. It should be noted that the following examples are only for illustration, but not for limiting the present invention. Various changes made by those skilled in the art according to the teaching of the present invention shall be within the scope of protection required by the claims of the present application.

Example 1

2-(2-fluoro-4-(2-phenoxyacetylamino)phenoxy)acetic acid (I-1)

first step

Methyl 2-(4-(2-chloroacetylamino)-2-fluorophenoxy)acetate (1c)

Methyl 2-fluoro-4-aminophenoxyacetate 1b (2.0 g, 10.1 mmol) was dissolved in CH ₂ Cl ₂ (50 mL), triethylamine (2.7 mL, 20.2 mmol) and a catalytic amount of DMAP were added, cooled To 0°C, slowly add chloroacetyl chloride 1a (1.5mL, 15.1mmol) dissolved in CH ₂ Cl ₂ dropwise, react at 0°C for 2h, after the reaction is complete by TLC, add water to quench the reaction, CH ₂ Cl ₂ (30ml×4 ) extraction, the combined organic phases were successively washed with 1N NaOH (20ml × 1), 1N HCl (20ml × 1), saturated NaCl solution (20ml × 2), dried, concentrated, and recrystallized from EtOH to obtain 2.2g of a white solid. The yield was 75.9%.

second step

Methyl 2-(2-fluoro-4-(2-phenoxyacetamido)phenoxy)acetate (1d)

Dissolve methyl 2-(4-(2-chloroacetamido)-2-fluorophenoxy)acetate 1c (0.20 g, 0.73 mmol) and phenol (0.14, 1.45 mmol) in CH ₃ CN (10 mL), add K ₂ CO ₃ (0.20g, 1.45mmol) and a catalytic amount of KI were added and heated to reflux at 65°C for 12h. After the reaction was complete as detected by TLC, cool and filter with suction. The filtrate was evaporated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography. (Petroleum ether/ethyl acetate, 80:20, v/v) was purified to obtain 130 mg of white solid with a yield of 54.2%.

third step

2-(2-fluoro-4-(2-phenoxyacetylamino)phenoxy)acetic acid (I-1)

Dissolve methyl 2-(2-fluoro-4-(2-phenoxyacetamido)phenoxy)acetate 1c (0.13g, 0.39mmol) in a mixed solvent of THF/CH ₃ OH, add 2N NaOH (31mg , 0.78mmol), reacted at room temperature for 2h after the addition, added 1N HCl to acidify, the solid precipitated, and suction filtered to obtain a white solid 110mg, the yield was 88.7%, mp: 182-184°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.13(s, 1H), 7.62, 7.58(dd, J=1.8, 13.6Hz, 1H), 7.31-7.29(m, 3H ), 7.06 (d, J=9.3Hz, 1H), 7.01-6.95 (m, 3H), 4.73 (s, 2H), 4.66 (s, 2H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.84, 166.52, 157.68, 152.41, 149.20, 141.73, 132.25, 132.12, 129.49, 121.22, 115.65, 114.99, 114.64, 108.49, 67.01, 65.23; ESI ^- MS m/z: 318.1 ([M.

Example 2

2-(2-fluoro-4-(2-(o-tolyloxy)acetamide)phenoxy)acetic acid (I-2)

Referring to the preparation method of I-1, 103 mg of white solid was obtained, the yield was 50.4%, and mp: 172-174°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.02(s, 1H), 10.13(s, 1H), 7.62, 7.58(dd, J=1.8, 13.6Hz, 1H), 7.28(d, J=7.4 Hz, 1H), 7.15-7.05(m, 3H), 6.87-6.84(m, 2H), 4.73(s, 2H), 4.68(s, 2H), 2.24(s, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.84, 166.63, 155.95, 152.44, 141.55, 132.32, 132.19, 126.87, 126.16, 120.94, 118.23, 115.45, 112.13, 109.36, 67.36, 65.14, 133.06 (ES m/z; [MH] ^- ).

Example 3

2-(2-Fluoro-4-(2-(m-tolyloxy)acetamide)phenoxy)acetic acid (I-3)

Referring to the preparation method of I-1, 115 mg of white solid was obtained, the yield was 47.1%, and mp: 157-159°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.09(s, 1H), 7.62, 7.58(dd, J=1.8, 13.6Hz, 1H), 7.31(d, J=8.6 Hz, 1H), 7.18(t, J=8.6Hz, 1H), 7.05(t, J=9.3Hz, 1H), 6.83-6.78(m, 3H), 4.73(s, 2H), 4.64(s, 2H ), 2.27(s, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.83, 166.57, 157.70, 152.40, 149.20, 139.01, 132.26, 129.22, 121.98, 115.65, 114.99, 113.12, 108.009, 65.28, 21.04; ESI-MS m/z: 332.1 ([MH] ^- ).

Example 4

2-(2-Fluoro-4-(2-(p-tolyloxy)acetamide)phenoxy)acetic acid (I-4)

Referring to the preparation method of I-1, 153 mg of white solid was obtained, the yield was 58.3%, and mp: 189-191°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.09(s, 1H), 7.62, 7.58(dd, J=1.8, 13.6Hz, 1H), 7.31(d, J=9.0 Hz, 1H), 7.12(d, J=8.4Hz, 2H), 7.03(d, J=9.2Hz, 1H), 6.89(d, J=8.4Hz, 2H), 4.72(s, 2H), 4.61( s, 2H), 2.23 (s, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.85, 166.62, 155.61, 152.37, 149.16, 132.41, 130.73, 130.05, 118.26, 115.54, 114.51, 111.43, 67.2 , 65.17, 20.03; ESI-MS m/z: 332.0 ([MH] ^- ).

Example 5

2-(4-(2-(4-Ethylphenoxy)acetamide)-2-fluorophenoxy)acetic acid (I-5)

Referring to the preparation method of I-1, 103 mg of white solid was obtained, the yield was 43.2%, and mp: 177-179°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.10(s, 1H), 7.62, 7.58(dd, J=1.8, 13.5Hz, 1H), 7.31(d, J=8.8 Hz, 1H), 7.13(d, J=8.3Hz, 2H), 7.07-7.04(m, 1H), 6.91(d, J=8.3Hz, 2H), 4.73(s, 2H), 4.62(s, 2H ), 2.53 (q, J=7.5Hz, 2H), 1.13 (t, J=7.5Hz, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.85, 166.64, 155.78, 152.38, 149.17, 136.61 , 132.43, 129.82, 118.23, 116.12, 114.52, 111.13, 67.22, 65.18, 27.26, 15.85; ESI-MS m/z: 346.1 ([MH] ^- ).

Example 6

2-(2-fluoro-4-(2-(3-isopropylphenoxy)acetamide)phenoxy)acetic acid (I-6)

Referring to the preparation method of I-1, 123 mg of white solid was obtained, the yield was 41.0%, and mp: 143-145°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.10(s, 1H), 7.62, 7.58(dd, J=1.9, 13.3Hz, 1H), 7.31(d, J=8.4 Hz, 1H), 7.21(t, J=7.7Hz, 1H), 7.08-7.03(m, 1H), 6.89-6.84(m, 2H), 6.79(d, J=7.8Hz, 1H), 4.73(s , 2H), 4, 64 (s, 2H), 2.89-2.80 (m, 1H), 1.18 (d, J=6.7Hz, 6H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.83, 166.60 , 157.75, 152.41, 150.12, 145.20, 132.25, 129.29, 119.34, 115.69, 113.04, 111.62, 108.53, 67.09, 65.24, 33.27, 23.73; ESI-MS m/z: 360.1 ([MH] ^- ).

Example 7

2-(2-fluoro-4-(2-(4-isopropylphenoxy)acetamide)phenoxy)acetic acid (I-7)

Referring to the preparation method of I-1, 167mg of white solid was obtained, the yield was 47.8%, and mp: 165-167°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.10(s, 1H), 7.62, 7.58(dd, J=1.7, 13.5Hz, 1H), 7.31(d, J=8.8 Hz, 1H), 7.16(d, J=8.4Hz, 2H), 7.08-7.03(m, 1H), 6.91(d, J=8.4Hz, 2H), 4.72(s, 2H), 4.63(s, 2H ), 2.87-2.78 (m, 1H), 1.16 (d, J=6.9Hz, 6H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.83, 166.69, 155.81, 152.42, 145.20, 141.72, 132.45, 127.18, 118.21, 115.63, 114.07, 111.12, 67.19, 65.25, 32.55, 24.02; ESI-MS m/z: 360.1 ([MH] ^- ).

Example 8

2-(4-(2-(3-(tert-butyl)phenoxy)acetamide)-2-fluorophenoxy)acetic acid (I-8)

Referring to the preparation method of I-1, 152 mg of white solid was obtained, the yield was 45.5%, and mp: 178-180°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.11(s, 1H), 7.61, 7.58(dd, J=2.0, 13.6Hz, 1H), 7.31(d, J=8.8 Hz, 1H), 7.23-7.20(m, 1H), 7.07(d, J=9.3Hz, 1H), 7.01(d, J=7.8Hz, 1H), 6.80-6.77(m, 2H), 4.73(s , 2H), 4.65(s, 2H), 1.26(s, 9H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.82, 166.65, 157.53, 152.42, 152.31, 145.12, 132.24, 129.03, 118.21, 117.34 , 115.68, 112.34, 111.06, 108.55, 67.14, 65.24, 34.39, 31.01; ESI-MS m/z: 374.1 ([MH] ^- ).

Example 9

2-(4-(2-(4-(tert-butyl)phenoxy)acetamide)-2-fluorophenoxy)acetic acid (I-9)

Referring to the preparation method of I-1, 102 mg of white solid was obtained with a yield of 47.9%, mp: 205-207°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.10(s, 1H), 7.61, 7.58(dd, J=2.1, 13.6Hz, 1H), 7.54(d, J=8.5 Hz, 2H), 7.31-7.29(m, 1H), 7.05(t, J=9.3Hz, 1H), 6.91(d, J=8.5Hz, 2H), 4.72(s, 2H), 4.63(s, 2H ), 1.24(s, 9H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.85, 166.70, 155.46, 152.41, 145.19, 143.43, 132.28, 126.08, 115.57, 114.96, 114.10, 111.46, 67.11, 65 33.73, 31.24; ESI-MS m/z: 374.1 ([MH] ^- ).

Example 10

2-(2-fluoro-4-(2-(3-methylphenoxy)acetamide)phenoxy)acetic acid (I-10)

Referring to the preparation method of I-1, 97 mg of white solid was obtained, the yield was 37.9%, and mp: 151-153°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.10(s, 1H), 7.62, 7.58(dd, J=2.2, 13.6Hz, 1H), 7.31(d, J=8.9 Hz, 1H), 7.21(t, J=7.8Hz, 1H), 7.06-7.02(m, 1H), 6.58-6.55(m, 3H), 4.73(s, 2H), 4.65(s, 2H), 3.74 (s, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.85, 166.40, 160.40, 158.90, 152.40, 149.17, 132.24, 129.99, 118.15, 115.62, 111.97, 106.90, 101.12, 67.224, 55 ;ESI-MS m/z: 348.1 ([MH] ^- ).

Example 11

2-(2-fluoro-4-(2-(4-methylphenoxy)acetamide)phenoxy)acetic acid (I-11)

Referring to the preparation method of I-1, 104 mg of white solid was obtained, the yield was 42.7%, and mp: 167-169°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.08(s, 1H), 7.63, 7.59(dd, J=2.3, 13.6Hz, 1H), 7.32(d, J=8.9 Hz, 1H), 7.05-7.01(m, 1H), 6.94(d, J=9.2Hz, 2H), 6.88(d, J=9.2Hz, 2H), 4.73(s, 2H), 4.60(s, 2H ), 3.69 (s, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.85, 166.73, 153.83, 152.38, 151.70, 145.36, 132.27, 118.27, 116.12, 115.72, 111.17, 67.86, 6302, 55. ESI-MS m/z: 348.0 ([MH] ^- ).

Example 12

2-(2-fluoro-4-(2-(4-(trifluoromethoxy)phenoxy)acetamide)phenoxy)acetic acid (I-12)

Referring to the preparation method of I-1, 108 mg of white solid was obtained, the yield was 50.4%, and mp: 182-183°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.16(s, 1H), 7.62, 7.58(dd, J=2.2, 13.5Hz, 1H), 7.33(d, J=8.9 Hz, 1H), 7.05-7.01(m, 1H), 6.97(d, J=9.5Hz, 2H), 6.83(d, J=9.5Hz, 2H), 4.80(s, 2H), 4.74(s, 2H ); ¹³ CNMR (75MHz, DMSO-d ₆ )δ: 169.84, 166.14, 152.40, 149.19, 145.13, 142.15, 132.21, 129.78, 122.48, 115.95, 114.98, 111.14, 67.27, 65.21: ESI-MS2 m/z ([MH] ^- ).

Example 13

2-(2-fluoro-4-(2-(3-(trifluoromethyl)phenoxy)acetamide)phenoxy)acetic acid (I-13)

Referring to the preparation method of I-1, 112mg of white solid was obtained, the yield was 52.2%, and mp: 133-135°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.16(s, 1H), 7.61, 7.57(dd, J=1.9, 13.9Hz, 1H), 7.54(d, J=8.0 Hz, 1H), 7.34-7.29(m, 3H), 7.06-7.02(m, 2H), 4.80(s, 2H), 4.74(s, 2H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.84, 165.99, 157.99, 152.40, 149.19, 132.14, 132.05, 130.01, 124.4, 118.69, 117.72, 115.62, 111.64 ^, 108.50, 67.10, 65.20;

Example 14

2-(2-fluoro-4-(2-(5-isopropyl-2-methylphenoxy)acetamide)phenoxy)acetic acid (I-14)

Referring to the preparation method of I-1, 95 mg of white solid was obtained with a yield of 38.4%, mp: 136-138°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.10(s, 1H), 7.61, 7.57(dd, J=1.9, 13.9Hz, 1H), 7.28(d, J=8.8 Hz, 1H), 7.09-7.03(m, 2H), 6.75(d, J=8.0Hz, 2H), 4.73(s, 2H), 4.68(s, 2H), 2.85-2.76(m, 1H), 2.19 (s, 3H), 1.15 (d, J=6.8Hz, 6H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.85, 166.71, 155.84, 152.42, 149.21, 147.35, 132.29, 130.32, 123.43, 118.59 , 115.50, 111.83, 108.37, 67.48, 65.18, 33.29, 23.84, 15.70; ESI-MS m/z: 374.1 ([MH] ^- ).

Example 15

2-(2-Fluoro-4-(2-phenoxypropionamido)phenoxy)acetic acid (I-15)

Referring to the preparation method of I-1, 132 mg of white solid was obtained, the yield was 36.8%, and mp: 137-139°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.23(s, 1H), 7.62, 7.58(dd, J=1.8, 13.7Hz, 1H), 7.28(d, J=8.8 Hz, 1H), 7.05-6.94(m, 4H), 6.83-6.78(m, 2H), 4.85(q, J=5.2Hz, 1H), 4.70(s, 2H), 1.53(d, J=5.1Hz , 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 169.95, 169.87, 157.18, 152.37, 149.16, 132.33, 129.53, 121.17, 118.17, 115.50, 114.95, 111.12, 73.69, 65.37; ESIMS-18.57 m/z: 332.1 ([MH] ^- ).

Example 16

2-(4-(2-(3,4-Dimethylphenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-16)

Referring to the preparation method of I-1, 105 mg of white solid was obtained with a yield of 33.7%, and mp: 126-128°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.11(s, 1H), 7.61, 7.57(dd, J=1.8, 13.6Hz, 1H), 7.30(d, J=8.8 Hz, 1H), 7.04-7.01(m, 2H), 6.78(s, 1H), 6.68(d, J=8.1Hz, 1H), 4.80(q, J=6.5Hz, 1H), 4.69(s, 2H ), 2.16(s, 3H), 2.12(s, 3H), 1.50(d, J=6.5Hz, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 170.19, 169.83, 155.24, 152.36, 149.15 , 141.66, 132.39, 130.15, 128.93, 118.21, 116.84, 115.53, 111.14, 73.96, 65.18, 19.60, 18.56, 18.37; ESI-MS m/z: 360.1 ([MH] ^- ).

Example 17

2-(4-(2-(3,5-Dimethylphenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-17)

Referring to the preparation method of I-1, 132mg of white solid was obtained, the yield was 43.6%, and mp: 146-148°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.10(s, 1H), 7.62, 7.58(dd, J=2.3, 13.6Hz, 1H), 7.31(d, J=8.9 Hz, 1H), 7.05-7.02(m, 2H), 6.68(d, J=7.6Hz, 2H), 4.80(q, J=6.6Hz, 1H), 4.73(s, 2H), 2.21(s, 6H ), 1.51 (d, J=6.5Hz, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 170.08, 169.83, 157.20, 152.37, 149.16, 141.70, 132.37, 122.85, 118.23, 116.15, 111.12, 110.22 , 73.72, 65.18, 21.01, 18.54; ESI-MS m/z: 360.1 ([MH] ^- ).

Example 18

2-(4-(2-(2,5-Dimethylphenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-18)

Referring to the preparation method of I-1, 87 mg of white solid was obtained, the yield was 31.5%, and mp: 158-160°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.10(s, 1H), 10.08(s, 1H), 7.62, 7.58(dd, J=1.7, 13.6Hz, 1H), 7.29(d, J=8.8 Hz, 1H), 7.08-7.02(m, 2H), 6.81(s, 1H), 6.69-6.66(m, 1H), 4.80(q, J=6.4Hz, 1H), 4.74(s, 2H), 2.21 (s, 3H), 2.19 (s, 3H), 1.53 (d, J=6.5Hz, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 170.05, 169.84, 155.36, 152.40, 149.18, 135.96, 132.38, 130.42, 123.53, 121.57, 118.15, 116.57, 111.17, 74.10, 65.18, 20.98, 18.61, 15.77; ESI-MS m/z: 360.1 ([MH] ^- ).

Example 19

2-(2-fluoro-4-(2-(5-isopropyl-2-methylphenoxy)propionamido)phenoxy)acetic acid (I-19)

Referring to the preparation method of I-1, 102 mg of white solid was obtained with a yield of 30.4%, and mp: 114-116°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.17(s, 1H), 7.63, 7.59(dd, J=1.9, 13.5Hz, 1H), 7.27(d, J=8.7 Hz, 1H), 7.08-7.02(m, 2H), 6.75-6.71(m, 2H), 4.83(q, J=6.2Hz, 1H), 4.73(s, 2H), 2.81-2.72(m, 1H) , 2.19 (s, 3H), 1.54 (d, J=6.4Hz, 3H), 1.11 (d, J=7.2Hz, 6H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 170.16, 169.84, 155.37 , 152.38, 147.17, 145.23, 132.32, 130.38, 123.86, 118.77, 115.55, 111.41, 107.32, 73.94, 65.19, 33.23, 23.95, 23.68, 18.52, 15.73; ESI ^- MS m/z: 388.

Example 20

2-(4-(2-(2-Ethoxyphenoxy)propionamido)phenoxy)acetic acid (I-20)

Referring to the preparation method of I-1, 79 mg of white solid was obtained with a yield of 37.8%, and mp: 123-125°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.16(s, 1H), 7.62, 7.58(dd, J=2.3, 13.6Hz, 1H), 7.28(d, J=8.9 Hz, 1H), 7.13-7.08(m, 3H), 6.88(d, J=7.3Hz, 1H), 6.83(d, J=8.1Hz, 1H), 4.84(q, J=6.4Hz, 1H), 4.73(s, 2H), 2.73(q, J=6.9Hz, 2H), 1.55(d, J=6.5Hz, 3H), 1.28(t, J=6.9Hz, 3H); ¹³ C NMR (75MHz, DMSO -d ₆ ) δ: 169.95, 169.84, 152.42, 149.20, 145.23, 141.68, 132.4, 121.04, 120.95, 118.23, 116.12, 115.41, 111.15, 73.68, 65.20, 55.76, 18.61, 13.15; ([MH] ^- ).

Example 21

2-(2-Fluoro-4-(2-(3-(trifluoromethyl)phenoxy)propionamido)phenoxy)acetic acid (I-21)

Referring to the preparation method of I-1, 103 mg of white solid was obtained, the yield was 40.9%, and mp: 127-129°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.53(s, 1H), 7.61, 7.57(dd, J=1.8, 13.4Hz, 1H), 7.52(d, J=8.8 Hz, 1H), 7.32-7.26(m, 4H), 6.97(d, J=9.2Hz, 1H), 5.08(q, J=6.3Hz, 1H), 4.51(s, 2H), 1.55(d, J =6.5Hz, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 171.92, 169.23, 157.43, 152.3, 142.32, 131.62, 131.50, 130.81, 124.46, 118.9, 117.64, 115.53, 114.78, 1112.03 109.02, 73.71, 66.61, 18.35; ESI-MS m/z: 400.0 ([MH] ^- ).

Example 22

2-(4-(2-(3-(tert-butyl)phenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-22)

Referring to the preparation method of I-1, 105 mg of white solid was obtained with a yield of 34.8%, and mp: 102-104°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.09(s, 1H), 10.26(s, 1H), 7.61, 7.57(d, J=13.5Hz, 1H), 7.29(d, J=8.5Hz, 1H), 7.20(t, J=7.7Hz, 2H), 7.06-6.99(m, 2H), 6.74(d, J=7.3Hz, 1H), 4.85(q, J=5.7Hz, 1H), 4.71( s, 2H), 1.53 (d, J=5.7Hz, 3H), 1.24 (s, 9H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 170.14, 169.97, 157.01, 152.40, 149.14, 145.75, 132.31 , 128.64, 118.06, 115.53, 114.91, 112.67, 111.50, 73.64, 65.30, 34.38, 30.98, 18.56, 18.27; ESI-MS m/z: 388.1 ([MH] ^- ).

Example 23

2-(4-(2-(4-ethoxyphenoxy)propionamido)-2-fluorophenoxy)acetic acid (I-23)

Referring to the preparation method of I-1, 99 mg of white solid was obtained with a yield of 38.8%, and mp: 146-148°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.10(s, 1H), 10.12(s, 1H), 7.62, 7.58(dd, J=2.2, 13.6Hz, 1H), 7.31(d, J=8.9 Hz, 1H), 7.04(t, J=9.3Hz, 1H), 6.92-6.83(m, 4H), 4.85(q, J=6.1Hz, 1H), 4.71(s, 2H), 3.93(q, J =6.9Hz, 2H), 1.50(d, J=6.1Hz, 3H), 1.28(t, J=6.9Hz, 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 170.24, 169.83, 153.12, 152.36, 151.01, 145.15, 132.39, 118.32, 116.46, 115.48, 111.14, 74.78, 65.18, 63.21, 18.60, 14.67; ESI-MS m/z: 376.1 ([MH] ^- ).

Example 24

2-(2-fluoro-4-(2-(2-fluorophenoxy)propionamido)phenoxy)acetic acid (I-24)

Referring to the preparation method of I-1, 109 mg of white solid was obtained, the product ratio was 40.3%, and mp: 135-137°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 13.12(s, 1H), 10.36(s, 1H), 7.63, 7.59(dd, J=2.3, 13.6Hz, 1H), 7.31(d, J=9.1 Hz, 1H), 7.25-7.21(m, 1H), 7.14-6.94(m, 4H), 4.91(q, J=6.5Hz, 1H), 4.74(s, 2H), 1.57(d, J=6.6Hz , 3H); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 170.34, 169.83, 152.39, 146.19, 132.33, 124.78, 122.01, 118.23, 116.43, 114.98, 111.32, 74.95, 65.21, 18.52/; ESI-MS m z: 350.1 ([MH] ^- ).

Example 25

Tablets containing active agent I-3:

Sieve the active ingredient, pregelatinized starch and microcrystalline cellulose, mix well, add polyvinylpyrrolidone solution, mix, make soft material, sieve, make wet granules, dry at 50-60°C, and carboxymethyl starch Sodium salt, magnesium stearate and talcum powder are sieved and added to the above granules and compressed into tablets.

It has been verified that the above composition also has excellent hypoglycemic activity in vivo.

Claims (8)

1. the compound shown in a general formula (I) or its pharmaceutically useful salt:

Wherein:

Ring A is selected from aryl or heteroaryl;

R ₁independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl separately, wherein said alkyl, cycloalkyl, alkoxyl group optionally further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl group replace;

R ₂and R ₃independently be selected from hydrogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl separately;

R ₄independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR separately ₈,-OC (O) R ₈,-C (O) R ₈,-NHC (O) R ₈,-NR ₉r ₁₀,-OC (O) NR ₉r ₁₀,-NHC (O) NR ₉r ₁₀or-S (O) _qr ₈, wherein said alkyl, cycloalkyl, alkoxyl group, heterocyclic radical, aryl or heteroaryl are optionally selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more further ₈,-OC (O) R ₈,-C (O) R ₈,-NHC (O) R ₈,-NR ₉r ₁₀,-OC (O) NR ₉r ₁₀,-NHC (O) NR ₉r ₁₀or-S (O) _qr ₉group replaced;

R ₅and R ₆independently be selected from hydrogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl separately;

R ₇be selected from hydrogen atom or alkyl;

R ₈be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another optional further by one or more be selected from alkyl, halogen, hydroxyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid group or carboxylic acid ester groups substituting group replace;

R ₉or R ₁₀independently be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another optional further by one or more be selected from alkyl, halogen, hydroxyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid group or carboxylic acid ester groups substituting group replace;

M is 0 or 1;

N is 0,1,2,3 or 4;

P is 0,1,2,3,4 or 5; And q is 0,1 or 2.

2. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, it is the compound shown in general formula (II) or its pharmaceutically useful salt:

Wherein:

Ring A is selected from aryl or heteroaryl;

R ₁independently be selected from hydrogen, halogen, cyano group, alkyl, alkoxyl group separately, wherein said alkyl, alkoxyl group optionally further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl group replace;

R ₂and R ₃independently be selected from hydrogen, alkyl, alkoxyl group separately;

R ₄independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl separately, wherein said alkyl, cycloalkyl, alkoxyl group, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl group replace;

N is 0,1,2,3 or 4;

P is 0,1,2,3,4 or 5.

3. the compound shown in general formula according to claim 2 (II) or its pharmaceutically useful salt, it is the compound shown in general formula (III) or its pharmaceutically useful salt:

Wherein:

R ₂and R ₃independently be selected from hydrogen, alkyl, alkoxyl group separately;

R ₄independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl separately, wherein said alkyl, cycloalkyl, alkoxyl group, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl group replace;

P is 0,1,2,3,4 or 5.

4. compound or its pharmaceutically useful salt of what claim 3 defined have general formula (III):

Wherein:

R ₂and R ₃respective independence is preferably from hydrogen, replacement or do not replace C ₁-C ₆alkyl;

R ₄respective independence preferably from hydrogen, halogen, hydroxyl, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, wherein said alkyl, cycloalkyl, alkoxyl group, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl group replace;

P is preferably 0,1,2 or 3.

5. the compound that defines of claim 1-4 or its pharmaceutically useful salt, described compound is selected from:

2-(the fluoro-4-of 2-(2-benzene oxygen kharophen) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(oxy-o-cresyl) ethanamide) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(tolyloxy) ethanamide) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(to tolyloxy) ethanamide) benzene oxygen) acetic acid;

2-(4-(2-(4-ethyl phenoxy group) ethanamide)-2-fluorobenzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(3-sec.-propyl phenoxy group) ethanamide) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(4-sec.-propyl phenoxy group) ethanamide) benzene oxygen) acetic acid;

2-(4-(2-(3-(tertiary butyl) phenoxy group) ethanamide)-2-fluorobenzene oxygen) acetic acid;

2-(4-(2-(4-(tertiary butyl) phenoxy group) ethanamide)-2-fluorobenzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(3-methylphenoxy) ethanamide) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(4-methylphenoxy) ethanamide) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(4-(trifluoromethoxy) phenoxy group) ethanamide) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(3-(trifluoromethyl) phenoxy group) ethanamide) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(5-sec.-propyl-2-methylphenoxy) ethanamide) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-phenoxypropionamide base) benzene oxygen) acetic acid;

2-(4-(2-(3,4-xylyloxy) propionamido-)-2-fluorobenzene oxygen) acetic acid;

2-(4-(2-(3,5-xylyloxy) propionamido-)-2-fluorobenzene oxygen) acetic acid;

2-(4-(2-(2,5-xylyloxy) propionamido-)-2-fluorobenzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(5-sec.-propyl-2-methylphenoxy) propionamido-) benzene oxygen) acetic acid;

2-(4-(2-(2-ethoxy phenoxy) propionamido-) benzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(3-(trifluoromethyl) phenoxy group) propionamido-) benzene oxygen) acetic acid;

2-(4-(2-(3-(tertiary butyl) phenoxy group) propionamido-)-2-fluorobenzene oxygen) acetic acid;

2-(4-(2-(4-ethoxy phenoxy) propionamido-)-2-fluorobenzene oxygen) acetic acid;

2-(the fluoro-4-of 2-(2-(2-fluorobenzene oxygen) propionamido-) benzene oxygen) acetic acid.

6. prepare a method for general formula according to claim 1 (I) compound or pharmaceutically acceptable salt thereof, the method comprises:

Compound (IA) carries out ether building-up reactions in the basic conditions with alcohol or phenol, and carry out Ester hydrolysis in the basic conditions further, obtain compound (I), the reagent of alkalescence is provided to comprise mineral alkali and organic bases, described mineral alkali can be mentioned such as, and alkaline carbonate class is sodium carbonate, salt of wormwood, cesium carbonate etc. such as; Alkali metal hydrocarbonate class such as saleratus etc.; Alkali metal hydroxide is lithium hydroxide, sodium hydroxide, potassium hydroxide etc. such as; Described organic bases can mention such as triethylamine, pyridine, lutidine, n-Butyl Lithium, tertiary butyl potassium etc.

Wherein: ring A, R ₁~ R ₇, n, m and p definition as described in the appended claim 1, R represents and to replace or without the alkyl replaced, X represents leavings group, can mention the C of such as Cl, Br, I, optional halo ₁-C ₆alkyl sulphonyl oxygen base (such as, methylsulfonyl oxygen base, ethylsulfonyl oxygen base, three chloromethanesulfonyl), optionally there is substituent C ₆-C ₁₀aryl sulfonyl oxygen base (such as, phenyl sulfonyl oxygen base, p-toluenesulfonyl oxygen base, m-nitrobenzenesulfonyl oxygen base etc.) etc.

7. a pharmaceutical composition, containing the compound or pharmaceutically acceptable salt thereof one of claim 1-5 Suo Shu and suitable carrier or vehicle.

8. the compound that defines of Claims 1 to 5 any one or its pharmaceutically useful salt or the purposes of its pharmaceutical composition in preparation treatment diabetes and Metabolic syndrome disease drug.