GPR120 protein receptor inhibitor and preparation and application thereof
阅读说明：本技术 一种gpr120蛋白受体抑制剂及其制备和应用 (GPR120 protein receptor inhibitor and preparation and application thereof ) 是由 范国煌 于 2021-01-15 设计创作，主要内容包括：本发明提供了一种GPR120蛋白受体抑制剂及其制备和应用,具体地,本发明提供了一种如下式I所示的化合物,或其药学上可接受的盐。所述的化合物具有优异的GPR120蛋白抑制活性。(The invention provides a GPR120 protein receptor inhibitors and preparation and application thereof, in particular to a compound shown as a formula I below or pharmaceutically acceptable salt thereof. The compound has excellent GPR120 protein inhibition activity.)
1. A compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
n is 0, 1,2 or 3;
m is 0, 1 or 2;
p is 1 or 2;
R1and R2Selected from the group consisting of: H. halogen, CN, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group; or two R on adjacent carbon atoms1Together with the carbon atom to which they are attached form C6-C10An aryl group;
x is selected from the group consisting of: CH or N; and when X is CH, R2May be located on X;
y is selected from the group consisting of: substituted or unsubstituted C1-C2An alkylene group;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halogenated C1-C6Alkoxy radical, C3-C8A cycloalkyl group.
2. The compound of claim 1, wherein the compound of formula I has the structure shown in formula II:
wherein R is3And R4Each independently selected from the group consisting of: H. c1-C4An alkyl group.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the structure shown in formula III below:
wherein R is1Selected from the group consisting of: H. halogen, CN, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R3and R4Each independently selected from the group consisting of: H. c1-C4An alkyl group.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the structure shown in formula IV below:
wherein R is2Selected from the group consisting of: H. c1-C6An alkyl group.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof,
R1and R2Selected from the group consisting of: H. halogen, CN, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted cyclopropyl; or two R on adjacent carbon atoms1Together with the carbon atom to which they are attached form C6-C10An aryl group;
the term "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting ofGeneration: halogen, C1-C4Alkyl radical, C1-C4Alkoxy, halogenated C1-C4Alkoxy radical, C3-C6A cycloalkyl group.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from the group consisting of:
7. a pharmaceutical composition comprising (1) a compound of claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; (2) a pharmaceutically acceptable carrier.
8. Use of a compound according to claim 1 or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 7, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of a disease associated with the activity or the amount of expression of the GPR120 protein receptor.
9. The use according to claim 8, wherein the disease is selected from the group consisting of: diabetes, hyperlipidemia, obesity and inflammation-related diseases.
10. The use according to claim 8, wherein the disease is selected from the group consisting of: diabetes, obesity, hyperlipidemia, NASH or inflammation-related diseases.
Technical Field
The invention relates to the field of small molecule protein inhibitors, and particularly provides preparation and application of a compound with a GPR120 protein regulation effect.
Background
GPR120, a G protein-coupled receptor, induces intracellular signaling by binding to unsaturated long chain fatty acids such as α -linoleic acid, thereby inducing a variety of biological responses. The action of GPR120 and its ligands has been reported to promote the secretion of glucagon-like peptide 1 ("GLP-1") and thereby lower blood glucose levels in gastrointestinal cell lines. GLP-1, a peptide hormone, has been found to induce insulin secretion depending on blood glucose levels. It has also been suggested to use GLP-1 to delay apoptosis of beta cells in type II diabetes.
GPR120 is expressed in adipocytes. It has been found that GPR120 is increasingly expressed by induction of adipogenic differentiation. In addition, it has been reported that the action of GPR120 and its ligand inhibits lipolysis in adipose differentiated cells. It is known that high blood lipid levels are one of the causes of insulin resistance, and therefore, inhibition of lipolysis by GPR120 agonists is expected to lower free fatty acid levels in the blood to normalize blood lipid levels and possibly lead to an improvement in insulin resistance.
GPR120 is also expressed in the pituitary and GPR120 ligands have been reported to inhibit corticotropin secretion. Corticotropin promotes glucocorticoid secretion downstream thereof to induce effects such as promotion of gluconeogenesis in the liver, inhibition of glucose uptake in muscle and peripheral tissues, lipolysis in adipose tissues or release of fatty acids or glycerol. Therefore, GPR120 is considered to exhibit a hypoglycemic effect or a hypolipidemic effect even centrally through an inhibitory effect on corticotropin secretion.
More recently, GPR120 has been shown to play a role in obesity in mice and humans. GPR120 knockout mice fed a high fat diet develop obesity, glucose intolerance and fatty liver, decreased adipocyte differentiation and adipogenesis, and increased hepatic adipogenesis. In this study, insulin resistance in these mice was associated with decreased insulin signaling and increased adipose tissue inflammation. In humans, GPR120 expression in adipose tissue is significantly higher in obese subjects than in lean subjects.
GPR120 has also been shown to play a role in inflammation. Wild type mice treated with omega-3 fatty acids inhibited macrophage-induced tissue inflammation and enhanced systemic insulin sensitivity. However, this effect was not observed in GPR120 knockout mice.
According to the above description, the compounds having GPR120 agonist activity are considered to be useful as drugs for treating and/or preventing diabetes, obesity, hyperlipidemia, fatty liver (including nonalcoholic steatohepatitis or NASH), and inflammation-related diseases.
In view of the above, there is a strong need in the art to develop novel GPR120 protein receptor inhibitors.
Disclosure of Invention
The invention aims to provide a novel GPR120 protein receptor inhibitor.
In a first aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
n is 0, 1,2 or 3;
m is 0, 1 or 2;
p is 1 or 2;
R1and R2Selected from the group consisting of: H. halogen, CN, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group; or two R on adjacent carbon atoms1Together with the carbon atom to which they are attached form C6-C10An aryl group;
x is selected from the group consisting of: CH or N; and when X is CH, R2May be located on X;
y is selected from the group consisting of: substituted or unsubstituted C1-C2An alkylene group;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halogenated C1-C6Alkoxy radical, C3-C8A cycloalkyl group.
In another preferred embodiment, the compound of formula I has the structure shown in formula II below:
wherein R is3And R4Each independently selected from the group consisting of: H. c1-C4An alkyl group.
In another preferred embodiment, the compound of formula I has the structure shown in formula III below:
wherein R is1Selected from the group consisting of: H. halogen, CN, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R3and R4Each independently selected from the group consisting of: H. c1-C4An alkyl group.
In another preferred embodiment, the compound of formula I has the structure shown in formula IV below:
wherein R is2Selected from the group consisting of: H. c1-C6An alkyl group.
In another preferred embodiment, R1And R2Selected from the group consisting of: H. halogen, CN, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted cyclopropyl; or two on adjacent carbon atomsR1Together with the carbon atom to which they are attached form C6-C10An aryl group;
the term "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Alkoxy, halogenated C1-C4Alkoxy radical, C3-C6A cycloalkyl group.
In another preferred embodiment, the compound of formula I is selected from the group consisting of:
in a second aspect of the present invention, there is provided a pharmaceutical composition comprising (1) a compound according to the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (2) a pharmaceutically acceptable carrier.
In a third aspect of the present invention, there is provided a use of a compound according to the first aspect of the present invention, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second aspect of the present invention, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of a disease associated with an activity or an expression level of a GPR120 protein receptor.
In another preferred embodiment, the disease is selected from the group consisting of: diabetes, hyperlipidemia, obesity and inflammation-related diseases.
In another preferred embodiment, the disease is selected from the group consisting of: diabetes, obesity, hyperlipidemia, NASH or inflammation-related diseases.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted extensive and intensive studies and have designed and synthesized a novel class of GPR120 protein receptor inhibitors. On this basis, the inventors have completed the present invention.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C8Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C2-C6Alkenyl means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C2-C6Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
As used herein, the term“C3-C8Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.
As used herein, the term "C1-C8Alkoxy "means a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
As used herein, the term "C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless otherwise specified, the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, haloGeneration C1-C6Alkyl, halo C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.
As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio.
A compound of formula I
The invention provides a compound shown as the following formula I, a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof:
wherein the content of the first and second substances,
n is 0, 1,2 or 3;
m is 0, 1 or 2;
p is 1 or 2;
R1and R2Selected from the group consisting of: H. halogen, CN, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group; or two R on adjacent carbon atoms1Together with the carbon atom to which they are attached form C6-C10An aryl group;
x is selected from the group consisting of: CH or N; and when X is CH, R2May be located on X;
y is selected from the group consisting of: substituted or unsubstituted C1-C2An alkylene group;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, halogenated C1-C6Alkoxy radical, C3-C8A cycloalkyl group.
Preferred compounds of formula I are the specific compounds shown in the examples of this application.
Preparation of Compounds of formula I
The present invention also provides a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of:
reacting an alcohol Ia with a phenol Ib in a suitable solvent to obtain a compound Ic, and deprotecting to obtain a compound of formula I, wherein LG is a leaving group, preferably C1-C4An alkyl group.
Pharmaceutical compositions and methods of administration
The compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound as a main active ingredient are useful for the prevention and/or treatment of diseases (e.g., cancer) associated with the GPR120 signaling pathway, because the compound of the present invention has excellent inhibitory activity against GPR 120.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When administered in combination, the pharmaceutical composition further comprises one or more other pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with a compound of the invention.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
3- (4- ((2-isopropyl-5-methylbenzyl) oxy) -3-methylphenyl) propionic acid
Step 1: synthesis of (2-isopropyl-5-methylphenyl) methanol
A solution of 2-isopropyl-5-methylbenzaldehyde (100mg, 0.62mol) in THF (5mL) was cooled to-78 deg.C. LAH (1.0M in THF, 0.8mL, 0.8mmol) was added at this temperature and the reaction was allowed to warm to room temperature. The reaction was poured into a mixture of ice and water and extracted with ethyl acetate (20mL x 2). The combined organic layers were washed with brine (10mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title compound as a yellow oil (80mg, 80% yield). Ms (esi): m/z 165.5(M + H)+。
Step 2: synthesis of methyl 3- (4- (((2-isopropyl-5-methylbenzyl) oxy) -3-methylphenyl) propionate
(2-isopropyl-5-methylphenyl) methanol (80mg, 0.49mmol), methyl 3- (4-hydroxy-3-methylphenyl) propionate (105mg, 0.54mmol) and PPh3(140mg, 0.54mmol) of the solution was stirred in dry THF (10mL) at 0 ℃ under a nitrogen atmosphere. DIAD (0.15mL, 0.54mmol) was added dropwise to the mixture over 5 min, and the reaction was stirred at room temperature for 12 h. The reaction was washed with water (10mL) and CH2Cl2(20mL × 2) extraction. The combined organic layers were washed with brine (10mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography to give the title compound (70mg, 42%) as a yellow solid. Ms (esi): m/z 341.5(M + H)+。
And step 3: synthesis of 3- (4- ((2-isopropyl-5-methylbenzyl) oxy) -3-methylphenyl) propionic acid
A solution of methyl 3- (4- (((2-isopropyl-5-methylbenzyloxy) -3-methylphenyl) propionate (70mg, 0.21mmol) in THF (5mL) and water (1 mL.) 24mg, 1.0mmol) was added the mixture was stirred at room temperature for 5 hours, the solution was neutralized with 0.1N HCl and extracted with ethyl acetate (20mL x 2.) the combined organic layers were washed with brine (10mL), dried over magnesium sulfate, filtered and concentrated the residue was purified by flash chromatography,the title compound (30mg, 45%) was obtained as a yellow solid. Ms (esi): m/z 327.5(M + H)+。1HNMR(DMSO-d6，400MHz)12.00(s，br，1H)，7.00-7.40(m，5H)，6.70(d，J＝7.8Hz，1H)，5.20(s，2H)，2.70-2.80(m，1H)，2.50-2.70(m，4H)，2.10(s，3H)，1.00-1.20(m，6H)。
The following compounds were prepared according to a similar method to example 1:
bioassay examples GPR120 TANGO analysis
For GPR120 TANGO assay, the TANGO cells were plated in 96 well cell culture plates overnight at a density of 10000 cells/well in DMEM supplemented with 10% FBS. On the following day (day 2), the compounds tested were preincubated with cells for 1 hour, then GPCR 120 agonist was added to each well, and the cells were incubated for an additional 48 hours. Fluorescence of TANGO cells was observed using a plate reader (Infinite 200, Tecan) and IC was calculated50。
The results are shown in the following table, when IC50Below 100nM, the activity range is shown as +++. When measured IC50At 100 and 500nM, the activity range was recorded as ++; when IC50Above 500nM, the activity range is recorded +.
The results show that the compounds of the present invention have excellent half GPR120 inhibitory activity.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
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