Phenylpropionic acid derivatives, process for their preparation and use thereof

Abstract

The present application provides a compound as shown in the following formula I-1, a tautomer thereof or a pharmaceutically acceptable salt thereof, and application thereof as a GPR40 agonist.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a series of phenylpropionic acid derivatives and their preparation methods, as well as their applications as GPR40 agonists, particularly intestinal-restricted GPR40 agonists and their applications. Background Technology

[0002] G protein coupled receptor 40 (GPR40), also known as free fatty acid receptor 1, is a specific free fatty acid (FFA) receptor expressed in human (and rodent) pancreatic β-cells and insulin-secreting cell lines. In pancreatic β-cells, it promotes glucose-dependent insulin secretion and regulates the insulin secretion effects stimulated by long-chain saturated fatty acids or monounsaturated and polyunsaturated fatty acids. In the gut, GPR40 stimulates the secretion of incretin hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), cholecystokinin (CCK), and yY peptide (PYY). Therefore, compounds targeting this receptor hold promise for development into drugs to treat a variety of diseases. Currently, there are no drugs targeting GPR40 agonists on the market globally.

[0003] Takeda Pharmaceuticals of Japan previously developed a GPR40 agonist codenamed TAK 875 (fasiglifam), and clinical data showed that TAK-875 had effective antidiabetic effects. Unfortunately, the Phase III clinical trial was terminated due to hepatotoxicity. Meanwhile, Takeda Pharmaceuticals' GPR40 agonist codenamed SCO 267 is currently in Phase I clinical trials, and clinical data also show that SCO 267 is effective in improving glycemic control and weight loss, with a bioavailability of 26% in mice (see J. Med. Chem. 2020, 63, 18, 10352–10379, Design and Identification of aGPR40 Full Agonist (SCO-267) Possessing a 2-Carbamoylphenyl Piperidine Moiety). The structures of TAK 875 and SCO 267 are as follows:

[0004]

[0005] Intestinal-restricted drugs, based on their unique distribution properties in the intestinal restrictive tissues, enable the concentration of the drug at the target site to effectively act on the target site and regulate the corresponding pathways. At the same time, they reduce systemic exposure and the bioavailability of the drug itself, thereby reducing the absorption of the drug through systemic circulation and causing side effects, improving drug safety, and providing a new treatment approach for a variety of diseases.

[0006] Therefore, developing safer and more effective GPR40 agonists remains a pressing clinical need. In particular, developing intestinal-restricted GPR40 agonists can avoid systemic drug exposure, thus providing a safer treatment option. Summary of the Invention

[0007] This invention provides a compound of formula I, its tautomer, or a pharmaceutically acceptable salt thereof.

[0008]

[0009] in:

[0010] Y is selected from: single bond, -O-, -S-, and -NH-; n is selected from 0, 1, and 2; m is selected from 0, 1, and 2;

[0011] R1 can be hydrogen, hydroxyl, cyano, halogen, or -(CH2). 1-3 -OH, optionally substituted with halogens: 3-6 membered cycloalkyl, C1-6 alkenyl, C1-6 ynyl, CH3O-(CH2) 1-6 - C1-6 alkyl;

[0012] R2 is hydrogen, hydroxyl, cyano, halogen, optionally substituted with halogen: C1-6 alkyl, C1-C6 alkylhexyl, 3-6 membered cycloalkyl;

[0013] R3 is hydrogen, hydroxyl, cyano, carboxyl, halogen, optionally substituted with halogen: C1-8 alkyl, C1-8 alkenyl, C1-8 alkynyl, C1-8 cycloalkyl;

[0014] R4 is hydrogen, hydroxyl, cyano, carboxyl, halogen, optionally substituted with halogen: C1-6 alkyl or C1-6 alkyl.

[0015] R5 is hydrogen, optionally substituted by Ra: phenyl, benzyl, C1-10 straight-chain or branched alkyl;

[0016] Ra can be hydroxyl, cyano, carboxyl, halogen, C1-3 alkyl, or C1-3 alkyl.

[0017] R6 is hydrogen, hydroxyl, or cyano, optionally substituted with a halogen: C6-18 straight-chain or branched alkyl group. Where p is selected from 9, 10, 11, and 12;

[0018] The number of substitutions for Ra and halogen can be independently selected from 1, 2, 3, 4, and 5, respectively.

[0019] In some embodiments of the present invention, Y is selected from -O-, -S- and -NH-, and other variables are as defined in the present invention.

[0020] In some embodiments of the present invention, Y is -O-, and other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, n is 1, and other variables are as defined in the present invention.

[0022] In some embodiments of the present invention, m is 0, and other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, R1 is hydrogen, hydroxyl, cyano, F, Cl, Br, -CH2-OH, -(CH2)2-OH, optionally substituted with a halogen: -CH=CH-CH3, -CH≡CH-CH3, CH3OCH2-, methyl, ethyl, and other variables as defined in this invention.

[0024] In some embodiments of the present invention, R1 is hydrogen, hydroxyl, cyano, F, Cl, Br, -CH2-OH, -(CH2)2-OH, optionally substituted with F: -CH=CH-CH3, -CH≡CH-CH3, CH3OCH2-, methyl, ethyl, and other variables as defined in this invention.

[0025] In some embodiments of the present invention, R1 is hydrogen, hydroxyl, cyano, F, Cl, Br, -CH2-OH, -(CH2)2-OH. -CH=CH-CH3, -CH≡CH-CH3, CH3OCH2-, methyl, trifluoromethyl, ethyl, and other variables as defined in this invention.

[0026] In some embodiments of the present invention, R2 is hydrogen, hydroxyl, cyano, F, Cl, Br, optionally substituted with halogen: C1-3 alkyl, C1-3 alkoxy, 3- to 6-membered cycloalkyl.

[0027] In some embodiments of the present invention, R2 is hydrogen, hydroxyl, cyano, F, Cl, Br, and optionally substituted with F: methyl, ethyl, isopropyl, Other variables are as defined in this invention.

[0028] In some embodiments of the present invention, R2 is hydrogen, hydroxyl, cyano, F, Cl, Br, methyl, trifluoromethyl, isopropyl, Other variables are as defined in this invention.

[0029] In some embodiments of the present invention, R3 is hydrogen, hydroxyl, carboxyl, cyano, F, Cl, Br, optionally substituted with halogen: C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 cycloalkyl, and other variables as defined in the present invention.

[0030] In some embodiments of the present invention, R3 is hydrogen, hydroxyl, carboxyl, cyano, F, Cl, Br, optionally substituted with F: methyl, butyl, vinyl, ethynyl, Other variables are as defined in this invention.

[0031] In some embodiments of the present invention, R3 is hydrogen, hydroxyl, carboxyl, cyano, F, Cl, Br, methyl, trifluoromethyl, butyl, vinyl, ethynyl, etc. Other variables are as defined in this invention.

[0032] In some embodiments of the present invention, R4 is hydrogen, hydroxyl, cyano, carboxyl, F, Cl, Br, optionally substituted with halogen: C1-3 alkyl or C1-3 alkyl, and other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, R4 is hydrogen, hydroxyl, cyano, carboxyl, F, Cl, Br, optionally substituted by F: C1-3 alkoxy, C1-3 alkylthio, C1-3 alkyl, and other variables as defined in the present invention.

[0034] In some embodiments of the present invention, R4 is hydrogen, hydroxyl, cyano, carboxyl, F, Cl, Br, methyl, trifluoromethyl, ethyl. Other variables are as defined in this invention.

[0035] In some embodiments of the present invention, Ra is hydroxyl, cyano, carboxyl, F, Cl, Br, C1-3 alkoxy, methyl, ethyl, and other variables as defined in the present invention.

[0036] In some embodiments of the present invention, Ra is a hydroxyl group, a cyano group, a carboxyl group, F, Cl, or Br. Methyl, ethyl, and other variables are as defined in this invention.

[0037] In some embodiments of the present invention, R5 is hydrogen, optionally substituted with Ra: phenyl, benzyl, C1-8 linear or branched alkyl, and other variables as defined in the present invention.

[0038] In some embodiments of the present invention, R5 is hydrogen. Methyl, ethyl, Other variables are as defined in this invention.

[0039] In some embodiments of the present invention, p is selected from 9, 10, and 11, and other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, p is selected from 10, and other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, R6 is hydrogen, hydroxyl, cyano, optionally substituted with a halogen: C6-16 straight-chain or branched alkyl group, Other variables are as defined in this invention.

[0042] In some embodiments of the present invention, R6 is hydrogen, hydroxyl, cyano, optionally substituted with F: C8-16 straight-chain or branched alkyl group, Other variables are as defined in this invention.

[0043] In some embodiments of the present invention, R6 is hydrogen, hydroxyl, cyano, undecyl, dodecyl, tetradecyl, hexadecyl, etc. Other variables are as defined in this invention.

[0044] In some embodiments of the present invention, R6 is hydrogen, hydroxyl, cyano, undecyl, dodecyl, tetradecyl, hexadecyl, etc. Other variables are as defined in this invention.

[0045] In some embodiments of the present invention, the above-mentioned compound I is shown in formula I-1, wherein R1, R2, R3, R4, R5, R6 are defined as described in any of the preceding claims:

[0046]

[0047] In some embodiments of the present invention, the above-mentioned compound I is shown in formula I-2, wherein R2, R3, R4, R5, and R6 are defined as described in any of the preceding claims:

[0048]

[0049] Some solutions in this invention are derived from arbitrary combinations of the above-mentioned variables.

[0050] Some specific compounds of the present invention, their tautomers, or pharmaceutically acceptable salts thereof, wherein the compounds may be any one of the following:

[0051]

[0052] Some specific compounds of the present invention, their tautomers, or pharmaceutically acceptable salts thereof, wherein the compounds may be any one of the following:

[0053]

[0054] A second object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound and / or its tautomers and / or its pharmaceutically acceptable salts and pharmaceutically acceptable carriers.

[0055] In some embodiments of the present invention, the mass ratio of the compound and / or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.01 to 99.99%.

[0056] In some embodiments of the present invention, the mass ratio of the compound and / or its tautomers and / or its pharmaceutically acceptable salts in the pharmaceutical composition is 0.1 to 99.9%.

[0057] In some embodiments of the present invention, the mass ratio of the compound and / or its tautomers and / or its pharmaceutically acceptable salts in the pharmaceutical composition is 1.0 to 99.0%.

[0058] A third objective of this invention is to provide a method for treating diseases associated with GPR40 agonists, comprising administering the aforementioned compounds of this invention and / or their tautomers and / or their pharmaceutically acceptable salts, or administering the aforementioned pharmaceutical compositions of this invention.

[0059] In some embodiments of the present invention, the compound described herein, its tautomers, or a pharmaceutically acceptable salt thereof are administered in combination with other therapeutic agents.

[0060] The compounds described in this invention can be used as intestinal-restricting drugs.

[0061] The diseases related to GPR40 agonists described in this invention include, but are not limited to: diabetes and related conditions, diabetes-related microvascular complications, diabetes-related macrovascular complications, cardiovascular diseases, metabolic syndrome and its constituent conditions, glucose metabolism disorders, obesity and other diseases (malady).

[0062] The compound described in this invention has a hypoglycemic effect and can be used as a drug for treating diabetes.

[0063] The compound described in this invention has the efficacy of treating diabetic nephropathy and other diabetic complications, and can be used as a drug for treating diabetic nephropathy and other diabetic complications.

[0064] The compounds described in this invention can reduce body weight and have potential use as drugs for treating obesity.

[0065] The present invention has the following advantages and beneficial effects compared with the prior art:

[0066] 1. A series of novel phenylpropionic acid derivatives were provided, which have the effect of GPR40 agonists and show potential for development as intestinal-restricting drugs;

[0067] 2. A pharmaceutical composition is provided comprising a therapeutically effective amount of the aforementioned compound and / or its tautomers and / or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier, the pharmaceutical composition being able to exert the effect of a phenylpropionic acid derivative as a GPR40 agonist;

[0068] 3. A method for treating diseases associated with GPR40 agonists, the method comprising administering the aforementioned compounds of the present invention and / or their tautomers and / or their pharmaceutically acceptable salts, or administering the aforementioned pharmaceutical compositions of the present invention;

[0069] 4. A method for synthesizing the compound of the present invention is provided, for preparing a drug for treating a variety of diseases or conditions related to GPR40.

[0070] Definitions and Explanations

[0071] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0072] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0073] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; salts of amino acids (such as arginine); and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0074] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0075] "Pharmaceutical composition" means containing one or more of the compounds described in this application, their isomers or pharmaceutically acceptable salts thereof, and other components such as physiologically / pharmaceuticalally acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0076] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0077] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0078] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0079] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0080] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0081] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0082] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0083] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0084] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0085] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0086] The compounds of this invention may contain non-natural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes such as tritium (3H), iodine-125 (125I), or C-14 (14C). As another example, deuterium may be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All variations in the isotopic composition of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0087] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0088] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0089] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0090] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0091] When the number of a substituent is 0, it means that the substituent does not exist. For example, -A-(R)0 means that the structure is actually -A.

[0092] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0093] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0094] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond with any atom on that ring, for example, structural units. This indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridyl group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0095] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring A in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and A' can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0096] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the diagram indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2.

[0097] Unless otherwise specified, “halogen” or “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I); “halogenated” or “halogen substituted” refers to monohalogenated or polyhalogenated, such as “halogenated alkane” referring to monohalogenated or polyhalogenated alkyl, and “halogenated C1-6 alkoxy” referring to halogenated C1-6 alkoxy; the polyhalogenated can be the same halogen atom or different halogen atoms; specifically, halogenated methyl includes but is not limited to chloromethyl, dichloromethyl, trifluoromethyl, etc., and specifically, halogenated methoxy includes but is not limited to chloromethoxy, dichloromethoxy, trichloromethoxy, and trifluoromethoxy.

[0098] "Alkoxy" refers to the aforementioned alkyl group having a specific number of carbon atoms connected by an oxygen bridge. Unless otherwise specified, C1-6 alkoxy groups include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S-pentoxy.

[0099] Unless otherwise specified, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which may be monosubstituted or polysubstituted, monovalent, divalent, or polyvalent, and may be monocyclic or polycyclic (e.g., one to three rings; at least one of which is aromatic), fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In an exemplary example, the heteroatoms are selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule via heteroatoms. Non-limiting examples of aryl or heteroaryl compounds include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazoleyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isoxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyrimidinyl, benzothiazolyl, purineyl, benzimidazolyl, indolyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxolinyl, 5-quinoxolinyl, 3-quinolinyl, and 6-quinolinyl.

[0100] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as affinity substitution). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

[0101] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenemethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0102] Unless otherwise specified, C n-n+m Alkyl or C n -C n+m Alkyl groups include saturated hydrocarbon groups of any specific number of carbons from n to n+m, such as C 1-12 Alkyl groups include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C6. 10 C 11 and C 12 Alkyl groups, including any range from n to n+m, such as C 1-12 Alkyl groups include C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Alkyl groups; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine), for example, C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.

[0103] Unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds at any point in the chain, and can be monosubstituted or polysubstituted, and can be monovalent, divalent, or polyvalent. Examples of alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

[0104] Unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds at any point in the chain, and can be monosubstituted or polysubstituted, and can be monovalent, divalent, or polyvalent. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and pentyynyl.

[0105] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring; for example, a "5-7 elemental ring" refers to a "ring" with 5-7 atoms arranged around it; "C 3-n "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to n carbon atoms, including monocyclic, bicyclic, and tricyclic systems. Bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings, for example, "C...". 3-10 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, including monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. The C 3-10 Cycloalkyl groups include C 3-8 C 3-6 C 3-5 C 4-10 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornelalkyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, etc.

[0106] Unless otherwise specified, cycloalkenyl groups include any stable cyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds at any site of the ring, and can be monosubstituted or polysubstituted, and can be monovalent, divalent, or polyvalent. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, etc.

[0107] Unless otherwise specified, cycloalkynyl groups include any stable cyclic or polycyclic hydrocarbon group containing one or more carbon-carbon triple bonds at any position on the ring, and can be monosubstituted or polysubstituted, and can be monovalent, divalent or polyvalent.

[0108] Unless otherwise specified, the term "3-n-membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 to n ring atoms, wherein the heteroatoms of the heterocyclic alkyl group are independently selected from O, S, N, P and Se, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur and phosphorus heteroatoms are optionally oxidized (i.e. NO, S(O)). p and P(O) p (where p is 1 or 2). It includes monocyclic, bicyclic, and tricyclic systems, with bicyclic and tricyclic systems including spirocyclic, fused, and bridged rings. For example, "3-10 membered heterocyclic alkyl" alone or in combination with other terms respectively represents a saturated cyclic group consisting of 3 to 10 ring atoms, whose heteroatoms are independently selected from O, S, N, P, and Se, with the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms may optionally be oxidized (i.e., NO, S(O)). p and P(O) p (where p is 1 or 2). It includes monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. The "3-10 membered heterocyclic alkyl" also includes 3-9 membered, 3-8 membered, 3-6 membered, 5-9 membered, 5 membered, 6 membered, 7 membered, 8 membered, and 9 membered heterocyclic alkyls, etc. Specifically, the "3-10 membered heterocyclic alkyl" may include, but is not limited to, nitrogen-containing heterocyclic butyl, oxocyclic butyl, thiocyclic butyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and...). Tetrahydrothiophene-3-yl, etc., tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazine (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl or dioxaneheptyl, etc.

[0109] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0110] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0111] The solvent used in this invention is commercially available.

[0112] This invention uses the following abbreviations:

[0113] EA Ethyl acetate Bn benzyl TBAI Tetrabutylammonium iodide MeOH methanol Boc tert-Butoxycarbonyl DMSO Dimethyl sulfoxide PE petroleum ether TFA Trifluoroacetic acid THF Tetrahydrofuran DCM dichloromethane Tf Trifluoromethanesulfonyl

[0114] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0115] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0116] Example 1: 3-Cyclopropyl-3-(3-((1-(2-((4-(dodecyloxy)phenyl)(neopentyl)carbamoyl) (1)-5-methoxyphenyl)piperidin-4-yl)methoxyphenyl)propionic acid

[0117]

[0118] Synthesis route:

[0119]

[0120] Step 1: 5-(3-hydroxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1-1-2)

[0121] Add m-hydroxybenzaldehyde (9.24 g, 75.66 mmol) and water (277.2 mL) to a clean 500 mL single-necked flask. Then add cyclo(isopropyl)malonic acid (10.9 g, 75.66 mmol) in portions to the above reaction system and stir the reaction at room temperature.

[0122] Post-treatment: Add ethyl acetate (100 mL) and separate the layers. Extract the aqueous phase with ethyl acetate 100 mL*2. Combine the organic phases and wash them once with saturated brine (200 mL). Dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow solid (18.87 g, 100%).

[0123] Step 2: 5-(cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1-1-3)

[0124] In a clean 250 mL single-necked flask, 5-(3-hydroxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (18.87 g, 76.02 mmol) and tetrahydrofuran (190 mL) were added. The mixture was then slowly added dropwise with 1 mol / L cyclopropylmagnesium bromide (456 mL, 456.12 mmol) at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature. Post-treatment: The pH was adjusted to weakly acidic by adding 1 mol / L hydrochloric acid (360 mL). The mixture was extracted twice with ethyl acetate (200 mL each). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily compound (21.92 g, 100%).

[0125] Step 3: 3-Cyclopropyl-3-(3-hydroxyphenyl)propionic acid (1-1-4)

[0126] In a clean 500 mL single-necked flask, add 21.92 g (75.50 mmol) of 5-(cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione, 21.92 mL of DMF, and 21 mL of H₂O. Heat to 90 °C and react. Post-treatment: Add 100 mL of ethyl acetate and 100 mL of water for extraction and separation. Extract the aqueous phase with ethyl acetate (100 mL x 2). Combine the organic phases, wash once with saturated brine (100 mL), dry to anhydrous sodium sulfate, filter, and concentrate to obtain a yellowish-brown oil (11 g, 70.65%).

[0127] Step 4: Methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propionate (1-1-5)

[0128] 3-Cyclopropyl-3-(3-hydroxyphenyl)propionic acid (11 g, 53.34 mmol), concentrated sulfuric acid (523.07 mg, 5.33 mmol), and methanol (55 mL) were added to a clean 250 mL single-necked flask, and the mixture was heated to 64 °C and stirred. Post-treatment: The pH was adjusted to neutral with sodium bicarbonate, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, washed with saturated brine (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 5 / 1) to give the title compound as a yellowish-brown oil (1.95 g, 16.6%).

[0129] Step 5: 4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (1-1-6)

[0130] In a clean 100 mL single-necked flask, methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propionate (1.9 g, 8.63 mmol), tert-butyl 4-((toluyloxy)methyl)piperidin-1-carboxylate (3.19 g, 8.63 mmol), potassium carbonate (3.58 g, 25.88 mmol), and anhydrous DMF (15 mL) were added, and the mixture was heated to 90 °C with stirring. Post-treatment: The mixture was extracted with ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with water (50 mL * 2), then with saturated brine (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 10 / 1) to give the title compound as a colorless oil (1.94 g, 53.8%).

[0131] MS:(ESI,pos.ion)m / z:440.2457[M+Na]+

[0132] Step 6: Methyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (1-1)

[0133] In a clean 50 mL single-necked flask, tert-butyl 4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidine-1-carboxylic acid (tert-butyl ester) (1.94 g, 4.65 mmol), TFA (2.65 g, 23.23 mmol), and dichloromethane (16 mL) were added and the mixture was stirred at room temperature. Post-treatment: The pH was adjusted to neutral with sodium bicarbonate. Dichloromethane (20 mL) and water (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellowish-brown oil (1.47 g, 100%). MS: (ESI, pos.ion) m / z: 318.2266 [M+H] +

[0134] Step 7: 4-(benzyloxy)-N-neopentaniline (1-5-2)

[0135] In a clean 250 mL single-necked flask, 4-(benzyloxy)aniline (3 g, 15.06 mmol), trimethylacetaldehyde (1.95 g, 22.59 mmol), acetic acid (0.452 g, 7.53 mmol), and methanol (24 mL) were added, and the mixture was heated to 50 °C and stirred for 1 h. The reaction solution was cooled to 0 °C, and sodium cyanoborohydride (2.37 g, 37.65 mmol) was added in portions. The mixture was then allowed to return to room temperature, and the reaction was continued with stirring. Post-treatment: Direct column chromatography with stirring yielded a light brown oil (3.2 g, 78.8%). MS: (ESI, pos.ion) m / z: 270.1964 [M+H] +

[0136] Step 8: tert-butyl(4-(benzyloxy)phenyl)(neopentyl)carbamate (1-5-3)

[0137] Add 3.2 g (11.88 mmol) and 6.4 mL of tetrahydrofuran to a clean 100 mL single-necked flask. Dissolve 2.0 g (2.376 mmol) in 32 mL of H2O and add it to the above reaction flask. Stir at room temperature for 1 h, then add 7.78 g (35.64 mmol) of ditert-butyl dicarbonate to the above reaction flask and continue stirring at room temperature. Post-treatment: Ethyl acetate (30 mL) was added and the mixture was separated. The aqueous phase was extracted with ethyl acetate (30 mL * 2). The organic phases were combined and washed with water (30 mL) and saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography. Di-tert-butyl dicarbonate was first eluted with PE / EA (V / V) = 50 / 1, and then purified by PE / EA (V / V) = 10 / 1 to give the title compound as a white solid (4.2 g, 95.7%). MS: (ESI, pos.ion) m / z: 392.224 [M + Na] +

[0138] Step 9: tert-butyl(4-hydroxyphenyl)(neopentyl)carbamate (1-5-4)

[0139] In a clean 100 mL single-necked flask, tert-butyl(4-(benzyloxy)phenyl)(neopentyl)carbamate (4.2 g, 11.37 mmol), Pd / C (1.26 g), and methanol (33.6 mL) were added, and the mixture was stirred at room temperature. Post-treatment: The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by column chromatography (PE / EA(V / V) = 5 / 1) to give the title compound as a white solid (3.12 g, 98%). MS: (ESI, pos.ion) m / z: 224.1332 [M-56+H] +

[0140] Step 10: tert-butyl(4-(dodecyloxy)phenyl)(neopentyl)carbamate (1-5-5)

[0141] In a clean 100 mL single-necked flask, tert-butyl(4-hydroxyphenyl)(neopentyl)carbamate (3 g, 10.74 mmol), iododecane (4.77 g, 16.11 mmol), potassium carbonate (2.94 g, 21.48 mmol), and acetonitrile (30 mL) were added, and the mixture was heated to 90 °C and stirred. Post-treatment: Direct stirred column chromatography (PE / EA(V / V) = 5 / 1) yielded the title compound as a light brown oil (4.32 g, 89.8%).

[0142] 1 H NMR(600MHz,Chloroform-d)δ7.13(s,2H),6.83(d,J=8.3Hz,2H),3.95(t,J=6.6Hz,2H),3.57(s ,2H),1.79(p,J=6.8Hz,2H),1.53–1.30(m,18H),1.29(s,9H),0.91(t,J=7.0Hz,3H),0.85(s,9H)

[0143] Step 11: 4-(dodecyloxy)-N-neopentylaniline (1-5)

[0144] In a clean 100 mL single-necked flask, tert-butyl(4-(dodecyloxy)phenyl)(neopentyl)carbamate (4.32 g, 9.65 mmol), trifluoroacetic acid (11.01 g, 96.5 mmol), and dichloromethane (44 mL) were added, and the mixture was stirred at room temperature. Post-treatment: The pH was adjusted to neutral or weakly alkaline with saturated sodium bicarbonate solution, and then dichloromethane (30 mL) and water (30 mL) were added. The mixture was separated, and the aqueous phase was extracted with dichloromethane (30 mL * 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 10 / 1) to give the title compound as a light brown oil (3.5 g, 100%).

[0145] 1 H NMR(600MHz,Chloroform-d)δ6.79(d,J=8.9Hz,2H),6.62(d,J=8.4Hz,2H),3.90(s,2H),2.87(s,2 H),1.79–1.72(m,2H),1.47–1.43(m,2H),1.36–1.27(m,16H),1.02(s,9H),0.91(t,J=7.0Hz,3H).

[0146] Step 12: 2-(4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidin-1-yl)-4-methoxybenzoate tert-butyl ester (1-3)

[0147] In a clean 100 mL single-necked flask, methyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (1.1 g, 3.47 mmol), tert-butyl 4-methoxy-2-((trifluoromethyl)sulfonyl)oxybenzoate (2.47 g, 6.93 mmol), palladium acetate (311.62 mg, 1.39 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.30 g, 2.08 mmol), cesium carbonate (2.83 g, 8.68 mmol), and toluene (20 mL) were added, and the mixture was heated to 110 °C and stirred. Post-treatment: Direct column chromatography purification (PE / EA(V / V) = 4 / 1) yielded the title compound as a light brown oil (1.1 g, 60.77%). MS:(ESI,pos.ion)m / z:524.3197[M+H] +

[0148] Step 13: 2-(4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidin-1-yl)-4-methoxybenzoic acid (1-4)

[0149] In a clean 100 mL single-necked flask, tert-butyl 2-(4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidin-1-yl)-4-methoxybenzoate (1.1 g, 2.10 mmol), zinc chloride (1.43 g, 10.50 mmol), and dichloromethane (11 mL) were added, and the mixture was stirred at room temperature for 6 h. Then, dichloromethane (11 mL) and water (110 mL) were added to the above system, and the mixture was stirred at room temperature for another 2 h. Post-processing: Dichloromethane (30 mL) and water (30 mL) were added to the reaction system and separated. The aqueous phase was extracted with dichloromethane (30 mL * 2). The organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography. First, the starting material was obtained by chromatography with (PE / EA (V / V) = 5 / 1), and then the title compound was obtained by chromatography with (DCM / MeOH (V / V) = 20 / 1) as a colorless oil (540 mg, 54.98%).

[0150] Step 14: Synthesis of methyl 3-cyclopropyl-3-(3-((1-(2-((4-(dodecyloxy)phenyl))(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (1-6)

[0151] Add 2-(4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidin-1-yl)-4-methoxybenzoic acid (390 mg, 0.83 mmol) and tetrahydrofuran (4 mL) to a clean 100 mL single-necked flask. Replace with N2 for protection, cool to 0 °C, add 1-chloro-N,N,2-trimethylpropenylamine (557.27 mg, 4.17 mmol), transfer to room temperature and stir for 0.5–1 h, then cool to 0 °C. Add 4-(dodecyloxy)-N-neopentylaniline (434.89 mg, 1.25 mmol) and triethylamine (506.42 mg, 5.00 mmol) to the above reaction system, and heat to room temperature to continue the reaction. Post-treatment: Ethyl acetate (20 mL) and water (20 mL) were added to the reaction system, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine (20 mL * 2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA (V / V) = 2 / 1) to give a brown oily substance (590 mg, 88.73%). MS: (ESI, pos.ion) m / z: 797.5479 [M + H] +

[0152] 1 H NMR (600MHz, DMSO-d6) δ7.20(t,J=7.9Hz,1H),7.02(d,J=8.4Hz,2H),6.88–6.81(m,2H),6.79(ddd,J=8.2,2.6,0.9Hz,1H),6.61(d,J=8.5Hz,2H),6.46 (dd,J=8.4,2.4Hz,1H),6.27(d,J=2.4Hz,1H),4.00–3.75(m,6H),3.65(s,3 H),3.52(s,3H),3.46(t,J=7.6Hz,1H),2.81–2.69(m,3H),2.61(d,J=13.5H z,1H),2.37(d,J=27.8Hz,1H),2.26(dt,J=9.6,7.5Hz,1H),1.92–1.79(m,2 H),1.78–1.72(m,1H),1.60(p,J=6.8Hz,2H),1.51(d,J=11.2Hz,2H),1.32( q,J=6.7Hz,2H),1.24(s,16H),1.07–1.01(m,1H),0.85(d,J=7.8Hz,12H),0 .54–0.50(m,1H),0.36–0.31(m,1H),0.24–0.19(m,1H),0.15–0.11(m,1H).

[0153] Step 15: Synthesis of 3-cyclopropyl-3-(3-((1-(2-((4-(dodecyloxy)phenyl))(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionic acid (1)

[0154] In a clean 100 mL single-necked flask, add methyl 3-cyclopropyl-3-(3-((1-(2-((4-(dodecoxy)phenyl))(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (590 mg, 0.74 mmol), sodium hydroxide (201.30 mg, 5.03 mmol), tetrahydrofuran (5.9 mL), methanol (2.95 mL), and water (5.9 mL), and heat to 50 °C with stirring to react. Post-treatment: Adjust the pH to neutral or weakly acidic with dilute hydrochloric acid, add dichloromethane (20 mL) and water (20 mL), separate the layers, extract the aqueous phase with dichloromethane (20 mL * 2), combine the organic phases, wash with saturated brine (20 mL * 2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (PE / EA(V / V) = 2 / 1) to obtain a brown oily substance (460 mg, 78.0%). MS: (ESI, pos.ion) m / z: 783.5404 [M+H] +

[0155] 1 H NMR(600MHz,Chloroform-d)δ7.25(t,J=7.9Hz,1H),7.14(d,J=8.4Hz,1H),6.94(d,J=8.5Hz,2H),6.87–6.82(m,2H),6.81(dd,J=8.0,2.5Hz,1H), 6.57(d,J=8.4Hz,2H),6.46(dd,J=8.4,2.4Hz,1H),6.26(s,1H),3.92–3. 86(m,2H),3.83(t,J=6.7Hz,2H),3.74(s,3H),3.59(s,2H),2.92–2.58(m, 5H),2.44(s,1H),2.41–2.36(m,1H),1.89(s,3H),1.72(p,J=6.8Hz,2H), 1.43(d,J=12.3Hz,2H),1.29(dd,J=14.2,6.1Hz,18H),1.09–1.04(m,1H) ,0.91(d,J=7.3Hz,12H),0.61(dq,J=4.6,1.4Hz,1H),0.47(ddt,J=13.7, 8.8,4.9Hz,1H),0.33(dq,J=9.9,5.0Hz,1H),0.20(dq,J=9.9,5.1Hz,1H).

[0156] Example 2: 3-Cyclopropyl-3-(3-((1-(2-(dodecyl(phenyl)carbamoyl)-5-methoxyphenyl) Piperidin-4-yl)methoxy)phenyl)propionic acid (2)

[0157]

[0158] Synthesis route:

[0159]

[0160] Step 1: N-Dodecylaniline (2-2)

[0161] Aniline (1.0 g, 10.74 mmol), iodododecane (4.77 g, 16.11 mmol), and potassium carbonate (3.0 g, 21.48 mmol) were added to a clean single-necked flask, followed by DMF (10 mL). The mixture was stirred at 80 °C for 4 h. Post-treatment: Ethyl acetate (20 mL) and water (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 20 / 1) to give the title compound as a colorless oil (0.856 g, 30.46%).

[0162] MS:(ESI,pos.ion)m / z:262.2521[M+H] +

[0163] Step 2: N-Dodecyl-2-fluoro-4-methoxy-N-phenylbenzamide (2-3)

[0164] In a clean single-necked flask, 2-fluoro-4-methoxybenzoic acid (2.0 g, 11.76 mmol) was added, followed by DCM (20 mL), DMF (91 mL), and nitrogen purging three times. The mixture was stirred at 0 °C, and oxaloyl chloride (4.77 mL, 56.42 mmol) was added. After the addition was complete, the mixture was allowed to react at room temperature for 4 h, and then concentrated to constant weight. This concentrated solution was labeled as acyl chloride for later use. In another clean single-necked flask, N-dodecylaniline (0.85 g, 3.25 mmol) was dissolved in THF (9 mL). Triethylamine (1.8 mL, 13 mmol) was added under ice bath conditions, followed by dropwise addition of 2-fluoro-4-methoxybenzoyl chloride (1.23 g, 6.5 mmol) dissolved in THF (2 mL). After the addition was complete, the mixture was allowed to react at room temperature for 2 h. Post-processing: The reaction was quenched by adding saturated ammonium chloride solution, and ethyl acetate (20 mL) was added for separation. The aqueous phase was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (20 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA (V / V) = 3 / 1) to obtain the title compound as a colorless oil (0.89 g, 66.20%).

[0165] MS:(ESI,pos.ion)m / z:414.2770[M+H] +

[0166] Step 3: 3-Cyclopropyl-3-(3-(1-(2-(dodecyl(phenyl)carbamoyl)-5-methoxyphenyl)piperyl) Methyl 2-4-pyridyl)methoxy)phenyl)propionate

[0167] In a 25 mL single-necked flask, N-dodecyl-2-fluoro-4-methoxy-N-phenylbenzamide (380 mg, 0.9188 mmol), methyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate amide (349.99 mg, 1.1 mmol), cesium carbonate (600 mg, 1.837 mmol), and tetrabutylammonium iodide (17 mg, 0.046 mmol) were added sequentially, followed by anhydrous DMF (0.4 mL). The mixture was stirred at 145 °C for 14 h. Post-treatment: 10 mL of water and 10 mL of ethyl acetate were added for separation. The aqueous phase was extracted with ethyl acetate (5 mL * 2), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA(V / V) = 4 / 1) to obtain the title compound as a colorless oil (97 mg, 14.8%). MS:(ESI,pos.ion)m / z:711.4772[M+H] +

[0168] Step 4: 3-Cyclopropyl-3-(3-(1-(2-(dodecyl(phenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionic acid (2)

[0169] In a clean 50 mL single-necked flask, methyl 3-cyclopropyl-3-(3-(1-(2-(dodecyl(phenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (97 mg, 0.1364 mmol), NaOH (54.57 mg, 1.36 mmol), THF (2 mL), methanol (2 mL), and water (1 mL) were added sequentially, and the mixture was reacted at 50 °C for 3 h. Post-treatment: The pH was adjusted to 4-6 by adding 1 mol / L dilute hydrochloric acid, and ethyl acetate was added for separation. The aqueous phase was extracted with ethyl acetate (10 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by PE:EA (V:V = 1 / 2) thin-layer chromatography. The title compound (80 mg, 84.13%) was obtained as a yellow oil. MS-ESI: (ESI, pos.ion) m / z: 697.4565 [M+H] +

[0170] 1 H NMR(600MHz,Chloroform-d)δ7.25(t,J=7.9Hz,2H),7.17–6.97(m,5H),6.87(d,J=7.7Hz,1H),6.84(s,1H),6.80(dd,J=8.2,2 .5Hz,1H),6.46(d,J=8.3Hz,1H),6.21(s,1H),3.98–3.82(m,4H),3.73(s,3H),2.81(dd,J=11.3,7.5Hz,2H),2.65(s,2H),2.64 –2.48(m,2H),2.41–2.36(m,1H),2.07(s,1H),1.89(s,2H),1.59(d,J=43.0Hz,4H),1.30–1.23(m,18H),1.08–1.04(m,1H),0. 89(d,J=7.2Hz,3H),0.64–0.59(m,1H),0.46(td,J=8.8,4.5Hz,1H),0.33(dt,J=9.8,4.8Hz,1H),0.20(dt,J=10.0,5.0Hz,1H).

[0171] Example 3: 3-Cyclopropyl-3-(3-((1-(2-(dodecyl(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionic acid (3)

[0172]

[0173] Synthesis route:

[0174]

[0175] Step 1: N-neopentyldodecane-1-amine (3-2)

[0176] Dodecylamine (1.00 g, 5.40 mmol), trimethylacetaldehyde (0.70 g, 8.09 mmol), acetic acid (0.16 g, 2.70 mmol), and methanol (10 mL) were added to a clean 50 mL reaction flask. The mixture was heated to 50 °C and stirred for 2 h, then cooled to 0 °C. Sodium cyanoborohydride (0.85 g, 13.5 mmol) was added, and the mixture was allowed to react at room temperature. Post-treatment: 30 mL of saturated sodium bicarbonate solution and 30 mL of dichloromethane were added and stirred for 10 min. The mixture was separated, and the aqueous phase was extracted once more with 30 mL of dichloromethane. The organic phases were combined and washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless liquid containing the title compound (1.55 g, 100%). MS: (ESI, pos.ion) m / z: 256.3141 [M+H] +

[0177] Step 2: N-Dodecyl-2-fluoro-4-methoxy-N-neopentylbenzamide (3-3)

[0178] In a clean 100 mL reaction flask, 2-fluoro-4-methoxybenzoic acid (1.47 g, 8.61 mmol), anhydrous THF (10 mL), and three drops of DMF were added. After dissolving by stirring at room temperature, oxaloyl chloride (1.5 mL, 17.60 mmol) was added under nitrogen protection. After the color of 2-fluoro-4-methoxybenzoic acid disappeared by TLC, the solution was concentrated to constant weight, dried under vacuum, and dissolved in anhydrous THF (1 mL), labeled as acyl chloride solution. In another 50 mL reaction flask, N-neopentyldodecane-1-amine (1.0 g, 3.91 mmol) was added, dissolved in anhydrous THF (10 mL), and triethylamine (1.98 g, 19.55 mmol) was added. The acyl chloride solution was added dropwise under nitrogen protection at 0 °C. After the addition was complete, the mixture was transferred to room temperature and reacted for 2 h. Post-processing: 20 mL of saturated potassium carbonate aqueous solution and 30 mL of ethyl acetate were added, and the mixture was stirred for 10 min. The liquid was separated, and the organic phase was washed with 25 mL of saturated brine. The mixture was then subjected to column chromatography (PE / EA = 5 / 1) and concentrated to constant weight to obtain a colorless oily substance of the title compound (1.085 g, 67.88%). MS: (ESI, pos.ion) m / z: 408.3247 [M+H] +

[0179] 1H NMR(600MHz,Chloroform-d)δ7.34–7.29(m,1H),6.74(ddd,J=13.7,8.5,2.4Hz,1H),6.61(ddd,J=21.0,11.4,2.4Hz,1H ),3.84(d,J=3.1Hz,3H),3.53–3.04(m,4H),1.69–1.63(m,2H),1.42–1.12(m,18H),1.03(s,9H),0.90(t,J=7.0Hz,3H).

[0180] Step 3: Methyl 3-cyclopropyl-3-(3-((1-(2-(dodecyl(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (3-4)

[0181] In a clean 50 mL reaction flask, N-dodecyl-2-fluoro-4-methoxy-N-neopentylbenzamide (0.36 g, 0.88 mmol), methyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (0.336 g, 1.06 mmol), cesium carbonate (0.58 g, 2.54 mmol), TBAI (0.016 g, 0.064 mmol), and anhydrous DMF (0.36 mL) were added sequentially. The mixture was heated to 145 °C and stirred for 24 h. Post-treatment: 15 mL of EA and 10 mL of water were added and stirred for 10 min. The mixture was then separated, and the aqueous phase was extracted once more with 15 mL of EA. The organic phases were combined, washed with 10 mL of saturated brine three times, and subjected to column chromatography (PE / EA = 3 / 1). The solution was concentrated to constant weight to obtain the title compound as a yellow oil (0.070 g, 11.29%).

[0182] Step 4: 3-Cyclopropyl-3-(3-((1-(2-(dodecyl(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionic acid (3)

[0183] Methyl 3-cyclopropyl-3-(3-((1-(2-(dodecyl(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (0.070 g, 0.10 mmol), MeOH (0.7 mL), and THF (1.4 mL) were added to a clean 50 mL reaction flask. After stirring to dissolve, sodium hydroxide (0.032 g, 0.794 mmol) dissolved in water (1.4 mL) was added. The mixture was stirred at 50 °C for 4 h. Post-treatment: The solution was concentrated under reduced pressure, and the pH was adjusted to 4-5 with 1 mol / L hydrochloric acid. Extraction was performed with ethyl acetate (10 mL x 2). Column chromatography (DCM / MeOH = 20 / 1) was performed, and the solution was concentrated to give a yellow oil (52 mg, 75.79%). MS: (ESI, pos.ion) m / z: 691.5082 [M+H] +

[0184] 1 H NMR(600MHz,Chloroform-d)δ7.25–7.22(m,1H),7.15(d,J=8.3Hz,1H),6.85(d,J=7.6Hz,1H),6.81(d,J=2.7Hz,1H),6.78(dd,J=8.2,2.3Hz,1H),6.61(dd, J=18.8,9.8Hz,2H),3.99–3.86(m,2H),3.84(d,J=7.0Hz,3H),3.53(q,J=14.3 ,13.4Hz,2H),3.38–3.21(m,2H),3.16(s,2H),2.97–2.87(m,1H),2.81(tt,J=1 5.2,7.1Hz,2H),2.54(s,2H),2.40–2.35(m,1H),1.79(s,2H),1.44(s,2H),1. 35(dd,J=7.4,4.2Hz,2H),1.32(s,2H),1.27(d,J=4.8Hz,16H),1.20–1.16(m, 1H),1.07(s,9H),0.90(t,J=7.0Hz,3H),0.61(tt,J=8.8,5.0Hz,1H),0.46(tq ,J=9.0,4.5Hz,1H),0.32(dq,J=9.9,4.9Hz,1H),0.20(dq,J=10.1,5.2Hz,1H).

[0185] Example 4: 3-Cyclopropyl-3-(3-((1-(2-(dodecyl(4-methoxyphenyl)carbamoyl)-5-methyl (4) Piperidin-4-yl)methoxy)phenyl)propionic acid

[0186]

[0187] Synthesis route:

[0188]

[0189] Step 1: Synthesis of N-dodecyl-4-methoxyaniline (4-2)

[0190] 4-Methoxyaniline (3.0 g, 24.36 mmol), iododecane (7.94 g, 26.80 mmol), potassium carbonate (6.73 g, 48.72 mmol), and DMF (30 mL) were added to a clean 100 mL single-necked flask, and the mixture was heated to 90 °C and stirred. Post-treatment: Column chromatography purification (PE / EA(V / V) = 5 / 1) yielded the title compound as a white solid (4.0 g, 56.34%).

[0191] Step 2: Synthesis of methyl 3-cyclopropyl-3-(3-((1-(2-(dodecyl(4-methoxyphenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (4-3)

[0192] Add 2-(4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidin-1-yl)-4-methoxybenzoic acid (100 mg, 0.214 mmol) and tetrahydrofuran (2 mL) to a clean 100 mL single-necked flask. Cool to 0 °C under N2 protection. Add 1-chloro-N,N,2-trimethylpropyleneamine (142.89 mg, 1.07 mmol). Stir at room temperature for 0.5–1 h. Cool to 0 °C again. Add N-dodecyl-4-methoxyaniline (93.51 mg, 0.321 mmol) and triethylamine (129.52 mg, 1.28 mmol) to the above reaction system. Heat to room temperature and continue the reaction. Post-treatment: Ethyl acetate (10 mL) and water (10 mL) were added to the reaction system and separated. The aqueous phase was extracted with ethyl acetate (10 mL * 2). The organic phases were combined and washed with saturated brine (10 mL * 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA (V / V) = 2 / 1) to obtain the title compound as a colorless oil (158.72 mg, 100%).

[0193] Step 3: Synthesis of 3-cyclopropyl-3-(3-((1-(2-(dodecyl(4-methoxyphenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionic acid (4)

[0194] In a clean 100 mL single-necked flask, add methyl 3-cyclopropyl-3-(3-((1-(2-(dodecyl(4-methoxyphenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (370 mg, 0.5 mmol), sodium hydroxide (135.80 mg, 3.40 mmol), tetrahydrofuran (4 mL), methanol (2 mL), and water (4 mL), and heat to 90 °C with stirring to react. Post-treatment: Adjust the pH to neutral or weakly acidic with dilute hydrochloric acid, add dichloromethane (20 mL) and water (20 mL), separate the layers, extract the aqueous phase with dichloromethane (20 mL * 2), combine the organic phases, wash with saturated brine (20 mL * 2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (DCM / MeOH (V / V) = 20 / 1) to obtain the title compound as a brown oil (330 mg, 90.2%). MS: (ESI, pos.ion) m / z: 727.4084 [M+H] +

[0195] 1 H NMR(600MHz,Chloroform-d)δ7.25(t,J=7.9Hz,1H),7.18(d,J=8.4Hz,1H),6.95(d,J=8.5Hz,2H),6.86(d,J=7.7Hz,1H),6.84(t,J=2.0Hz,1 H),6.82–6.78(m,1H),6.62(d,J=8.7Hz,2H),6.47–6.42(m,1H),6.24(s,1H),3.90(d,J=5.8Hz,2H),3.85(d,J=9.0Hz,2H),3.73(d,J=5.4Hz ,6H),2.97(d,J=7.3Hz,1H),2.86–2.42(m,6H),2.39(dt,J=9.7,7.5Hz,1H),1.63–1.52(m,4H),1.28(dd,J=15.0,7.8Hz,20H),1.06(ddd,J= 9.7,4.8,2.5Hz,1H),0.90(t,J=7.0Hz,3H),0.64–0.59(m,1H),0.49–0.44(m,1H),0.33(dd,J=9.6,4.9Hz,1H),0.20(dd,J=9.6,4.9Hz,1H).

[0196] Example 5: 3-Cyclopropyl-3-(3-((1-(2-(dodecyl(2,4,5-trifluorophenyl)carbamoyl)-5- Methoxyphenyl)piperidin-4-yl)methoxyphenyl)propionic acid (5)

[0197]

[0198] Synthesis route:

[0199]

[0200] Step 1: n-Dodecyl-2,4,5-trifluoroaniline (5-2)

[0201] 2,4,5-Trifluoroaniline (2.00 g, 13.60 mmol), DMF (16 mL), and potassium carbonate (4.70 g, 34.0 mmol) were added to a clean single-necked flask. After stirring at room temperature for 10 min, 1-iodododecane (5.23 g, 17.68 mmol) was added, and the mixture was heated to 90 °C and reacted for 6 h. Post-treatment: Water (50 mL) and ethyl acetate (30 mL) were added, and the mixture was stirred for 10 min. The aqueous phase was then extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL × 4), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EA(V / V) = 20 / 1) to give the title compound as a colorless oil (1.24 g, 28.90%). MS: (ESI, pos.ion) m / z: 316.2284 [M+H] + .

[0202] Step 2: N-dodecyl-2-fluoro-4-methoxy-N-(2,4,5-trifluorophenyl)benzamide (5-3)

[0203] In a clean single-necked flask, 2-fluoro-4-methoxybenzoic acid (1.23 g, 7.23 mmol), anhydrous THF (5 mL), and three drops of DMF were added. After stirring and dissolving at room temperature, oxaloyl chloride (2.27 mL, 26.63 mmol) was added. The reaction was continued at room temperature until the color of 2-fluoro-4-methoxybenzoic acid disappeared as detected by TLC. The solution was then concentrated to constant weight, dissolved in anhydrous THF (1 mL), and labeled as acyl chloride solution. In another clean single-necked flask, n-dodecyl-2,4,5-trifluoroaniline (1.2 g, 3.80 mmol) was added, dissolved in anhydrous THF (12 mL), and triethylamine (2.38 mL, 17.12 mmol) was added. The acyl chloride solution was added dropwise at 0 °C. After 0.5 h of addition, the mixture was transferred to room temperature and reacted for 3 h. Post-treatment: 30 mL of saturated potassium carbonate aqueous solution and 30 mL of ethyl acetate were added and stirred for 10 min. The mixture was separated, and the aqueous phase was extracted again with ethyl acetate (20 mL × 1). The organic phases were combined and washed with saturated brine (20 mL × 1). The mixture was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EA (V / V) = 10 / 1) to give the title compound as a colorless oil (1.285 g, 72.19%). MS: (ESI, pos.ion) m / z: 468.2512 [M+H] +

[0204] Step 3: Methyl 3-cyclopropyl-3-(3-((1-(2-(dodecyl(2,4,5-trifluorophenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (5-4)

[0205] In a clean single-necked flask, add N-dodecyl-2-fluoro-4-methoxy-N-(2,4,5-trifluorophenyl)benzamide (0.6 g, 1.28 mmol), anhydrous DMF (0.6 mL), methyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (0.448 g, 1.41 mmol), cesium carbonate (0.83 g, 2.56 mmol), and TBAI (0.024 g, 0.064 mmol), and heat to 145 °C and react for 20 h. Post-treatment: Add ethyl acetate (20 mL) and water (20 mL), stir for 10 min, filter through a diatomaceous earth filter, separate the phases, extract the aqueous phase once more with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine (30 mL × 4), dry with anhydrous sodium sulfate, filter, and purify by column chromatography (PE / EA (V / V) = 3 / 1) to obtain the title compound as a yellow oil (330 mg, 33.60%). MS: (ESI, pos.ion) m / z: 803.4032 [M+K] +

[0206] Step 4: Methyl 3-cyclopropyl-3-(3-((1-(2-(dodecyl(2,4,5-trifluorophenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (5)

[0207] In a clean single-necked flask, methyl 3-cyclopropyl-3-(3-((1-(2-(dodecyl(2,4,5-trifluorophenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionate (0.31 g, 0.405 mmol), MeOH (1.55 mL), and THF (3.1 mL) were added. After stirring to dissolve, sodium hydroxide (0.13 g, 3.24 mmol) dissolved in water (3.1 mL) was added, and the mixture was stirred at 50 °C for 4 h. Post-treatment: The pH was adjusted to 3-4 with 1 N hydrochloric acid, and the mixture was extracted with dichloromethane (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM / MeOH (V / V) = 20 / 1) to give the title compound as a yellow solid (0.289 g, 95.06%). MS:(ESI,pos.ion)m / z:751.4325[M+H] +

[0208] 1H NMR(600MHz,Chloroform-d)δ7.25(dt,J=16.0,8.6Hz,2H),6.84(t,J=7.5Hz,2H),6.80(t,J=2.0Hz,1H),6.77(dd,J=8.1,2.5Hz,1H),6.56(ddd,J=19. 4,10.1,5.1Hz,2H),6.37(dd,J=11.4,2.4Hz,1H),3.85(d,J=5.8Hz,2H),3. 79(d,J=7.4Hz,2H),3.75(s,3H),3.54(s,1H),3.43(d,J=11.1Hz,1H),2.90 –2.73(m,3H),2.68(d,J=13.1Hz,2H),2.37(dt,J=9.7,7.5Hz,1H),1.98–1. 94(m,2H),1.57(d,J=12.8Hz,4H),1.38–1.26(m,18H),1.05(ddt,J=8.0,5. 0,2.5Hz,1H),0.90(t,J=7.0Hz,3H),0.63–0.58(m,1H),0.45(ddt,J=13.8, 8.9,5.0Hz,1H),0.32(dq,J=9.9,5.0Hz,1H),0.19(dq,J=10.0,5.1Hz,1H).

[0209] Example 6: 3-(3-((1-(2-((2-chloro-4-fluorophenyl)(dodecyl)carbamoyl)-5-methoxybenzene) (6) Piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionic acid

[0210]

[0211] Synthesis route:

[0212]

[0213] Step 1: 2-Chloro-N-dodecyl-4-fluoroaniline (6-2)

[0214] 2-Chloro-4-fluoroaniline (3.0 g, 20.61 mmol), DMF (24 mL), and potassium carbonate (5.70 g, 41.22 mmol) were added to a clean 250 mL single-necked flask. After stirring at room temperature for 15 min, iodododecane (6.72 g, 22.67 mmol) was added, and the mixture was heated to 90 °C with stirring. Post-treatment: Ethyl acetate (50 mL) and water (90 mL) were added and separated. The aqueous phase was extracted with ethyl acetate (50 mL * 2). The organic phases were combined and washed with saturated brine (50 mL * 4), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EA(V / V) = 10 / 1) to give the title compound as a colorless oil (2.718 g, 42.01%). MS: (ESI, pos.ion) m / z: 314.2067 [M+H] +

[0215] Step 2: N-(2-chloro-4-fluorophenyl)-N-dodecyl-2-fluoro-4-methoxybenzamide (6-3)

[0216] In a clean 50 mL single-necked flask, add 2-fluoro-4-methoxybenzoic acid (1.13 g, 6.63 mmol) and anhydrous tetrahydrofuran (3.9 mL), DMF (3 drops), and oxalyl chloride (2.12 mL, 24.84 mmol). Stir the reaction at room temperature for 4 h, then concentrate under reduced pressure. Dissolve the concentrate in tetrahydrofuran (5 mL) and label it as acyl chloride. In a clean 100 mL single-necked flask, add 2-chloro-N-dodecyl-4-fluoroaniline (1.3 g, 4.14 mmol), anhydrous tetrahydrofuran (9 mL), and triethylamine (2.59 mL, 18.63 mmol). Place the flask at 0 °C and slowly add acyl chloride dropwise to the above reaction system. After the addition is complete, transfer the flask to room temperature and stir the reaction mixture. Post-treatment: Potassium carbonate solution (30 mL) and ethyl acetate (30 mL) were added, stirred for 15 min, and separated. The aqueous phase was then extracted with ethyl acetate (30 mL x 2). The organic phases were combined and purified by column chromatography (PE / EA (V / V) = 10 / 1) to obtain the title compound as a colorless oil (1.458 g, 75.5%). MS: (ESI, pos.ion) m / z: 466.2354 [M+H] +

[0217] Step 3: Methyl 3-(3-((1-(2-(((2-chloro-4-fluorophenyl)(dodecyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionate (6-4)

[0218] In a clean 50 mL single-necked flask, N-(2-chloro-4-fluorophenyl)-N-dodecyl-2-fluoro-4-methoxybenzamide (0.6 g, 1.29 mmol), methyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (449.57 mg, 1.42 mmol), cesium carbonate (0.839 mg, 2.58 mmol), DMF (0.6 mL), and TBAI (0.024 g, 0.064 mmol) were added, and the mixture was heated to 145 °C and stirred. Post-treatment: Ethyl acetate (5 mL) and water (6 mL) were added for extraction and separation. The aqueous phase was extracted with ethyl acetate (5 mL), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL * 4) and purified by column chromatography (PE / EA (V / V) = 4 / 1) to give the title compound as a yellow oil (94 mg, 9.56%).

[0219] Step 4: 3-(3-((1-(2-(((2-chloro-4-fluorophenyl)(dodecyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionic acid (6)

[0220] Add methyl 3-(3-((1-(2-(((2-chloro-4-fluorophenyl)(dodecyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionate (0.090 g, 0.118 mmol), tetrahydrofuran (0.9 mL), methanol (0.45 mL), and water (0.9 mL) to a clean 50 mL single-necked flask, and heat to 50 °C while stirring to react. Post-treatment: Adjust pH to 4-6 with 1 mol / L dilute hydrochloric acid, add ethyl acetate (10 mL) and water (10 mL), separate the layers, extract the aqueous phase with ethyl acetate (10 mL * 2), combine the organic phases, concentrate under reduced pressure, and purify by column chromatography (PE / EA (V / V) = 1 / 1) to obtain the title compound as a yellowish-brown oil (68 mg, 76.97%). MS: (ESI, pos.ion) m / z: 749.4119 [M + H] +

[0221] 1H NMR(600MHz,Chloroform-d)δ7.24(dt,J=9.4,8.0Hz,2H),7.09(d,J=8.7Hz,1H),6.92–6 .81(m,2H),6.79(t,J=2.1Hz,1H),6.77–6.74(m,1H),6.73–6.62(m,1H),6.51(dd,J=8.6 ,2.4Hz,1H),6.38(dd,J=11.5,2.4Hz,1H),3.84(d,J=5.8Hz,2H),3.72(s,3H),3.68(d,J =8.0Hz,2H),3.43(ddd,J=13.3,9.9,5.2Hz,1H),2.79(qd,J=15.2,7.5Hz,4H),2.36(dt, J=9.9,7.5Hz,1H),1.97(d,J=11.9Hz,2H),1.67–1.59(m,2H),1.53–1.44(m,2H),1.28(d ,J=3.2Hz,20H),1.05(dddd,J=9.7,4.8,2.4Hz,1H),0.91(d,J=6.8Hz,3H),0.61(dddd,J= 9.0, 7.8, 5.7, 4.4 Hz, 1H), 0.48–0.42 (m, 1H), 0.31 (dq, J = 9.9, 4.9 Hz, 1H), 0.21–0.16 (m, 1H). Example 7: (S)-3-cyclopropyl-3-(3-((1-(2-(dodecyl(phenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionic acid (7)

[0222]

[0223] Synthesis route:

[0224]

[0225]

[0226] Step 1: 3-(3-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionic acid (7-1)

[0227] Following the synthetic method of step 15 in Example 1, the title compound was obtained as a pale yellow oil (4.7 g, 64.0%). MS: (ESI, pos.ion) m / z: 426.2324 [M+Na] +

[0228] Step 2: (S)-3-(3-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionate (S)-1-phenylethyl-1-amine salt (7-2)

[0229] 3-(3-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionic acid (4.7 g, 11.65 mmol) and EtOH (29.14 mL) were added to a clean 250 mL single-necked flask and stirred at room temperature until dissolved. Then, S-1-phenylethylamine (1.41 g, 11.65 mmol) dissolved in EA (58.28 mL) was added dropwise. After the addition was complete, stirring was continued at room temperature for 16 h. Post-treatment: The filter cake was filtered, washed with 48 mL of a mixed solution (EtOH:EA = 1:2), and dried under reduced pressure at 50 °C to obtain the title compound as a white solid (1.94 g, 31.75%, 96.87% ee).

[0230] Step 3: Methyl (S)-3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (7-3)

[0231] Add (S)-1-phenylethyl-1-amine(S)-3-(3-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionate (1.90 g, 3.62 mmol) and EA (32.3 mL) to a clean single-necked flask. Add 1N HCl (4.71 mL, 4.71 mmol) at 0 °C. After the addition is complete, stir for 10 min and adjust the pH to about 4 with 6% citric acid. Then separate the liquid and extract the aqueous phase with 20 mL of (EA:THF = 1:1) twice. Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and then add MeOH (38 mL). After stirring to dissolve, add concentrated sulfuric acid (0.89 g, 9.05 mmol) and heat to 65 °C for 2 h. Post-treatment: Concentrate under reduced pressure, add 30 mL of (EA:THF = 1:1) and saturated sodium bicarbonate solution at 0℃ to adjust pH to 7-8, separate the phases, extract the aqueous phase again with 30 mL of (EA:THF = 1:1) twice, combine the organic phases, wash with 30 mL of saturated brine once, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the title compound as a white solid (1.245 g, based on 100%).

[0232] MS:(ESI,pos.ion)m / z:318.2264[M+H] +

[0233] Step 4: (S)-2-(4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidin-1-yl)-4-methoxybenzoate tert-butyl ester (7-4)

[0234] Following the synthetic method of step 12 in Example 1, the title compound was obtained as a pale yellow oil (1.05 g, 54.95%). MS: (ESI, pos.ion) m / z: 524.3275 [M+H] +

[0235] Step 5: (S)-2-(4-((3-(1-cyclopropyl-3-methoxy-3-oxopropyl)phenoxy)methyl)piperidin-1-yl)-4-methoxybenzoic acid (7-5)

[0236] Following the synthetic method of step 13 in Example 1, the title compound was obtained as a pale yellow oil (0.65 g, 51.7%). MS: (ESI, pos.ion) m / z: 468.2436 [M+H] + .

[0237] Step 6: Methyl (S)-3-cyclopropyl-3-(3-((1-(5-methoxy-2-(phenyl(undecyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)phenyl)propionate (7-6)

[0238] Following the synthetic method of step 14 in Example 1, the title compound was obtained as a pale yellow oil (0.82 g, 84.78%). MS: (ESI, pos.ion) m / z: 711.4868 [M+H] + .

[0239] Step 7: (S)-3-cyclopropyl-3-(3-((1-(2-(dodecyl(phenyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propionic acid (7)

[0240] Following the synthetic method of step 15 in Example 1, the title compound was obtained as a pale yellow oil (0.674 g, 83.83%). MS: (ESI, pos.ion) m / z: 696.4607 [M+H] + . 1H NMR(600MHz,Chloroform-d)δ7.25(t,J=7.9Hz,2H),7.18–6.96(m,5H),6.86(d,J=7.7Hz,1H),6.84(d,J=2.2Hz,1H),6.80(dd,J=8.2, 2.4Hz,1H),6.46(d,J=8.4Hz,1H),6.21(s,1H),4.01–3.81(m,4H),3.73(s,3H),2.81(dp,J=15.2,7.2Hz,2H),2.68–2.51(m,2H),2.39( dt,J=9.9,7.5Hz,1H),1.89(s,3H),1.64(d,J=8.8Hz,2H),1.55(s,2H),1.38–1.23(m,20H),1.06(ddt,J=8.2,5.1,2.5Hz,1H),0.90(t, J=7.0Hz,3H),0.61(ddt,J=9.1,8.0,2.8Hz,1H),0.46(tt,J=9.0,4.1Hz,1H),0.33(dq,J=9.9,4.9Hz,1H),0.20(dq,J=9.9,5.2Hz,1H).

[0241] Example 8: (S)-3-(3-((1-(2-(((2-chloro-4-fluorophenyl)(hexadecyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionic acid (8)

[0242]

[0243] Synthesis route:

[0244]

[0245] Step 1: 2-Chloro-4-fluoro-N-hexadecylaniline (8-2)

[0246] Following the method described in step 1 of Example 6, the title compound was obtained as a colorless oil (3.55 g, 46.53%).

[0247] Step 2: Methyl (S)-3-(3-((1-(2-(((2-chloro-4-fluorophenyl)(hexadecyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionate (8-3)

[0248] Following the synthetic method of step 14 in Example 1, the title compound was obtained as a light brown oil (0.21 g, 47.92%).

[0249] Step 3: (S)-3-(3-((1-(2-(((2-chloro-4-fluorophenyl)(hexadecyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropionic acid (8)

[0250] Following the synthetic method of step 15 in Example 1, the title compound was obtained as a colorless oil (0.19 g, 92.23%). MS-ESI: (ESI, pos.ion) m / z: 805.4744 [M+H] +

[0251] 1 H NMR(600MHz,Chloroform-d)δ7.53–7.37(m,1H),7.24(q,J=7.8Hz,2H),6.97(d,J=7.4Hz,1H),6.86(d,J=7.6Hz,1H),6.83(s,1H),6.79(dd,J=8.9,1.8Hz ,1H),6.76(d,J=9.2Hz,1H),6.41(d,J=8.4Hz,1H),6.32(s,1H),3.97–3.86( m,2H),3.72(s,3H),3.34(s,2H),2.98(s,1H),2.81(qd,J=15.2,7.4Hz,4H),2 .38(dt,J=9.7,7.3Hz,1H),1.93(d,J=41.8Hz,2H),1.73–1.63(m,2H),1.60( dd,J=8.8,4.3Hz,2H),1.40(d,J=26.2Hz,2H),1.35–1.10(m,26H),1.06(dd, J=8.8,4.5Hz,1H),0.90(t,J=7.0Hz,3H),0.64–0.59(m,1H),0.47(ddt,J=13 .7,8.9,5.0Hz,1H),0.33(dq,J=9.8,4.9Hz,1H),0.20(dq,J=9.8,5.0Hz,1H).

[0252] Biological test data

[0253] Experimental Example 9: In vitro GPR40 agonist activity assay

[0254] A: Main materials:

[0255] 1) Cell line: This cell line was constructed using Kanglong chemical synthesis. See the table below for details.

[0256] GPR40 HEK293 N / A

[0257] 2) Reagents and Consumables

[0258]

[0259] 3) Instruments

[0260] FLIPR Molecular Devices FLIPR Tetra

[0261] B. Method

[0262] I) Preparation of experimental reagents:

[0263] 1) Complete culture medium: DMEM, High Glucose (10566016) + 10% fetal bovine serum + 1X penicillin-streptomycin + 400μg / mL neomycin;

[0264] 2) Experimental buffer: HBSS + 20mM HEPES

[0265] 3) 20X Component A (calcium ion indicator): Equilibrate the experimental buffer and Component A powder to room temperature, add 10 mL of experimental buffer to Component A, shake for 1-2 min to mix, aliquot and store at -20℃.

[0266] II) Experimental Methods

[0267] a) Cell culture and seeding:

[0268] 1) HEK293-hGPR40 cell lines were cultured in complete culture medium at 37℃ and 5% CO2.

[0269] 2) After TrypLE digestion, the cells were resuspended in complete culture medium and seeded into 384 cell culture plates at a seeding density of 10,000 cells per well and a seeding volume of 25 μL per well. The cells were cultured overnight at 37°C and 5% CO2.

[0270] b) Agonistaltic activity assay

[0271] 1) Freeze-thaw 20X Component A to room temperature, dilute it with experimental buffer to 2X working concentration, and store at room temperature until use;

[0272] 2) Equilibrate the cell culture plate at room temperature for 10 minutes, remove the culture medium, add 20 μL of experimental buffer and 20 μL of 2X Component A, centrifuge at 200g for 3-5 seconds at room temperature, and then incubate at 37℃ for 2 hours.

[0273] 3) Using FLIPR Tetra, add 10 μL of the 5X compound working solution to the corresponding experimental well and collect data. Collect data once per second for a total of 3 minutes (Ex = 470-495 nm, Em = 515-575 nm).

[0274] c) Data Analysis

[0275] 1)Z'factor=1-3*(SDMax+SDMin) / (MeanMax-MeanMin);

[0276] 2)CVMax=(SDMax / MeanMax)*100%;

[0277] 3)CVMin=(SDMin / MeanMin)*100%;

[0278] 4) S / B = Single / Background;

[0279] 5) Calculate compound EC50 using GraphPad nonlinear fitting formula:

[0280] "Y=Bottom+(Top-Bottom) / (1+10^((LogEC50-X)*HillSlope))

[0281] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0282] X: Log value of compound concentration; Y: cAMP accumulation (% of GLP-1max)

[0283] C Experiment Results

[0284] Table 1: GPR40 agonistic activity

[0285] TAK-875 543.3 SCO 267 74.35 2 80.4 3 34.4 4 22.8 7 11.11

[0286] Conclusion: The compounds of this invention exhibit strong agonistic activity towards GPR40, significantly superior to TAK 875; and overall, their activity is superior to or no worse than that of SCO 267.

[0287] Experimental Example 10: Mouse Pharmacokinetic Study

[0288] This study used male SD rats as test animals and employed LC / MS / MS to quantitatively determine the plasma concentrations of the test compound administered intravenously and by gavage at different time points to evaluate the pharmacokinetic characteristics of the test drug in mice. The test compound solution was administered orally and by gavage to rats (fasted overnight, 6-8 weeks old). Following intravenous administration, 0.25 mL of blood was collected from the saphenous vein of rats at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h, and placed in anticoagulant tubes containing heparin sodium. The plasma was collected by centrifugation at 3200g for 10 min at 4°C. After processing, the plasma drug concentration was determined using LC-MS / MS. Following oral administration, 40 μL of blood was collected from the saphenous vein of mice at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24.0 h. The blood samples were placed in anticoagulant tubes containing heparin sodium and centrifuged at 3200 g for 10 min at 4 °C to collect plasma. After processing, the plasma samples were analyzed by LC-MS / MS to determine the drug concentration. The experimental results are shown in Table 2.

[0289] Table 2. Pharmacokinetic parameters of the compounds in SD rats

[0290]

[0291] Conclusion: Pharmacokinetic data show that the compound of the present invention exhibits good pharmacokinetic properties in SD rats when administered intravenously. When administered by gavage, the compound of the present invention has a low drug concentration in the blood and low bioavailability, and can be developed as an intestinal-limiting drug.

[0292] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A compound of formula I-1, its tautomer, or a pharmaceutically acceptable salt thereof, Formula I-1 in: R1 is a 3-6 membered cycloalkyl group; R2 is hydrogen; R3 is hydrogen; R4 is , ; R5 is optionally substituted with Ra: phenyl, C1-10 straight-chain or branched alkyl; Ra is a halogen, , ; The number of substitutions for Ra can be independently selected from 1, 2, 3, 4, and 5; R6 is a dodecyl, tetradecyl, or hexadecyl group.

2. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein R1 is... , , .

3. The compound according to claim 1, its tautomer, or a pharmaceutically acceptable salt thereof, wherein Ra is F, Cl, Br, , .

4. The compound according to claim 1, its tautomers, or a pharmaceutically acceptable salt thereof, wherein R5 is... , , , , .

5. A compound of the following formula, its tautomer, or a pharmaceutically acceptable salt thereof, 。 6. A compound of the following formula, its tautomer, or a pharmaceutically acceptable salt thereof, 。 7. A pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or the composition according to claim 7, in the preparation of a medicament for treating GPR40-related conditions.

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