Aromatic ester propionic acid derivative as well as preparation method and application thereof

Abstract

The invention discloses an aromatic ester propionic acid derivative as well as a preparation method and application thereof. The invention provides an aromatic ester propionic acid derivative as shown in a formula (I) or a pharmaceutically acceptable salt thereof. The invention further discloses application of the compound shown in the formula (I) or the pharmaceutically acceptable salt of the compound in preparation of drugs, and the compound has the effect of a GPR40 target agonist, so that the effects of reducing blood glucose and reducing weight are achieved. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an aromatic ester propionic acid derivative, a preparation method thereof and an application thereof. Background Art

[0002] GPR40 (FFAR1 or FFA1) belongs to the GPCR family and is a G protein-coupled receptor, which is mainly expressed in pancreatic islet β cells, intestinal endocrine cells and the brain. When GPR40 is activated by its endogenous ligand (medium / long-chain fatty acids), it can induce insulin secretion only at a relatively high blood glucose level. Therefore, there is no risk of hypoglycemia, which can greatly reduce the risk of hypoglycemia. At the same time, it can promote the secretion of intestinal hormones such as GLP-1 and achieve the purpose of weight loss by inhibiting central nervous appetite. This makes GPR40 an important target for the treatment of diabetes and weight loss. At present, many GPR40 agonists have been developed and studied, and some compounds have entered the clinical stage. For example, SCO-267 of Scohia Company has entered Phase I clinical trials, TAK-875 of Takeda Company has entered Phase III clinical trials, AMG837, AM1638, AM5262, etc. of Amgen Company, and LY-2922470 and LY2881835, etc. of Eli Lilly Company.

[0003] Although GPR40 agonists have been developed for many years, due to many possible problems in aspects such as drug metabolism, bioavailability and compound toxicity of GPR40 series agonists, the progress has been poor. For example, the development of TAK-875 was stopped due to liver toxicity. TAK-875 showed dose-dependent hypoglycemic activity (0.3 - 3 mg / kg) in the oGTT model of obese Wistar rats. In the rat and dog models, the half-lives of TAK-875 after oral administration were 4.1 and 7.5 h respectively, and the bioavailabilities were 76% and 92.4% respectively. Although TAK-875 showed good efficacy, due to the liver toxicity problem, Takeda Pharmaceutical Company terminated the clinical trial of TAK-875 in December 2013.

[0004] Therefore, new molecules are needed to improve the compound properties, enhance the compound activity, reduce the drug dosage, so as to reduce potential liver toxicity, etc.

[0005] GPR40 plays a hypoglycemic and weight loss role mainly through the following aspects.

[0006] 1. The GPR40 gene is expressed in multiple parts of the body, with the highest expression level in pancreatic tissue, indicating that there are specific transcriptional regulatory factors for the GPR40 gene in the pancreas. Research has found that the HR2 region in the complete genomic sequence from the end of the CD22 gene to the GPR40 gene has strong islet β-cell-specific enhancer activity, which can direct the specific expression of the GPR40 gene in islet β-cells and act together with other factors to achieve hypoglycemic effects by regulating islet β-cells.

[0007] The GPR40 protein is mainly distributed in pancreatic tissue and affects the function of pancreatic islet cells after activation by binding to appropriate ligands. Research shows that free fatty acids can enhance the insulin secretion response of islet β-cells under glucose stimulation.

[0008] 2. GPR40 is also generally expressed in intestinal endocrine cells. Endogenous medium- and long-chain fatty acids can activate downstream pathways by binding to GPR40 to promote the secretion of GLP-1 and PYY by intestinal endocrine L-cells, the secretion of GIP by intestinal endocrine K-cells, and the secretion of CCK by intestinal endocrine I-cells. Therefore, the GPR40 receptor can be used as a therapeutic target for obesity and diabetes. When GPR40 agonists have no or very little exposure in the blood system, it may be possible to reduce the potential toxicity caused by systemic exposure. It can be predicted that if these GPR40 agonist drugs can be highly enriched in intestinal tissues with a large number of GPR40 receptors and are rapidly metabolized and inactivated after entering the liver through the intestine, the potential hepatotoxicity can be greatly reduced.

[0009] Generally, for intestine-restricted drugs, the concentration in the gastrointestinal tract will be much higher than EC 50 , while the concentration in the blood is much lower than EC 50 ; or they are not absorbed, or have very weak absorption, or even if absorbed, they can be rapidly metabolized into inactive metabolites in the liver or blood.

[0010] The compounds of the present invention improve the activity of the compounds and reduce the drug dosage through structural improvement. These drugs are all ester compounds and are rapidly metabolized and inactivated after reaching the liver tissue, reducing the risk of potential hepatotoxicity. Summary of the Invention

[0011] Aiming at the deficiencies of current GPR40 series agonists in aspects such as drug metabolism and compound toxicity, the present invention provides a class of compounds with GPR40 receptor agonist activity, which have one or more of the advantages of high activity, low dose, and low toxicity.

[0012] The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof,

[0013]

[0014] R 1 ,R 2 Each independently is H, halogen, optionally substituted: C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0015] R 3 ,R 4 Each independently is H, halogen, cyano, optionally substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- or 6-membered heterocyclic group or 5- or 6-membered heteroaryl;

[0016] Or R 3 ,R 4 Together with the adjacent carbon atom forms a 3- to 6-membered cycloalkyl group or 3- to 6-membered heterocycloalkyl group;

[0017] R 5 is H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;

[0018] R 6 ,R 7 Each independently is H, halogen, optionally substituted: C 1-6 alkyl or C 3-6 cycloalkyl;

[0019] R 8 is -OR 9 or -NR 10 R 11 ;

[0020] R 9 is optionally substituted by halogen, hydroxy, C 1-6 alkoxy or trifluoromethyl: C 1-12 alkyl, C 3-8 cycloalkyl or C 4-8 heterocycloalkyl;

[0021] R 10 is optionally substituted by halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl-substituted pyridyl or phenyl;

[0022] R 11 is -(CH2) n -OCO-R 12or -(CH2) n -COO-R 12 ; n is an integer from 0 to 6;

[0023] R 12 is optionally substituted by halogen, hydroxy, C 1-6 alkoxy or trifluoromethyl: C 1-12 alkyl, C 3-8 cycloalkyl or C 4-8 heterocycloalkyl;

[0024] X is CH or N;

[0025] Y is CH or N;

[0026] A is optionally substituted aryl or heteroaryl, aryl or heteroaryl fused to a 5- to 12-membered heterocyclic group;

[0027] The number of said substitutions is one or more, and when selected from multiple ones, they are independently the same and different;

[0028] Preferably, R 1 , R 2 are each independently halogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are each optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halo C 3-6 cycloalkyl and halo C 1-6 alkoxy;

[0029] R 3 , R 4 are each independently halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclic group or 5- to 6-membered heteroaryl; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted by 1 or more substituents selected from H, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halo C 3-6 cycloalkyl and halo C 1-6 alkoxy;

[0030] Or R3 and R 4 forms a 3- to 6-membered cycloalkyl or 3- to 6-membered heteroalkyl with an adjacent carbon atom;

[0031] R 5 is H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;

[0032] R 6 and R 7 are each independently H, halogen, C 1-6 alkyl or C 3-6 cycloalkyl; the C 1-6 alkyl and C 3-6 cycloalkyl are each optionally substituted with one or more substituents selected from halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 3-6 cycloalkyl and halo-C 1-6 alkoxy;

[0033] R 8 is -OR 9 or -NR 10 R 11 ;

[0034] R 9 is C 1-6 alkyl, C 3-6 cycloalkyl or C 4-8 heteroalkyl; the C 1-6 alkyl, C 3-6 cycloalkyl and C 4-8 heteroalkyl are each optionally substituted with one or more substituents selected from halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 3-6 cycloalkyl and halo-C 1-6 alkoxy; the C 4-8 heteroalkyl has heteroatoms of N, O or S and the number of heteroatoms is 1, 2, 3 or 4;

[0035] R 10 is C 6-10 aryl or 5- to 12-membered heteroaryl; the R 10 is optionally substituted with one or more substituents selected from H, halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 3-6 cycloalkyl and halo-C 1-6 alkoxy;

[0036] R11 is -(CH2) n -OCO-R 12 or -(CH2) n -COO-R 12 ; n is an integer from 1 to 5;

[0037] R 12 is C 1-6 alkyl, C 3-6 cycloalkyl or C 4-8 heterocycloalkyl; the C 1-6 alkyl, C 3-6 cycloalkyl and C 4-8 heterocycloalkyl are each optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 3-6 cycloalkyl and halo-C 1-6 alkoxy; the C 4-8 heterocycloalkyl has heteroatoms of N, O or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0038] X is CH or N;

[0039] Y is CH or N;

[0040] Ring A is C 6-10 aryl, 5- to 12-membered heteroaryl or C 6-10 aryl-fused 5- to 12-membered heterocyclic group; the C 6-10 aryl and 5- to 12-membered heteroaryl are each optionally substituted by one or more A 1 ; the C 6-10 aryl-fused 5- to 12-membered heterocyclic group is optionally substituted by one or more substituents selected from H, halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 3-6 cycloalkyl and halo-C 1-6 alkoxy, wherein C 6-10 aryl is linked to the amide bond; A 1 is independently selected from C 1-6 alkoxy, 5- to 12-membered heterocyclic group, 5- to 12-membered heteroaryl and C 3-6 cycloalkyl; the A 1 is optionally substituted by one or more A 1-1 ;

[0041] A 1-1 is independently selected from hydroxyl, C 1-6 alkyl and C 1-6 alkoxy.

[0042] In one embodiment of the present invention, the said R1 , R 2 are each independently H, halogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more halogens or C 1-6 alkyl substituted by one or more cyano groups.

[0043] In one embodiment of the present invention, the R 3 , R 4 are each independently H, halogen, cyano, C 1-6 alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl, C 1-6 alkyl substituted by one or more halogens or C 1-6 alkyl substituted by one or more cyano groups; in the 5-6 membered heterocyclic group and 5-6 membered heteroaryl, the heteroatoms are N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0044] Or, R 3 , R 4 together with adjacent carbon atoms form a 3-6 membered cycloalkyl.

[0045] In one embodiment of the present invention, the R 5 is H, halogen, C 1-6 alkyl.

[0046] In one embodiment of the present invention, R 6 , R 7 are each independently H, halogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more halogens or C 1-6 alkyl substituted by one or more cyano groups.

[0047] In one embodiment of the present invention, the R 8 is -OR 9 or -NR 10 R 11 .

[0048] In one embodiment of the present invention, the R 9 is C 1-6 alkyl, C 3-6 cycloalkyl, C 4-8 heterocycloalkyl or C 4-8 heterocycloalkyl substituted by one or more haloalkyl groups; in the C 4-8 heterocycloalkyl and C 4-8 heterocycloalkyl substituted by one or more haloalkyl groups, the C 4-8 heterocycloalkyl has heteroatoms of N, O or S, and the number of heteroatoms is 1, 2 or 3.

[0049] In one embodiment of the present invention, the R 10 is C 6-10 aryl, 5- to 12-membered heteroaryl, C 1-6 aryl substituted with one or more C 6-10 alkyl groups, C 1-6 aryl substituted with one or more C 6-10 alkoxy groups, or 5- to 12-membered heteroaryl substituted with one or more C 1-6 alkyl groups; the heteroatoms in the 5- to 12-membered heteroaryl are N, O, or S, and the number of heteroatoms is 1, 2, or 3.

[0050] In one embodiment of the present invention, the R 11 is -(CH2) n -OCO-R 12 or -(CH2) n -COO-R 12 ; n is 1, 2, 3, or 4.

[0051] In one embodiment of the present invention, the R 12 is C 1-6 alkyl.

[0052] In one embodiment of the present invention, the X is N.

[0053] In one embodiment of the present invention, the Y is CH.

[0054] In one embodiment of the present invention, the ring A is C 6-10 aryl, 5- to 12-membered heteroaryl, C 6-10 aryl-fused 5- to 12-membered heterocyclic group, C 1-6 aryl substituted with one or more C 6-10 alkoxy groups; the heteroatoms in the 5- to 12-membered heteroaryl are N, O, or S, and the number of heteroatoms is 1, 2, or 3; the heteroatoms in the 5- to 12-membered heterocyclic group in the C 6-10 aryl-fused 5- to 12-membered heterocyclic group are N, O, or S, and the number of heteroatoms is 1, 2, or 3.

[0055] In one embodiment of the present invention, in each R 1 , R 2 , the halogen, or the C 1-6 alkyl group substituted with one or more halogens, the halogen is F, Cl, Br, or I.

[0056] In one embodiment of the present invention, in each R 1 , R 2 , the C 1-6 alkyl group, the C 1-6 alkyl group substituted with one or more halogens, the C1-6 C in the alkyl group 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0057] In a certain embodiment of the present invention, in each R 3 , R 4 Among them, the C 1-6 alkyl group, C 1-6 alkyl group substituted by one or more halogen atoms, C 1-6 alkyl group substituted by one or more cyano groups 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0058] In a certain embodiment of the present invention, in each R 3 , R 4 Among them, the halogen, or the halogen in the C 1-6 alkyl group substituted by one or more halogen atoms is F, Cl, Br or I.

[0059] In a certain embodiment of the present invention, in each R 3 , R 4 Among them, the 3- to 6-membered cycloalkyl group is cyclopropyl, cyclobutyl or cyclopentyl.

[0060] In a certain embodiment of the present invention, in R 9 Among them, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or tert-butylmethylene.

[0061] In a certain embodiment of the present invention, in R 9 Among them, the C 4-8 heterocycloalkyl group and the C 4-8 heterocycloalkyl group substituted by one or more haloalkyl groups 4-8 The heteroatom in the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3.

[0062] In a certain embodiment of the present invention, in R 9 Among them, the halogen in the C 4-8 heterocycloalkyl group substituted by one or more haloalkyl groups is F, Cl, Br or I.

[0063] In a certain embodiment of the present invention, in R 10 Among them, the C 6-10 aryl group, C 1-6 aryl group substituted by one or more C 6-10 alkyl groups, C 1-6 aryl group substituted by one or more C 6-10 alkoxy groups 6-10The aryl group is a phenyl group.

[0064] In one embodiment of the present invention, in R 10 Among them, the C 1-6 aryl group substituted by one or more C 6-10 alkyl groups, and the C 1-6 in the 5-12 membered heteroaryl group substituted by one or more C 1-6 alkyl groups, the C

[0065] In one embodiment of the present invention, in R 10 Among them, the C 1-6 aryl group substituted by one or more C 6-10 alkoxy groups, the C 1-6 alkoxy groups are -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)3, -O(CH2)2CH(CH3)2 or -O(CH2)4CH3.

[0066] In one embodiment of the present invention, in R 10 Among them, the 5-12 membered heteroaryl group, and the 5-12 membered heteroaryl group in the 5-12 membered heteroaryl group substituted by one or more C 1-6 alkyl groups is a 6-membered heteroaryl group, the heteroatom is N, and the number of heteroatoms is 1 or 2.

[0067] In one embodiment of the present invention, in R 12 Among them, the C 1-6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or tert-butylmethylene.

[0068] In one embodiment of the present invention, in ring A, the C 6-10 aryl group, and the C 1-6 aryl group substituted by one or more C 6-10 alkoxy groups, the C 6-10 aryl group is a phenyl group.

[0069] In one embodiment of the present invention, in ring A, the C 1-6 aryl group substituted by one or more C 6-10 alkoxy groups, the C 1-6 alkoxy groups are -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)3, -O(CH2)2CH(CH3)2 or -O(CH2)4CH3.

[0070] In one embodiment of the present invention, in ring A, the C 6-10The aryl-fused 5- to 12-membered heterocyclic group is a phenyl-fused 5- to 6-membered heterocyclic group, and the heteroatom in the 5- to 6-membered heterocyclic group is O, and the number of heteroatoms is 1, 2, or 3.

[0071] In one embodiment of the present invention, the R 1 , R 2 are each independently H.

[0072] In one embodiment of the present invention, the R 3 , R 4 are each independently H or a 3- to 6-membered cycloalkyl group.

[0073] In one embodiment of the present invention, the R 5 is H.

[0074] In one embodiment of the present invention, the R 6 , R 7 are each independently H.

[0075] In one embodiment of the present invention, the R 8 is -OR 9 or -NR 10 R 11 .

[0076] In one embodiment of the present invention, the R 9 is C 1-6 alkyl or C 4-8 heterocycloalkyl substituted with one or more haloalkyl groups.

[0077] In one embodiment of the present invention, the R 10 is a 5- to 12-membered heteroaryl group substituted with one or more C 1-6 alkyl groups.

[0078] In one embodiment of the present invention, the R 11 is -(CH2) n -OCO-R 12 or -(CH2) n -COO-R 12 ; n is 1, 2, 3, or 4.

[0079] In one embodiment of the present invention, the R 12 is C 1-6 alkyl.

[0080] In one embodiment of the present invention, the ring A is a C 1-6 aryl group or a C 6-10 aryl-fused 5- to 12-membered heterocyclic group substituted with one or more C 6-10 alkoxy groups.

[0081] In one embodiment of the present invention, the R 3 , R 4 is H or is preferably

[0082] In one embodiment of the present invention, the R 9 is

[0083] In one embodiment of the present invention, the R 10 is

[0084] In one embodiment of the present invention, the R 11 is -(CH2)2-OCO-R 12 or -(CH2)-COO-R 12 .

[0085] In one embodiment of the present invention, the R 12 is methyl, isopropyl, tert-butyl or tert-butylmethylene, preferably isopropyl, tert-butyl or tert-butylmethylene.

[0086] In one embodiment of the present invention, the ring A is preferably

[0087] In one embodiment of the present invention, the R 8 is

[0088] preferably

[0089] Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure shown in formula (II) as follows:

[0090]

[0091] Wherein, R 1 , R 2 , R 3 , R 4 , R 9 , X, Y, and the ring A are as described in any one of the compounds of formula (I) of the present invention.

[0092] Preferably, R 1 , R 2 are each independently H, halogen or optionally substituted C 1-6 alkyl;

[0093] R 3 , R4 Each independently is H, halogen, cyano, C 1-6 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl or C 1-6 alkyl-substituted five-membered heteroaryl;

[0094] R 9 is optionally substituted by halogen, hydroxy, C 1-6 alkoxy or trifluoromethyl: C 1-12 alkyl, C 1-12 alkoxy, C 3-8 cycloalkyl or C 4-8 heterocycloalkyl;

[0095] X is CH or N;

[0096] Y is CH or N;

[0097] A is optionally substituted: phenyl, pyridine, benzo 5-6-membered heteroaryl;

[0098] Further preferably, in the compound of formula II or its pharmaceutically acceptable salt, R 9 is C 3-8 alkyl or optionally trifluoromethyl-substituted C 4-8 heterocycloalkyl;

[0099] More preferably, the compound of formula (I) or its pharmaceutically acceptable salt has the structure shown in formula (III) as follows:

[0100]

[0101] Wherein, R 1 , R 2 , R 3 , R 4 , R 10 , R 11 , R 12 , X, Y, and ring A are as described in any one of the compounds of formula (I) of the present invention;

[0102] Preferably, R 1 , R 2 each independently is H, halogen or optionally substituted C 1-6 alkyl;

[0103] R 3 , R 4 each independently is H, halogen, cyano, C 1-6 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, halogenated C 1-6Alkyl or C 1-6 alkyl-substituted five-membered heteroaryl;

[0104] R 10 is optionally substituted by halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl-substituted pyridyl or phenyl;

[0105] R 11 is -(CH2) m -OCO-R 12 or -(CH2) n -COO-R 12 ;

[0106] R 12 is optionally substituted by halogen, hydroxy, C 1-6 alkoxy or trifluoromethyl: C 1-12 alkyl, C 1-12 alkoxy, C 3-8 cycloalkyl, C 4-8 heterocycloalkyl;

[0107] X is CH or N;

[0108] Y is CH or N;

[0109] A is optionally substituted: phenyl, pyridine, benzo 5-6-membered heteroaryl;

[0110] m is 1, 2 or 3;

[0111] n is 1, 2 or 3;

[0112] Further preferably, in the compound of formula III or its pharmaceutically acceptable salt, R 10 is pyridyl optionally substituted by C 1-6 alkyl; R 11 is -(CH2)2-OCO-R 12 or -CH2COO-R 12 ; R 12 is C 1-12 alkyl optionally substituted by halogen;

[0113] Even more preferably, in the compounds of formula I, formula II and formula III or their pharmaceutically acceptable salts,

[0114] R 1 , R 2 are each independently H or methyl;

[0115] R 3 , R 4 are each independently H, C 2-6Alkynyl, C 3-6 Cycloalkyl or CF3;

[0116] Y is CH;

[0117] A is optionally substituted: phenyl, pyridine, The substituents are selected from: C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-10 Alkoxy, optionally substituted 4-8 membered heterocycloalkyl and halogen;

[0118] Even more preferably, in certain preferred embodiments of the present invention, in the compounds of formula I, formula II and formula III or their pharmaceutically acceptable salts,

[0119] R 1 , R 2 Are each independently H;

[0120] R 3 , R 4 Are each independently H or C 3-6 Cycloalkyl;

[0121] A is optionally substituted: phenyl, pyridine, The substituents are selected from: C 1-10 Alkoxy or 4-8 membered heterocycloalkyl optionally substituted by C 1-6 Alkyl;

[0122] Even more preferably, in certain preferred embodiments of the present invention, in the compounds of formula I, formula II and formula III or their pharmaceutically acceptable salts, preferably R 3 , R 4 Are each independently H or cyclopropyl; A is phenyl or pyridine optionally substituted by C 1-10 Alkoxy.

[0123] In one aspect of the present invention, the compound of formula (I) is the following general formula (II) to formula (III):

[0124]

[0125] Wherein, R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , R 11 , X, Y and ring A are as described in claim 1.

[0126] In one aspect of the present invention, the compound according to formula (I) of the present invention is selected from one of the following compounds:

[0127]

[0128] The present invention also provides a compound represented by formula (IA), or a pharmaceutically acceptable salt thereof,

[0129]

[0130] wherein R is benzyl or C 1-12 alkyl or C 1-12 alkoxy-substituted benzyl; more preferably, R is benzyl; and

[0131] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 ,R 10 ,R 11 ,R 12 ,X, Y, and A are as described in any one of the schemes of formula (I).

[0132] In some embodiments, the compound represented by formula (IA) of the present invention or a pharmaceutically acceptable salt thereof may be a compound represented by formula (IIA) or a pharmaceutically acceptable salt thereof,

[0133]

[0134] wherein R is benzyl or C 1-12 alkyl or C 1-12 alkoxy-substituted benzyl; more preferably, R is benzyl; and

[0135] R 1 、R 2 、R 3 、R 4 、R 9 、X, Y and ring A are as described in any one of the schemes of formula (I).

[0136] In some embodiments, the compound represented by formula (IA) of the present invention or a pharmaceutically acceptable salt thereof may be a compound represented by formula (IIIA) or a pharmaceutically acceptable salt thereof,

[0137]

[0138] wherein R is benzyl or C 1-12 alkyl or C 1-12 alkoxy-substituted benzyl; more preferably, R is benzyl; and

[0139] R 1 、R2 , R 3 , R 4 , R 10 , R 11 , R 12 , X, Y and ring A are as described in any one of the schemes of formula (I).

[0140] In one aspect of the present invention, the compound represented by formula (IA) of the present invention has any of the following structures:

[0141]

[0142] The present invention also provides a method for preparing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

[0143] In an organic solvent, the compound represented by general formula (IA) is subjected to a hydrogenation reaction with a reducing agent to obtain the compound represented by general formula (I);

[0144]

[0145] Among them, R is benzyl or C 1-12 alkyl or C 1-12 alkoxy-substituted benzyl; more preferably, R is benzyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X, Y, and ring A are as described in any one of the schemes of the compound represented by the formula;

[0146] Preferably, the preparation method satisfies one or more of the following conditions:

[0147] The organic solvent is a mixed solution of ether and alcohol solvents, preferably methanol;

[0148] The reducing agent is an inorganic reducing agent, preferably hydrogen;

[0149] The catalyst for the hydrogenation reaction is palladium on carbon;

[0150] The reaction temperature of the preparation method is room temperature;

[0151] The dosage of the organic solvent is 2 - 6 ml, preferably 3 ml; the reaction time is 1 - 3 h, preferably 2 h;

[0152] After the reaction is completed, post-treatment is further included, and the post-treatment includes the following steps: filtration, concentration, and purification;

[0153] The progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC, or NMR), and generally, the disappearance or no longer reaction of the compound represented by the formula (IA), or when the product no longer increases, is taken as the end point of the reaction.

[0154] In some embodiments, a method for preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof includes the following steps:

[0155] In an organic solvent, the compound represented by the general formula (IIA) is subjected to a hydrogenation reaction with a reducing agent to obtain the compound represented by the general formula (II);

[0156]

[0157] wherein,

[0158] R is benzyl or C 1-12 alkyl or C 1-12 alkoxy-substituted benzyl; more preferably, R is benzyl; and R 1 、R 2 、R 3 、R 4 、R 9 、X, Y, and ring A are as described in any one of the compounds represented by the formula (II), and the reaction conditions are as defined in the compound represented by the formula (IA).

[0159] In some embodiments, a method for preparing a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof includes the following steps:

[0160] In an organic solvent, the compound represented by the general formula (IIIA) is subjected to a hydrogenation reaction with a reducing agent to obtain the compound represented by the general formula (III);

[0161]

[0162] wherein,

[0163] R is benzyl or C 1-12 alkyl or C 1-12 alkoxy-substituted benzyl; more preferably, R is benzyl; and R 1 、R 2 、R 3 、R 4 、R 10 、R 11 、R 12, X, Y, and ring A are as described in any of the compounds of formula (III), and the reaction conditions are as defined in the compounds of formula (IA).

[0164] The present invention provides a pharmaceutical composition, which comprises (a therapeutically effective amount of) the compounds represented by the above formula (I), formula (II), formula (III) or their pharmaceutically acceptable salts (as active ingredients), and pharmaceutically acceptable excipients.

[0165] The present invention provides the use of the above compounds, or the above pharmaceutical composition (as an active ingredient) in the preparation of a GPR40 receptor agonist.

[0166] In the said use, the GPR40 receptor agonist can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: providing comparison as a standard sample or control sample, or being made into a kit according to the conventional methods in the art to provide a rapid detection for the agonist effect of the GPR40 receptor.

[0167] The present invention provides the use of the above compounds, or the above pharmaceutical composition (as an active ingredient) in the preparation of a drug for preventing and / or treating metabolic-related diseases.

[0168] The present invention provides the use of the above compounds, or the above pharmaceutical composition (as an active ingredient) in the preparation of a drug for preventing and / or treating metabolic-related diseases by activating the GPR40 receptor.

[0169] In a specific embodiment, the metabolic-related diseases are selected from any one of the diseases such as glucose intolerance, hyperglycemia, dyslipidemia, syndrome X (microvascular angina), insulin resistance, arteriosclerosis, hypertension, obesity, non-alcoholic fatty liver, cirrhosis, and lethargy.

[0170] The metabolic-related diseases can also be selected from any one of the diseases such as hyperglycemia, type 1 diabetes (T1D), type 2 diabetes (T2D), diabetic dyslipidemia, hyperlipidemia, atherosclerosis, non-alcoholic steatohepatitis, and liver fibrosis.

[0171] The metabolic-related diseases can also be selected from hypertriglyceridemia.

[0172] Hereinafter, the present invention will be described in detail. Before the description, it should be understood that the terms used in this specification and the appended claims should not be construed as limited to the general meaning and dictionary meaning, but should be interpreted based on the principle that allows the inventor to appropriately define the terms for the best interpretation, according to the meanings and concepts corresponding to the technical aspects of the present invention. Therefore, the description presented here is only for illustrative purposes. Without departing from the spirit and scope of the present invention, other equivalent means or improvement means can be obtained therefrom.

[0173] When used alone or in combination with other groups in the present application, the term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or pentyl, isopentyl, neopentyl, hexyl. The alkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyl, cyano, amino, nitro.

[0174] When used alone or in combination with other groups in the present application, the term "alkenyl" refers to a straight-chain or branched-chain, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 2-6 ) and having a carbon-carbon sp 2 double bond. Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro.

[0175] When used alone or in combination with other groups in the present application, the term "alkynyl" refers to a straight-chain or branched-chain, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 2-6 ) and having a carbon-carbon sp triple bond. Alkynyl groups include, but are not limited to: etc.

[0176] When used alone or in combination with other groups in the present application, the term "alkoxy" means that an oxygen atom is connected to the alkyl group as described above in the parent molecular moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, pentyloxy, etc.

[0177] As used herein, alone or in combination with other groups, the term "cycloalkyl group" refers to a saturated or partially unsaturated all-carbon ring, preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group). The "cycloalkyl group" can be saturated, such as "cycloalkyl"; or, the "cycloalkyl group" can be partially unsaturated, such as "cycloalkenyl". For example, in one embodiment, a monocyclic cycloalkyl group is preferred.

[0178] Non-limiting examples of the cycloalkyl group include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0179] In one embodiment, a monocyclic cycloalkenyl group is preferred. Non-limiting examples of the monocyclic cycloalkenyl group include: cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.

[0180] As used herein, alone or in combination with other groups, the term "heterocyclic group" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom selected from N, O, and S as a ring member. Preferably, the number of heteroatoms is 1, 2, 3, or 4. More preferably, the heteroatom is N or O, and the number of heteroatoms is 1, 2, or 3. The heterocyclic group can be monocyclic or polycyclic, and the polycyclic can be a fused ring, spiro ring, and bridged ring structure. For example, a 3- to 6-membered heterocyclic group. In addition, the heterocyclic group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point.

[0181] The term "aryl group" refers to an aromatic system, including an aryl group or a heteroaryl group; in the heteroaryl group, the number of heteroatoms is 1, 2, 3, or 4, and the types of heteroatoms are selected from N, O, or S. Among them, aryl groups include, but are not limited to: phenyl, naphthyl. Heteroaryl groups include, but are not limited to: thiazolyl, thiophenyl, pyridyl, pyrimidinyl.

[0182] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0183] As used herein, the term "hydroxyl group" refers to -OH.

[0184] As used herein, the term "cyano group" refers to -CN.

[0185] As used herein, alone or in combination with other groups, the term "halogen atom substitution" means that one or more hydrogen atoms are replaced by a halogen. For example, the term "halogenated C 1-6 alkyl" refers to C 1-6Alkyl. Those skilled in the art should understand that when there is more than one halogen substituent, the halogens can be the same or different and can be located on the same or different C atoms. Examples of haloalkyls are, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0186] As used in this application, the term "independently of each other" means that at least two groups (or segments) with the same or similar range of values present in a structure can have the same or different meanings under specific circumstances.

[0187] The term "one or more" or a similar expression "at least one" can represent, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0188] As used in this application, the term "substituted" and its other variant forms herein mean that one or more (such as 1, 2, 3 or 4) atoms or atomic groups (such as hydrogen atoms) on the specified atom are replaced by other equivalents, provided that the normal valence of the specified atom or atomic group in the current situation is not exceeded and a stable compound can be formed. If an atom or atomic group is described as "optionally substituted by...", it can either be substituted or unsubstituted. Unless otherwise specified, the connection site of the substituent can be from any suitable position of the substituent. When the connecting bond in the substituent is shown as a chemical bond passing between two interconnected atoms in a ring system, it means that the substituent can be connected to any ring-forming atom in the ring system.

[0189] In this application, a solid line (-), a solid wedge or a dashed wedge can be used to depict the carbon-carbon bonds of the compounds of the present invention. Using a solid line to depict a bond connected to an asymmetric carbon atom is intended to indicate all possible stereoisomers including those at that carbon atom (for example, specific enantiomers, racemic mixtures, etc.). Using a solid or dashed wedge to depict a bond connected to an asymmetric carbon atom is intended to indicate the presence of the depicted stereoisomer. When present in a racemic mixture, solid and dashed wedges are used to define the relative stereochemistry rather than the absolute stereochemistry. Unless otherwise specified, the compounds of the present invention can exist in the form of stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereoisomers, geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof). The compounds of the present invention can exhibit more than one type of isomerism and consist of mixtures thereof (such as racemic mixtures and diastereoisomer pairs).

[0190] In this application, Indicates that this position is connected to other groups.

[0191] The compounds represented by formula (I), the compounds represented by formula (II), the compounds represented by formula (III), and the compounds represented by formula 1-14 provided by the present invention, or their pharmaceutical drug compositions, etc. can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, etc., and can be present in a suitable solid or liquid carrier or diluent and in a suitable sterilized device for injection or infusion.

[0192] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to the conventional preparation methods in the pharmaceutical field. For example, the unit dose of its formulation contains 0.1-1000 mg of the compounds of formula (I), formula (II), formula (III), and formula 1-14. Preferably, the unit dose of the formulation contains 1 mg-500 mg of the compounds of formula (I), formula (II), formula (III), and formula 1-14.

[0193] The compounds and pharmaceutical compositions represented by formula I of the present invention can be clinically used in mammals, including humans and animals, and can be administered through routes such as oral, nasal, skin, lung, or gastrointestinal tract, etc. The most preferred is oral administration. The optimal daily dose is preferably 1-300 mg / kg body weight, taken once, or 1-300 mg / kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined according to the specific treatment. Usually, it starts from a small dose and gradually increases the dose until the most suitable dose is found.

[0194] In the present invention, the term "(therapeutically) effective amount" can refer to the effective amount of the dose and time period required to achieve the desired effect. This effective amount may vary due to certain factors, such as the type of disease or the symptoms of the disease during treatment, the structure of the specific target organ to which it is administered, the size of the patient individual, or the severity of the disease or symptom. Those with ordinary knowledge in the art can determine the effective amount of a specific compound by experience without excessive experimentation.

[0195] Typical formulations are prepared by mixing the compounds represented by formula (I), formula (II), and formula (III) of the present invention with carriers, diluents, or excipients. Suitable carriers, diluents, or excipients are well-known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc.

[0196] The specific carrier, diluent or excipient used will depend on the mode of use and purpose of the compounds of the present invention. Generally, the solvent is selected based on a solvent that those skilled in the art consider to be safe and effective for administration to mammals. Generally speaking, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, light-shielding agents, glidants, processing aids, coloring agents, sweeteners, flavoring agents, flavor enhancers or other known additives to make the drug manufactured or used in an acceptable form.

[0197] When the compounds of formula (I), formula (II) and formula (III) described in the present invention are used in combination with at least one other drug, the two drugs or multiple drugs can be used separately or in combination, and are preferably administered in the form of a pharmaceutical composition. The compounds of formula (I), formula (II) and formula (III) or the pharmaceutical composition of the present invention can be administered to a subject separately or together in any known oral, intravenous injection, rectal administration, vaginal administration, transdermal absorption, other local or systemic administration forms.

[0198] The pharmaceutical composition may also contain one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, light-shielding agents, glidants, processing aids, coloring agents, sweeteners, flavoring agents, flavor enhancers or other known additives to make the pharmaceutical composition manufactured or used in an acceptable form.

[0199] The drugs of the present invention are preferably administered by the oral route. Solid dosage forms for oral administration may include capsules, tablets, powder or granule preparations. In the solid dosage form, the compounds or pharmaceutical compositions of the present invention are mixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or calcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerol, etc.; disintegrants such as agar, calcium carbonate, potato or tapioca starch, certain complex silicates, sodium carbonate, etc.; solution blockers such as paraffin, etc.; absorption promoters such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules, using lactose and high molecular weight polyethylene glycol, etc. as excipients.

[0200] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds of the present invention or their pharmaceutical compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or mixtures of several of these substances, etc.

[0201] In addition to these inert diluents, the composition may also include excipients, such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.

[0202] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0203] The reagents and raw materials used in the present invention are all commercially available.

[0204] The positive and progressive effects of the present invention are as follows: The present invention synthesizes a novel class of GPR40 receptor agonist compounds, and pharmacological experiments confirm that these compounds have good agonist activity, so they can be used for the treatment of GPR40 receptor-related metabolic diseases. In addition, the compounds of the present invention also show excellent drug metabolism properties.

[0205] According to the present invention, unless otherwise specified, all terms cited herein have the same meaning as those understood by those skilled in the art for the present invention. Detailed Description of the Invention

[0206] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0207] The present invention will be further described in detail below with reference to specific examples, but the present invention is not limited to the following examples. The examples are for better illustrating certain specific embodiments of the present invention and cannot be construed as limiting the scope of the present invention in any way. The conditions not specified in the examples are conventional conditions. Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available products.

[0208] Column chromatography or purification generally uses silica gel with 200-300 mesh as the carrier.

[0209] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20 - 30 degrees Celsius.

[0210] The elution machine systems used in column chromatography in the examples include: A: dichloromethane and methanol system, B: n - hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone and petroleum ether system, and the volume ratio of the solvents is adjusted according to the polarity of the compounds.

[0211] Example 1:

[0212] Compound 1, 3 - cyclopropyl - 3-(2 - ((1-(2 - ((2-(isobutyric acid)ethyl)(6 - methylpyridin - 2 - yl)carbamoyl)-5 - methoxyphenyl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid

[0213]

[0214] Compound 1 was prepared according to the following route.

[0215]

[0216] Step 1: N-(2-(tert - butyldimethylsilyloxy)ethyl)-6 - methyl - 2 - pyridinamine (1 - 1)

[0217] 2 - Methyl - 5 - bromopyridine (5.16 g, 30 mmol), 2-(tert - butyldimethylsilyloxy)-1 - ethylamine (6.3 g, 36 mmol), sodium tert - butoxide (8.64 g, 90 mmol), 2 - dicyclohexylphosphino - 2',4',6'-triisopropylbiphenyl (1.431 g, 30 mmol) were added to tetrahydrofuran (100 ml), and tris(dibenzylideneacetone)dipalladium (2.75 g, 3 mmol) was added. The mixture was stirred at 70 °C overnight. After monitoring the reaction to completion, it was filtered, concentrated, and purified by column chromatography to obtain a red oil 1 - 1 (5.33 g, yield: 66.9%).

[0218] 1 H NMR(400MHz,CDCl3):7.33 - 7.29(t,J = 8Hz,1H),6.44~6.42(d,J = 8Hz,1H),6.22~6.20(d,J = 8Hz,1H),4.76(s,1H),3.81~3.78(m,2H),3.39~3.35(m,2H),2.36(s,3H),0.90(s,9H),0.06(s,3H),m / z:267.25[M + 1].

[0219] Step 2: N-(2-((tert-Butyldimethylsilyloxy)ethyl)-2-fluoro-4-methoxy-N-(6-methylpyridin-2-yl)benzamide (1-2)

[0220] Dissolve 2-fluoro-4-methoxybenzoic acid (4.25 g, 25 mmol) in tetrahydrofuran (40 ml), add 2 drops of N,N-dimethylformamide, add oxalyl chloride (3.49 g, 27.5 mmol), stir at room temperature for 1 hour, and concentrate to dryness for later use. Dissolve N-(2-(tert-butyldimethylsilyloxy)ethyl)-6-methyl-2-pyridinamine (1-1) (5.33 g, 20 mmol) and triethylamine (10.1 ml, 75 mmol) in tetrahydrofuran (40 ml), cool to 0 °C, add the above-prepared acyl chloride, and stir at room Warm stir the reaction overnight. The reaction After completion, concentrate and perform column chromatography to obtain a brown oil 1-2 (6.54 g, yield: 78.3%). m / z: 419.30 [M+1].

[0221] Step 3: 3-Cyclopropyl-(2-methoxypyridin-4-yl)methanol (1-3)

[0222] Add 2-methoxy-4-pyridinecarboxaldehyde (10.0 g, 7.29 mmol, 1.0 eq) to tetrahydrofuran (80 mL). Under an ice-water bath, dropwise add 1 mol / L cyclopropylmagnesium bromide in tetrahydrofuran solution (213 mL, 0.213 mol, 3.0 eq). Stir at room temperature for 1 hour. After the reaction is completed, add saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate, dry and concentrate, and purify by column chromatography to obtain product 1-3 (11.4 g, 87%).

[0223] 1 H NMR (400 MHz, DMSO-d6): δ 8.08 - 8.07 (d, J = 4.0 Hz, 1H), 6.99 - 6.98 (d, J = 4.0 Hz, 1H), 6.77 (s, 1H), 5.35 - 5.34 (d, J = 4.0 Hz, 1H), 3.95 - 3.93 (m, 1H), 3.83 (s, 1H), 1.04 - 0.90 (m, 1H), 0.51 - 0.20 (m, 4H). m / z: 180.15 [M+1]

[0224] Step 4: Cyclopropyl(2-methylpyridin-4-yl)methyl ketone (1-4)

[0225] Dissolve cyclopropyl(2-methoxypyridin-4-yl)methanol(1-3)(10.3g,0.0575mol,1.0eq) in dimethyl sulfoxide(50ml). At room temperature, add triethylamine(46.56g,0.460mol,8.0eq), and add pyridine sulfur trioxide(36.62g,0.230mol,4.0eq) in three portions, and stir at room temperature for 10 minutes. The reaction is complete. Quench the reaction mixture with water(200ml), extract twice with ethyl acetate(200ml), combine the organic phases, wash once with water and once with saturated brine, and purify by column chromatography to obtain a pale yellow liquid 1-4(6.50g,64%).

[0226] 1 H NMR(400MHz,DMSO-d6):δ8.37-8.35(d,J=8.0Hz,1H),7.45-7.43(d,J=8.0Hz,1H),7.35(s,1H),3.92(s,3H),2.95-2.83(s,1H),1.18-1.11(m,4H),0.51-0.20(m,4H).m / z:178.15[M+1]

[0227] Step 5: Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)acrylate(1-5)

[0228] Dissolve sodium hydride(2.94g,0.0734mol,2.0eq) in tetrahydrofuran(35ml), protect with nitrogen, cool to 0°C, add dropwise ethyl phosphonoacetate(16.466g,0.0734mol,2.0eq). After addition, stir at 0°C for 0.5 hour, add dropwise a solution of cyclopropyl(2-methylpyridin-4-yl)methyl ketone(1-4)(6.50g,0.0367mol,1.0eq) in tetrahydrofuran(35ml). After the addition is complete, raise the temperature to room temperature and then reflux at 80°C for 3 hours. The reaction is complete. Cool the reaction mixture to room temperature, quench it slowly into a saturated ammonium chloride solution in ice, extract twice with ethyl acetate(35ml), combine the organic phases, wash with water and saturated sodium chloride, and purify by column chromatography to obtain a pale yellow oil 1-5(9.45g,100%).

[0229] 11H NMR (400 MHz, DMSO-d6): δ 7.64 - 7.63 (d, J = 8.0 Hz, 1H), 6.81 - 6.80 (s, 1H), 6.22 - 6.20 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 4.27 - 4.19 (q, J = 4.0 Hz 2H), 1.42 - 1.40 (m, 1H), 1.25 - 1.23 (t, J = 4.0 Hz, 3H), 0.55 - 0.51 (m, 2H), 0.25 - 0.22 (m, 2H). m / z: 248.20 [M+1]

[0230] Step 5: Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (1-6)

[0231] Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)acrylate (1-5) (9.45 g, 0.0383 mol, 1.0 eq) was dissolved in acetic acid (45 ml), and zinc powder (14.93 g, 0.23 mol, 6.0 eq) was added portionwise. There was a slight exothermic phenomenon. The mixture was stirred at room temperature for 0.5 h, and the reaction was completed. The reaction solution was filtered through diatomaceous earth, and the filter cake was rinsed with ethyl acetate (45 ml × 2). The filtrate was concentrated to dryness, dissolved in ethyl acetate (45 ml), washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain yellow oil 1-6 (9.85 g, 100%). It was directly used for the next step.

[0232] 1 1H NMR (400 MHz, DMSO-d6): δ 8.05 - 8.03 (d, J = 8.0 Hz, 1H), 6.92 - 6.90 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 4.03 - 3.99 (m, 2H), 3.83 (s, 3H), 2.75 - 2.73 (m, 2H), 2.29 - 2.20 (m, 1H), 1.08 - 1.04 (t, J = 8.0 Hz, 3H), 1.02 - 0.94 (m, 1H), 0.56 - 0.51 (m, 1H), 0.40 - 0.37 (m, 1H), 0.29 - 0.20 (m, 1H), 0.18 - 0.10 (m, 1H) m / z: 250.15 [M+1]

[0233] Step 6: 3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (1-7)

[0234] Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (1-6) (7.30 g, 29.1 mmol, 1.0 eq) was dissolved in methanol (50 ml), and 2 mol / L sodium hydroxide (58 ml, 116 mmol, 4.0 eq) solution was added. The system was in a turbid state. Tetrahydrofuran (50 ml) was added, and the system became clear. The reaction was carried out at room temperature for 2 hours and then completed. The reaction solution was concentrated to dryness, and the pH value was adjusted to 4.0 with 1 mol / L citric acid solution. Ethyl acetate (50 ml) was added for liquid separation, and the organic phase was washed with saturated brine to obtain crystalline solid 1-7 (6.30 g, 97%).

[0235] 1 H NMR (400 MHz, DMSO-d6): δ 8.02 - 8.00 (d, J = 8.0 Hz, 1H), 6.91 - 6.89 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 3.83 (s, 3H), 2.74 - 2.72 (m, 2H), 2.29 - 2.20 (m, 1H), 1.02 - 0.94 (m, 1H), 0.55 - 0.50 (m, 1H), 0.38 - 0.35 (m, 1H), 0.27 - 0.18 (m, 1H), 0.18 - 0.10 (m, 1H), m / z: 222.20 [M+1].

[0236] Step 8: 3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (1-8)

[0237] 3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (1-7) (6.00 g, 27.1 mmol, 1.2 eq) was dissolved in acetonitrile (50 ml), stirred, and potassium carbonate (9.4 g, 67.8 mmol, 2.5 eq) and benzyl bromide (5.60 g, 32.5 mmol, 1.2 eq) were added. The temperature was raised to 50 °C, and the reaction was carried out for 1 hour and then completed. The reaction solution was concentrated, and the residue was dissolved in dichloromethane (50 ml), washed with water. After the organic phase was concentrated, the residue was purified by column chromatography to obtain crystalline solid 1-8 (5.50 g, 95%).

[0238] 11H NMR (400 MHz, DMSO-d6): δ 7.78 - 7.76 (d, J = 8.0 Hz, 1H), 6.90 - 6.88 (d, J = 8.0 Hz, 1H), 7.35 - 7.30 (m, 5H), 6.68 (s, 1H), 5.35 (abs, 2H), 3.83 (s, 3H), 2.74 - 2.72 (m, 2H), 2.29 - 2.20 (m, 1H), 1.02 - 0.96 (m, 1H), 0.58 - 0.52 (m, 1H), 0.40 - 0.36 (m, 1H), 0.28 - 0.20 (m, 1H), 0.19 - 0.12 (m, 1H), m / z: 312.15 [M+1].

[0239] Step 9: Benzyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate (1-9)

[0240] Benzyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (1-8) (5.50 g, 17.6 mmol, 1.0 eq) was added to N,N-dimethylformamide (55 ml), pyridine hydrochloride (4.2 g, 35.2 mmol, 2.00 eq) was added, the system was purged with nitrogen, heated to 120 °C and reacted for 3.0 h. After the reaction was completed, the temperature was cooled to room temperature, water (50 ml) and ethyl acetate (55 ml) were added, stirred for 5 minutes, separated, the organic phase was concentrated and purified by column chromatography to obtain colorless oil 1-9 (4.80 g, 92%).

[0241] 1 1H NMR (400 MHz, DMSO-d6): δ 11.49 (s, 1H), 7.36 - 7.33 (m, 1H), 7.39 - 7.37 (d, J = 8.0 Hz, 1H), 6.45 - 6.40 (m, 1H), 6.19 (s, 1H), 5.31 - 5.29 (abs, 1H), 3.25 - 3.21 (m, 1H), 2.75 - 2.70 (m, 1H), 2.38 - 2.30 (m, 1H), 1.02 - 0.93 (m, 1H), 0.58 - 0.50 (m, 1H), 0.43 - 0.37 (m, 1H), 0.29 - 0.20 (m, 1H), 0.24 - 0.12 (m, 1H). m / z: 298.15 [M+1].

[0242] Step 10: tert-Butyl 4-(((4-(1-cyclopropyl-3-benzyloxy-3-propionylpyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (1-10)

[0243] Under nitrogen atmosphere, benzyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate (1-9) (4.70 g, 15.8 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (3.40 g, 15.8 mmol) were added to toluene (40 mL), stirred, and then cyanomethylenetributylphosphorane (7.70 g, 40 mmol) was added. The temperature was raised to 100 °C and the reaction was carried out for 2 - 3 hours. After stopping the reaction, the product was purified by column chromatography to obtain a foamy solid 1-10 (5.90 g, yield: 75.1%).

[0244] 1 H NMR (400 MHz, CDCl3): δ 8.09 - 8.08 (d, J = 4.0 Hz, 1H), 7.33 (m, 1H), 6.77 - 6.76 (d, J = 4.0 Hz, 1H), 6.63 (1H, s), 5.20 - 5.05 (Abs, 2H), 4.17 - 4.05 (m, 2H), 3.65 - 3.62 (m, 2H), 3.55 - 3.52 (m, 2H), 3.21 - 3.18 (m, 1H), 2.79 - 2.76 (m, 1H), 2.40 - 2.36 (m, 1H), 2.03 - 1.89 (m, 1H), 1.85 - 1.83 (m, 2H), 1.49 (s, 9H), 1.45 - 1.26 (m, 2H), 1.07 - 0.88 (m, 1H), 0.66 - 0.55 (m, 1H), 0.55 - 0.40 (m, 1H), 0.35 - 0.29 (m, 1H), 0.22 - 0.15 (m, 1H), m / z: 395.35 [M-CO2-C3H6].

[0245] Step 11: Benzyl 3-cyclopropyl-3-(2-(piperidin-4-yloxy)pyridin-4-yl)propionate (1-11)

[0246] tert-Butyl 4-(((4-(1-cyclopropyl-3-benzyloxy-3-propionylpyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (1-11) (5.50 g, 11.12 mmol) was added to dichloromethane (25 mL), stirred until dissolved, and then trifluoroacetic acid (6.30 g, 55.7 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, it was washed with saturated sodium bicarbonate solution and brine, and then separated. The organic phase was dried over sodium sulfate to obtain a white solid 1-11 (4.30 g, yield: 98.0%).

[0247] 11H NMR (400 MHz, CDCl3): δ 8.09 - 8.07 (d, J = 8.0 Hz, 1H), 7.35 - 7.30 (m, 5H), 6.96 - 6.94 (d, J = 4.0 Hz, 1H), 6.61 (m, 1H), 5.20 - 5.05 (Abs, 2H), 4.13 - 3.99 (m, 2H), 3.21 - 3.18 (d, 2H), 2.79 - 2.63 (m, 5H), 2.33 - 2.24 (m, 1H), 2.03 - 1.89 (m, 1H), 1.85 - 1.82 (m, 2H), 1.35 - 1.26 (m, 2H), 1.05 - 0.95 (m, 1H), 0.67 - 0.59 (m, 1H), 0.53 - 0.42 (m, 1H), 0.37 - 0.27 (m, 1H), 0.20 - 0.10 (m, 1H). m / z: 395.50 [M+1].

[0248] Step 12: Benzyl 3-cyclopropyl-3-(2-((1-(2-((2-(tert-butyldimethylsilyloxy)ethyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (1-12)

[0249] Mix N-(2-((tert-butyldimethylsilyloxy)ethyl)-2-fluoro-4-methoxy-N-(6-methylpyridin-2-yl)benzamide (1-2) (1.67 g, 4 mmol), benzyl 3-cyclopropyl-3-(2-(piperidin-4-ylmethoxy)pyridin-4-yl)propionate (1-11) (2.21 g), and cesium carbonate (2.61 g, 8 mmol), and stir the reaction mixture at 130 °C overnight. After the reaction is completed, add dichloromethane to stir and dissolve, filter, concentrate, and perform column chromatography to obtain a colorless oily substance 1-12 (1.06 g, yield: 33.5%).

[0250] m / z: 793.70 [M+1].

[0251] Step 13: Benzyl 3-cyclopropyl-3-(2-((1-(2-((2-ethoxy)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (1-13)

[0252] Dissolve benzyl 3-cyclopropyl-3-(2-((1-(2-((2-(tert-butyldimethylsilyloxy)ethyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (1.06 g, 1.34 mmol) in tetrahydrofuran (10 ml), add 1 mol / L tetrabutylammonium fluoride (1.6 ml, 1.6 mmol), and stir the reaction at room temperature overnight. After the reaction is completed, add water (10 ml), stir with ethyl acetate (10 ml * 3), separate the layers, extract with ethyl acetate (10 ml * 2), combine the organic phases, wash with brine, concentrate, and perform column chromatography to obtain a colorless oil 1-13 (709 mg, yield: 100%).

[0253] m / z: 679.60 [M+1].

[0254] Step 14: Benzyl 3-cyclopropyl-3-(2-((1-(2-((2-(isobutyric acid)ethyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (1-14)

[0255] Dissolve benzyl 3-cyclopropyl-3-(2-((1-(2-((2-ethoxy)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (366 mg, 0.54 mmol) in dichloromethane (10 ml), add triethylamine (109 mg, 1.08 mmol), add isobutyryl chloride (63 mg, 0.6 mmol), and stir the reaction at room temperature overnight. After the reaction is completed, concentrate and perform column chromatography to obtain a colorless oil 1-14 (287 mg, yield: 80.0%).

[0256] m / z: 749.60 [M+1]

[0257] Step 15: 3-Cyclopropyl-3-(2-((1-(2-((2-(isobutyric acid)ethyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionic acid (Compound 1)

[0258] Dissolve benzyl 3-cyclopropyl-3-(2-((1-(2-((2-(isobutyric acid)ethyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (280 mg) in methanol (3 ml), add 10% palladium on carbon (56 mg), introduce hydrogen gas, and stir the reaction at room temperature for 2 hours. After the reaction is completed, filter, concentrate, and purify to obtain white solid Compound 1 (170 mg, yield: 22.7%).

[0259] 1 1H NMR (400 MHz, CDCl3): δ 8.06 - 8.05 (d, J = 8 Hz, 1H), 7.41 - 7.39 (d, J = 8 Hz, 1H), 7.11 (s, 1H), 6.77 - 6.72 (m, 2H), 6.63 (s, 1H), 6.53 - 6.50 (m, 1H), 6.29 - 6.18 (m, 2H), 4.62 - 4.34 (m, 4H), 4.13 - 4.10 (m, 2H), 3.76 (s, 3H), 3.44 - 3.07 (m, 1H), 2.82 - 2.70 (m, 2H), 2.64 - 2.44 (m, 6H), 2.33 - 2.25 (m, 2H), 1.85 - 1.55 (m, 4H), 1.18 - 1.16 (m, 1H), 0.96 - 0.94 (d, 7H), 0.61 - 0.59 (m, 1H), 0.44 - 0.41 (m, 1H), 0.31 - 0.29 (m, 1H), 0.17 - 0.15 (m, 1H), m / z: 659.55 [M+1].

[0260] Example 2:

[0261]

[0262] Compound 2: 3 - Cyclopropyl - 3 - (2 - ((1 - (2 - ((2 - ((3,3 - dimethylbutanoyl)oxy)ethyl)(6 - methylpyridin - 2 - yl)carbamoyl)-5 - methoxyphenyl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid

[0263] According to a synthetic method similar to that of Example 1, 3,3 - dimethylbutanoyl chloride was used to replace isobutyryl chloride to prepare Compound 2.

[0264] Yield: 70.0%. 11H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.34 - 7.32 (m, 1H), 7.06 (s, 1H), 6.69 (s, 2H), 6.57 (s, 1H), 6.46 - 6.45 (m, 1H), 6.27 - 6.13 (m, 2H), 4.51 (s, 1H), 4.26 (s, 2H), 4.07 (s, 2H), 3.71 (s, 3H), 3.19 (s, 1H), 2.70 - 2.68 (m, 2H), 2.43 - 2.38 (m, 5H), 2.27 - 2.14 (m, 2H), 1.92 (s, 2H), 1.74 - 1.65 (m, 4H), 1.21 - 1.19 (m, 1H), 0.98 - 0.95 (m, 1H), 0.86 - 0.84 (m, 10H), 0.55 (s, 1H), 0.40 (s, 1H), 0.25 (s, 1H), 0.11 (s, 1H), m / z: 687.50 [M+1].

[0265] Example 3:

[0266]

[0267] Compound 3: 3-Cyclopropyl-3-(2-((1-(5-methoxy-2-((6-methylpyridin-2-yl)(2-(pivaloyloxy)ethyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0268] According to a synthetic method similar to that of Example 1, using pivaloyl chloride as the raw material instead of isobutyryl chloride, Compound 3 was prepared.

[0269] Yield: 79.6%. 1 1H NMR (400 MHz, CDCl3): δ 8.05 - 8.03 (d, J = 8 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.11 (s, 1H), 6.74 - 6.72 (m, 1H), 6.83 - 6.81 (m, 2H), 6.63 - 6.61 (s, 1H), 6.52 - 6.50 (m, 1H), 6.27 - 6.25 (m, 1H), 6.17 - 6.15 (m, 1H), 4.62 - 4.12 (m, 6H), 3.76 (s, 3H), 3.25 - 3.23 (m, 1H), 2.76 - 2.30 (m, 9H), 1.71 - 1.68 (m, 4H), 1.25 - 1.23 (m, 2H), 0.96 (s, 9H), 0.60~0.58 (m, 1H), 0.46~0.44 (m, 1H), 0.30 - 0.29 (m, 1H), 0.16 - 0.14 (m, 1H).

[0270] m / z: 673.50 [M+1] 695.55 [M+Na].

[0271] Example 4:

[0272]

[0273] Compound 4: 3-Cyclopropyl-3-(2-((1-(2-((2-Isopropyl-2-acetoxy)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0274] Compound 4 was prepared according to the following route.

[0275]

[0276] Step 1: Methyl N-(2-fluoro-4-methoxybenzoyl)-N-(6-methylpyridin-2-yl)glycinate (4-1)

[0277] 2-Fluoro-4-methoxybenzoic acid (2.50 g, 14.7 mmol, 1.0 eq) was added to tetrahydrofuran (15 ml), N,N-dimethylformamide (0.02 ml), and oxalyl chloride (2.05 g, 16.0 mmol, 1.1 eq) were added, and the reaction was carried out at room temperature for 1.0 hour. After the reaction was complete, the solvent was evaporated, and then tetrahydrofuran (10 ml) was added and dropped into a mixed solution of methyl N-(6-methylpyridin-2-yl)glycinate (2.1 g, 11.7 mmol, 0.8 eq), tetrahydrofuran (20 ml), and triethylamine (4.45 g, 44 mmol, 3.0 eq). After addition, the reaction was carried out at room temperature overnight. After the reaction was complete, water was added, ethyl acetate (15 ml × 2) was added, dried over anhydrous sodium sulfate, the organic phase was evaporated, and column purification gave the product as a white solid 4-1 (2.10 g, 43%).

[0278] 1 1H NMR (400 MHz, CDCl3): 7.41 - 7.35 (t, 1H), 7.33~7.31 (t, 1H), 6.70~6.73 (m, 1H), 6.63 - 6.60 (m, 1H), 6.88~6.84 (m, 1H), 6.44~6.40 (dd, 1H), 4.87 (s, 2H), 3.77 (s, 3H), 3.74 (s, 3H), 2.48 (s, 3H). m / z: 333.20 [M+1].

[0279] Step 2: N-(2-Fluoro-4-methoxybenzoyl)-N-(6-methylpyridin-2-yl)glycine (4-2)

[0280] Methyl N-(2-fluoro-4-methoxybenzoyl)-N-(6-methylpyridin-2-yl)glycinate (2.10 g, 6.32 mmol, 1.0 eq) was added to methanol / tetrahydrofuran (12 ml / 4 ml), and 2 mol / L sodium hydroxide solution (6.32 ml, 12.6 mmol, 2.0 eq) was added. The mixture was heated to 45 °C and reacted for 1.0 hour. After the reaction was completed, the solvent was evaporated under reduced pressure. Water (2.0 ml) was added and stirred, and the pH value was adjusted to 5 - 6 with 1 mol / L citric acid aqueous solution. Ethyl acetate (10 ml) was added and stirred. The layers were separated, and the organic phase was concentrated and purified to obtain solid 4-2 (2.00 g, 100%).

[0281] 1 H NMR (400 MHz, CDCl3): 7.42 - 7.38 (t, 1H), 7.36~7.32 (t, 1H), 7.08~7.04 (m, 1H), 6.63 - 6.60 (m, 1H), 6.68~6.66 (m, 1H), 6.44~6.40 (dd, 1H), 4.74 (s, 2H), 3.78 (s, 3H), 2.58 (s, 3H), m / z: 319.10 [M+1].

[0282] Step 3: 4-Methoxybenzyloxy N-(2-fluoro-4-methoxybenzoyl)-N-(6-methylpyridin-2-yl)glycine-(4-methoxy)benzyl ester (4-3)

[0283] N-(2-Fluoro-4-methoxybenzoyl)-N-(6-methylpyridin-2-yl)glycine (1.80 g, 5.66 mmol, 1.0 eq) was added to N,N-dimethylformamide (0.02 ml), potassium carbonate (1.17 g, 8.44 mmol, 1.5 eq), 4-methoxybenzyl chloride (1.06 g, 6.79 mmol, 1.2 eq), and acetonitrile (10 ml) were added. The reaction was carried out at room temperature for 5 hours. After the reaction was completed, water (10 ml) was added and stirred, ethyl acetate (10 ml × 2) was added, and it was dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure and purified by column chromatography to obtain a pale white solid 4-3 (2.01 g, 81.3%).

[0284] 1 H NMR (400 MHz, CDCl3): 7.38 - 7.26 (m, 5H), 6.68~6.66 (m, 3H), 6.64~6.62 (m, 1H), 6.59~6.56 (m, 1H), 6.44~6.40 (dd, 1H), 5.11 (s, 2H), 4.87 (s, 2H), 3.77 (s, 3H), 3.81 (s, 3H), 2.45 (s, 3H), m / z: 439.30 [M+1], 461.25 [M+Na].

[0285] Step 4: Benzyl 3-cyclopropyl-3-(2-((1-(5-methoxy-2-((2-((4-methoxybenzyl)oxy)-2-oxoethyl)(6-methylpyridin-2-yl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (4-4)

[0286] Mix 4-methoxybenzyloxy N-(2-fluoro-4-methoxybenzoyl)-N-(6-methylpyridin-2-yl)glycine-(4-methoxy)benzyl ester (4-3) (0.92 g, 2.1 mmol, 1.0 eq), benzyl 3-cyclopropyl-3-(2-(piperidin-4-ylmethoxy)pyridin-4-yl)propionate (1-11) (1.24 g, 3.1 mmol, 1.5 eq), and cesium carbonate (1.36 g, 4.2 mmol, 2.0 eq) evenly, heat to 130 °C, react overnight. After the reaction is completed, cool to room temperature, add ethyl acetate (15 ml), filter through diatomaceous earth to obtain a filtrate, dry and concentrate, and purify to obtain product 4-4 (200 mg, 12%).

[0287] 1 H NMR (400 MHz, CDCl3): 8.03 - 8.02 (d, J = 4.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.24 - 7.22 (m, 5H), 7.20 - 7.15 (m, 4H), 6.83 - 6.80 (m, 2H), 6.73 - 6.70 (m, 2H), 6.52 - 6.49 (m, 2H), 6.25 (s, 1H), 5.30 (s, 1H), 5.07 - 5.03 (m, 4H), 4.13 - 4.10 (m, 3H), 3.80 (s, 5H), 2.80 - 2.76 (m, 2H), 2.57 - 2.51 (m, 2H), 2.41 (s, 2H), 2.25 - 2.21 (m, 1H), 2.05 (s, 1H), 1.80 - 1.75 (m, 1H), 1.62 (s, 2H), 1.29 - 1.26 (m, 4H), 0.95 - 0.90 (m, 2H), 0.52 (s, 1H), 0.44 (s, 1H), 0.23 (s, 1H), 0.15 (s, 1H), m / z: 813.70 [M+1].

[0288] Step 5: N-(2-(4-(((4-(3-(benzyloxy)-1-cyclopropyl-3-oxoisopropyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxybenzoyl)-N-(6-methylpyridin-2-yl)glycine (4-5)

[0289] Benzyl 3-cyclopropyl-3-(2-((1-(5-methoxy-2-((2-((4-methoxybenzyl)oxy)-2-oxoethyl)(6-methylpyridin-2-yl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (4-4) (200 mg, 0.25 mmol, 1.0 eq) was added to dichloromethane (10 ml), and trifluoroacetic acid (1.0 ml) was added. The reaction was carried out at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure. The pH value was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution. Ethyl acetate (15 mL) was added and stirred. The layers were separated. The organic layer was dried and concentrated. The product 4-5 (140 mg, 82%) was obtained by purification. m / z: 693.50 [M+1].

[0290] Step 6: Benzyl 3-cyclopropyl-3-(2-((1-(2-((2-isopropyl-2-acetoxy)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (4-6)

[0291] N-(2-(4-(((4-(3-(Benzyloxy)-1-cyclopropyl-3-oxoisopropyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxybenzoyl)-N-(6-methylpyridin-2-yl)glycine (4-5) (140 mg, 0.202 mmol, 1.0 eq) was added to isopropanol (2 ml), and thionyl chloride (48 mmol, 0.40 mmol, 2.0 eq) was added. The reaction was heated to 45 °C for 1.0 hour. After the reaction was completed, the reaction solution was evaporated under reduced pressure. The pH value was adjusted to 8.0-9.0 with saturated aqueous sodium bicarbonate solution. Ethyl acetate (10 ml) was added to extract the organic phase. The organic phase was dried and concentrated. The solid (80 mg, 54%) was obtained by purification.

[0292] m / z: 735.60 [M+1].

[0293] Step 7: 3-Cyclopropyl-3-(2-((1-(2-((2-isopropyl-2-acetoxy)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionic acid (Compound 4)

[0294] Benzyl 3-cyclopropyl-3-(2-((1-(2-((2-isopropyl-2-acetoxy)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (4-6) (80 mg, 0.109 mmol, 1.0 eq) was added to methanol (2 ml), and 10% palladium on carbon (16 mg, 20% content) was added. Hydrogen was introduced, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth and then filtered by suction. The solid compound 4 (20 mg, 28%) was obtained by column chromatography purification.

[0295] 1 1H NMR (400 MHz, CDCl3): δ 8.05 - 8.04 (d, J = 8 Hz, 1H), 7.40 - 7.38 (d, J = 8 Hz, 1H), 7.10 (s, 1H), 6.77 - 6.72 (m, 2H), 6.62 (s, 1H), 6.53 - 6.51 (m, 1H), 6.27 - 6.20 (m, 2H), 4.71 - 4.62 (m, 1H), 4.13 - 4.10 (m, 2H), 3.76 (s, 3H), 3.44 - 3.07 (m, 2H), 2.82 - 2.70 (m, 2H), 2.64 - 2.44 (m, 6H), 2.33 - 2.25 (m, 2H), 1.85 - 1.55 (m, 2H), 1.18 - 1.16 (m, 2H), 1.10 - 1.08 (m, 7H), 0.61 - 0.59 (m, 1H), 0.44 - 0.41 (m, 1H), 0.31 - 0.29 (m, 1H), 0.16 - 0.14 (m, 1H). m / z: 645.50 [M+1].

[0296] Example 5:

[0297]

[0298] Compound 5: 3-(2-((1-(2-((2-Ethoxycarbonyl)ethyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)-3-cyclopropylpropanoic acid

[0299] According to the similar synthesis of Example 1, using acetyl chloride to replace isobutyryl chloride, Compound 5 was obtained.

[0300] Yield: 75.3%. 1 1H NMR (400 MHz, CDCl3): δ 8.06 - 8.05 (m, 1H), 7.40 - 7.39 (d, J = 8 Hz, 1H), 7.14 (s, 1H), 6.76 - 6.72 (m, 2H), 6.63 (s, 1H), 6.52 - 6.50 (m, 1H), 6.41 - 6.20 (m, 2H), 4.59 - 4.35 (m, 4H), 4.13 - 4.10 (m, 2H), 3.77 (s, 3H), 3.26 - 3.20 (m, 1H), 2.76 - 2.31 (m, 10H), 1.82 - 1.60 (m, 7H), 0.99 - 0.97 (m, 1H), 0.60 - 0.58 (m, 1H), 0.31 - 0.29 (m, 1H), 0.17 - 0.15 (m, 1H).

[0301] m / z: 631.55 [M+1].

[0302] Example 6:

[0303]

[0304] Compound 6: 3-Cyclopropyl-3-(2-((1-(5-methoxy-2-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)carbonyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0305] According to a similar synthesis method as in Example 1, using the raw material 1-(2,2,2-trifluoroethyl)piperidin-4-ol to replace 1-2, Compound 6 was prepared.

[0306] Yield: 68.0%. 1 H NMR (400 MHz, DMSO-d6): 12.10 (br s, 1H), 8.06 - 8.03 (t, J = 12.0 Hz, 12.0 Hz, 1H), 7.65 - 7.63 (d, J = 8.0 Hz, 1H), 6.92 - 6.91 (m, 1H), 6.71 (s, 1H), 6.56 - 6.54 (m, 2H), 4.86 (s, 1H), 4.15 - 4.13 (m, 2H), 3.79 (s, 3H), 3.29 - 3.27 (m, 3H), 3.20 - 3.18 (m, 2H), 2.67 - 2.64 (m, 4H), 2.63 - 2.59 (m, 2H), 2.21 - 2.17 (m, 1H), 2.03 - 1.91 (m, 2H), 1.69 - 1.68 (m, 2H), 1.63 - 1.61 (m, 2H), 1.00 - 0.98 (m, 1H), 0.51 - 0.49 (m, 1H), 0.32 - 0.28 (m, 2H), 0.17 - 0.16 (m, 1H).

[0307] m / z: 620.55 [M+1]

[0308] Example 7:

[0309]

[0310] Compound 7: 3-Cyclopropyl-3-(2-((1-(5-methoxy-2-((pivalyloxy)carbonyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0311] Compound 7 was synthesized according to the following route.

[0312] According to a synthetic method similar to that of Example 4, using the above route, replace methyl (6-methylpyridin-2-yl)glycinate with the raw material 2,2-dimethylpropanol to prepare Compound 7.

[0313] Yield: 80.0%. 1 1H NMR (400 MHz, DMSO-d6): 12.00 (brs, 1H), 8.09 - 8.07 (d, J = 8.0 Hz, 1H), 7.65 - 7.63 (d, J = 8.0 Hz, 1H), 6.96 - 6.94 (m, 1H), 6.68 (s, 1H), 6.56 - 6.54 (m, 2H), 4.14 - 4.11 (m, 2H), 3.86 (m, 2H), 3.79 (s, 3H), 3.27 - 3.25 (m, 2H), 3.20 - 3.18 (m, 3H), 2.62 - 2.60 (m, 1H), 2.20 -

[0314]

[0315] 2.15 (m, 1H), 2.00 - 1.90 (m, 1H), 1.69 - 1.68 (m, 2H), 1.63 - 1.61 (m, 2H), 1.00 - 0.98 (m, 1H), 0.96 (s, 9H), 0.51 - 0.49 (m, 1H), 0.32 - 0.28 (m, 2H), 0.17 - 0.16 (m, 1H), m / z: 525.30 [M + 1].

[0316] Example 8:

[0317]

[0318] Compound 8: 3-cyclopropyl-3-(2-((1-(5-methoxy-2-((neopentyloxy)carbonyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0319] Compound 8 was prepared according to the following route.

[0320]

[0321] Step 1: 5-(3-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8-1)

[0322] m-Hydroxybenzaldehyde (15.00 g, 0.122 mol) was added to water (120 ml), and the mixture was heated to 85 °C until the reaction system became clear. Isopropylidene malonate (17.7 g, 0.122 mol) was added portionwise. After addition, the reaction solution was heated to 85 °C and stirred for 16 hours. The reaction was completed. The reaction solution was naturally cooled to room temperature, filtered, and the filter cake was washed twice with water and then dried to obtain 8-1, a white solid (15.20 g, yield: 50.0%).

[0323] 1H NMR (400 MHz, CDCl3) 9.79 (s, 1H), 8.37 (s, 1H), 7.78 - 7.77 (t, J = 2 Hz, 1H), 7.48 - 7.46 (d, J = 8.0, 1H), 7.438 - 7.36 (d, J = 8.0, 1H), 7.09 - 7.07 (m, 1H) 5.73 (s, 1H), 1.80 (s, 6H), m / z: 260.10 [M+Na].

[0324] Step 2: 5-(Cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (8-2)

[0325] 5-(3-Hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8-1) (11.00 g, 0.048 mol, 1.0 eq) was added to tetrahydrofuran (50 ml), and the temperature was lowered to -10 °C. 1 mol / L cyclopropylmagnesium bromide (220 ml, 3.0 eq) was added dropwise, and the reaction was carried out at room temperature for 1.5 hours. The reaction of the raw materials was monitored to be complete. The reaction solution was quenched with 1 mol / L hydrochloric acid, and the pH value was adjusted to 2.0 - 3.0. It was extracted with ethyl acetate (100 ml * 3), the organic phases were combined, washed with saturated brine (300 ml), and dried over anhydrous sodium sulfate. The organic phase was purified by column chromatography to obtain 8-2, a pale yellow liquid (11.5 g, yield: 81%).

[0326] 1 1H NMR (400 MHz, CDCl3) δ: 9.30 (s, 1H); 7.18 - 7.14 (t, J = 8.0 Hz, 1H); 6.75 (s, 1H); 6.69 - 6.67 (d, 1H); 6.70 - 6.95 (m, 1H); 4.56 (s, 1H); 2.69 - 2.66 (m, 1H); 1.75 (s, 3H); 1.74 - 1.72 (m, 1H); 1.44 (s, 3H); 0.60 - 0.56 (m, 2H); 0.37 - 0.35 (m, 1H); 0.13 - 0.10 (m, 1H).

[0327] Step 3: Ethyl 3-cyclopropyl-3-(3-hydroxyphenyl)propionate (8-3)

[0328] Under nitrogen conditions, 5-(cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (8-2) (11.5 g, 0.039 mol) was dissolved in N,N-dimethylformamide (12 ml) and ethanol (6 ml), stirred, and the reaction solution was heated to 100 °C for 5 hours to complete the reaction. After concentration, it was dissolved in ethyl acetate (50 ml), washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and the organic phase was purified by column chromatography to obtain a colorless liquid 8-3 (5.00 g, yield: 53.8%).

[0329] 1 H NMR (400 MHz, CDCl3) δ: 7.16 - 7.12 (t, J = 8.0 Hz, 1H), 6.80 - 6.78 (d, J = 8.0 Hz, 1H), 6.75 - 6.65 (m, 2H), 4.87 (s, 1H), 4.14 - 3.99 (m, 2H), 2.80 - 2.63 (m, 2H), 2.37 - 2.26 (m, 1H), 1.17 - 1.13 (t, J = 8.0 Hz, 3H), 1.08 - 0.93 (m, 1H), 0.63 - 0.51 (m, 1H), 0.49 - 0.37 (m, 1H), 0.27 - 0.23 (m, 1H), 0.15 - 0.12 (m, 1H). m / z: 256.10 [M+Na]

[0330] Step 4: tert-Butyl 4-((3-(1-cyclopropyl-3-ethoxy-3-oxopropyl)phenoxy)methyl)piperidine-1-carboxylate (8-4)

[0331] Ethyl 3-cyclopropyl-3-(3-hydroxyphenyl)propionate (8-3) (5 g, 0.021 mol) was dissolved in acetone (50 ml), N-tert-butoxycarbonyl-4-piperidinemethanol (4.59 g, 0.021 mmol) was added, the mixture was purged with H2 five times and then cyanomethylenetributylphosphine (10.14, 0.042 mmol) was added, and the mixture was heated to 100 °C for 1 hour to monitor the completion of the reaction. After the reaction solution was cooled, it was concentrated and purified by column chromatography to obtain a colorless liquid 8-4 (6.70 g, yield: 73.2%).

[0332] m / z: 332.30 [M+1-Boc]

[0333] Step 5: 3-(3-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropanoic acid (8-5)

[0334] Dissolve tert-butyl 4-((3-(1-cyclopropyl-3-ethoxy-3-oxopropyl)phenoxy)methyl)piperidine-1-carboxylate (8-4) (6.5 g, 15.06 mmol) in tetrahydrofuran (20 ml) and methanol (20 ml), add 2 mol / L sodium hydroxide solution (75 ml, 150 mmol), and stir the reaction at 50 °C for 1 hour. After monitoring shows the reaction is complete, concentrate, add 1 mol / L citric acid to adjust the pH to 5.0 - 6.0, extract with ethyl acetate 3 times, wash with ice water, concentrate, and obtain white solid 8-5 (5.80 g, yield: 95.0%) after purification.

[0335] 1 H NMR(400MHz,CDCl3):7.25-7.21(t,J=8.0Hz,1H),6.99-6.94(m,2H),6.76 -6.74(d,J=8.0Hz,1H),4.06-4.02(m,2H),3.69-3.58(m,4H),2.90-2.75(m,2H),2.38-2.34(m,1H),2.15-2.13(m,1H),1.76-1.72(m,2H),1.53-1.49(m,2H),1.46(s,9H),1.08-1.06(m,1H),0.60-0.59(m,1H),0.39-0.28(m,2H),0.11-0.07(m,1H),m / z:304.30[M+1-Boc]。

[0336] Step 6: tert-Butyl 4-((3-(3-(benzyloxy)-1-cyclopropyl-3-oxopropyl)phenoxy)methyl)piperidine-1-carboxylate (8-6)

[0337] Dissolve 3-(3-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)phenyl)-3-cyclopropylpropanoic acid (8-5) (5.50 g, 13.63 mmol) in N,N-dimethylformamide (10 ml), add potassium carbonate (4.70 g, 34 mmol), benzyl bromide (2.50 g, 15.0 mmol), and stir the reaction at 25 °C for 1 hour. After the reaction is complete, add water (50 ml) and ethyl acetate (50 ml), stir, separate the layers, extract the aqueous phase with ethyl acetate (50 ml × 2), combine the organic phases, wash with saturated brine, concentrate, and obtain an oily substance 8-6 (6.10 g, yield: 90.0%) after purifying the organic phase.

[0338] 11H NMR (400 MHz, CDCl3): δ 7.35 - 7.31 (m, 5H), 7.29 - 7.25 (t, J = 8.0 Hz, 1H), 7.01 - 6.98 (m, 2H), 6.78 - 6.78 (d, J = 8.0 Hz, 1H), 5.26 - 5.22 (abs, 2H), 4.10 - 4.06 (m, 2H), 3.71 - 3.60 (m, 4H), 2.91 - 2.77 (m, 2H), 2.39 - 2.35 (m, 1H), 2.17 - 2.15 (m, 1H), 1.76 - 1.72 (m, 2H), 1.53 - 1.49 (m, 2H), 1.46 (s, 9H), 1.08 - 1.06 (m, 1H), 0.61 - 0.59 (m, 1H), 0.39 - 0.29 (m, 2H), 0.11 - 0.08 (m, 1H). m / z: 394.30 [M+1 - Boc].

[0339] Step 7: Ethyl 3 - cyclopropyl - 3-(3-(piperidin - 4 - ylmethoxy)phenyl)propionate (8 - 7)

[0340] Dissolve tert - butyl 4 - ((3-(3 - (benzyloxy)-1 - cyclopropyl - 3 - propionyl)phenyl)oxymethyl)piperidine - 1 - carboxylate (8 - 6) (6.00 g, 12.15 mmol) in isopropanol (10 ml), add hydrogen chloride isopropanol solution (25 ml, 4 mol / L, 100 mmol), stir the reaction at room temperature for 4 hours, and monitor the completion of the reaction. Concentrate the reaction solution, disperse it with ethyl acetate (20 ml), add saturated sodium carbonate for neutralization, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the organic phase to obtain an oily substance 8 - 7 (3.80 g, yield: 88.0%).

[0341] According to a similar synthetic method as in Example 7, replace 1 - 11 with raw material 8 - 7 to prepare Compound 8.

[0342] 3 - Cyclopropyl - 3-(3 - ((1-(5 - methoxy - 2-(neopentyl formate)phenyl)piperidin - 4 - yl)methoxy)phenyl)propanoic acid (Compound 8)

[0343] Yield: 88.7%. 11H NMR (400 MHz, CDCl3): δ 7.85 - 7.83 (d, J = 8.0 Hz, 1H), 7.25 - 7.21 (t, J = 8.0 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.78 - 6.76 (d, J = 8.0 Hz, 1H), 6.46 - 6.39 (m, 2H), 4.34 (s, 2H), 3.86 (m, 2H), 3.78 (s, 3H), 3.27 - 3.22 (m, 2H), 3.05 - 2.90 (m, 3H), 2.63 - 2.60 (m, 1H), 2.38 - 2.34 (m, 1H), 2.11 - 2.09 (m, 1H), 1.63 - 1.61 (m, 2H), 1.42 - 1.39 (m, 2H), 1.26 (s, 9H), 1.02 - 0.99 (m, 1H), 0.61 - 0.59 (m, 1H), 0.35 - 0.32 (m, 1H), 0.22 - 0.19 (m, 1H), 0.10 - 0.07 (m, 1H), m / z: 524.35 [M+1].

[0344] Example 9:

[0345]

[0346] Compound 9: 3-Cyclopropyl-3-(2-((1-(6-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)carbonyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0347] Compound 9 was prepared according to the following route.

[0348] Step 1: 2-Fluoro-4,5-dihydroxybenzaldehyde (9-1)

[0349] 2-Fluoro-4,5-dimethoxybenzaldehyde (5.0 g, 0.0272 mol, 1.0 eq) was dissolved in dichloromethane (30 mL), protected by nitrogen, cooled to -70 °C, and boron tribromide (81 mL, 0.081 mol, 3.0 eq, 1 mol / L) was added dropwise. During the addition, the temperature was controlled below -65 °C. After the addition, the mixture was transferred to room temperature and stirred overnight. After the reaction was complete, it was cooled to 0 °C, methanol (33 mL) was added dropwise, concentrated to dryness, methanol (40 mL) was added again, concentrated to dryness again, dissolved in dichloromethane, and purified by column chromatography.

[0350] The product, yellow solid 9-1 (4.15 g, 98.8%), was obtained.

[0351] m / z: 157.05 [M+1].

[0352] Step 2: 6-Fluorobenzo[d][1,3]dioxole-5-carbaldehyde (9-2)

[0353] 2-Fluoro-4,5-dihydroxybenzaldehyde (9-1) (4.15 g, 0.026 mol, 1.0 eq) was added to N,N-dimethylformamide (40.0 ml), potassium carbonate (9.2 g, 0.066 mol, 2.5 eq), and dibromomethane (5.10 g, 0.029 mol, 1.1 eq) were added. Under nitrogen protection, the mixture was heated to 80 °C and reacted overnight. After the reaction was completed, water (40.0 ml) and ethyl acetate (40.0 ml) were added, stirred, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the product as a white solid 9-2 (3.50 g, 78%).

[0354] 1 1H NMR (400 MHz, CDCl3): 10.18 (s, 1H), 7.23 - 7.21 (d, J = 8.0 Hz, 1H), 6.65 - 6.63 (d, J = 8.0 Hz, 1H), 6.08 (s, 2H), m / z: 169.05 [M+1].

[0355] Step 3: 6-Fluorobenzo[d][1,3]dioxole-5-carboxylic acid (9-3)

[0356] 6-Fluorobenzo[d][1,3]dioxole-5-carbaldehyde (9-2) (3.50 g, 20 mmol, 1.0 eq) was added to tert-butanol (80 ml), 80% aqueous sodium chlorite solution (4.70 g, 41 mmol, 2.0 eq, 42 ml), sodium dihydrogen phosphate dihydrate (14.30 g, 104 mmol, 5.0 eq), and 2-methyl-2-butene (11.70 g, 167 mmol, 8.0 eq). The reaction was carried out at room temperature for 0.5 h. After the reaction was completed, ethyl acetate (80 ml) was added. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified to obtain a pale white solid 9-3 (3.60 g, 94.0%).

[0357] 1 1H NMR (400 MHz, CDCl3): 7.30 - 7.29 (d, J = 4.0 Hz, 1H), 6.75 - 6.72 (d, J = 12.0 Hz, 1H), 6.08 (s, 2H), m / z: 185.05 [M+1].

[0358] Step 4: 1-(2,2,2-Trifluoroethyl)piperidin-4-yl 6-fluorobenzo[d][1,3]dioxole-5-carboxylate (9-4)

[0359] 6-Fluorobenzo[d][1,3]dioxole-5-carboxylic acid (9-3) (1.60 g, 8.6 mmol, 1.0 eq) was added to dichloromethane (20 ml), N,N-dimethylformamide (0.05 ml) and oxalyl chloride (2.20 g, 17 mmol, 2.0 eq) were added, and the reaction was carried out at room temperature for 3.0 h. After the reaction was completed, the solvent was evaporated under reduced pressure. Dichloromethane (10 ml) was added and stirred until dissolved, and then the solution was added dropwise to a mixed solution of 1-(2,2,2-trifluoroethyl)piperidin-4-ol (1.30 g, 6.9 mmol, 0.8 eq) in dichloromethane (10 ml) and triethylamine (2.63 g, 26 mmol, 3.0 eq). After the addition was complete, the reaction was carried out at room temperature for 16 h. After the reaction was completed, water (10 mL) was added, stirred, and the layers were separated. The organic layer was evaporated under reduced pressure, and the product was obtained as a white solid 9-4 (2.00 g, 67%) by column chromatography.

[0360] 1 H NMR (400 MHz, CDCl3): 7.34 - 7.30 (m, 1H), 6.88 - 6.86 (d, J = 8.0 Hz, 1H), 6.67 - 6.65 (m, 2H), 6.37 - 6.35 (d, J = 8.0 Hz, 1H), 5.93 (s, 2H), 4.10 (s, 2H), 2.47 (s, 3H), 0.85 (s, 9H), m / z: 345.15 [M+1].

[0361] According to a synthetic method similar to that of Example 7, using raw material 9-4 to replace 7-1, compound 9 was prepared.

[0362] 3-Cyclopropyl-3-(2-((1-(6-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)carbonyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 9)

[0363] Yield: 85.0%. 11H NMR (400 MHz, DMSO-d6): 12.08 (br s, 1H), 8.09 - 8.06 (t, J = 12.0 Hz, 1H), 7.35 (s, 1H), 6.96 - 6.94 (m, 1H), 6.53 - 6.51 (m, 1H), 6.11 (s, 1H), 6.05 (s, 2H), 4.84 (m, 1H), 4.13 - 4.12 (m, 2H), 3.29 - 3.27 (m, 2H), 3.20 - 3.18 (m, 3H), 2.67 - 2.64 (m, 4H), 2.63 - 2.59 (m, 1H), 2.41 - 2.38 (m, 3H), 2.03 - 1.91 (m, 3H), 1.79 - 1.68 (m, 2H), 1.63 - 1.61 (m, 2H), 1.45 - 1.31 (m, 2H), 1.00 - 0.98 (m, 1H), 0.60 - 0.55 (m, 1H), 0.28 - 0.25 (m, 2H), 0.15 - 0.08 (m, 1H), m / z: 634.35 [M+1].

[0364] Example 10:

[0365] Compound 10: 3-Cyclopropyl-3-(2-((1-(7-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)carbonyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0366]

[0367] According to a synthetic method similar to Example 9, using 1,3-dibromoethane as the raw material to replace dibromomethane, Compound 10 was prepared.

[0368] Yield: 65.0%. 11H NMR (400 MHz, DMSO-d6): 12.08 (brs, 1H), 8.09 - 8.06 (t, J = 12.0 Hz, 1H), 7.30 (s, 1H), 6.96 - 6.94 (m, 1H), 6.48 - 6.45 (s, 1H), 6.11 (s, 1H), 4.84 (m, 1H), 4.34 - 4.31 (m, 4H), 4.13 - 4.10 (m, 2H), 3.29 - 3.27 (m, 2H), 3.20 - 3.18 (m, 3H), 2.67 - 2.64 (m, 4H), 2.63 - 2.59 (m, 1H), 2.41 - 2.38 (m, 3H), 2.03 - 1.91 (m, 3H), 1.79 - 1.68 (m, 2H), 1.63 - 1.61 (m, 2H), 1.45 - 1.31 (m, 2H), 1.00 - 0.98 (m, 1H), 0.62 - 0.57 (m, 1H), 0.29 - 0.26 (m, 2H), 0.16 - 0.09 (m, 1H), m / z: 648.30 [M+1]

[0369] Example 11:

[0370]

[0371] Compound 11: 3-Cyclopropyl-3-(2-((1-(6-((Pivaloyloxy)carbonyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)piperidin-4-yl)propanoic acid

[0372] According to a synthetic method similar to that of Example 11, using pivalol as the raw material to replace 1-(2,2,2-trifluoroethyl)piperidin-4-ol, Compound 11 was prepared.

[0373] Yield: 80.0%. 11H NMR (400 MHz, DMSO-d6): 12.08 (brs, 1H), 8.09 - 8.06 (t, J = 12.0 Hz, 1H), 7.30 (s, 1H), 6.96 - 6.94 (m, 1H), 6.48 - 6.45 (s, 1H), 6.11 (s, 1H), 6.06 (s, 2H), 4.36 (s, 2H), 3.86 (m, 2H), 3.27 - 3.22 (m, 2H), 3.05 - 2.90 (m, 3H), 2.63 - 2.60 (m, 1H), 2.38 - 2.33 (m, 1H), 2.10 - 2.08 (m, 1H), 1.62 - 1.60 (m, 2H), 1.40 - 1.38 (m, 2H), 1.27 (s, 9H), 1.02 - 0.99 (m, 1H), 0.60 - 0.57 (m, 1H), 0.33 - 0.30 (m, 1H), 0.20 - 0.19 (m, 1H), 0.12 - 0.09 (m, 1H), m / z: 539.30 [M+1]

[0374] Example 12:

[0375] Compound 12: (S)-3-Cyclopropyl-3-(2-((1-(2-((2-Isopropyloxy-2-oxoethyl)(6-methylpyridin-2-yl)carbonyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)piperidin-4-yl)propanoic acid

[0376]

[0377] Compound 12 was prepared according to the following route.

[0378]

[0379] Step 1: 3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid.(S)-1-(p-tolyl)ethylamine salt (12-1)

[0380] Dissolve 3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (1-7) (12.50 g, 56 mmol, 1.0 eq) in absolute ethanol (280 ml), add (S)-1-(p-tolyl)ethylamine (7.63 g, 56 mmol, 1.0 eq) dissolved in ethyl acetate (560 ml). After addition, stir at room temperature overnight. Filter, wash the filter cake with absolute ethanol:ethyl acetate (1:2), drain, and dry the filter cake to obtain a white solid (4.90 g). Dissolve the white solid in absolute ethanol (96 ml), heat to 70 °C, stir to dissolve, control the temperature at 50 - 60 °C, slowly add n-heptane (144 ml), stir at 50 °C for 1.5 hours, and then leave at room temperature overnight. Cool to 0 °C in an ice bath and stir for 1 hour. Filter, wash the filter cake with n-heptane, drain, and dry the filter cake to obtain a white solid 12-1 (3.74 g, yield: 19%).

[0381] Step 3: (S)-3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (12-2)

[0382] Dissolve the salt of 3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid and (S)-1-(p-tolyl)ethylamine (12-1) (3.74 g, 0.0105 mol, 1.0 eq) in ethyl acetate, cool to 0 - 10 °C, add 1 mol / L hydrochloric acid (37.4 ml), stir at room temperature for 10 minutes, wash with ethyl acetate (60 ml × 2), combine the organic phases, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a solid 12-2 (2.30 g, 100%).

[0383] 1 H NMR (400 MHz, DMSO-d6): δ 8.02 - 8.00 (d, J = 8.0 Hz, 1H), 6.90 - 6.88 (d, J = 8.0 Hz, 1H), 6.69 (s, 1H), 3.84 (s, 3H), 2.74 - 2.72 (m, 2H), 2.29 - 2.20 (m, 1H), 1.02 - 0.94 (m, 1H), 0.55 - 0.50 (m, 1H), 0.38 - 0.35 (m, 1H), 0.28 - 0.22 (m, 1H), 0.19 - 0.11 (m, 1H), m / z: 222.20 [M + 1], ee value: 99.8%. Chiral purity test conditions:

[0384] Analyticals FC conditions Instrument: UPOC (Waters)

[0385] Column: OJ-3 4.6 * 100 mm 3um

[0386] Column temperature: 40 °C

[0387] Mobile phase: CO2 / EtOH[1% NH3(7M in MeOH)] = 90 / 10

[0388] Flow: 3.0 ml / min

[0389] Back Pressure: 2000 psi - njection

[0390] Volume: 1 μl

[0391] For the subsequent steps, compound 12 was prepared in a similar synthetic manner as in Example 1, replacing 1 - 7 with raw material 12 - 2.

[0392] Yield: 40%. 1 1H NMR(400 MHz, CDCl3): 8.06 - 8.04(d, J = 8 Hz, 1H), 7.41~7.39(m, 1H), 7.11 - 7.09(m, 1H), 6.77 - 6.75(m, 2H), 6.63 - 6.61(s, 1H), 6.52 - 6.50(m, 1H), 6.27 - 6.25(m, 1H), 6.17 - 6.15(m, 1H), 4.62~4.12(m, 6H), 3.77(s, 3H), 3.25 - 3.23(m, 1H), 2.76 - 2.30(m, 9H), 1.71 - 1.68(m, 4H), 1.25 - 1.23(m, 2H), 1.02 - 0.96(m, 10H), 0.61~0.58(m, 1H), 0.47~0.45(m, 1H), 0.31~0.29(m, 1H), 0.17~0.15(m, 1H),

[0393] m / z: 673.50[M + 1], 695.55[M + Na]. ee value: 99.8%.

[0394] Chiral purity test conditions:

[0395] Analyticals FC conditions Instrument: UPOC(Waters)

[0396] Column: (R,R)Whelk - O1 4.6 * 100 mm 3.5 μm

[0397] Column temperature: 40 °C

[0398] Mobile phase: CO2 / MeOH[0.2%NH3(7M in MeOH)]=85 / 15

[0399] Flow: 3.0 ml / min

[0400] Back Pressure: 2000 psi - njection

[0401] volume: 5 ul

[0402] Example 13:

[0403] Compound 13:

[0404] (S)-3 - Cyclopropyl - 3-(2 - ((1-(5 - methoxy - 2 - ((neopentyloxy)carbonyl)phenyl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid

[0405]

[0406] According to a synthetic method similar to that of Example 4 and Example 7, using raw material 12 - 6 to replace 1 - 11, Compound 13 was prepared.

[0407] Yield: 80.0%. 1 H NMR(400 MHz, DMSO - d6): 12.01(brs, 1H), 8.09 - 8.06(t, J = 12.0 Hz, 12.0 Hz, 1H), 7.66 - 7.64(d, J = 8.0 Hz, 1H), 6.96 - 6.94(m, 1H), 6.68(s, 1H), 6.56 - 6.54(m, 2H), 4.14 - 4.11(m, 2H), 3.87(m, 2H), 3.79(s, 3H), 3.29 - 3.27(m, 2H), 3.20 - 3.18(m, 3H), 2.63 - 2.60(m, 1H), 2.21 - 2.17(m, 1H), 2.03 - 1.91(m, 1H), 1.69 - 1.68(m, 2H), 1.63 - 1.61(m, 2H), 1.00 - 0.98(m, 1H), 0.96(s, 9H), 0.51 - 0.49(m, 1H), 0.32 - 0.28(m, 2H), 0.17 - 0.16(m, 1H), m / z: 525.30[M + 1].[[]END]]

[0408] ee value: 99.8%. The test conditions are the same as those in Example 12.

[0409] Example 14:

[0410] Compound 14:

[0411] (S)-3-Cyclopropyl-3-(2-((1-(6-(((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)carbonyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0412]

[0413] Following a synthetic procedure similar to that of Example 9, replacing 1-11 with starting material 12-6, compound 14 was prepared.

[0414] Yield: 85.0%. 1 1H NMR (400 MHz, CDCl3): δ 8.08 - 8.06 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.78 - 6.75 (m, 1H), 6.64 (s, 1H), 6.30 (s, 1H), 5.92 - 5.87 (d, J = 20.0 Hz, 2H), 5.15 (m, 1H), 4.27 - 4.24 (m, 2H), 4.16 - 4.15 (m, 2H), 3.86 - 3.83 (m, 2H), 3.31 - 3.29 (m, 1H), 2.88 (s, 2H), 2.77 - 2.75 (m, 3H), 2.55 - 2.38 (m, 3H), 2.06 - 2.00 (m, 3H), 1.82 - 1.76 (m, 4H), 1.37 - 1.29 (m, 2H), 0.98 - 0.91 (m, 1H), 0.60 - 0.58 (m, 1H), 0.46 - 0.47 (m, 1H), 0.33 - 0.31 (m, 1H), 0.18 - 0.17 (m, 1H), m / z: 634.35 [M+1].

[0415] ee value: 99.8%. The testing conditions were the same as those in Example 12.

[0416] Reference Example 1: SCO-267 (Ref01)

[0417] Lit1: [Journal of Medicinal Chemistry, 2020, vol.63, #18, p.10352 - 10379]

[0418]

[0419] Reference Example 2: TAK-875 (Ref02)

[0420] Lit2: [ACS Med.Chem.Lett. 2010, 1, 290–294]

[0421]

[0422] Test Example 1: GPR40 Assay Activity Test

[0423] This experiment aims to verify the agonist activity of the compounds of the present invention against the GPR40 receptor.

[0424] Cell line

[0425] GPR40 / CHO

[0426] Medium

[0427] F12, Gibco (Cat#11765-047) DFBS, Biological Industiries (Cat#04-011-1A) Geneticin, Invitrogen (Cat#10131-027)

[0428] Main reagents

[0429] Fluo-4 Direct, (Invitrogen, Cat#F10471) Assay buffer: 1X HBSS:1M HEPES = 49:1, with 0.2% fatty acids free BSA 1X HBSS, (Gibco, Cat#14025-076) BSA, (Sigma, Cat#SRE0098-50G)

[0430] Main equipment

[0431] 384-well plate, Greiner#781090 Vi-cell XR Cell Viability Analyzer, Beckman Coulter, No.2785631 FLIPR, Molecular Devices, No.668115 Incubator, Thermo, No.1153447

[0432] Test method

[0433] Control and compound plates: The control was diluted 10-fold in buffer in a 1:3 sequence, and the test compound was diluted in buffer in a 1:4 sequence. Then, 750 μl of the compound was transferred to the destination plate. 30 μl of the assay buffer was added to each well.

[0434] a) Remove the cell plate from the incubator, discard the culture medium, and gently pipette 20 μl of the experimental buffer and 20 μl of the 2XFluo-4 DirectTM wash-free loading buffer into a 384-well cell culture plate.

[0435] b) Incubate at 37 °C in 5% CO2 for 50 minutes and then at room temperature for 10 minutes.

[0436] c) Remove the cell plate from the incubator and place it in the FLIPR. Place the compound plate and the tip box in the flir.

[0437] d) Compound plate (agonist test):

[0438] 1) Run the protocol on the FLIPR TETRA;

[0439] 2) Transfer 10 μl of the compound to the cell plate;

[0440] 3) Read the fluorescence signal;

[0441] 4) Calculate "Max - Min" starting from Read 0 to Maximum allowed.

[0442] e) Analyze the data using Prism.

[0443] See the following table for specific test data.

[0444] Compound EC50, (nM) Compound EC50, (nM) Compound EC50, (nM) 1 2.867 2 2.593 3 1.971 4 3.864 5 18.92 6 17.900 7 4.882 8 5.788 9 6.980 10 20.225 11 15.820 12 0.657 13 2.569 14 2.327 Ref01 3.736 Ref02 207.600

[0445] Conclusion: The compounds in the present invention all showed good GPR40 receptor agonist activity.

[0446] Test Example 2: Pharmacokinetics Evaluation in Rats

[0447] Using rats as test animals, the drug concentrations in plasma at different times after intragastric administration of the compounds were measured. The pharmacokinetic behavior of the compounds of the present invention in rats was studied to evaluate their drug metabolism characteristics. Three rats with similar body weights were selected for each example, and the oral dose was 3 mg / kg, with a single administration. Blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after animal administration. The content of the compound in plasma was detected by LC - MS / MS analysis method. The lower limit of quantification of the method was 20 ng / mL. The concentration data in plasma were statistically analyzed using pharmacokinetic data analysis software WinNonlin 7.0, and pharmacokinetic parameters were calculated using the non - compartmental model method (NCA).

[0448] Experimental drugs: The compounds of the present invention and reference compounds.

[0449] Drug preparation:

[0450] Intravenous group: The test article with a final concentration of 0.1 mg / mL was used for intravenous administration. The preparation solvent was 5% DMSO + 45% PEG400 + 50% aqueous solution. After preparation, all were clear and transparent solutions.

[0451] Oral group: The test article with final concentrations of 0.3 mg / mL was used for oral administration. The preparation solvent was 0.5% CMC aqueous solution. After preparation, all were clear and transparent solutions.

[0452] Drug administration: After the rats were fasted overnight (12 hours), they were given intragastric administration with a dose of 3 mg / kg.

[0453] Operation: The rats were given intragastric administration. Tail vein blood was collected before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration, placed in heparinized sample tubes, centrifuged at 3500 rpm for 10 minutes at 4°C to separate plasma, and stored at - 20°C. The rats were allowed to eat 2 hours after administration.

[0454] Determination of the content of the compound to be measured in the plasma of rats after intragastric administration of the drug: After thawing the plasma samples at room temperature, 300 μL of internal standard (terfenadine 200 ng / mL, acetonitrile) was added respectively. After vortex mixing for 1 min, centrifugation was carried out at 4°C and 15400 rpm for 10 min. 80% acetonitrile-water was used to dilute the supernatant 20 times and then injected for analysis by LC / MS / MS.

[0455]

[0456] Note: "-" was not calculated because Cmax was below the detection limit. BLOQ: Below the detection limit

[0457] In addition, for Compound 12, 4-hour small intestine tissues were collected, and the measured concentration of C4h was: 8325 ng / g.

[0458] Conclusion: The compounds in the above examples had almost no oral absorption, less drug entry into the blood compared with the control drug, were highly enriched in the small intestine, had lower potential hepatotoxicity, and had greater development value.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 Each independently is H, halogen, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 3 , R 4 Each independently represents H, halogen, cyano, optionally substituted: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl; or R 3 , R 4 Together with the adjacent carbon atoms, it forms a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl group; R 5 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy; R 6 , R 7 Each independently is H, halogen, optionally substituted: C 1-6 Alkyl or C 3-6 Cycloalkyl; R 8 For-OR 9 or -NR 10 R 11 ; R 9 is optionally substituted with halogen, hydroxyl, C 1-6 Alkoxy or trifluoromethyl substituted: C 1-12 Alkyl, C 3-8 Cycloalkyl and C 4-8 Heterocycloalkyl; R 10 is optionally substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl-substituted pyridyl or phenyl; R 11 -(CH2) n -OCO-R 12 or -(CH2) n -COO-R 12 ; n is an integer from 0 to 6; R 12 is optionally substituted with halogen, hydroxyl, C 1-6 Alkoxy or trifluoromethyl substituted: C 1-12 Alkyl, C 3-8 Cycloalkyl, C 4-8 Heterocycloalkyl; X is CH or N; Y is CH or N; Ring A is an optionally substituted aryl or heteroaryl group, an aryl or heteroaryl group and a 5-12-membered heterocyclic group; The number of the substitutions is one or more, and when selected from a plurality, they are independently the same and different.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1 , R 2 are independently H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 The cycloalkyl groups are each optionally substituted with one or more radicals selected from H, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Substitution of alkoxy groups; R 3 , R 4 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted by one or more selected from H, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Substitution of alkoxy groups; or R 3 , R 4 Together with the adjacent carbon atoms, it forms a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; R 5 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy; R 6 , R 7 are independently H, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; said C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted by one or more groups selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Substitution of alkoxy groups; R 8 For-OR 9 or -NR 10 R 11 ; R 9 C 1-6 Alkyl, C 3-6 Cycloalkyl or C 4-8 Heterocycloalkyl; said C 1-6 Alkyl, C 3-6 Cycloalkyl and C 4-8 The heterocycloalkyl groups are each optionally substituted with one or more radicals selected from H, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 The substituent of the alkoxy group is substituted; the C 4-8 The heteroatom in the heterocycloalkyl group is N, O or S, and the number of heteroatoms is 1, 2, 3 or 4; R 10 C 6-10 Aryl or 5-12 membered heteroaryl; said R 10 Optionally, one or more selected from H, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Substitution of alkoxy groups; R 11 -(CH2) n -OCO-R 12 or -(CH2) n -COO-R 12 ; n is an integer from 1 to 5; R 12 C 1-6 Alkyl, C 3-6 Cycloalkyl or C 4-8 Heterocycloalkyl; said C 1-6 Alkyl, C 3-6 Cycloalkyl and C 4-8 The heterocycloalkyl groups are each optionally substituted with one or more radicals selected from H, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 The substituent of the alkoxy group is substituted; the C 4-8 The heteroatom in the heterocycloalkyl group is N, O or S, and the number of heteroatoms is 1, 2, 3 or 4; X is CH or N; Y is CH or N; Ring A is C 6-10 Aryl, 5-12 membered heteroaryl or C 6-10 Aryl and 5-12 membered heterocyclic group; said C 6-10 Aryl and 5-12 membered heteroaryl are each optionally substituted by one or more A 1 Replacement; said C 6-10 The aryl and 5-12 membered heterocyclic groups are optionally substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 The substituents of the alkoxy group are substituted, wherein C 6-10 The aromatic group is connected to the amide bond; A 1 Independently selected from C 1-6 Alkoxy, 5-12 membered heterocyclic, 5-12 membered heteroaryl and C 3-6 Cycloalkyl; said A 1 Optionally one or more A 1-1 replace; Wherein, the heteroatom in the 5-12 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-4; 6-10 The heteroatom in the 5-12-membered heterocyclic group of the aryl group is N, O or S, and the number of heteroatoms is 1-4; A 1-1 Independently selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: (1) R 1 , R 2 are independently H, halogen, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl or C substituted by one or more cyano groups 1-6 alkyl; (2) R 3 , R 4 are independently H, halogen, cyano, C 1-6 alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C 1-6 Alkyl or C substituted by one or more cyano groups 1-6 Alkyl; the heteroatom in the 5-6 membered heterocyclic group and the 5-6 membered heteroaryl group is N, O or S, and the number of heteroatoms is 1, 2 or 3; or R 3 , R 4 Together with the adjacent carbon atoms, it forms a 3-6 membered cycloalkyl group; (3) R 5 H, halogen, C 1-6 alkyl; (4)R 6 , R 7 are independently H, halogen, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl or C substituted by one or more cyano groups 1-6 alkyl; (5) R 9 C 1-6 Alkyl, C 3-6 Cycloalkyl, C 4-8 Heterocycloalkyl or C substituted by one or more haloalkyl 4-8 Heterocycloalkyl; the C 4-8 Heterocycloalkyl and C substituted by one or more haloalkyl 4-8 C in heterocycloalkyl 4-8 The heteroatom in the heterocycloalkyl group is N, O or S, and the number of heteroatoms is 1, 2 or 3; (6) R 10 C 6-10 Aryl, 5-12 membered heteroaryl, substituted by one or more C 1-6 Alkyl substituted C 6-10 Aryl, with one or more C 1-6 Alkoxy substituted C 6-10 Aryl or one or more C 1-6 Alkyl-substituted 5-12-membered heteroaryl; wherein the heteroatom in the 5-12-membered heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3; (7) R 11 -(CH2) n -OCO-R 12 or -(CH2) n -COO-R 12 ; n is 1, 2, 3 or 4; (8) R 12 C 1-6 alkyl; (9) X is N; (10) Y is CH; (11) The ring A is C 6-10 Aryl, 5-12 membered heteroaryl, C 6-10 Aryl and 5-12 membered heterocyclic group, one or more C 1-6 Alkoxy substituted C 6-10 Aryl; the heteroatom in the 5-12 membered heteroaryl is N, O or S, and the number of heteroatoms is 1, 2 or 3; the C 6-10 The heteroatom of the 5- to 12-membered heterocyclic group in the aryl 5- to 12-membered heterocyclic group is N, O or S, and the number of the heteroatoms is 1, 2 or 3.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: (1) In each R 1 , R 2 wherein the halogen or C substituted by one or more halogens 1-6 The halogen in the alkyl group is F, Cl, Br or I; (2) In each R 1 , R 2 In the C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, C substituted with one or more cyano groups 1-6 C in the alkyl group 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3) In each R 3 , R 4 In the C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, C substituted with one or more cyano groups 1-6 C in the alkyl group 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (4) In each R 3 , R 4 wherein the halogen or C substituted by one or more halogens 1-6 The halogen in the alkyl group is F, Cl, Br or I; (5) In each R 3 , R 4 wherein the 3-6 membered cycloalkyl group is cyclopropyl, cyclobutyl or cyclopentyl; (6) In R 9 In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or tert-butylmethylene; (7) In R 9 In the C 4-8 Heterocycloalkyl and C substituted by one or more haloalkyl 4-8 C in heterocycloalkyl 4-8 The heteroatom in the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3; (8) In R 9 wherein the C 4-8 The halogen in the heterocycloalkyl group is F, Cl, Br or I; (9) In R 10 In the C 6-10 Aryl, with one or more C 1-6 Alkyl substituted C 6-10 Aryl, with one or more C 1-6 Alkoxy substituted C 6-10 C in aromatic groups 6-10 Aryl is phenyl; (10) In R 10 In the above, the one or more C 1-6 Alkyl substituted C 6-10 Aryl, with one or more C 1-6 The C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (11) In R 10 In the above, the one or more C 1-6 Alkoxy substituted C 6-10 C in aromatic groups 1-6 Alkoxy is -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)3, -O(CH2)2CH(CH3)2 or -O(CH2)4CH3; (12) In R 10 wherein the 5-12 membered heteroaryl group is replaced by one or more C 1-6 The 5-12-membered heteroaryl in the 5-12-membered heteroaryl substituted by an alkyl group is a 6-membered heteroaryl, the heteroatom is N, and the number of heteroatoms is 1 or 2; (13) In R 12 In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or tert-butylmethylene; (14) In ring A, the C 6-10 Aryl, with one or more C 1-6 Alkoxy substituted C 6-10 C in aromatic groups 6-10 Aryl is phenyl; (15) In ring A, the 1-6 Alkoxy substituted C 6-10 C in aromatic groups 1-6 Alkoxy is -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)3, -O(CH2)2CH(CH3)2 or -O(CH2)4CH3; (16) In ring A, the C 6-10 The aryl 5-12-membered heterocyclic group is a phenyl 5-6-membered heterocyclic group, wherein the hetero atom in the 5-6-membered heterocyclic group is O, and the number of the hetero atoms is 1, 2 or 3.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: (1) R 1 , R 2 Each independently is H; (2) R 3 , R 4 Each is independently H or a 3-6 membered cycloalkyl group; (3) R 5 is H; (4) R 6 , R 7 Each independently is H; (5) R 8 For-OR 9 or -NR 10 R 11 ; (6) R 9 C 1-6 Alkyl or C substituted by one or more haloalkyl 4-8 Heterocycloalkyl; (7) R 10 For one or more C 1-6 Alkyl-substituted 5-12 membered heteroaryl; (8) R 11 -(CH2) n -OCO-R 12 or -(CH2) n -COO-R 12 ; n is 1, 2, 3 or 4; (9) R 12 C 1-6 alkyl; (10) X is CH; (11) Y is N; (12) The ring A is surrounded by one or more C 1-6 Alkoxy substituted C 6-10 Aryl or C 6-10 Aryl and 5-12 membered heterocyclic group.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: (1) R 3 , R 4 H or Preferably (2) R 9 for (3) R 10 for (4) R 11 -(CH2)2-OCO-R 12 or -(CH2)-COO-R 12 ; (5) R 12 is methyl, isopropyl, tert-butyl or tert-butylmethylene, preferably isopropyl, tert-butyl or tert-butylmethylene; (6) The ring A is Preferably 7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The R 8 for Preferably 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound or its pharmaceutically acceptable salt has a structure shown in the following formula (II): Among them, R 1 , R 2 , R 3 , R 4 , R 9 , X, Y and ring A are as described in right 1; For example, R 1 , R 2 are each independently H, halogen, optionally substituted C 1-6 alkyl; R 3 , R 4 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl-substituted five-membered heteroaryl; R 9 is optionally substituted with halogen, hydroxyl, C 1-6 Alkoxy or trifluoromethyl substituted: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-8 Cycloalkyl, C 4-8 Heterocycloalkyl; X is CH or N; Y is CH or N; A is optionally substituted: phenyl, pyridine, benzo 5-6 membered heterocyclic group; Preferably, R 9 C 3-8 alkyl or optionally substituted with trifluoromethyl 4-8 Heterocycloalkyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound or its pharmaceutically acceptable salt has a structure shown in the following formula (III): Among them, R 1 , R 2 , R 3 , R 4 , R 10 , R 11 , X, Y and ring A are as described in right 1; For example, R 1 , R 2 are each independently H, halogen, optionally substituted C 1-6 alkyl; R 3 , R 4 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl-substituted five-membered heteroaryl; R 10 is optionally substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl-substituted pyridyl or phenyl; R 11 -(CH2) m -OCO-R 12 or -(CH2) n -COO-R 12 ; R 12 is optionally substituted with halogen, hydroxyl, C 1-6 Alkoxy or trifluoromethyl substituted: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-8 Cycloalkyl, C 4-8 Heterocycloalkyl; X is CH or N; Y is CH or N; A is optionally substituted: phenyl, pyridine, benzo 5-6 membered heterocyclic group; m is 1, 2 or 3; n is 1, 2 or 3; More preferably, R 10 For optional C 1-6 Alkyl substituted pyridyl; R 11 -(CH2)2-OCO-R 12 or -CH2COO-R 12 ; R 12 is C optionally substituted by halogen 1-12 alkyl; More preferably, R 1 , R 2 are each independently H or methyl; R 3 , R 4 Each independently is H, C 2-6 Alkynyl, C 3-6 Cycloalkyl or CF3; Y is CH; A is optionally substituted by a substituent: phenyl, pyridine, The substituent is selected from: 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-10 Alkoxy, optionally substituted 4-8 membered heterocycloalkyl and halogen; Preferably, R 1 , R 2 Each independently is H; R 3 , R 4 Each independently is H or C 3-6 Cycloalkyl; A is optionally substituted by a substituent: phenyl, pyridine, The substituent is selected from: 1-10 Alkoxy and C 1-6 Alkyl-substituted 4-8 membered heterocycloalkyl; Preferably, R 3 , R 4 Each is independently H or cyclopropyl; A is accessible by C 1-10 Alkoxy substituted: phenyl or pyridine.

10. The compound according to claims 1-9 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from one of the following compounds:

11. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, comprising the following steps: In an organic solvent, a compound represented by formula (IA) is subjected to a hydrogenation reaction with a reducing agent to obtain a compound represented by formula (I); Wherein, R is benzyl or C 1-12 Alkyl or C 1-12 Alkoxy substituted benzyl; More preferably, R is benzyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X, Y and ring A are as described in any one of claims 1-10; Preferably, the preparation method satisfies one or more of the following conditions: The organic solvent is a mixture of ether and alcohol solvents, preferably methanol; The reducing agent is an inorganic reducing agent, preferably hydrogen; The catalyst for the hydrogenation reaction is palladium on carbon; The reaction temperature of the preparation method is room temperature; The amount of the organic solvent is 2-6 ml, preferably 3 ml; The reaction time is 1-3h, preferably 2h; After the reaction is completed, post-processing is also included, and the post-processing includes the following steps: filtration, concentration and purification; Preferably, the method for preparing the compound represented by formula (II) or a pharmaceutically acceptable salt thereof comprises the following steps: In an organic solvent, the compound represented by formula (IIA) undergoes a hydrogenation reaction with a reducing agent to obtain a compound represented by formula (II); Wherein, R is benzyl or C 1-12 Alkyl or C 1-12 Alkoxy substituted benzyl; More preferably, R is benzyl; and R 1 , R 2 , R 3 , R 4 , R 9 , X, Y, and ring A are as described in any one of claims 1 to 10, and the reaction conditions are the same as those defined for the compound represented by formula (IA); More preferably, the method for preparing the compound represented by formula (III) or a pharmaceutically acceptable salt thereof comprises the following steps: In an organic solvent, the compound represented by formula (IIIA) undergoes a hydrogenation reaction with a reducing agent to obtain a compound represented by formula (III); in, R is benzyl or C 1-12 Alkyl or C 1-12 Alkoxy substituted benzyl; More preferably, R is benzyl; and R 1 , R 2 , R 3 , R 4 , R 10 , R 11 , R 12 , X, Y, and ring A are as described in any one of claims 1 to 10, and the reaction conditions are the same as those defined for the compound represented by formula (IA).

12. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10 as an active ingredient, and a pharmaceutically acceptable excipient.

13. Use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 12 in the preparation of a GPR40 receptor agonist or a drug; Preferably, the drug is used for preventing and / or treating metabolic-related diseases by activating the GPR40 receptor; or, the drug is used for treating and / or treating metabolic-related diseases; The metabolic-related disease is selected from any one of glucose intolerance, dyslipidemia, syndrome X (microvascular angina), insulin resistance, arteriosclerosis, hypertension, obesity, non-alcoholic fatty liver disease, cirrhosis and lethargy; Preferably, the metabolism-related disease is also selected from any one of hyperglycemia, type 1 diabetes (T1D), type 2 diabetes (T2D), diabetic dyslipidemia, hyperlipidemia, atherosclerosis, and liver fibrosis; for example, the metabolism-related disease is also selected from hypertriglyceridemia.

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