Aromatic propionic acid derivative as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses an aromatic propionic acid derivative as well as a preparation method, a pharmaceutical composition and application thereof. The invention specifically discloses a compound shown in a formula (I) or pharmaceutically acceptable salt thereof. The invention further discloses a pharmaceutical composition which comprises the compound shown in the formula (I), pharmaceutically acceptable salt of the compound and pharmaceutic adjuvants. The invention also discloses application of the compound as shown in the formula (I), the pharmaceutically acceptable salt of the compound or the pharmaceutical composition in preparation of drugs, and the drugs have GPR40 receptor agonistic activity and have one or more of the advantages of good activity, high targeting property, low toxicity and the like. # imgabs0 #

Description

Technical Field

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

[0002] GPR40 (FFAR1 or FFA1) belongs to the GPCR family and is a G protein-coupled receptor that is mainly expressed in pancreatic islet β cells, enteroendocrine cells and the brain. When GPR40 is activated by its endogenous ligand (medium / long-chain fatty acids), insulin secretion can only be induced at relatively high blood glucose levels. Therefore, there is no risk of hypoglycemia, which can greatly reduce the risk of hypoglycemia. At the same time, it can activate the GLP-1 pathway, promote GLP secretion, inhibit glucagon secretion, and achieve weight loss by inhibiting central nervous appetite. This makes GPR40 an important therapeutic target for diabetes and weight loss. Currently, 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 of Eli Lilly and Company.

[0003] GPR40 exerts hypoglycemic and weight loss effects mainly through the following aspects.

[0004] 1. The GPR40 gene is expressed in multiple parts of the body. Among them, the expression level is the highest in pancreatic tissue. This indicates 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 thus 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.

[0005] The GPR40 protein is mainly distributed in pancreatic tissue. After being activated by binding to an appropriate ligand, it affects the function of pancreatic islet cells. Research shows that free fatty acids can enhance the insulin secretion response of islet β cells under glucose stimulation.

[0006] 2. GPR40 is also ubiquitously expressed in intestinal endocrine cells. Endogenous medium- and long-chain fats 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, GPR40 agonists can be used as therapeutic targets for obesity.

[0007] The inventors have found that in recent years, although GPR40 agonists have been developed for many years, due to the poor progress of GPR40 series agonists in aspects such as drug metabolism and compound hepatotoxicity, new molecular structures are needed to improve the properties of compounds, increase activity, reduce oral drug absorption, and be enriched in the intestine to exert drug effects. SUMMARY OF THE INVENTION

[0008] In view of the poor progress of the existing GPR40 series agonists in aspects such as drug metabolism and compound toxicity, the present invention provides a class of compounds having GPR40 receptor agonist activity, which have one or more of good activity, less drug entry into the blood, low systemic exposure, and lower potential hepatotoxicity.

[0009] The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.

[0010]

[0011] Wherein,

[0012] R 1 and R 2 are each independently H, halogen, optionally substituted: C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0013] R 3 and R 4 are each independently H, halogen, cyano, optionally substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclic group or 5-6 membered heteroaryl;

[0014] Or R 3 and R 4 together with the adjacent carbon atoms form a 3-6 membered cycloalkyl group or 3-6 membered heterocycloalkyl group;

[0015] R 5 is H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;

[0016] R 6 and R 7 are each independently H, halogen, optionally substituted: C 1-6 alkyl or C 3-6 cycloalkyl; or R 6 and R 7 together are an oxo group or a thio group;

[0017] R 8 is halogen or optionally substituted: C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0018] R 9 is C 1-6 alkyl, -COOR 9-1 , -CON(R 10 R 11 ), halogen or 5- to 10-membered heteroalkyl substituted by R 9-2 , wherein the heteroatoms in the 5- to 10-membered heteroalkyl are selected from one or more of N, O, and S, and the number of heteroatoms is 1 to 4;

[0019] R 9-1 is C 1-6 alkyl or C 9-1-1 alkyl substituted by R 1-6 ;

[0020] R 9-2 is C 1-6 alkyl or C 1-6 alkyl substituted by 1 to 3 halogen atoms;

[0021] R 9-1-1 is C 1-6 alkoxy;

[0022] R 10 is optionally substituted by halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl-substituted 5- to 10-membered heteroaryl;

[0023] R 11 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 heteroalkyl;

[0024] X1, X2, X3 are independently N or CH.

[0025] Y1 and Y3 are O, Y2 and Y4 are CH2 or Y2 and Y4 are CH2, Y1 and Y3 are O.

[0026] Preferably, R 1 , R 2 are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6Naphthenyl; said C 1-6 alkyl, C 1-6 alkoxy and C 3-6 naphthenyl are each optionally substituted by one or more halogens, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halo C 3-6 naphthenyl and halo C 1-6 alkoxy;

[0027] R 3 and R 4 are each independently H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 naphthenyl, 5- or 6-membered heterocyclic group or 5- or 6-membered heteroaryl group; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 naphthenyl, 5- or 6-membered heterocyclic group and 5- or 6-membered heteroaryl group are each optionally substituted by one or more halogens, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halo C 3-6 naphthenyl and halo C 1-6 alkoxy; the heteroatoms in said 5- or 6-membered heterocyclic alkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4; the heteroatoms in said 5- or 6-membered heteroaryl group are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4;

[0028] or R 3 , R 4 together with the adjacent carbon atom forms a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl group;

[0029] R 5 is independently H, halogen, cyano, C 1-6 alkyl, C 3-6 naphthenyl or C 1-6 alkoxy;

[0030] R 6 and R 7 are each independently halogen, C 1-6 alkyl or C 3-6 naphthenyl; R 6 and R 7 together are an oxo group or a thio group; said C 1-6 alkyl and C 3-6 naphthenyl are each optionally substituted by one or more H, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halo C 3-6 naphthenyl and halo C 1-6 alkoxy;

[0031] R 8 is 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 halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 3-6 cycloalkyl and halo-C 1-6 alkoxy;

[0032] R 9 is independently C 1-6 alkyl, -COOR 9-1 , -CON(R 10 R 11 ), halogen or a 5- to 10-membered heteroalkyl substituted by R 9-2 , wherein the heteroatoms in the 5- to 10-membered heteroalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4;

[0033] R 9-1 is independently C 1-6 alkyl or C 9-1-1 alkyl substituted by R 1-6 ;

[0034] R 9-2 is independently C 1-6 alkyl or C 1-6 alkyl substituted by 1 to 3 halogen atoms;

[0035] R 9-1-1 is independently C 1-6 alkoxy;

[0036] R 10 is optionally substituted by one or more halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituted 5- to 10-membered heteroaryl; wherein the heteroatoms in the 5- to 10-membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4;

[0037] R 11 is optionally substituted by one or more halogen, hydroxy, C 1-6 alkoxy or trifluoromethyl substituted C 1-12 alkyl, C 1-12 alkoxy, C 3-8 cycloalkyl, C 4-8Heterocycloalkyl; the C 4-8 In the heterocycloalkyl, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1 to 4.

[0038] X1, X2, X3 are independently N or CH;

[0039] Y1 and Y3 are O, Y2 and Y4 are CH2 or Y2 and Y4 are CH2, Y1 and Y3 are O.

[0040] For the compound of formula I or its pharmaceutically acceptable salt as described above, the definitions of some groups are as described below, and the definitions of the remaining groups are as described in any other embodiment.

[0041] In one embodiment, the R 1 and R 2 The C 1-6 alkyl is independently C 1-4 alkyl, preferably are methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further step is preferably methyl.

[0042] In one embodiment, the R 3 and R 4 The C 1-6 alkyl is independently C 1-4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and more preferably ethyl.

[0043] In one embodiment, the R 3 and R 4 The C 2-6 alkenyl is independently C 3-5 alkenyl, preferably allyl, propenyl, n-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, and more preferably 2-methylpropenyl.

[0044] In one embodiment, the R 3 and R 4 The C 2-6 alkynyl is independently ethynyl, propynyl, butynyl, pentynyl, 2-methylpropynyl, 3-methylbutynyl, preferably propynyl.

[0045] In one embodiment, the R 3 and R 4 The C 3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, preferably cyclopropyl.

[0046] In one embodiment, the oxo group in the R 6 and R 7 is

[0047] In one embodiment, the R 8 in the C 1-6 alkoxy groups are independently C 1-4 alkoxy groups, preferably methoxy, ethoxy, propoxy, butoxy or isopropoxy, more preferably methoxy.

[0048] In one embodiment, the R 9 in the C 1-6 alkyl groups are independently C 1-4 alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl or neohexyl, more preferably neohexyl, for example, 2-methylpentyl.

[0049] In one embodiment, the halogen in the R 9 is independently F, Cl, Br, I, preferably F.

[0050] In one embodiment, the R 9-1 in the C 1-6 alkyl groups are independently C 1-4 alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably isopropyl.

[0051] In one embodiment, the C 9-1-1 in the R 1-6 alkoxy groups are independently C 1-4 alkoxy groups, preferably methoxy, ethoxy, propoxy, butoxy or isopropoxy, more preferably isopropoxy.

[0052] In one embodiment, the 5- to 10-membered heterocycloalkyl group substituted by R 9-2 is a 5- to 6-membered heterocycloalkyl group, such as a 6-membered heterocycloalkyl group.

[0053] In one embodiment, the heteroatom in the 5- to 10-membered heterocycloalkyl group substituted by R 9-2 is N, O, S, preferably N.

[0054] In one embodiment, the number of heteroatoms in the 5- to 10-membered heterocycloalkyl group substituted by R 9-2 is 1 to 4, preferably 1, 2, 3 or 4, more preferably 1.

[0055] In one embodiment, the 5- to 10-membered heterocycloalkyl group substituted by R 9-2 is piperidinyl, for example

[0056]

[0057] In one embodiment, the R 9-2 In, the C 1-6 alkyl substituted by 1 - 3 halogen atoms, the halogen atoms are independently F, Cl, Br, I, preferably F.

[0058] In one embodiment, the R 9-2 In, the C 1-6 alkyl substituted by 1 - 3 halogen atoms, the number of halogen atoms is independently 1, 2 or 3, preferably 3.

[0059] In one embodiment, the R 9-2 In, the C 1-6 alkyl in the alkyl substituted by 1 - 3 halogen atoms is C 1-6 alkyl, preferably methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl or tert - butyl, more preferably ethyl. 1-4 alkyl, preferably methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl, tert - butyl or neopentyl, more preferably neopentyl.

[0060] In one embodiment, the R 10 and R 11 In the C 1-6 alkyl is methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl, tert - butyl or neopentyl, more preferably neopentyl.

[0061] In one embodiment, the 5 - 10 - membered heteroaryl in the R 10 is a 5 - 6 - membered heteroaryl, such as a 6 - membered heteroaryl.

[0062] In one embodiment, the heteroatoms in the 5 - 10 - membered heteroaryl in the R 10 are N, O, S, preferably N.

[0063] In one embodiment, the number of heteroatoms in the 5 - 10 - membered heteroaryl in the R 10 is 1 - 4, preferably 1, 2, 3 or 4, more preferably 1.

[0064] In one embodiment, the 5 - 10 - membered heteroaryl in the R 10 is pyridyl; for example

[0065]

[0066] In one embodiment, the R 1 and R 2 are independently H or C 1-6 alkyl.

[0067] In one embodiment, the R3 and R 4 are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl.

[0068] In one embodiment, said R 6 and R 7 are independently H or together are

[0069] In one embodiment, said R 8 is independently C 1-6 alkoxy.

[0070] In one embodiment, said R 10 is independently C 1-6 alkyl or 5-10 membered heteroaryl substituted with C 1-6 alkyl; the heteroatoms in said 5-10 membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4.

[0071] In one embodiment, X1 is N or CH.

[0072] In one embodiment, X2 is N or CH, and X3 is CH.

[0073] In one embodiment, said R 1 and R 2 one of which is H and the other is H or C 1-6 alkyl; for example, both are H.

[0074] In one embodiment, said R 3 and R 4 one of which is H and the other is C 3-6 cycloalkyl.

[0075] In one embodiment, said R 9 is independently C 1-6 alkyl, -COOR 9-1 , halogen or 5-10 membered heterocycloalkyl substituted with R 9-2 ; the heteroatoms in said 5-10 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4.

[0076] In one embodiment, said R 9-1 is independently C 1-6 alkyl.

[0077] In one embodiment, said R 1 and R 2Independently H or C 1-6 Alkyl, R 3 And R 4 Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl; R 6 And R 7 Independently H or together are R 8 Is C 1-6 Alkoxy; R 9 Independently C 1-6 Alkyl, -COOR 9-1 、-CON(R 10 R 11 )、halogen or 5- to 10-membered heteroalkyl substituted by R 9-2 , wherein the heteroatoms in the 5- to 10-membered heteroalkyl are selected from one or more of N, O, and S, and the number of heteroatoms is 1 to 4; R 9-1 Independently C 1-6 Alkyl or alkyl substituted by R 9-1-1 ; R 9-2 Is C 1-6 Alkyl substituted by 1 to 3 halogen atoms; R 9-1-1 Independently C 1-6 Alkoxy; R 10 Is C 1-6 Alkyl or 5- to 10-membered heteroaryl substituted by C 1-6 Alkyl; wherein the heteroatoms in the 5- to 10-membered heteroaryl are selected from one or more of N, O, and S, and the number of heteroatoms is 1 to 4; R 11-1 Is C 1-6 Alkyl; X1, X2, X3 are N or CH; Y2 and Y4 are O, Y3 and Y1 are CH2 or Y2 and Y4 are CH2, Y3 and Y1 are O.

[0078] In one embodiment, the R 1 And R 2 Independently H or C 1-6 Alkyl; the R 3 And R 4 Independently C 3-6 Cycloalkyl. The R 6 And R 7 Independently H or together are The R 8 Independently C 1-6 Alkoxy; the R 9 Independently C 1-6 Alkyl, -COOR 9-1 、halogen or substituted by R9-2 A substituted 5- to 10-membered heterocycloalkyl group, wherein the heteroatoms in the 5- to 10-membered heterocycloalkyl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1 to 4; said R 9-1 is independently C 1-6 alkyl; said R 9-2 is independently C 1-6 alkyl substituted by 1 to 3 halogen atoms; X1, X2, and X3 are N or CH; Y2 and Y4 are O, Y3 and Y1 are CH2, or Y2 and Y4 are CH2, Y3 and Y1 are O.

[0079] In one embodiment, said R 9 is independently -COOR 9-1 , and said R 9-1 is independently C 9-1-1 alkyl substituted by R 1-6 ; when R 9-1 is isopropoxy-ethyl.

[0080] In one embodiment, said R 9 is independently a 5- to 10-membered heterocycloalkyl group substituted by R 9-2 ; said 5- to 10-membered heterocycloalkyl group is said R 9-2 is independently trifluoroethyl.

[0081] In one embodiment, said R 9 is independently -CON(R 10 R 11 ); in R 10 , the 5- to 10-membered heteroaryl group substituted by C 1-6 alkyl is a 6-membered pyridyl group substituted by C 1-4 alkyl; for example, a pyridyl group substituted by methyl; and for another example

[0082] In one embodiment, said R 10 , R 11 are independently C 1-6 alkyl, such as neopentyl.

[0083] In one embodiment, said R 11 is independently C 1-6 alkyl, and R 10 is a 5- to 10-membered heteroaryl group substituted by C 1-6 alkyl.

[0084] In one embodiment, said R 1 and R 2 are H or methyl.

[0085] In one embodiment, the R 3 and R 4 are H, ethyl,

[0086] In one embodiment, the is

[0087] In one embodiment, the R 5 is hydrogen.

[0088] In one embodiment, the R 6 and R 7 are H or together are

[0089] In one embodiment, the R 8 is methoxy.

[0090] In one embodiment, the R 9 is F,

[0091] In one embodiment, X1 and X2 are N or CH, and X3 is CH.

[0092] Preferably, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof has the structure shown in formula (II) as follows:

[0093]

[0094] Wherein,

[0095] R 1 , R 2 are each independently H, halogen, optionally substituted C 1-6 alkyl;

[0096] R 3 , R 4 are each 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.

[0097] R 6 , R 7 are each independently H or R 6 and R 7 together are an oxo group or a thio group;

[0098] R 8 is optionally substituted: C1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0099] R 9 is C 1-6 alkyl, -COOR 9-1 , -CON(R 10 R 11 ), halogen or 5- to 10-membered heterocycloalkyl substituted by R 9-2 , wherein the heteroatoms in the 5- to 10-membered heterocycloalkyl are selected from one or more of N, O, and S, and the number of heteroatoms is 1 to 4;

[0100] R 9-1 is C 1-6 alkyl or C 9-1-1 alkyl substituted by R 1-6 ;

[0101] R 9-2 is C 1-6 alkyl or C 1-6 alkyl substituted by 1 to 3 halogen atoms;

[0102] R 9-1-1 is C 1-6 alkoxy;

[0103] R 10 is optionally substituted by halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl-substituted pyridyl or phenyl;

[0104] R 11 is optionally substituted by halogen, hydroxyl, C 1-6 alkoxy or trifluoromethyl: C 1-12 alkyl, C 1-12 alkoxy, C 3-8 cycloalkyl, C 4-8 heterocycloalkyl;

[0105] X1, X2, X3 are independently N or CH.

[0106] Preferably, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof has the structure shown in the following formula (III):

[0107]

[0108] wherein,

[0109] R 1 , R 2 are each independently H, halogen, optionally substituted C 1-6Alkyl;

[0110] R 3 , R 4 are each 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.

[0111] R 6 , R 7 are each independently H or R 6 and R 7 together are an oxo group or a thio group;

[0112] R 8 is optionally substituted with: C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0113] R 9 is C 1-6 alkyl, -COOR 9-1 , -CON(R 10 R 11 ), halogen or 5- to 10-membered heterocycloalkyl substituted with R 9-2 , wherein the heteroatoms in the 5- to 10-membered heterocycloalkyl are selected from one or more of N, O, and S, and the number of heteroatoms is 1 to 4;

[0114] R 9-1 is C 1-6 alkyl or C 9-1-1 alkyl substituted with R 1-6 ;

[0115] R 9-2 is C 1-6 alkyl or C 1-6 alkyl substituted with 1 to 3 halogen atoms;

[0116] R 9-1-1 is C 1-6 alkoxy;

[0117] R 10 is optionally substituted with halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl-substituted pyridyl or phenyl;

[0118] R 11 is optionally substituted with halogen, hydroxy, C 1-6 alkoxy or trifluoromethyl: C 1-12Alkyl, C 1-12 Alkoxy, C 3-8 Cycloalkyl, C 4-8 Heterocycloalkyl;

[0119] X1, X2, X3 are independently N or CH.

[0120] More preferably, the R 1 , R 2 are each independently H, methyl; R 3 , R 4 are each independently H, C 1-6 alkane group, C 2-6 alkene group, C 2-6 alkyne group, C 3-6 cycloalkyl; R 6 , R 7 are each independently H or R 6 and R 7 together are an oxo group; R 8 is C 1-6 alkoxy; R 9 is C 1-6 alkyl, -COOR 9-1 , -CON(R 10 R 11 ), halogen or 5-10 membered heterocycloalkyl substituted by R 9-2 , wherein the heteroatoms in the 5-10 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1-4; R 9-1 is C 1-6 alkyl or C 9-1-1 alkyl substituted by R 1-6 ; R 9-2 is C 1-6 alkyl or C 1-6 alkyl substituted by 1-3 halogen atoms; R 9-1-1 is C 1-6 alkoxy; 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; R 11 is optionally substituted by halogen, hydroxy, C 1-6 alkoxy or trifluoromethyl substituted: C 1-12 alkyl, C 1-12 alkoxy, C 3-8 cycloalkyl, C 4-8 heterocycloalkyl;

[0121] X1, X2, X3 are independently N or CH.

[0122] More preferably, the R 1 , R 2 are each independently H; R 3 , R 4 are each independentlyH, C 3-6 Cycloalkyl; R 8 is methoxy; R 9 is C 1-6 alkyl; or -COOC 1-6 alkyl; or R 9 is R 9-2 substituted the said R 9-2 is halogen-substituted C 1-6 alkyl; or R 9 is -CON(R 10 R 11 ), the said R 10 is optionally halogen-, hydroxy-, C 1-6 alkyl-, C 1-6 alkoxy- or C 3-6 cycloalkyl-substituted pyridyl, the said R 11 is C 1-6 alkyl.

[0123] 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, R 3 , R 4 are each independently H, cyclopropyl; R 9 is C 1-6 alkyl; or -COOC 1-6 alkyl.

[0124] 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, R 3 , R 4 are each independently H, cyclopropyl; R 9 is R 9-2 substituted the said R 9-2 is trifluoroethyl.

[0125] 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, R 3 , R 4 are each independently H, cyclopropyl;

[0126] R 9 is -CON(R 10 R 11 ), the said R 10 is the said R 11 is neopentyl.

[0127] More preferably, the compound according to the present invention is selected from one of the following compounds:

[0128]

[0129] The present invention provides a compound represented by formula (Ia), or a pharmaceutically acceptable salt thereof,

[0130]

[0131] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , X1, X2, Y1, X3, Y2, Y3, Y4 are as defined in the aforementioned formula (I);

[0132] R is C 1-6 alkyl or benzyl.

[0133] In one embodiment, the C 1-6 alkyl in the R is independently C 1-4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and more preferably ethyl;

[0134] Preferably, the present invention has the following structural compounds 1a-24a:

[0135]

[0136] 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:

[0137] (1) When R is C 1-6 alkyl, the compound (Ia) is subjected to a deprotection reaction in a solvent in the presence of a base to obtain the compound (I);

[0138] In one embodiment, the solvent is a mixed solvent of tetrahydrofuran and methanol.

[0139] In one embodiment, the base is a sodium hydroxide solution.

[0140] In one embodiment, the concentration of the base is 1-3 mol / L, preferably 2 mol / L.

[0141] In one embodiment, the temperature of the reaction is 40 - 80 °C, preferably 60 °C.

[0142] In one embodiment, the progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC - Ms or NMR). Generally, the reaction end point is determined when the carbonyl compound shown in formula (Ia) disappears or no longer reacts, or when the product no longer increases. The reaction time is 0.5 h - 5 h, preferably 0.5 h.

[0143] In one embodiment, the ratio of compound (Ia) to the base in the reaction is 1:1 - 6, preferably 1:4.

[0144] In one embodiment, the ratio of compound (Ia) to the solvent in the reaction is 30 - 80 mg / mL, preferably 55.75 mg / mL.

[0145] In one embodiment, the organic solvent in the reaction is an aprotic solvent, preferably ethyl acetate.

[0146] In one embodiment, the pH regulator is citric acid.

[0147] In one embodiment, the concentration of the pH regulator is 0.5 - 2 mol / L, preferably 1 mol / L.

[0148] (2) When R is benzyl, compound (Ia) is subjected to a debenzylation reaction in a solvent under a hydrogen atmosphere in the presence of 10% Pd / C to obtain compound (I);

[0149] The reaction temperature is 10 - 25 °C, preferably 25 °C.

[0150] The reaction time is 3 - 8 h, preferably 5 h.

[0151] Wherein, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 9-1 、R 9-2 、R 9-1-1 、X1, X2, X3, Y2, Y3, Y4, Y1 are as defined in the aforementioned formula (I).

[0152]

[0153] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 9-1 , R 9-2 , R 9-1-1 , X1, X2, Y1, X3, Y2, Y3, Y4 are defined as in the aforementioned formula (I);

[0154] R is C 1-6 alkyl or benzyl.

[0155] In some embodiments, the method for preparing the compound represented by the general formula (II) includes the following steps:

[0156] (1) When R is C 1-6 alkyl, the compound (IIa) is subjected to a deprotection reaction in a solvent in the presence of a base to obtain the compound (II);

[0157] In one embodiment, the solvent is a mixed solvent of tetrahydrofuran and methanol.

[0158] In one embodiment, the base is a sodium hydroxide solution.

[0159] In one embodiment, the concentration of the base is 1 - 3 mol / L, preferably 2 mol / L.

[0160] In one embodiment, the reaction temperature is 40 - 80 °C, preferably 60 °C.

[0161] In one embodiment, the progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC - Ms or NMR). Generally, when the carbonyl compound represented by the formula (IIa) disappears or no longer reacts, or the product no longer increases, it is taken as the end point of the reaction. The reaction time is 0.5 h - 5 h, preferably 0.5 h.

[0162] In one embodiment, the ratio of the compound (IIa) to the base in the reaction is 1:1 - 6, preferably 1:4.

[0163] In one embodiment, the ratio of the compound (IIa) to the solvent in the reaction is 30 - 80 mg / mL, preferably 55.75 mg / mL.

[0164] In one embodiment, the organic solvent in the reaction is an aprotic solvent, preferably ethyl acetate.

[0165] In one embodiment, the pH regulator is citric acid.

[0166] In one embodiment, the concentration of the pH regulator is 0.5 - 2 mol / L, preferably 1 mol / L.

[0167] (2) When R is benzyl, the compound (Ⅱa) is subjected to a debenzylation reaction in a solvent under a hydrogen atmosphere in the presence of 10% Pd / C to obtain the compound (Ⅱ);

[0168] The reaction temperature is 10 - 25 °C, preferably 25 °C.

[0169] The reaction time is 3 - 8 h, preferably 5 h.

[0170] Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 9-1 , R 9-2 , R 9-1-1 , X1, X2, X3, Y2, Y3, Y4, Y1 are as defined in the foregoing formula (Ⅰ).

[0171]

[0172] Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 9-1 , R 9-2 , R 9-1-1 , X1, X2 are as defined in the foregoing formula (Ⅰ);

[0173] R is C 1-6 alkyl or benzyl.

[0174] In some embodiments, the method for preparing the compound represented by the general formula (III) comprises the following steps:

[0175] (1) When R is C 1-6 When R is an alkyl group, the deprotection reaction of compound (IIIa) is carried out in a solvent in the presence of a base to obtain compound (III);

[0176] In one embodiment, the solvent is a mixed solvent of tetrahydrofuran and methanol.

[0177] In one embodiment, the base is a sodium hydroxide solution.

[0178] In one embodiment, the concentration of the base is 1 - 3 mol / L, preferably 2 mol / L.

[0179] In one embodiment, the temperature of the reaction is 40 - 80 °C, preferably 60 °C.

[0180] In one embodiment, the progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC - Ms or NMR). Generally, the reaction end point is determined when the carbonyl compound shown in formula (IIIa) disappears or no longer reacts, or when the product no longer increases. The reaction time is 0.5 h - 5 h, preferably 0.5 h.

[0181] In one embodiment, the ratio of compound (IIIa) to the base in the reaction is 1:1 - 6, preferably 1:4.

[0182] In one embodiment, the ratio of compound (IIIa) to the solvent in the reaction is 30 - 80 mg / mL, preferably 55.75 mg / mL.

[0183] In one embodiment, the organic solvent in the reaction is an aprotic solvent, preferably ethyl acetate.

[0184] In one embodiment, the pH is adjusted with citric acid.

[0185] In one embodiment, the concentration of the pH regulator is 0.5 - 2 mol / L, preferably 1 mol / L.

[0186] (2) When R is a benzyl group, the debenzylation reaction of compound (IIIa) is carried out in a solvent under a hydrogen atmosphere in the presence of 10% Pd / C to obtain compound (III);

[0187] The reaction temperature is 10 - 25 °C, preferably 25 °C.

[0188] The reaction time is 3 - 8 h, preferably 5 h.

[0189] Wherein, R 1 、R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 9-1 , R 9-2 , R 9-1-1 , X1, X2, X3, Y2, Y3, Y4, Y1 are defined as in the foregoing formula (I).

[0190]

[0191] Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 9-1 , R 9-2 , R 9-1-1 , X1, X2 are defined as in the foregoing formula (I);

[0192] R is C 1-6 alkyl or benzyl.

[0193] 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 pharmaceutically acceptable salts thereof (as active ingredients), and pharmaceutically acceptable excipients.

[0194] 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.

[0195] 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.

[0196] 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: as a standard sample or a control sample for comparison, or 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.

[0197] The present invention provides the use of the above-mentioned compound or the above-mentioned pharmaceutical composition (as an active ingredient) in the preparation of a medicament for preventing and / or treating metabolic-related diseases. The diseases may be metabolic-related diseases.

[0198] The present invention provides the use of the above-mentioned compound or the above-mentioned pharmaceutical composition (as an active ingredient) in the preparation of a medicament for preventing and / or treating metabolic-related diseases by activating the GPR40 receptor.

[0199] In a specific embodiment, the metabolic-related diseases are selected from any one of the following diseases: glucose intolerance, hyperglycemia, dyslipidemia, syndrome X (microvascular angina), insulin resistance, arteriosclerosis, hypertension, obesity, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, somnolence, etc.

[0200] The metabolic-related diseases may also be selected from any one of the following diseases: hyperglycemia, type 1 diabetes (T1D), type 2 diabetes (T2D), diabetic dyslipidemia, hyperlipidemia, atherosclerosis, non-alcoholic steatohepatitis, and liver fibrosis.

[0201] The metabolic-related diseases may also be selected from hypertriglyceridemia. 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 according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that allows the inventor to appropriately define the terms for the best interpretation. Therefore, the description presented here is only a preferred example for illustrative purposes and is not intended to limit the scope of the present invention. Thus, it should be understood that other equivalent ways or improved ways can be obtained without departing from the spirit and scope of the present invention.

[0202] 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 in relation to the present invention.

[0203] When used alone or in combination with other groups in the present application, the term "alkyl" refers to a straight-chain or branched-chain alkyl having a specified number of carbon atoms (e.g., C1-C6). For example, the term "C 1-6 alkyl" refers to containing 1- alkyl groups with 6 carbon atoms. The 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, heptyl, octyl.

[0204] When used alone or in combination with other groups in the present application, the term "alkenyl" refers to having a specified number of carbon atoms (e.g., C 2-6A straight-chain or branched unsaturated monovalent hydrocarbon group having a carbon-carbon sp2 double bond. Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc.

[0205] As used herein, alone or in combination with other groups, the term "alkynyl" refers to a straight-chain or branched unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 2-6 ) having a carbon-carbon sp triple bond. Alkynyl groups include, but are not limited to: etc.

[0206] As used herein, alone or in combination with other groups, the term "alkoxy" refers to the group RX-O-, where RX is an alkyl group as defined above.

[0207] As used herein, alone or in combination with other groups, the term "cycloalkyl" refers to a saturated or partially unsaturated all-carbon ring, preferably a cycloalkyl having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl). The "cycloalkyl" can be saturated, such as "cycloalkyl"; or, the "cycloalkyl" can be partially unsaturated, such as "cycloalkenyl". For example, in one embodiment, a monocyclic cycloalkyl is preferred.

[0208] Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0209] As used herein, alone or in combination with other groups, the term "heterocyclic group or heterocycle" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one ring member that is a heteroatom selected from N, O, and S. 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, or 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.

[0210] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0211] As used herein, the term "hydroxyl" refers to -OH.

[0212] As used herein, the term "cyano" refers to -CN.

[0213] As used herein, the term "benzyl" refers to -Bn.

[0214] As used herein, alone or in combination with other groups, the term "haloalkyl" refers to an alkyl group as described above, wherein one or more hydrogen atoms are replaced by halogen. For example, the term "C1-6 haloalkyl" refers to a C1-6 alkyl group optionally substituted with one or more (such as 1-3) halogen atoms. Those skilled in the art will understand that when there are 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 haloalkyl groups include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0215] As used herein, the term "each independently" means that at least two groups (or moieties) having the same or similar range of values present in a structure can have the same or different meanings in a particular situation. For example, if substituents A and B are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, then when substituent A is hydrogen, substituent B can be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl; similarly, when substituent B is hydrogen, substituent A can be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl.

[0216] The term "one (or) or more (or)" or a similar expression "at least one (or)" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0217] As used herein, the term "substituted" and other variant forms thereof in this text mean that one or more (such as 1, 2, 3 or 4) atoms or groups of atoms (such as hydrogen atoms) on the designated atom are replaced by other equivalents, provided that the normal valence of the designated atom or group of atoms in the current situation is not exceeded and a stable compound can be formed. If an atom or group of atoms is described as "optionally substituted with...", it can be either substituted or unsubstituted. Unless otherwise specified, the attachment site of a substituent can be from any suitable position of the substituent. When the connecting bond in a substituent is shown as a chemical bond passing between two interconnected atoms in a ring system, it means that the substituent can be attached to any ring-forming atom in the ring system.

[0218] In the present application, a solid line can be used a solid wedge or a dashed wedge to depict the carbon-carbon bonds of the compounds of the present invention. Using a solid line to depict a bond attached to an asymmetric carbon atom is intended to indicate that, including the all possible stereoisomers at the carbon atom (e.g., specific enantiomers, racemic mixtures etc.). The use of solid or dashed wedges to depict bonds attached to an asymmetric carbon atom is intended to indicate the presence of the depicted stereoisomers. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not 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 (e.g., 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 (e.g., racemic mixtures and diastereoisomer pairs).

[0219] The compounds represented by formula (I), (II), and (III) and formula 1-24 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 apparatus for injection or infusion.

[0220] The various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to 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), (II), and (III) and formula 1-24. Preferably, the unit dose of the formulation contains 1 mg-500 mg of the compounds of formula (I), (II), and (III) and formula 1-24.

[0221] 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 administration method, 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.

[0222] In the present invention, the term "(therapeutically) effective amount" can refer to an effective amount of a dose and period required to achieve the desired effect. This effective amount may vary due to certain factors, such as the type of disease or the condition 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.

[0223] A typical formulation is prepared by mixing the compound represented by formula (I) of the present invention with a carrier, diluent, or excipients prepared with. Suitable carriers, diluents or excipients are well-known to those skilled in the art, It includes substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc.

[0224] The specific carrier, diluent or excipient used will depend on the mode of use and purpose of the compound 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 administering 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 be manufactured or used in an acceptable form.

[0225] When the compound of formula (I) described in the present invention is 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 compound of formula (I) or the pharmaceutical composition of the present invention can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal absorption, other local or systemic administration forms.

[0226] 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 be manufactured or used in an acceptable form.

[0227] The drug of the present invention is 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 compound or pharmaceutical composition of the present invention is 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, special certain complex silicates, sodium carbonate, etc.; solution blockers such as paraffin wax, etc.; absorption promoters such as quaternary ammonium compounds Substances, 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.

[0228] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds or pharmaceutical compositions of the present invention, 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.

[0229] In addition to these inert diluents, the composition may also include excipients such as one or more of wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents and perfuming agents.

[0230] 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 metabolic properties.

[0231] On the basis of conforming to common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0232] The reagents and raw materials used in the present invention are all commercially available. Detailed Description of the Invention

[0233] The following further describes the present invention in detail with 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.

[0234] Column chromatography or purification generally uses silica gel 200 - 300 mesh silica gel as the carrier.

[0235] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20 - 30 °C.

[0236] The elution machine system of column chromatography used in the examples includes: 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 compound.

[0237] The following further describes the present invention in detail with specific examples, but the present invention is not limited to the following examples. The examples are for better explaining certain specific embodiments of the present invention and should not 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 commercially available products.

[0238] In the following examples, the structures of the compounds are determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR chemical shift (δ) is given in units of 10 -6 (ppm). The NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and the solvents for the measurements are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0239] The MS measurements are performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0240] Example 1:

[0241]

[0242] Compound 1 is prepared according to the following route.

[0243]

[0244] Step 1: 5-Fluoro-2-methoxypyridine-4-methanol (1-1)

[0245] Under room temperature conditions, while passing nitrogen, a borane tetrahydrofuran solution (115.7 ml, 115.7 mmol, 1 M) is added dropwise to a tetrahydrofuran solution (200 ml) of (5-fluoro-2-methoxypyridin-4-yl) formic acid (4.00 g, 25.74 mmol). Stir for 3 h, slowly add dropwise methanol (100 ml), evaporate to dryness, and then evaporate to dryness again after adding methanol (100 ml * 2). The mixture is directly subjected to column chromatography, and after evaporation to dryness, a white solid 1-1 (3.49 g, yield 85%) is obtained.

[0246] 11H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 4.76 (s, 2H), 6.84 - 6.87 - 8.22 (m, 1H), 7.92 (d, 1H). m / z: 158.05 [M+1].

[0247] Step 2: 5-Fluoro-2-methoxypyridine-4-carbaldehyde (1-2)

[0248] Dissolve (5-fluoro-2-methoxypyridin-4-yl)methanol (1-1) (3.00 g, 19.09 mmol) in dichloromethane (100 ml), stir, and slowly add a dichloromethane solution (100 ml) of Dess-Martin periodinane (9.72 g, 22.91 mmol) to the above dichloromethane solution. Stir the reaction at room temperature for 3 h. Add sodium hydroxide solution and stir, wash twice with water, dry with magnesium sulfate, filter and then evaporate to dryness to obtain a yellow oil (1-2). (1.92 g, 65%).

[0249] 1 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H), 7.08 - 7.11 (m, 1H), 8.20 - 8.22 (m, 1H), 10.32 (s, 1H). m / z: 156 [M+1].

[0250] Step 3: Cyclopropyl(2-methoxypyridin-4-yl)methanol (1-3)

[0251] Add 2-methoxypyridine-4-carbaldehyde (10.0 g, 7.29 mmol, 1.0 eq) to tetrahydrofuran (80 mL), add 1 mol / L cyclopropylmagnesium bromide in tetrahydrofuran solution (213 mL, 0.213 mol, 3.0 eq) dropwise in an ice-water bath, stir at room temperature for 1 h. After the reaction is completed, quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate, dry and concentrate, and purify by column chromatography to obtain product 1-3 (11.40 g, 87%).

[0252] 1 1H 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]

[0253] Step 4: Cyclopropyl(2-methylpyridin-4-yl)methyl ketone (1-4)

[0254] Dissolve cyclopropyl(2-methoxypyridin-4-yl)methanol(1-3)(10.30 g, 0.0575 mol, 1.0 eq) in dimethyl sulfoxide(50 ml). Add triethylamine(46.56 g, 0.460 mol, 8.0 eq) at room temperature. Add pyridine sulfur trioxide(36.62 g, 0.230 mol, 4.0 eq) in three portions and stir at room temperature for 10 minutes. The reaction is complete. Quench the reaction mixture with water(200 ml), extract twice with ethyl acetate(200 ml), 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(6.50 g, 64%).

[0255] 1 H NMR(400 MHz, DMSO-d6): δ8.37 - 8.35(d, J = 8.0 Hz, 1H), 7.45 - 7.43(d, J = 8.0 Hz, 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]

[0256] Step 5: Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)acrylate(1-5)

[0257] Dissolve sodium hydride(2.94 g, 0.0734 mol, 2.0 eq) in tetrahydrofuran(35 ml), protect with nitrogen, cool to 0 °C, add ethyl phosphonoacetate(16.47 g, 0.0734 mol, 2.0 eq) dropwise. After addition, stir at 0 °C for half an hour, add cyclopropyl(2-methylpyridin-4-yl)methyl ketone(1-4)(6.50 g, 0.0367 mol, 1.0 eq) dissolved in tetrahydrofuran(35 ml) dropwise, then slowly return to room temperature and then heat to 80 °C for reflux reaction for 3 h. The reaction is complete. Cool the reaction mixture to room temperature and pour it into ice-cold saturated ammonium chloride solution to quench, add Add ethyl acetate (35 ml) and extract twice. Combine the organic phases, wash with water, wash with saturated sodium chloride, and perform column chromatography Purify to obtain a pale yellow oil 1-5(9.45 g, 100%).

[0258] 1 H NMR(400 MHz, DMSO-d6): δ7.64 - 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]

[0259] Step 6: Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (1-6)

[0260] Dissolve ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)acrylate (1-5) (9.45 g, 0.0383 mol, 1.0 eq) in acetic acid (45 ml), and add zinc powder (14.93 g, 0.230 mol, 6.0 eq) in batches. There is a slight exothermic phenomenon. Stir at room temperature for 0.5 h until the reaction is complete. Filter the reaction solution through diatomaceous earth, and wash the filter cake twice with ethyl acetate (45 ml). Concentrate the filtrate to dryness to remove acetic acid, add ethyl acetate (45 ml) to dissolve, wash with saturated sodium bicarbonate solution until the system is alkaline, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain a yellow oil 1-6 (9.85 g, 100%). Directly use it for the next step.

[0261] 1 H 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]

[0262] Step 7: Ethyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate (1-7)

[0263] Add ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (1-6) (7.50 g, 30 mmol, 1.0 eq) to N,N-dimethylformamide (75 mL), add pyridine hydrochloride (34.80 g, 30 mmol, 1.00 eq), displace with nitrogen, heat to 120 °C and react for 3.0 h. After the reaction is completed, cool to room temperature, add water, extract with ethyl acetate (75 mL) to obtain the organic phase, dry and concentrate, and purify by column chromatography to obtain a colorless oil 1-7 (7.00 g, 90%).

[0264] 11H NMR (400 MHz, DMSO-d6): δ 11.49 (s, 1H), 7.29 - 7.27 (d, J = 8.0 Hz, 1H), 6.25 - 6.20 (m, 1H), 6.19 (s, 1H), 4.08 - 3.96 (m, 2H), 2.75 - 2.70 (m, 2H), 2.18 - 2.10 (m, 1H), 1.11 - 1.07 (t, J = 8.0 Hz, 3H), 1.02 - 0.93 (m, 1H), 0.58 - 0.50 (m, 1H),

[0265] 0.43 - 0.37 (m, 1H), 0.29 - 0.20 (m, 1H), 0.24 - 0.12 (m, 1H). m / z: 236.15 [M+1].

[0266] Step 8: Ethyl 3-cyclopropyl-3-(2-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)pyridin-4-yl)propionate (1-8)

[0267] Under a nitrogen atmosphere, ethyl 3-cyclopropane-3-(2-hydroxypyridin-4-yl)propionate (1-7) (4.70 g, 20 mmol), (2,2-dimethyl-1,3-dioxan-5-yl)methanol (2.92 g, 20 mmol) were added to toluene (40 ml), stirred, cyanomethylenetributylphosphorane (9.7 g, 40 mmol) was added, the temperature was raised to 100 °C and the reaction was carried out for 3 h. The reaction was stopped, and after purification by column chromatography, a foamy solid 1-8 (6.25 g, yield: 86.1%) was obtained.

[0268] 1 1H NMR (400 MHz, CDCl3): δ 8.09 - 8.07 (d, J = 8.0 Hz, 1H), 6.77 - 6.76 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 4.15 - 4.13 (d, J = 8.0 Hz, 2H), 3.96 - 3.62 (m, 6H), 3.20 - 3.17 (m, 6H), 2.66 - 2.62 (m, 1H), 2.43 - 2.40 (m, 1H), 2.23 - 2.20 (m, 1H), 1.18 - 1.16 (s, 6H), 1.18 - 1.16 (t, J = 8.0 Hz, 3H), 1.07 - 0.88 (m, 1H), 0.66 - 0.55 (m, 1H), 0.55 - 0.40 (1H, m), 0.35 - 0.29 (m, 1H), 0.22 - 0.15 (m, 1H), m / z: 364.20 [M+1].

[0269] Step 9: Ethyl 3-cyclopropyl-3-(2-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridin-4-yl)propionate (1-9)

[0270] Ethyl 3-cyclopropyl-3-(2-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)pyridin-4-yl)propionate (1-8) (6.00 g, 16.52 mmol) was added to ethanol (30 ml), stirred until dissolved, pyridinium p-toluenesulfonate (8.20 g, 32 mmol) was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, ethanol was distilled off under reduced pressure, dichloromethane was added, washed with water, saturated sodium bicarbonate solution, brine, and dried over sodium sulfate to obtain a white solid 1-9 (5.18 g, yield: 97.0%).

[0271] 1 HNMR (400 MHz, CDCl3): δ 8.05 - 8.04 (d, J = 8.0 Hz, 1H), 6.75 - 6.74 (d, J = 8.0 Hz, 1H), 6.61 (s, 1H), 4.12 - 4.10 (d, J = 8.0 Hz, 2H), 4.30 (br, 2H), 3.86 - 3.64 (m, 2H), 3.52 - 3.49 (m, 4H), 3.22 - 3.19 (m, 1H), 2.69 - 2.65 (m, 1H), 2.35 - 2.33 (m, 1H), 2.03 - 1.89 (m, 1H), 1.18 - 1.16 (3H, t, J = 8.0 Hz), 1.05 - 0.86 (1H, m), 0.66 - 0.55 (m, 1H), 0.51 - 0.38 (m, 1H), 0.35 - 0.24 (m, 1H). 0.20 - 0.07 (m, 1H), m / z: 324.25 [M + 1].

[0272] Step 10: Ethyl 3-cyclopropyl-3-(2-((2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-5-yl)methoxy)pyridin-4-yl)propionate (1-10)

[0273] 5-Fluoro-2-methoxypyridine-4-carbaldehyde (1-1) (1.09 g, 7 mmol), ethyl 3-cyclopropyl-3-(2-(3-hydroxy-2-(hydroxymethyl)propyl)pyridine-4-propionate (2.26 g, 7 mmol), and p-toluenesulfonic acid monohydrate (139 mg, 0.7 mmol) were added to toluene (20 ml), and the mixture was refluxed with water separation overnight. Monitoring showed that the reaction was completed, concentrated, and column chromatography gave a colorless oil 1-10 (1.70 g).

[0274] 11H NMR (400 MHz, CDCl3), δ 8.07 - 8.03 (m, 1H), 7.98 - 7.97 (m, 1H), 6.98 - 6.97 (d, J = 4 Hz, 1H), 6.80 - 6.77 (m, 1H), 6.63 - 6.64 (m, 1H), 5.74 - 5.70 (d, 1H), 4.67 - 4.65 (d, J = 8 Hz, 1H), 4.39 - 4.31 (m, 2H), 4.18 - 4.12 (m, 2H), 4.08 - 4.06 (q, J = 8 Hz, 2H), 3.89 - 3.88 (m, 3H), 3.84 - 3.81 (m, 1H), 2.90 - 2.65 (m, 3H), 2.33 - 2.27 (m, 1H), 1.20 - 1.18 (t, J = 8 Hz, 3H), 1.04 - 0.93 (m, 1H), 0.64 - 0.59 (m, 1H), 0.50 - 0.42 (m, 1H), 0.34 - 0.28 (m, 1H), 0.20 - 0.12 (m, 1H). m / z: 461.2 [M + 1].

[0275] Step 11: 3 - Cyclopropyl - 3 - (2 - ((2 - (5 - fluoro - 2 - methoxypyridin - 4 - yl) - 1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 1)

[0276] Dissolve ethyl 3 - cyclopropyl - 3 - (2 - ((2 - (5 - fluoro - 2 - methoxypyridin - 4 - yl) - 1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propanoate (1 - 10) (223 mg, 0.5 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml), add 2 mol / L sodium hydroxide solution (1 ml, 2 mmol), and stir the reaction at 60 °C for 0.5 h. After monitoring shows the reaction is complete, concentrate, add 1 mol / L citric acid to adjust the pH value to 5 - 6, extract with ethyl acetate 3 times, wash with ice water, concentrate, and prepare the white solid compound 1 (150 mg, yield: 68.6%) by column chromatography.

[0277] 11H NMR (400 MHz, CDCl3): δ 8.08 - 8.04 (m, 1H), 7.98 - 7.97 (m, 1H), 6.99 - 6.98 (d, J = 4 Hz, 1H), 6.80 - 6.77 (m, 1H), 6.64 - 6.63 (m, 1H), 5.75 - 5.71 (d, 1H), 4.68 - 4.66 (d, J = 8 Hz, 1H), 4.39 - 4.31 (m, 2H), 4.18 - 4.12 (m, 2H), 3.89 - 3.88 (m, 3H), 3.84 - 3.81 (m, 1H), 2.86 - 2.59 (m, 3H), 2.33 - 2.27 (m, 1H), 1.04 - 0.93 (m, 1H), 0.66~0.58 (m, 1H), 0.51~ 0.41 (m, 1H), 0.35~0.28 (m, 1H), 0.21~0.13 (m, 1H).

[0278] m / z: 433 [M+1], 455.0 [M+Na].

[0279] Example 2:

[0280]

[0281] Compound 2 was prepared according to the following route.

[0282]

[0283] Step 1: 4-(5-((Benzyloxy)methyl)-1,3-dioxolan-2-yl)-5-fluoro-2-methoxypyridine (2-1)

[0284] 5-Fluoro-2-methoxypyridine-4-carbaldehyde (1-2) (620 mg, 4 mmol), 2-((benzyloxy)methyl)-1,3-propanediol (940 mg, 4.8 mmol), and p-toluenesulfonic acid monohydrate (80 mg, 0.4 mmol) were dissolved in toluene (12 ml), and the mixture was refluxed with water separation and stirred overnight. After monitoring the completion of the reaction, the mixture was concentrated, and column chromatography was performed to obtain colorless oily substance 2-1 (1.27 g, yield: 95.0%).

[0285] 11H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 4 Hz, 1H), 7.39 - 7.29 (m, 5H), 6.98 - 6.92 (m, 1H), 5.70 (d, J = 36 Hz, 1H), 4.59 (s, 1H), 4.48 (s, 1H), 4.30 - 4.23 (m, 2H), 4.12 - 4.08 (m, 1H), 3.89 - 3.86 (m, 4H), 3.80 - 3.74 (m, 1H), 3.32 (d, J = 4.0 Hz, 1H), 2.55 - 2.46 (m, 1H), 1.85 - 1.78 (m, 1H). m / z: 334.10 [M+1].

[0286] Step 2: (2-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-5-yl)methanol (2-2)

[0287] Dissolve 4-(5-((benzyloxy)methyl)-1,3-dioxolan-2-yl)-5-fluoro-2-methoxypyridine (1.27 g) in methanol (12 ml), add 10% Pd / C (380 mg), and stir at room temperature for 5 h under a hydrogen balloon atmosphere. After the reaction is completed, filter and concentrate to obtain white solid 2-2 (780 mg, yield: 84.5%).

[0288] 1 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 6.99 - 6.93 (m, 1H), 5.71 (d, J = 36 Hz, 1H), 4.33 - 4.24 (m, 2H), 4.14 - 4.11 (m, 1H), 4.06 - 4.04 (m, 1H), 3.89 (s, 3H), 3.76 - 3.74 (m, 1H), 3.55 (d, J = 8 Hz, 1H), 2.45 - 2.37 (m, 1H), 1.73 - 1.69 (m, 1H). m / z: 244.05 [M+1].

[0289] Step 3: Methyl 3-cyclopropyl-2-methyl-3-oxopropionate (2-3)

[0290] Add methyl 3-cyclopropyl-3-oxopropionate (25.00 g, 0.176 mol, 1.0 eq) to tetrahydrofuran (160 ml), then add cesium carbonate (85.95 g, 0.264 mol, 1.5 eq), stir at room temperature for 30 minutes, add potassium iodide (27.5 g, 0.193 mol, 1.1 eq), heat to 40 °C and react for 3 h. After the reaction is completed, filter the reaction mixture through diatomaceous earth, wash the filter cake twice with ethyl acetate, and concentrate the filtrate to dryness to obtain crude white solid 2-3 (32.5 g), which is directly used in the next step.

[0291] 1 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 3H), 3.68 (q, J = 7.2 Hz, 1H), 2.08 - 2.03 (m, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.12 - 1.05 (m, 2H), 0.98 - 0.92 (m, 2H). LC-MS m / z 141.05 [M+1].

[0292] Step 4: Methyl 3-cyclopropyl-2-methyl-3-(p-toluenesulfonyl)acrylate (2-4)

[0293] Methyl 3-cyclopropyl-2-methyl-3-oxopropionate (2-3) (15.00 g, 0.096 mol, 1.0 eq) was added to tetrahydrofuran (100 ml), and the temperature was cooled to 0 °C. Sodium bis(trimethylsilyl)amide (120 ml, 1.3 eq) was added dropwise, and the reaction was carried out at room temperature for 0.5 h. A solution of p-toluenesulfonic anhydride (38.00 g, 0.115 mol, 1.2 eq) in tetrahydrofuran (160 ml) was added dropwise, and the reaction was carried out at room temperature for 2 h. The reaction was complete. Water (40 ml) was added, and the mixture 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 a pale green solid 5-3 (10.00 g, yield 33.5%).

[0294] 1 1H NMR (400 MHz, CDCl3): δ 7.85 - 7.80 (m, 2H), 7.34 (d, J = 8.0 Hz, 2 H), 3.59 (s, 3H), 2.46 (s, 3H), 2.02 (d, J = 1.2 Hz, 3H), 1.61 (s, 1H), 0.75 - 0.68 (m, 4H). MS m / z 311.05 [M+1].

[0295] Step 5: Methyl 3-(3-(benzyloxy)phenyl)-3-cyclopropyl-2-methylacrylate (2-5)

[0296] Methyl 3-cyclopropyl-2-methyl-3-(p-toluenesulfonyl)acrylate (2-4) (10.00 g, 0.032 mol, 1.0 eq) was dissolved in dioxane (50 ml) and water (5 ml), and then 3-benzyloxybenzeneboronic acid (8.1 g, 0.035 mol, 1.1 eq), cesium carbonate (11.56 g, 0.035 mol, 1.1 eq), and 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (1.18 g, 0.05%) were added. The reaction was heated to 100 °C under nitrogen protection for 2 h. The reaction was monitored to completion. Water (100 ml) was added, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic phases were combined, washed with saturated brine (150 ml), and dried over anhydrous sodium sulfate. Purification by column chromatography gave a colorless liquid 2-5 (6.00 g, yield 57.7%).

[0297] 1 1H NMR (400 MHz, CDCl3): δ 7.43 - 7.31 (m, 5H), 7.16 (t, J = 8.0 Hz, 1H), 6.85 - 6.83 (m, 1H), 6.59 - 6.55 (m, 2H), 5.03 (s, 2H), 3.34 (s, 3H), 2.13 (s, 3H), 1.84 - 1.80 (m, 1H), 0.73 - 0.69 (m, 2H), 0.32 - 0.28 (m, 2H). m / z 323.1 [M+1].

[0298] Step 6: Methyl 3 - cyclopropyl - 3-(3 - hydroxyphenyl)-2 - methylpropionate (2 - 6)

[0299] Dissolve methyl 3-(3-(benzyloxy)phenyl)-3 - cyclopropyl - 2 - methylacrylate (2 - 5) (6.00 g, 0.018 mmol, 1.0 eq) in a mixed solvent of methanol / tetrahydrofuran (30 ml), add 10% Pd / C (1.20 g, 20%), replace with hydrogen five times, react at room temperature for 16 h, and monitor the completion of the reaction. Filter the reaction solution through diatomaceous earth, wash the filter cake twice with ethyl acetate, concentrate the filtrate, and purify by column chromatography to obtain colorless liquid 2 - 6 (2.10 g, yield 48.1%).

[0300] 1 1H NMR (500 MHz, CDC13) δ 7.2 (m, 1H), 6.70 (m, 3H), 3.76 (s, 3H), 2.82 (m, 1H), 1.90 (m, 1H), 1.05 (m, 1H), 0.96 (d, 3H), 0.56 (m, 1H), 0.30 (m, 2H), 0.01 (m, 1H). m / z 235.15 [M+1].

[0301] Step 7: 3 - cyclopropyl - 3-(3 - hydroxyphenyl)-2 - methylpropanoic acid (2 - 7)

[0302] Methyl 3-cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropionate (2 - 6) (2.00 g, 8.54 mmol, Dissolve methyl 3 - cyclopropyl - 3-(3 - hydroxyphenyl)-2 - methylpropionate (2 - 6) (1.41 g, 6.15 mmol, 1.0 eq) in a mixed solvent of methanol / tetrahydrofuran (10 ml / 10 ml), add sodium hydroxide solution (8 ml, 20%), react at 40 °C for 4 h. After the reaction is completed, concentrate, add water and dichloromethane and stir, adjust the pH value with hydrochloric acid, clarify, separate the layers, and concentrate the organic phase to obtain liquid 2 - 7 (1.41 g, yield 75.0%).

[0303] m / z: 221.15 [M+1].

[0304] Step 8: Benzyl 3 - cyclopropyl - 3-(3 - hydroxyphenyl)-2 - methylpropionate (2 - 8)

[0305] 3-Cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropanoic acid (2-7) (479 mg, 0.0017 mol) was added to N,N-dimethylformamide (5 ml), potassium carbonate (470 mg, 0.0034 mol) was added, and then benzyl bromide (291 mg, 0.0017 mol) was added. The reaction was carried out at room temperature for 1 hour. The reaction was completed. 1 mol / L citric acid solution was added to the reaction solution, and ethyl acetate (20 ml × 3) was added for extraction. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified to obtain white solid 2-8 (260 mg, yield: 49%).

[0306] m / z: 311.15 [M+1].

[0307] Step 9: Benzyl 3-cyclopropyl-3-(3-((2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-5-yl)methoxy)phenyl)-2-methylpropanoate (2-9)

[0308] (2-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-5-yl)methanol (2-8) (69 mg, 0.284 mmol), benzyl 3-cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropanoate (80 mg, 0.26 mmol), and cyanomethylenetributylphosphorane (125 mg, 0.52 mmol) were dissolved in toluene (0.5 ml), and the reaction was stirred at 100 °C for 4 hours. The reaction was terminated, concentrated, and purified by column chromatography to obtain a colorless oil 2-9 (50 mg, yield: 32.9%).

[0309] m / z: 536.20 [M+1], m / z: 558.20 [M+Na].

[0310] Step 10: 3-Cyclopropyl-3-(3-((2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-5-yl)methoxy)phenyl)-2-methylpropanoic acid (Compound 2)

[0311] Benzyl 3-cyclopropyl-3-(3-((2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-5-yl)methoxy)phenyl)-2-methylpropanoate (2-9) (50 mg) was dissolved in tetrahydrofuran (1 ml), and 10% of Pd / C (5 mg), under a hydrogen balloon Stir the reaction at room temperature for 2 hours under an atmosphere. After the reaction is completed, filter, Concentrated and purified by column chromatography to obtain white solid Compound 2 (24 mg, yield: 57.8%).

[0312] 11H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.11 (d, J = 8 Hz, 2H), 7.00 (d, J = 24 Hz, 1H), 6.91 (d, J = 36 Hz, 2H), 5.74 (d, J = 24 Hz, 1H), 4.40 - 4.33 (m, 2H), 3.92 - 3.87 (m, 5H), 3.82 - 3.81 (m, 2H), 2.87 - 2.78 (m, 1H), 2.73 - 2.63 (m, 1H), 2.01 - 2.96 (m, 1H), 1.16 - 1.06 (m, 1H), 0.99 (d, J = 4 Hz, 3H), 0.68 - 0.59 (m, 1H), 0.44 - 0.33 (m, 1H). m / z: 446.40 [M+1].

[0313] Example 3:

[0314]

[0315] Compound 3 was prepared according to the following route.

[0316]

[0317] Step 1: 2-(2-Bromo-5-methoxyphenyl)-1,3-dioxolane (3-1)

[0318] Dissolve 2-bromo-5-methoxybenzaldehyde (5.0 g, 23.2 mmol) in toluene (300 ml), stir, add ethylene glycol (2.16 g, 34.2 mmol), p-toluenesulfonic acid (20 mg), heat under reflux to separate water for 12 hours. After the reaction is completed, cool to room temperature. Wash the organic phase with saturated sodium bicarbonate, separate the layers, and concentrate and purify the organic phase to obtain the product 3-1 (5.92 g, 98%).

[0319] 1 1H NMR (400 MHz; CDCl3): δ 7.44 (d, 1H); 7.16 (d, 1H); 6.78 (dd, 1H); 6.04 (s, 1H); 4.12 (m, 4H); 3.80 (s, 3H).

[0320] Step 2: 4-(2-(1,3-Dioxolan-2-yl)-4-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine (3-2)

[0321] Dissolve 2-(2-bromo-5-methoxyphenyl)-1,3-dioxolane (3-1) (500 mg, 1.9 mmol) in dioxane / water (20 ml / 4 ml), add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine (679 mg, 2.33 mmol), potassium phosphate (825 mg, 3.89 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (142 mg, 0.19 mmol, 0.1 eq), and heat at 90 °C for reaction overnight. After the reaction is complete, cool to room temperature, add water (10 ml) and ethyl acetate (20 ml) for liquid separation, dry and concentrate the organic phase, and purify by column chromatography to obtain solid 3-2 (535 mg, 80%).

[0322] 1 H NMR (400 MHz; CDCl3): δ 7.40 - 7.38 (d, 1H); 7.12 - 7.10 (d, 1H); 6.80 - 6.78 (d, 1H); 5.98 - 5.95 (m, 1H); 5.89 (s, 1H); 4.12 - 4.08 (m, 4H); 3.79 (s, 3H), 3.35 - 3.33 (m, 2H), 2.90 - 2.65 (m, 4H), 2.12 - 2.10 (m, 2H). m / z: 344.15 [M+1].

[0323] Step 3: 4-(2-(1,3-dioxolan-2-yl)-4-methoxyphenyl)-1-(2,2,2-trifluoroethyl)piperidine (3-3)

[0324] Add 4-(2-(1,3-dioxolan-2-yl)-4-methoxyphenyl)-1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine (3-2) (530 mg, 1.5 mmol) to methanol (10.0 ml), add 10% palladium / carbon (106 mg, 20%), introduce hydrogen gas, and react at room temperature for 2 hours. After the reaction is completed, filter, and rotary evaporate the filtrate to obtain product 3-3 (500 mg, 93%).

[0325] 1 H NMR (400 MHz; CDCl3): δ 7.39 - 7.37 (d, 1H); 7.11 - 7.09 (d, 1H); 6.80 - 6.77 (d, 1H); 5.89 (s, 1H); 4.09 - 4.02 (m, 4H); 3.79 (s, 3H), 3.05 (s, 2H), 2.79 - 2.75 (m, 1H), 2.65 - 2.55 (m, 4H), 1.75 - 1.72 (m, 2H). 1.52 - 1.49 (m, 2H). m / z: 346.15 [M+1].

[0326] Step 4: 5-Methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzaldehyde (3-4)

[0327] 4-(2-(1,3-Dioxolan-2-yl)-4-methoxyphenyl)-1-(2,2,2-trifluoroethyl)piperidine (3-3) (1.5 g, 4.3 mmol, 1.0 eq) is added to water (10 ml), formic acid (5.0 ml) is added, and heated to 90 was reacted at [specific temperature] for 2.0 h. After the reaction was complete, it was cooled to room temperature, the pH value was adjusted to 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, separated, the organic phase was dried and concentrated, and purified to obtain the product 3-4 (1.20 g, 92%).

[0328] 1 H NMR (400 MHz, CDCl3): 10.29 (s, 1H), 7.38 - 7.36 (d, J = 8.0 Hz, 1H), 7.34 - 7.33 (d, J = 4.0 Hz, 1H), 7.13 - 7.10 (m, 1H), 3.85 (s, 3H), 3.48 - 3.44 (m, 1H), 3.12 - 3.09 (m, 2H), 3.04 - 3.02 (m, 2H), 2.57 - 2.51 (m, 2H), 1.92 - 1.88 (m, 2H), 1.82 - 1.77 (m, 2H), m / z: 302.00 [M+1].

[0329] Step 5: Ethyl 3-cyclopropyl-3-(2-((2-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)-1,3-dioxolan-5-yl)methoxy)pyridin-4-yl)propionate (3-5)

[0330] 5-Methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzaldehyde (700 mg, 2.32 mmol), ethyl 3-cyclopropyl-3-(2-(3-hydroxy-2-(hydroxymethyl)propyl)pyridin-4-yl)propionate (1-9) (751 mg, 2.32 mmol), and p-toluenesulfonic acid monohydrate (46 mg, 0.232 mmol) were added to toluene (40 ml), and heated to reflux for water separation reaction overnight. After the reaction was completed, it was cooled to room temperature, evaporated to dryness, and the residue was purified by column chromatography to obtain the product 3-5 (340 mg, 26%).

[0331] 11H NMR (400 MHz, CDCl3): δ 8.08 (t, 1H), 7.24 - 7.21 (dd, J = 12.0 Hz, 1H), 7.18 - 7.12 (dd, J = 12.0 Hz, 1H), 6.88 - 6.84 (m, 1H), 6.81 - 6.77 (m, 1H), 6.65 - 6.64 (s, 1H), 5.66 - 5.60 (d, 24 Hz, 1H), 4.74 - 4.72 (dd, 8 Hz, 1H), 4.41 - 4.33 (m, 2H), 4.22 - 4.03 (m, 4H), 3.86 - 3.79 (m, 4H), 3.11 - 2.94 (m, 4H), 2.88 - 2.66 (m, 4H), 2.52 - 2.43 (q, 2H), 2.34 - 2.28 (m, 1H), 2.05 - 2.00 (m, 1H), 1.86 - 1.75 (m, 4H), 1.42 - 1.17 (m, 2H), 1.03 - 0.86 (m, 1H), 0.65 - 0.57 (m, 1H), 0.51 - 0.46 (m, 1H), 0.33 - 0.26 (m, 1H), 0.20 - 0.13 (m, 1H), m / z: 629.30 [M + Na].

[0332] Step 6: 3 - Cyclopropyl - 3-(2 - ((2-(5 - methoxy - 2-(1-(2,2,2 - trifluoroethyl)piperidin - 4 - yl)phenyl)-1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 3)

[0333] Ethyl 3 - cyclopropyl - 3-(2 - ((2-(5 - methoxy - 2-(1-(2,2,2 - trifluoroethyl)piperidin - 4 - yl)phenyl)-1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propanoate (310 mg, 0.51 mmol, 1.0 eq) was added methanol / tetrahydrof uran (4 ml / 4 ml) is added to 2 mol / L sodium hydroxide solution (0.5 mL, 1.02 mmol, 2.0 eq), heated to 40 °C for reaction. After the reaction was completed, the system was evaporated to dryness. Water (6.0 ml) was added, and the pH of the system was adjusted to 5 - 6 with 1 mol / L citric acid aqueous solution. Ethyl acetate (10 ml) was added, and the organic phase was extracted, dried, concentrated, and purified to obtain solid Compound 3 (179 mg, 61%).

[0334] 11H NMR (400 MHz, DMSO-d6): 12.12 (br s, 1H), 8.05 (s, 1H), 7.23 - 7.21 (d, J = 8.0 Hz, 1H), 7.00 - 6.87 (m, 3H), 6.75 - 6.73 (m, 1H), 5.66 - 5.63 (m, 1H), 4.61 - 4.59 (m, 2H), 4.26 - 4.24 (m, 1H), 4.15 - 4.10 (m, 2H), 3.83 - 3.80 (m, 1H), 3.70 (s, 3H), 3.33 - 3.31 (m, 1H), 2.95 - 2.91 (m, 3H), 2.22 - 2.20 (m, 1H), 2.01 - 1.99 (m, 1H), 1.27 - 1.22 (m, 4H), 1.27 - 1.25 (m, 2H), 1.01 - 0.98 (m, 1H), 0.87 - 0.82 (m, 1H), 0.51 - 0.32 (m, 2H), 0.18 - 0.16 (m, 2H). m / z: 579.55 [M + H].

[0335] Example 4:

[0336]

[0337] Compound 4 was prepared according to the following route.

[0338]

[0339] Step 1: 2-(1,3-dioxolan-2-yl)-4-methoxybenzaldehyde (4-1)

[0340] Under a nitrogen atmosphere, 2-(2-bromo-5-methoxyphenyl)-1,3-dioxolane (3-1) (3.20 g, 12.3 mmol) was dissolved in tetrahydrofuran (50 mL). The temperature was lowered to -78 °C, and the mixture was stirred. A solution of n-butyllithium in n-hexane (12.3 mL, 2.6 mol / L) was added dropwise. After stirring for 30 minutes, N,N-dimethylformamide (0.90 g, 12.3 mmol) was slowly added dropwise while maintaining the temperature at -78 °C. The mixture was stirred for 30 minutes and then allowed to warm to room temperature naturally. Water (25 mL) was added dropwise, and the mixture was stirred. The mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with water (2 × 100 mL), and the solvent was removed by rotary evaporation. The residue was purified by column chromatography to obtain a yellow oil, 4-1 (1.92 g, 75.0%).

[0341] 11H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.93 - 7.91 (d, 1H), 7.45 (s, 1H), 7.12 - 7.08 (d, 1H), 5.89 (s, 1H), 4.07 - 4.16 (m, 4H), m / z: 209.25 [M+H].

[0342] Step 2: 2-(5-Methoxy-2-(4-methylene-1-en-1-yl)phenyl)-1,3-dioxolane (4-2)

[0343] Isobutyltriphenylphosphonium bromide (7.95 g, 19.2 mmol) was dissolved in tetrahydrofuran (30 ml). The temperature was lowered to -10 °C, and 0.5 mol / L n-butyllithium (8.0 ml, 19.2 mmol) was added dropwise. After addition, the reaction was carried out at 0 °C for 0.5 h. 2-(2-Bromo-5-methoxyphenyl)-1,3-dioxolane (2.0 g, 9.6 mmol) dissolved in tetrahydrofuran (10 ml) was added, and the reaction was carried out at 0 °C for 3.0 h after addition. After the reaction was completed, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 30 ml), dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain product 4-2 (2.20 g, 88%).

[0344] 1 1H NMR (400 MHz, CDCl3): δ 7.43 - 7.41 (d, 1H), 7.28 - 7.13 (m, 2H), 6.90 - 6.71 (m, 1H), 6.08 - 5.73 (m, 2H), 4.20 - 4.19 (m, 2H), 4.09 - 4.02 (m, 2H), 3.85 (s, 3H), 2.04 - 2.00 (m, 2H), 1.78 - 1.62 (m, 1H), 0.97 - 0.89 (d, 6H). m / z: 263.10 [M+H].

[0345] Step 3: 2-(5-Methoxy-2-(4-methyl-pentane)phenyl)-1,3-dioxolane (4-3)

[0346] 2-(5-Methoxy-2-(4-methylene-1-en-1-yl)phenyl)-1,3-dioxolane (4-2) (2.15 g, 8.2 mmol) was added to methanol (20.0 ml), and palladium / carbon (200 mg, 20%) was added. Hydrogen was introduced, and the reaction was carried out at room temperature. After the reaction was complete, it was filtered, and the filtrate was evaporated to dryness to obtain product 4-3 (2.0 g, 92%).

[0347] m / z: 265.10 [M+H].

[0348] Step 4: 5-Methoxy-2-(4-methylpentane)benzaldehyde (4-4)

[0349] 2-(5-Methoxy-2-(4-methylpentyl)phenyl)-1,3-dioxolane (4-3) (2.00 g, 8 mmol, 1.0 eq) was added to water (20 ml), formic acid (6.0 ml) was added, and the mixture was heated to 90 °C and reacted for 2.0 h. After the reaction was complete, it was cooled to room temperature, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate (20 ml). After liquid separation, the organic phase was dried and concentrated, and the product 4-4 (1.50 g, 90%) was obtained by purification. 1 1H NMR (400 MHz, CDCl3): 10.23 (s, 1H), 7.29 - 7.28 (d, 1H), 7.12 - 7.10(d,

[0350] 1H), 7.01 - 6.99 (d, 1H), 3.77 (s, 3H), 2.87 - 2.84 (m, 2H), 1.64 - 1.62 (m, 1H), 1.54 - 1.49 (m, 2H), 1.15 - 1.13 (m, 2H), 0.81 - 0.79 (d, J = 8.0 Hz, 6H), m / z: 221.15 [M+H], 261.20 [M+Na+OH].

[0351] According to a synthetic method similar to that of Example 3, 3-4 was replaced with 4-4 to prepare Compound 4.

[0352] 3-Cyclopropyl-3-(2-((2-(5-methoxy-2-(4-methylpentyl)phenyl)-1,3-dioxolan-5-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 4)

[0353] Yield: 79%. 11H NMR (400 MHz, DMSO-d6): δ 12.06 (br s, 1H), 8.05 - 8.03 (t, J = 4.0 Hz, 4.0 Hz, 1H), 7.08 - 7.06 (d, J = 8.0 Hz, 1H), 7.00 - 6.99 (m, 1H), 6.96 - 6.93 (m, 1H), 6.83 - 6.81 (d, J = 8.0 Hz, 1H), 6.74 - 6.72 (m, 1H), 5.63 (s, 0.44H), 5.56 (s, 0.56H), 4.59 - 4.57 (m, 1H), 4.10 - 4.06 (m, 1H), 3.98 - 3.92 (m, 2H), 3.67 - 3.01 (m, 1H), 3.31 (s, 3H), 2.69 - 2.55 (m, 2H), 2.49 - 2.45 (m, 2H), 2.20 - 2.02 (m, 1H), 2.00 - 1.97 (m, 1H), 1.47 - 1.45 (m, 3H), 1.31 - 1.22 (m, 3H), 0.83 - 0.82 (m, 1H), 0.84 - 0.81 (m, 6H), 0.59 - 0.42 (m, 1H), 0.34 - 0.32 (m, 1H), 0.25 - 0.18 (m, 1H), 0.16 - 0.12 (m, 1H), m / z: 498.20 [M + H].

[0354] Example 5:

[0355]

[0356] Compound 5 was prepared according to the following route.

[0357]

[0358] Step 1: Isobutyl 2-bromo-4-methoxybenzoate (5-1)

[0359] 2-Bromo-4-methoxybenzoic acid (2.00 g, 8.6 mmol) and isobutanol (0.71 g, 9.5 mmol) were dissolved in tetrahydrofuran (20 ml). The temperature was lowered to 0 °C, and dicyclohexylcarbodiimide (2.31 g, 11.2 mmol) and 4-dimethylaminopyridine (0.11 g, 0.86 mmol) dissolved in tetrahydrofuran were added. After the addition, the reaction was carried out at room temperature overnight. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the organic phase was dried and concentrated. The product 5-1 (1.50 g, 60%) was obtained by column purification.

[0360] 11H NMR (400 MHz, CDCl3): δ 7.88 - 7.86 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 6.89 - 6.86 (m, 1H), 4.10 - 4.08 (d, J = 8.0 Hz, 2H), 3.84 (s, 3H), 2.14 - 2.05 (m, 1H), 1.03 - 1.01 (d, J = 8.0 Hz, 6H).

[0361] Step 2: Isobutyl 4-methoxy-2-vinylbenzoate (5-2)

[0362] Isobutyl 2-bromo-4-methoxybenzoate (5-1) (1.70 g, 5.9 mmol) was added to toluene (20.0 mL), and tributylvinyltin (3.78 g, 11.8 mmol) and palladium dichloride triphenylphosphine (0.42 g, 0.59 mmol) were added. The mixture was heated to reflux overnight. After the reaction was complete, it was cooled to room temperature, 10 mL of water was added, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain product 5-2 (1.25 g, 90%).

[0363] 1 1H NMR (400 MHz, CDCl3): δ 7.94 - 7.91 (d, J = 12.0 Hz, 1H), 7.58 - 7.51 (s, 1H), 6.89 - 6.86 (m, 1H), 4.10 - 4.08 (d, J = 8.0 Hz, 2H), 3.84 (s, 3H), 2.14 - 2.05 (m, 1H), 1.03 - 1.01 (d, J = 8.0 Hz, 6H).

[0364] Step 3: Isobutyl 2-formyl-4-methoxybenzoate (5-3)

[0365] Isobutyl 4-methoxy-2-vinylbenzoate (5-2) (1.22 g, 5.2 mmol) was dissolved in tetrahydrofuran / water (40 ml / 10 ml), and sodium periodate (3.34 g, 15 mmol) and potassium osmate dihydrate (192 mg, 0.52 mmol) were added. The reaction was carried out at room temperature for 4.0 hours. After the reaction was completed, it was filtered through diatomaceous earth, the filtrate was concentrated by rotary evaporation, and purified by column chromatography to obtain product 5-3 (1.00 g, 81.3%).

[0366] 11H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 8.01 - 7.99 (d, J = 8.0 Hz, 1H), 7.42 - 7.41 (d, J = 4.0 Hz, 1H), 7.14 - 7.11 (m, 1H), 4.15 - 4.13 (d, J = 8.0 Hz, 2H), 3.91 (s, 3H), 2.15 - 2.08 (m, 1H), 1.04 - 1.02 (d, J = 8.0 Hz, 6H).

[0367] Step 4: Isobutyl 2-(5-((benzyloxy)methyl)-1,3-dioxolan-2-yl)-4-methoxybenzoate (5-4)

[0368] Isobutyl 2-formyl-4-methoxybenzoate (5-3) (1.00 g, 4.2 mmol), 2-((benzyloxy)methyl)-1,3-propanediol (0.92 g, 5.08 mmol), and p-toluenesulfonic acid monohydrate (0.08 g, 0.42 mmol) were added to toluene (35 ml), and the mixture was heated to reflux for water separation reaction overnight. After completion of the reaction, it was cooled to room temperature, the system was rotary evaporated, and the product was purified by column chromatography (1.30 g, 74.2%).

[0369] 1 1H NMR (400 MHz, CDCl3): δ 7.91 - 7.89 (d, J = 12.0 Hz, 1H), 7.39 - 7.30 (m, 6H), 6.88 - 6.86 (d, J = 8.0 Hz, 1H), 6.42 - 6.33 (s, 1H), 4.59 (s, 1H), 4.48 (s, 1H), 4.29 - 4.10 (m, 3H), 4.17 - 4.15 (m, 2H), 3.82 - 3.77 (m, 5H), 3.31 - 3.30 (m, 1H), 2.09 - 2.02 (m, 1H), 1.02 - 1.00 (d, J = 8.0 Hz, 6H). m / z: 415.20 [M + H], 437.30 [M + Na].

[0370] Step 5: Isobutyl 2-(5-(hydroxymethyl)-1,3-dioxolan-2-yl)-4-methoxybenzoate (5-5)

[0371] Isobutyl 2-(5-((benzyloxy)methyl)-1,3-dioxolan-2-yl)-4-methoxybenzoate (5-4) (400 mg, 1.45 mmol) was added to methanol (6.0 ml), and palladium / carbon (80 mg, 20%) was added. The reaction was carried out at room temperature overnight. After completion of the reaction, it was filtered, and the filtrate was rotary evaporated to obtain product 5-5 (230 mg, 73%).

[0372] 1 1H NMR (400 MHz, CDCl3): δ 7.85 - 7.82 (d, J = 12.0 Hz, 1H), 7.33 - 7.27 (m, 6H),

[0373] 6.83 - 6.80 (t, J = 4.0 Hz, 1H), 6.36 - 6.27 (d, 1H), 4.23 - 3.98 (m, 6H), 3.69 (s, 3H), 3.55 (m, 1H), 3.46 - 3.45 (dd, 1H), 2.07 - 1.98 (t, 2H), 1.59 - 1.57 (m, 2H), 0.95 - 0.94 (d, 6H), m / z: 325.20 [M + H], 347.15 [M + Na].

[0374] Step 6: Benzyl 3 - cyclopropyl - 3-(2 - ((2-(2-(isobutylcarbonyl)-5 - methoxyphenyl)-1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propionate (5 - 6)

[0375] Dissolve isobutyl 2-(5 - (hydroxymethyl)-1,3 - dioxolan - 2 - yl)-4 - methoxybenzoate (5 - 5) (220 mg, 0.679 mmol), benzyl 3 - cyclopropyl - 3-(2-(3 - hydroxy - 2-(hydroxymethyl)propyl)pyridin - 4 - yl)propionate (242 mg, 0.814 mmol), and cyanomethylenetributylphosphine (327 mg, 1.35 mmol) in toluene (6 ml), heat to 100 °C and react for 1.0 hour. After the reaction is completed, evaporate the solvent in the system under reduced pressure and purify by column chromatography to obtain the product 5 - 6 (110 mg, 27%), m / z: 604.35 [M + H], 626.40 [M + Na].

[0376] Step 7: 3 - cyclopropyl - 3-(2 - ((2-(2-(isobutylcarbonyl)-5 - methoxyphenyl)-1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 5)

[0377] Add benzyl 3 - cyclopropyl - 3-(2 - ((2-(2-(isobutylcarbonyl)-5 - methoxyphenyl)-1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propionate (5 - 6) (110 mg, 0.18 mmol, 1.0 eq) to methanol (6.0 ml), add 10% palladium on carbon (22 mg, 20%), and react at room temperature for 2 hours. After the reaction is complete, filter, evaporate the filtrate under reduced pressure, and purify to obtain Compound 5 (62.0 mg, 66%).

[0378] 11H NMR (400 MHz, CDCl3): δ 8.06 - 8.05 (d, J = 4.0 Hz, 1H), 7.92 - 7.90 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 6.90 - 6.88 (m, 1H), 6.79 - 6.78 (d, J = 4.0 Hz, 1H), 6.64 (s, 1H), 6.39 (s, 1H), 4.38 - 4.37 (m, 2H), 4.35 - 4.34 (m, 2H), 4.11 - 4.05 (m, 2H), 3.93 - 3.90 (m, 1H), 3.88 (s, 3H), 2.81 - 2.66 (m, 3H), 2.32 - 2.29 (m, 1H), 2.12 - 2.02 (m, 1H), 1.02 - 1.00 (d, J = 8.0 Hz, 6H), 0.90 - 0.86 (m, 2H), 0.65 - 0.62 (m, 1H), 0.46 - 0.43 (m, 1H), 0.33 - 0.30 (m, 1H), 0.20 - 0.16 (m, 1H), m / z: 514.65 [M + H].

[0379] Example 6:

[0380]

[0381] According to a synthetic method similar to that of Example 5, compound 6 was prepared by replacing isobutanol with the raw material 2 - isopropoxyethanol.

[0382] 3 - Cyclopropyl - 3 - (2 - ((2 - (2 - ((2 - (isopropoxyethoxy)carbonyl)-5 - methoxyphenyl)-1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 6)

[0383] 11H NMR (400 MHz, CDCl3): δ 8.05 - 8.04 (d, J = 4.0 Hz, 1H), 7.82 - 7.80 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.85 - 6.83 (m, 1H), 6.68 - 6.67 (d, J = 4.0 Hz, 1H), 6.40 (s, 1H), 6.10 (s, 1H), 4.38 - 4.37 (m, 2H), 4.35 - 4.34 (m, 4H), 3.93 - 3.90 (m, 2H), 3.81 - 3.80 (m, 2H), 3.78 (s, 3H), 2.81 - 2.66 (m, 3H), 2.32 - 2.29 (m, 1H), 2.18 - 2.17 (m, 1H), 1.12 - 1.10 (d, J = 8.0 Hz, 6H), 0.98 - 0.94 (m, 2H), 0.64 - 0.61 (m, 1H), 0.45 - 0.42 (m, 1H), 0.34 - 0.31 (m, 1H), 0.20 - 0.15 (m, 1H), m / z: 544.45 [M + H], 566.40 [M + Na].

[0384] Example 7:

[0385]

[0386] According to a synthetic method similar to that of Example 5, compound 7 was prepared by replacing isobutanol with the raw material 6 - methyl - N - neopentylpyridin - 2 - amine.

[0387] 3 - cyclopropyl - 3 - (2 - ((2 - (2 - methoxy - 5 - ((6 - methylpyridin - 2 - yl)(neopentyl)carbamoyl)pyridin - 4 - yl)-1,3 - dioxan - 5 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 7)

[0388] 1 1H NMR (400 MHz, CDCl3): δ 7.90 - 7.87 (m, 1H), 7.09 - 6.98 (m, 2H), 6.71 - 6.44 (m, 5H), 6.25 (s, 1H), 5.96 (d, 1H), 4.50 (s, 1H), 4.29 - 3.39 (m, 10H), 2.69 - 2.48 (m, 2H), 2.32 (s, 3H), 2.17 - 2.14 (m, 1H), 1.86 - 1.81 (m, 1H), 0.81 (s, 1H), 0.66 (s, 9H), 0.43 - 0 (m, 4H).

[0389] m / z: 618.35 [M + H], 640.25 [M + Na].

[0390] Example 8:

[0391]

[0392] Compound 8 was prepared according to the following route.

[0393]

[0394] Step 1: 5-(3-Hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8-1)

[0395] 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 (17.70 g, 0.122 mol) was added in portions. After addition, the reaction solution was heated to 85 °C and stirred for 16 h. The reaction was completed. The reaction solution was cooled to room temperature naturally, filtered, and the filter cake was washed twice with water and then dried to obtain white solid 8-1 (15.20 g, yield: 50.0%).

[0396] 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].

[0397] Step 2: 5-(Cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (8-2)

[0398] 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 cooled to -10 °C. 1 M cyclopropylmagnesium bromide (220 ml, 3.0 eq) was added dropwise, and the reaction was carried out at room temperature for 1.5 h. The reaction of the starting material was monitored to be complete. The reaction solution was quenched with 1 M hydrochloric acid, and the pH value was adjusted to 2.0 - 3.0. The mixture was extracted with ethyl acetate (100 ml × 3), and the combined organic phases were washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate. The organic phase was purified by column chromatography to obtain pale yellow liquid 8-2 (11.50 g, yield: 81%).

[0399] 11H 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).

[0400] Step 3: Ethyl 3 - cyclopropyl - 3-(3 - hydroxyphenyl)propionate (8 - 3)

[0401] Under nitrogen, dissolve 5-(cyclopropyl(3 - hydroxyphenyl)methyl)-2,2 - dimethyl - 1,3 - dioxane - 4,6 - dione (8 - 2) (11.50 g, 0.039 mol) in N,N - dimethylformamide (12 ml) and ethanol (6 ml), stir, heat the reaction solution to 100 °C and react for 5 h. After the reaction is completed, concentrate, dissolve in ethyl acetate (50 ml), wash with saturated brine (50 ml), dry over anhydrous sodium sulfate, and purify the organic phase by column chromatography to obtain colorless liquid 8 - 3 (5.00 g, yield: 53.8%).

[0402] 1 1H 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]

[0403] Step 4: 3 - Cyclopropyl - 3-(3 - hydroxyphenyl)propionic acid (8 - 4)

[0404] Dissolve ethyl 3 - cyclopropyl - 3-(3 - hydroxyphenyl)propionate (8 - 3) (5.00 g, 0.021 mol) in tetrahydrofuran (20 ml) and methanol (20 ml), add 2 mol / L sodium hydroxide solution (75 ml, 150 mmol), stir and react at 50 °C for 1 h. After monitoring shows the reaction is completed, concentrate, adjust the pH value to 5.0 - 6.0 with 1 mol / L citric acid, extract with ethyl acetate 3 times, wash with ice water, concentrate, and purify to obtain white solid 8 - 5 (3.68 g, yield: 85.0%).

[0405] 1 1H NMR (400 MHz, CD3OD): δ = 7.13 - 7.07 (m, 1H), 6.67 - 6.60 (m, 3H), 2.88 - 2.85 (m, 1H), 2.76 - 2.70 (m, 1H), 2.42 - 2.40 (m, 1H), 1.08 (m, 1H), 0.63 - 0.53 (m, 1H), 0.37 - 0.26 (m, 2H), 0.03 - 0.06 (m, 1H), m / z: 207.10 [M+1].

[0406] Step 5: Benzyl 3 - cyclopropyl - 3-(3 - hydroxyphenyl)propionate (8 - 5)

[0407] Dissolve 3 - cyclopropyl - 3-(3 - hydroxyphenyl)propionic acid (8 - 4) (3.50 g, 17.0 mmol) in N,N - dimethylformamide (10 ml), add potassium carbonate (4.70 g, 34 mmol), benzyl bromide (3.11 g, 18.7 mmol), stir and react at 25 °C for 1 h. After the reaction is completed, 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 purify the organic phase to obtain an oily substance 8 - 5 (4.53 g, yield: 90.0%).

[0408] 1 1H NMR (400 MHz, CD3OD) 7.42 - 7.30 (m, 5H), 7.12 - 7.05 (m, 1H), 6.66 - 6.59 (m, 3H), 5.21 - 5.10 (m, 2H), 2.85 - 2.83 (m, 1H), 2.65 - 2.63 (m, 1H), 2.35 - 2.33 (m, 1H), 1.09 - 0.98 (m, 1H), 0.46 - 0.36 (m, 1H), 0.31 - 0.22 (m, 1H), 0.15 - 0.13 (m, 1H), 0.08 - 0.01 (m, 1H), m / z: 297.15 [M+1].

[0409] Step 6: Ethyl 2-(5 - fluoro - 2 - methoxypyridin - 4 - yl)-1,3 - dioxane - 5 - carboxylate (8 - 6 and 8 - 7)

[0410] 5-Fluoro-2-methoxypyridine-4-carbaldehyde (1-2) (1.61 g, 10.4 mmol), ethyl 3-hydroxy-2-(hydroxymethyl)propionate (1.54 g, 10.4 mmol), and p-toluenesulfonic acid monohydrate (0.20 g, 1.04 mmol) were added to toluene (40 ml), and the mixture was heated to reflux for water separation overnight. After completion of the reaction, it was cooled to room temperature, the system was rotary evaporated, and the product was purified by column chromatography to obtain product 8-6 (670 mg, 45.5%) and 8-7 (540 mg, 36.7%).

[0411] 8-6: 1 H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.26 (s, 1H), 6.96 - 6.94 (d, J = 8 Hz, 1H), 5.62 (s, 1H), 4.48 - 4.44 (dd, J = 8 Hz, 2H), 4.19 - 4.14 (q, J = 8 Hz, 2H), 4.02 - 3.99 (t, J = 12 Hz, 2H), 3.89 (s, 1H), 1.29 - 1.26 (t, J = 8 Hz, 2H). m / z: 286.05 [M+1].

[0412] 8-7: (540 mg, 36.7%). 1 H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.28 (s, 1H), 6.99 - 6.97 (d, J = 8 Hz, 1H), 5.80 (s, 1H), 4.48 - 4.44 (dd, J = 8 Hz, 2H), 4.20 - 4.06 (m, 4H), 3.89 (s, 1H), 1.29 - 1.26 (t, J = 8 Hz, 2H). m / z: 286.05 [M+1].

[0413] Step 7: 2-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxane-5-carboxylic acid (8-8)

[0414] Ethyl 2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxane-5-carboxylate (8-6) (310 mg, 1.08 mmol) was added to methanol / tetrahydrofuran / water (5 / 5 / 5 ml), and lithium hydroxide monohydrate (92 mg, 2.17 mmol) was added. The reaction was carried out at room temperature for 1.0 h. After completion of the reaction, the pH was adjusted to 4 - 5 with citric acid, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and rotary evaporated to obtain product 8-8 (260 mg, 93%).

[0415] m / z: 286.05 [M+1].

[0416] Step 8: 2-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxane-5-carboxylic acid 3-(-1-cyclopropyl-3-propionate benzyl) phenyl ester (8-9)

[0417] Dissolve 2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxane-5-carboxylic acid (8-8) (260 mg, 1.01 mmol) and 3-cyclopropyl-3-(3-hydroxyphenyl) propionate benzyl ester (8-5) (329.4 mg, 1.11 mmol) in dichloromethane (10 ml). Cool the solution to 0 °C, add dicyclohexylcarbodiimide (312 mg, 1.5 mmol) and 4-dimethylaminopyridine (62 mg, 0.505 mmol). After the addition, stir the reaction mixture at room temperature overnight. After the reaction is complete, filter through diatomaceous earth, dry and concentrate the organic phase, and purify by column chromatography to obtain the product (200 mg, 37%).

[0418] 1 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H), 7.08 - 7.11 (m, 1H), 8.20 - 8.22 (m, 1H),10.32 (s, 1H). m / z: 536.3 [M + 1], 558.3 [M + Na].

[0419] Step 9: 3-Cyclopropyl-3-(2-(((2S,5S)2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxanyl-5-yl) methoxy) pyridin-4-yl) propanoic acid (Compound 8)

[0420] Dissolve 2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxane-5-carboxylic acid 3-(-1-cyclopropyl-3-propionate benzyl) phenyl ester (8-9) (162 mg) in tetrahydrofuran (2 ml), add 10% palladium / carbon (80 mg), and stir the reaction mixture at room temperature under a hydrogen balloon atmosphere for 4 h. After detecting the end of the reaction, filter, concentrate, and obtain an oily substance after column chromatography (100 mg, yield 74.3%).

[0421] 11H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.74 (s, 1H), 7.34 - 7.30 (m, 1H), 7.14 - 7.12 (m, 1H), 6.99 - 6.93 (m, 3H), 5.68 (s, 1H), 4.63 - 4.59 (m, 2H), 4.17 - 4.11 (m, 2H), 3.90 (s, 3H), 3.44 - 3.36 (m, 1H), 2.84 - 2.72 (m, 2H), 2.42 - 2.36 (m, 1H), 1.06 - 0.97 (m, 1H), 0.64 - 0.57 (m, 1H), 0.49 - 0.42 (m, 1H), 0.33 - 0.27 (m, 1H), 0.19 - 0.13 (m, 1H), m / z: 446.6 [M+1].

[0422] Example 9:

[0423]

[0424] According to the synthesis method of Example 8, replace 8 - 6 with 8 - 7, and carry out the subsequent steps to prepare Compound 9.

[0425] 3 - Cyclopropyl - 3 - (2 - (((2r,5r) - 2 - (5 - fluoro - 2 - methoxypyridin - 4 - yl) - 1,3 - dioxolan - 5 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 9)

[0426] 1 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.26 - 7.24 (m, 1H), 7.08 - 7.06 (m, 1H), 6.93 - 6.87 (m, 3H), 5.62 (s, 1H), 4.57 - 4.53 (m, 2H), 4.11 - 4.05 (m, 2H), 3.84 (s, 3H), 3.38 - 3.34 (m, 1H), 2.77 - 2.70 (m, 1H), 2.36 - 2.32 (m, 1H), 0.95 - 0.94 (m, 1H), 0.58 - 0.55 (m, 1H), 0.39 - 0.37 (m, 1H), 0.26 - 0.23 (m, 1H), 0.23 - 0.17 (m, 1H), 0.12 - 0.08 (m, 1H), m / z: 446.45 [M+1].

[0427] Example 10:

[0428]

[0429] According to the synthesis method of Example 8, 5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzaldehyde (3-4) was used to replace 5-fluoro-2-methoxypyridine-4-carbaldehyde (1-2) to prepare Compound 10.

[0430] 3-Cyclopropyl-3-(3-((2-(5-methoxy-2-(1-(2,2,2-trifluoroethoxy)piperidin-4-yl)phenyl)-1,3-dioxane-5-carbonyl)oxy)phenyl)propanoic acid (Compound 10)

[0431] 1 H NMR (400 MHz, DMSO-d6): 12.02 (br s, 1H), 7.36 - 7.32 (t, J = 8.0 Hz, 8.0 Hz, 1H), 7.27 - 7.24 (d, J = 12.0 Hz, 1H), 7.19 - 7.17 (d, J = 8.0 Hz, 1H), 7.07 - 6.98 (m, 3H), 7.91 - 6.88 (m, 1H), 5.74 (s, 1H), 4.50 - 4.46 (m, 2H), 4.19 - 4.17 (m, 2H), 3.73 (s, 3H), 3.47 - 3.33 (m, 3H), 3.21 - 3.18 (m, 2H), 3.13 - 2.99 (m, 2H), 2.73 - 2.70 (m, 1H), 2.73 - 2.65 (m, 2H), 2.32 - 2.30 (m, 1H), 1.68 - 1.64 (m, 4H), 1.04 - 0.95 (m, 1H), 0.51 - 0.49 (m, 1H), 0.32 - 0.24 (m, 2H), 0.16 - 0.14 (m, 1H). m / z: 592.70 [M+1], 614.30 [M+Na].

[0432] Example 11:

[0433]

[0434] According to a synthesis method similar to that of Example 8, 5-methoxy-2-(4-methylpentane)benzaldehyde (4-4) was used to replace 5-fluoro-2-methoxypyridine-4-carbaldehyde (1-2) to prepare Compound 11.

[0435] 3-Cyclopropyl-3-(3-(((2s,5s)-2-(5-methoxy-2-(4-methylpentyl)phenyl)-1,3-dioxane-5-carbonyl)oxy)phenyl)propanoic acid (Compound 11)

[0436] 11H NMR (400 MHz, CDCl3): δ 7.35 - 7.31 (t, J = 8.0 Hz, 1H), 7.09 (d, 1H), 6.96 - 6.95 (d, J = 4.0 Hz, 2H), 6.87 - 6.84 (m, 2H), 6.75 - 6.73 (m, 1H), 5.62 (s, 1H), 4.64 - 4.60 (dd, 2H), 4.17 - 4.11 (t, J = 12 Hz, 2H), 3.82 (s, 3H), 3.47 - 3.39 (m, 1H), 2.85 - 2.73 (m, 2H), 2.59 - 2.55 (m, 2H), 2.43 - 2.37 (m, 1H), 1.63 - 1.51 (m, 3H), 1.29 - 1.23 (m, 3H), 1.08 - 0.98 (m, 1H), 0.90 - 0.89 (m, 6H), 0.56 - 0.54 (m, 1H), 0.51 - 0.49 (m, 1H), 0.42 - 0.35 (m, 1H), 0.22 - 0.12 (m, 1H). m / z: 511.40 [M+1], 533.40 [M+Na].

[0437] Example 12:

[0438]

[0439] According to a synthetic method similar to that of Example 8, 5 - methoxy - 2 - (4 - methylpentyl)benzaldehyde (4 - 4) was used to replace 5 - fluoro - 2 - methoxypyridine - 4 - carbaldehyde (1 - 2) to prepare Compound 12.

[0440] 3 - cyclopropyl - 3 - (3 - (((2r,5r)-2 - (5 - methoxy - 2 - (4 - methylpentyl)phenyl)-1,3 - dioxane - 5 - carbonyl))phenyl)propanoic acid (Compound 12)

[0441] 11H NMR (400 MHz, CDCl3): δ 7.35 - 7.31 (t, J = 8.0 Hz, 1H), 7.09 (d, 1H), 6.96 - 6.95 (d, J = 4.0 Hz, 2H), 6.86 - 6.84 (m, 2H), 6.75 - 6.73 (m, 1H), 5.62 (s, 1H), 4.64 - 4.60 (dd, 2H), 4.17 - 4.11 (t, J = 12 Hz, 2H), 3.82 (s, 3H), 3.47 - 3.40 (m, 1H), 2.85 - 2.73 (m, 2H), 2.62 - 2.56 (m, 2H), 2.43 - 2.37 (m, 1H), 1.63 - 1.51 (m, 3H), 1.29 - 1.23 (m, 3H), 1.08 - 0.98 (m, 1H), 0.95 - 0.89 (m, 6H), 0.64 - 0.60 (m, 1H), 0.57 - 0.53 (m, 1H), 0.36 - 0.25 (m, 1H), 0.21 - 0.12 (m, 1H). m / z: 511.40 [M+1], 533.40 [M+Na].

[0442] Example 13: Preparation of Compound 13

[0443]

[0444] According to a synthetic method similar to that of Example 2, after replacing benzyl 3-cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropionate (2-8) with benzyl 3-(2-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridin-4-yl)-4-hexynoate (WO2016 / 57731), Compound 13 was prepared.

[0445] 3-(2-((2-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxan-5-yl)methoxy)pyridin-4-yl)-4-hexenoic acid (Compound 13)

[0446] 1 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.72 (s, 1H), 7.32 - 7.28 (m, 1H), 7.10 - 7.09 (m, 1H), 6.96 - 6.90 (m, 3H), 5.64 (s, 1H), 4.63 - 4.59 (m, 1H), 4.17 - 4.11 (m, 4H), 3.89 (s, 3H), 3.72 - 3.68 (m, 2H), 2.84 - 2.74 (m, 2H), 2.42 - 2.36 (m, 1H), 1.96 (s, 3H). m / z: 431.35 [M+1].

[0447] Example 14: Preparation of Compound 14

[0448]

[0449] According to the synthesis methods of Example 1 and Example 2, after replacing ethyl 3-cyclopropyl-3-(2-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridin-4-yl)propionate (1-9) with benzyl 3-(2-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridin-4-yl)-5-methylhex-4-enoate, compound 14 was prepared.

[0450] 3-(2-((2-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxan-5-yl)methoxy)pyridin-4-yl)-5-methyl-4-hexenoic acid (Compound 14)

[0451] 1 H NMR (400 MHz, CDCl3): 7.98 (s, 1H), 7.72 (s, 1H), 7.32 - 7.28 (m, 1H), 7.10 - 7.09 (m, 1H), 6.96 - 6.90 (m, 3H), 5.64 (s, 1H), 5.48 (d, 1H), 4.17 - 4.11 (m, 3H), 4.10 - 4.08 (m, 2H), 3.89 (s, 3h), 3.72 - 3.68 (m, 2H), 2.84 - 2.74 (m, 1H), 2.64 - 2.60 (m, 1H), 2.42 - 2.36 (m, 1H), 1.96 (s, 3H), 1.80 (s, 3H), m / z: 447.35 [M+1].

[0452] Example 15: Preparation of Compound 15

[0453]

[0454] According to a synthesis method similar to that of Example 1 and 2, after replacing ethyl 3-cyclopropyl-3-(2-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridin-4-yl)propionate (1-9) with ethyl 3-(2-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridin-4-yl)pentanoate, compound 15 was prepared.

[0455] 3-(2-((2-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxan-5-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 15)

[0456] 11H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.72 (s, 1H), 7.32 - 7.28 (m, 1H), 7.10 - 7.09 (m, 1H), 6.96 - 6.90 (m, 3H), 5.64 (s, 1H), 4.64 - 4.58 (m, 1H), 4.16 - 4.10 (m, 4H), 3.88 (s, 3H), 3.72 - 3.66 (m, 2H), 2.79 - 2.74 (m, 2H), 2.38 - 2.36 (m, 1H), 1.53 (m, 2H), 0.93 (t, 3H), m / z: 421.45 [M + 1]

[0457] Example 16:

[0458]

[0459] Compound 16 was prepared according to the following route.

[0460]

[0461] Step 1: 5-Fluoro-4-iodo-2-methoxypyridine (16-1)

[0462] Compound 12,5-difluoro-4-iodopyridine (4.82 g, 20 mmol) was dissolved in methanol (20 ml), 30% sodium methoxide (12 ml, 60 mmol) was added, and the mixture was refluxed with stirring for 3 h. After the reaction was completed, it was cooled to room temperature, water was added and stirred, and the mixture was extracted with ethyl acetate three times, washed with ice water, concentrated, and purified by column chromatography to obtain white solid 16-1 (2.82 g, yield: 55.7%).

[0463] 1 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H) 7.19 - 7.17 (d, 1H) 3.89 (s, 3H); m / z: 253.90 [M + H].

[0464] Step 2: Diethyl 2-(5-fluoro-2-methoxypyridin-4-yl)malonate (16-2)

[0465] 5-Fluoro-4-iodo-2-methoxypyridine (16-1) (2.82 g, 12.65 mmol), diethyl malonate (2.4 g, 18.97 mmol), CuI (190 mg, 1.26 mmol), picolinic acid (246 mg, 2.53 mmol), and cesium carbonate (10.63 g, 41.24 mmol) were added to tetrahydrofuran (70 ml), and the mixture was stirred at 80 °C overnight. After the reaction was complete, water and ethyl acetate were added for extraction three times, washed with brine, concentrated, and purified to obtain anhydrous oil 16-2 (2.381 g, yield: 65.9%).

[0466] 1 H NMR (400 MHz, CDCl3) δ 8.01 - 7.99 (d, 1H), 6.83 - 6.80 (d, 1H), 5.17 - 5.24 (m, 4H), 4.99 (s, 1H), 3.89 (s, 3H), m / z: 286.10 [M+H].

[0467] Step 3: 2-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-propanediol (16-3)

[0468] Diethyl 2-(5-fluoro-2-methoxypyridin-4-yl)malonate (16-2) (1.2 g, 4.2 mmol) was dissolved in dichloromethane (50 ml), cooled to -70 °C, and 1 M diisobutylaluminum hydride (50 ml, 50 mmol) was added dropwise. The mixture was stirred at room temperature for 5 h. After the reaction was completed, Rochelle salt was slowly added, and the mixture was stirred vigorously overnight. Concentrated, extracted with ethyl acetate three times, washed with brine, and purified to obtain yellow-green oil 16-3 (600 mg, yield: 70.7%).

[0469] 1 H NMR (400 MHz, CDCl3) δ 7.52 - 7.50 (d, 1H), 6.05 - 6.01 (d, 1H), 4.99 (br, 2H), 3.85 - 3.81 (m, 4H), 3.79 (s, 3H), 2.78 (m, 1H), m / z: 202.10 [M+H].

[0470] Step 4: 4-(2-((Benzyloxy)methyl)-1,3-dioxolan-5-yl)-5-fluoro-2-methoxypyridine (16-4)

[0471] Dissolve 2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-propanediol (16-3) (582 mg, 2.9 mmol), 2-(benzyloxy)acetaldehyde (434 mg, 2.9 mmol), and p-toluenesulfonic acid monohydrate (58 mg, 0.29 mmol) in toluene (10 ml), and reflux with water separation overnight. After the reaction is completed, concentrate and purify by column chromatography to obtain a colorless oil 16-4 (617 mg, yield: 71.9%).

[0472] m / z: 334.05 [M+H].

[0473] Step 5: (5-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-2-yl)methanol (16-5)

[0474] Dissolve 4-(2-((benzyloxy)methyl)-1,3-dioxolan-5-yl)-5-fluoro-2-methoxypyridine (532 mg) in methanol (5 ml), add 10% palladium on carbon (270 mg), and stir the reaction at room temperature overnight under a hydrogen atmosphere. After the reaction is completed, filter and concentrate to obtain a colorless oil compound 16-5 (389 mg, yield: 100%).

[0475] m / z: 244.05 [M+H].

[0476] Step 6: Ethyl 3-cyclopropyl-3-(2-((5-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-2-yl)methoxy)pyridin-4-yl)propionate (16-6)

[0477] Dissolve (5-(5-Fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-2-yl)methanol (16-5) (389 mg, 1.6 mmol), ethyl 3-cyclopropyl-3-(2-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridin-4-yl)propionate (1-9) (376 mg, 1.6 mmol), cyanomethylenetributylphosphine (752 mg, 3.2 mmol), and 3-cyclo propyl-3-(2-hydroxypyridin-4- yl)propionate (1 - 7) (771 mg, 3.2 mmol) is dissolved in toluene (3 in ml), and stir the reaction at 100 °C for 4 h. After monitoring the completion of the reaction, concentrate and purify to obtain a colorless oil 16-6 (286 mg, yield: 62.1%).

[0478] m / z: 461.20 [M+H], 483.15 [M+Na].

[0479] Step 3: 3-Cyclopropyl-3-(2-((5-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-2-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 16)

[0480] Ethyl 3-cyclopropyl-3-(2-((5-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxolan-2-yl)methoxy)pyridin-4-yl)propionate (16-6) (286 mg, 0.62 mmol) was dissolved in tetrahydrofuran (3 ml) and methanol (3 ml), and 2 mol / L sodium hydroxide solution (1.25 ml, 2.49 mmol) was added. The mixture was stirred at 60 °C for 0.5 h. After monitoring showed the reaction was completed, it was concentrated, and 1 mol / L citric acid was added to adjust the pH to 5 - 6. It was extracted with ethyl acetate three times, washed with ice water, concentrated, and purified to obtain a white solid compound 16 (230 mg, yield: 85.8%).

[0481] 1 H NMR (400 MHz, CDCl3): 8.09 - 8.06 (m, 1H), 7.96 - 7.94 (m, 1H), 7.47 (d, J = 4 Hz, 1H), 6.82 - 6.76 (m, 2H), 6.50 - 6.49 (m, 1H), 5.11 - 5.01 (m, 1H), 4.45 (d, J = 4 Hz, 2H), 4.30 - 4.25 (m, 2H), 3.93 - 3.88 (m, 4H), 3.62 - 3.51 (m, 1H), 2.84 - 2.72 (m, 2H), 2.34 - 2.27 (m, 1H), 1.04 - 0.93 (m, 1H), 0.67 - 0.57 (m, 1H), 0.49 - 0.42 (m, 1H), 0.35 - 0.28 (m, 1H), 0.21 - 0.14 (m, 1H), m / z: 433.00 [M + H], 450.10 [M + Na].

[0482] Example 17: Preparation of Compound 17

[0483]

[0484] According to a synthetic method similar to that in Example 16, 2-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)-1,3-propanediol was used to replace 2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-propanediol to prepare Compound 17.

[0485] (S)-3-Cyclopropyl-3-(2-(((2r,5S)-5-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)-1,3-dioxolan-2-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 17)

[0486] 11H NMR (400 MHz, CDCl3): δ 8.05 - 8.04 (d, J = 4.0 Hz, 1H), 7.71 - 7.70 (d, J = 4.0 Hz, 1H), 7.19 - 7.16 (d, J = 12.0 Hz, 1H), 6.80 - 6.73 (m, 3H), 5.11 - 5.09 (m, 1H), 4.44 - 4.43 (m, 2H), 4.30 - 4.27 (m, 2H), 4.22 - 4.19 (m, 2H), 3.80 (s, 3H), 3.06 - 2.95 (m, 5H), 2.72 - 2.69 (m, 2H), 2.45 - 2.32 (m, 2H), 2.30 - 2.28 (m, 1H), 1.85 - 1.79 (m, 2H), 1.70 - 1.61 (m, 2H), 1.53 - 1.25 (m, 2H), 0.98 - 0.91 (m, 1H), 0.61 - 0.57 (m, 1H), 0.45 - 0.42 (m, 1H), 0.26 - 0.16 (m, 1H), 0.15 - 0.11 (m, 1H), m / z: 579.40 [M + H], 601.35 [M + Na].

[0487] Example 18:

[0488]

[0489] According to a synthetic method similar to that of Example 16, compound 18 was prepared by replacing 2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-propanediol with 2-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)-1,3-propanediol.

[0490] (S)-3-Cyclopropyl-3-(2-(((2r,5S)-5-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)-1,3-dioxan-2-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 18)

[0491] 11H NMR (400 MHz, CDCl3): δ 8.05 - 8.04 (d, J = 4.0 Hz, 1H), 7.71 - 7.70 (d, J = 4.0 Hz, 1H), 7.19 - 7.16 (d, J = 12.0 Hz, 1H), 6.80 - 6.73 (m, 3H), 5.11 - 5.09 (m, 1H), 4.54 - 4.52 (m, 2H), 4.27 - 4.24 (m, 2H), 4.29 - 4.26 (m, 2H), 3.80 (s, 3H), 3.06 - 2.95 (m, 5H), 2.72 - 2.69 (m, 2H), 2.45 - 2.32 (m, 2H), 2.32 - 2.30 (m, 1H), 1.85 - 1.79 (m, 2H), 1.78 - 1.72 (m, 2H), 1.49 - 1.45 (m, 2H), 0.98 - 0.91 (m, 1H), 0.61 - 0.57 (m, 1H), 0.45 - 0.42 (m, 1H), 0.26 - 0.16 (m, 1H), 0.15 - 0.11 (m, 1H), m / z: 579.70 [M + H], 601.35 [M + Na].

[0492] Example 19:

[0493]

[0494] According to a synthetic method similar to that of Example 16 and 2, compound 19 was prepared by replacing 2-(5-fluoro-2-methoxypyridin-4-yl)-1,3-propanediol with isobutyl 2-(1,3-dihydroxypropan-2-yl)-4-methoxybenzoate.

[0495] (S)-3-Cyclopropyl-3-(2-((5-(2-(isobutoxycarbonyl)-5-methoxyphenyl)-1,3-dioxolan-2-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 19)

[0496] 11H NMR (400 MHz, CDCl3): δ 8.09 - 8.08 (d, J = 4.0 Hz, 1H), 7.91 - 7.89 (d, J = 8.0 Hz, 1H), 6.81 - 6.79 (m, 2H), 6.77 - 6.74 (m, 2H), 5.05 - 5.03 (m, 1H), 4.45 - 4.33 (m, 2H), 4.32 - 4.30 (m, 3H), 4.08 - 4.07 (m, 2H), 3.91 - 3.87 (m, 1H), 3.84 (s, 3H), 3.48 (s, 3H), 2.83 - 2.72 (m, 2H), 2.33 - 2.30 (m, 1H), 2.13 - 2.05 (m, 1H), 1.03 - 1.02 (d, J = 4.0 Hz, 6H), 0.64 - 0.61 (m, 1H), 0.51 - 0.48 (m, 1H), 0.34 - 0.32 (m, 1H), 0.17 - 0.14 (m, 1H). m / z: 514.50 [M + H], 552.35 [M + K].

[0497] Example 20:

[0498]

[0499] Compound 20 was prepared according to the following route.

[0500]

[0501] Step 1: 2-(2-Bromo-5-methoxyphenyl)acetic acid (20-1)

[0502] 2-Methoxyphenylacetic acid (10.00 g, 60.24 mmol) was dissolved in dichloromethane (200 ml). The temperature was lowered to 0 °C, and bromine (3.09 ml, 60.24 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, saturated sodium sulfite solution was added and stirred. The layers were separated, and the aqueous phase was extracted with dichloromethane three times, washed with brine, and the organic phase was concentrated to obtain a light orange solid 20-1 (12.30 g, yield: 83.3%).

[0503] 1 1H NMR (400 MHz, CDCl3): δ 7.47 - 7.44 (m, 1H), 6.85 (s, 1H), 6.74 - 6.71 (m, 1H), 3.80 - 3.78 (m, 5H).

[0504] Step 2: Methyl 2-(2-bromo-5-methoxyphenyl)acetate (20-2)

[0505] Step 1: Dissolve 2-(2-bromo-5-methoxyphenyl)acetic acid (20-1) (12.30 g, 50 mmol) in methanol (123 ml), add thionyl chloride (5.47 ml, 75 mmol), and stir the reaction at room temperature for 2 h.

[0506] After the reaction is completed, concentrate the mixture, and obtain a pale yellow oily substance 20-2 (13.86 g, yield: 100%) by column chromatography.

[0507] 1 H NMR (400 MHz, CDCl3): 7.45 (d, J = 8 Hz, 1H), 6.84 (d, J = 8 Hz, 1H), 6.72 - 6.69 (m, 1H), 3.78 (s, 3H), 3.75 (s, 2H), 3.72 (s, 3H).

[0508] Step 3: Dimethyl 2-(2-bromo-5-methoxyphenyl)malonate (20-3)

[0509] Dissolve methyl 2-(2-bromo-5-methoxyphenyl)acetate (20-2) (13.86 g, 53.5 mmol) in tetrahydrofuran (214 ml), cool down to -70 °C, add lithium bis(trimethylsilyl)amide (64 ml, 64 mmol, 1.0 mol / L), and stir the reaction at -70 °C for 1 h. Add dimethyl carbonate (6.75 ml, 80 mmol), stir for 0.5 h, then warm up to room temperature and continue stirring the reaction overnight. After the reaction is completed, add saturated ammonium chloride and stir, extract with ethyl acetate (50 ml) three times, wash with brine, concentrate, and obtain a white solid 20-3 (6.55 g, yield: 41.1%) by column chromatography.

[0510] 1 H NMR (400 MHz, CDCl3): 7.48 (d, J = 8 Hz, 1H), 7.05 (d, J = 4 Hz, 1H), 6.78 - 6.75 (m, 1H), 5.22 (s, 1H), 3.79 - 3.78 (m, 9H). m / z: 316.90 [M + H].

[0511] Step 3: 2-(2-Bromo-5-methoxyphenyl)-1,3-propanediol (20-4)

[0512] Dissolve dimethyl 2-(2-bromo-5-methoxyphenyl)malonate (20-3) (4.40 g, 13.88 mmol) in dichloromethane (140 ml), cool to -70 °C, add 1 mol / L diisobutylaluminum hydride (74 ml, 111 mmol), and stir at room temperature for 6 h. After the reaction is complete, slowly add a potassium tartrate solution and stir overnight. Separate the layers, extract the aqueous phase with dichloromethane (50 ml × 3), combine the organic phases, wash with brine, concentrate, and perform column chromatography to obtain a colorless oil, 20-4 (4.01 g, yield: 100%).

[0513] 1 H NMR (400 MHz, CDCl3): 7.46 (d, J = 12 Hz, 1H), 6.83 (d, J = 4 Hz, 1H), 6.67 - 6.64 (m, 1H), 3.94 - 3.93 (m, 4H), 3.75 (s, 3H), 3.57 - 3.50 (m, 1H), 2.84 (s, 2H), m / z: 261.05 [M + H].

[0514] Step 4: (2S,5S)-2-((Benzyloxy)methyl)-5-(2-bromo-5-methoxyphenyl)-1,3-dioxane (20-5)

[0515] Dissolve 2-(2-bromo-5-methoxyphenyl)-1,3-propanediol (20-4) (3.00 g, 11.5 mmol), benzyloxyacetaldehyde (434 mg, 2.9 mmol), and p-toluenesulfonic acid monohydrate (229 mg, 1.15 mmol) in toluene (60 ml), and reflux with water separation overnight. After the reaction is complete, concentrate and perform column chromatography to obtain a colorless oil product 20 - 5 (1.33 g, yield: 29.5%) and 20 - 6 (0.92 g, yield: 20.3％)。

[0516] 20-5: 1 H NMR (400 MHz, CDCl3): 7.70 (d, 1H), 7.42 - 7.27 (m, 6H), 6.69 - 6.66 (m, 1H), 4.60 (s, 2H), 4.29 - 4.18 (m, 4H), 3.75 (s, 3H), 3.59 - 3.58 (m, 2H), 3.08 - 3.07 (m, 1H).

[0517] Step 6: (2S,5S)-2-(2-((Benzyloxy)methyl)-1,3-dioxan-5-yl)-4-methoxybenzonitrile (20-7)

[0518] Dissolve (2s,5s)-2-((benzyloxy)methyl)-5-(2-bromo-5-methoxyphenyl)-1,3-dioxane (20-5) (914 mg, 2.33 mmol) in N,N-dimethylformamide (10 ml), add cuprous cyanide (419 mg, 4.65 mmol), and stir the reaction at 140 °C overnight. After the reaction is completed, filter, wash the solid with dichloromethane (30 ml × 3), concentrate under reduced pressure, dissolve in dichloromethane, concentrate the aqueous and organic phases, and perform column chromatography to obtain a colorless oil 20-6 (667 mg, yield: 84.3%).

[0519] 1 H NMR (400 MHz, CDCl3): 7.76 (d, J = 4 Hz, 1H), 7.55~7.53 (m, 1H), 7.35~7.28 (m, 5H), 6.85~6.82 (m, 1H), 4.93~4.90 (m, 1H), 4.60 (s, 2H), 4.30~4.20 (m, 4H), 3.80 (s, 3H), 3.60~3.59 (m, 2H), 3.10~3.09 (m, 1H).

[0520] Step 6: (2s,5s)2-(2-((benzyloxy)methyl)-1,3-dioxan-5-yl)-4-methoxybenzaldehyde (20-8)

[0521] Dissolve the product from Step 6: (2s,5s)2-(2-((benzyloxy)methyl)-1,3-dioxan-5-yl)-4-methoxybenzonitrile (20-7) (667 mg, 1.97 mmol) in dichloromethane (12 ml), cool to 0 °C, add 1.5 mol / L diisobutylaluminum hydride (2 ml, 3 mmol), and stir the reaction at room temperature for 6 h. After the reaction is completed, slowly add a potassium tartrate solution and stir overnight. Extract with dichloromethane, wash with brine, concentrate, and perform column chromatography to obtain a colorless oil 20-7 (684 mg, yield: 100%).

[0522] 1 H NMR (400 MHz, CDCl3): 9.90 (s, 1H), 7.78~7.68 (m, 2H), 7.37~7.28 (m, 5H), 6.94~6.91 (m, 1H), 4.92~4.90 (m, 1H), 4.60 (s, 2H), 4.29~4.20 (m, 4H), 3.91 (s, 1H), 3.85 (s, 3H), 3.59~3.57 (m, 2H), m / z: 343.20 [M+H].

[0523] Step 7: (2s,5s)-2-((Benzyloxy)methyl)-5-(5-methoxy-2-(4-methyl-1-penten-1-yl)benzene yl)-1,3-dioxane (20-9)

[0524] Dissolve isopentyl triphenylphosphonium bromide (933 mg, 2.26 mmol) in tetrahydrofuran (3 ml), cool down to 0 °C, dropwise add 2.5 mol / L n-butyllithium (0.9 ml, 2.26 mmol), stir at 0 °C for 0.5 h, then dropwise add a solution of (2s,5s)-2-((benzyloxy)methyl)-4-methoxybenzaldehyde (20-8) (385 mg, 1.13 mmol) in tetrahydrofuran (2 ml), and stir the reaction at 0 °C for 2.5 h. After the reaction is completed, add saturated ammonium chloride solution (10 ml), extract the aqueous phase with ethyl acetate (15 ml × 3), combine the organic phases, wash with brine, concentrate, and perform column chromatography to obtain a colorless oil 20-9 (264 mg, yield: 58.9%).

[0525] m / z: 419.25 [M+H].

[0526] Step 8: (2s,5s)-2-((benzyloxy)methyl)-5-(5-methoxy-2-(4-methyl-1-penten-1-yl)phenyl)-1,3-dioxane (20-10)

[0527] Dissolve (2s,5s)-2-((benzyloxy)methyl)-5-(5-methoxy-2-(4-methyl-1-penten-1-yl)phenyl)-1,3-dioxane (20-9) (264 mg, 0.63 mmol) in methanol (2.5 ml), add 10% palladium / carbon (132 mg), pass hydrogen gas, and stir the reaction at room temperature for 5 h. After the reaction is completed, filter and concentrate to obtain an oil 20-10 (184 mg, yield: 94.5%).

[0528] m / z: 617.55 [2M+H], 639.60 [2M+Na].

[0529] Step 9: 3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (20-11)

[0530] Dissolve ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (1-6) (14.50 g, 58.2 mmol) in methanol (100 ml), add 2 mol / L sodium hydroxide (116 ml, 232 mmol) solution, the system is in a turbid state, add tetrahydrofuran (100 ml), the system becomes clear, react at room temperature for 2 h, and the reaction is completed. Concentrate the reaction solution to dryness to remove methanol, adjust the pH value to 4.0 with 1 mol / L citric acid solution, add ethyl acetate (100 ml) for extraction, wash the organic phase with saturated brine to obtain a crystalline solid 20-11 (12.50 g, yield: 97%).

[0531] 11H 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]

[0532] Step 10: 3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid.(S)-1-(p-tolyl)ethylamine salt (20 - 12)

[0533] Dissolve 3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (20 - 11) (12.5 g, 56 mmol) in absolute ethanol (280 ml), add (S)-1-(p-tolyl)ethylamine (7.63 g, 56 mmol) dissolved in ethyl acetate (560 ml). Immediately after addition, a small amount of white solid precipitates. 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 (4.9 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 h, and then at room temperature overnight. Cool to 0 °C in an ice bath and stir for 1 h. Filter, rinse the filter cake once with n-heptane, drain, and dry the filter cake to obtain white solid 20 - 12 (3.74 g, yield: 19%). ee value: 99.6%.

[0534] Chiral purity test conditions:

[0535] Analyticals FC conditions Instrument: UPOC (Waters)

[0536] Column: OJ-3 4.6 * 100 mm 3 um

[0537] Column tempe ra ture: 40 °C

[0538] Mobile phase: CO2 / EtOH[1% NH3 (7M in MeOH)] = 90 / 10

[0539] Flow: 3.0 ml / min

[0540] Back Pressure: 2000 psi - njection

[0541] Volume: 1 μl

[0542] Step 11: (S)-3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (20-13)

[0543] Dissolve 3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid.(S)-1-(p-tolyl)ethylamine salt (20-12) (3.74 g, 0.0105 mol, 1.0 eq) in ethyl acetate, cool down to 0 - 10 °C, add 1 mol / L hydrochloric acid (37.4 ml), stir at this temperature for 10 minutes, and the reaction is completed. Add ethyl acetate (60 ml × 2) Wash, combine the organic phases, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a solid Product 20-13 (2.3 g, 100%).

[0544] 1 1H 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%.

[0545] Chiral purity test conditions:

[0546] Analyticals FC conditions Instrument: UPOC (Waters)

[0547] Column: OJ-3 4.6 * 100 mm 3 μm

[0548] Column temperature: 40 °C

[0549] Mobile phase: CO2 / EtOH [1% NH3 (7M in MeOH)] = 90 / 10

[0550] Flow: 3.0 ml / min

[0551] Back Pressure: 2000 psi - injection

[0552] Volume: 1 μl

[0553] Step 12: Ethyl (S)-3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (20-14)

[0554] Ethyl alcohol (40 mL) was added to (S)-3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (20-13) (2.3 g, 0.0104 mol), and concentrated sulfuric acid (6.0 mL) was added thereto. The mixture was purged with nitrogen and heated to 80 °C for reaction for 1.0 h. After completion of the reaction, the mixture was cooled to room temperature, and the pH value was adjusted to alkaline with saturated sodium bicarbonate solution. The organic phase was obtained by extraction with ethyl acetate, dried and concentrated to obtain a colorless oily substance 20-14 (2.5 g, 96%).

[0555] 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].

[0556] Step 13: Ethyl (S)-3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate (20-15)

[0557] Ethyl (S)-3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (20-14) (2.5 g, 0.010 mol, 1.0 eq), add N,N-dimethylformamide (25 mL), add pyridine hydrochloride (11.6 g, 0.10 mol, 1.00 eq) was purged with nitrogen and heated to 120 °C for reaction for 1.0 h. After completion of the reaction, the mixture was cooled to room temperature, water was added, and the organic phase was obtained by extraction with ethyl acetate (25 mL). The organic phase was dried and concentrated, and purified by column chromatography to obtain a colorless oily substance 20-15 (2.2 g, 85%).

[0558] 11H NMR (400 MHz, DMSO-d6): δ 11.49 (s, 1H), 7.29 - 7.27 (d, J = 8.0 Hz, 1H), 6.25 - 6.20 (m, 1H), 6.19 (s, 1H), 4.08 - 3.96 (m, 2H), 2.75 - 2.70 (m, 2H), 2.18 - 2.10 (m, 1H), 1.11 - 1.07 (t, J = 8.0 Hz, 3H), 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: 236.15 [M + 1].

[0559] According to the similar synthesis method of Example 16, replace 16 - 5 with 20 - 10 and 1 - 7 with 20 - 15 to prepare Compound 20.

[0560] (S)-3-Cyclopropyl-3-(2-(((2S,5R)-5-(5-Methoxy-2-(4-methylpentyl)phenyl)-1,3-dioxan-2-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 20)

[0561] 1 1H NMR (400 MHz, CDCl3): 8.07 ~ 8.06 (m, 1H), 7.74 (s, 1H), 7.08 (d, J = 12 Hz, 1H), 6.78 ~ 6.75 (m, 3H), 5.13 ~ 5.12 (m, 1H), 4.46 ~ 4.45 (m, 2H), 4.30 ~ 4.21 (m, 4H), 3.81 (s, 3H), 2.90 (s, 1H), 2.82 ~ 2.70 (m, 2H), 2.46 ~ 2.42 (m, 2H), 2.33 ~ 2.27 (m, 1H), 1.58 ~ 1.43 (m, 3H), 1.32 ~ 1.19 (m, 2H), 1.01 ~ 0.98 (m, 1H), 0.94 ~ 0.86 (m, 6H), 0.66 ~ 0.55 (m, 1H), 0.49 ~ 0.40 (m, 1H), 0.35 ~ 0.26 (m, 1H), 0.20 ~ 0.11 (m, 1H). m / z: 498.60 [M + H], 536.35 [M + K]. ee value: 99.8%.

[0562] Chiral purity test conditions:

[0563] Analyticals FC conditions Instrument: UPOC (Waters)

[0564] Column: (R,R)Whelk - O1 4.6*100mm 3.5um

[0565] Column temperature: 40℃

[0566] Mobile phase: CO2 / MeOH[0.2%NH3(7M in MeOH)]=85 / 15

[0567] Flow: 3.0ml / min

[0568] Back Pressure: 2000psi - njection

[0569] Volume: 5ul

[0570] Example 21:

[0571]

[0572] According to the similar synthesis method of Example 20, replace 20 - 5 with 20 - 6 to prepare Compound 21.

[0573] (S)-3 - cyclopropyl - 3-(2 - (((2R,5S)-5-(5 - methoxy - 2-(4 - methylpentyl)phenyl)-1,3 - dioxolan - 2 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 21)

[0574] 1 HNMR(400MHz, CDCl3): 8.08(s, 1H), 7.12(d, J = 8Hz, 1H), 6.79~6.68(m, 4H), 5.06(s, 1H), 4.21~4.19(m, 2H), 3.93~3.88(m, 2H), 3.78(s, 3H), 3.59~3.47(m, 1H), 2.86~2.55(m, 4H), 2.38~2.25(m, 1H), 1.63~1.47(m, 3H), 1.26(s, 2H), 0.97(s, 1H), 0.89~0.87(m, 6H), 0.65~0.11(m, 4H). m / z: 498.45[M + H], 536.35[M + K], ee value: 99.8%.

[0575] Example 22:

[0576]

[0577] Prepare Compound 22 according to the following route.

[0578]

[0579] Step 1: 2-(5-Methoxy-2-(4-methylpentyl)phenyl)-1,3-propanediol (22-1)

[0580] Dissolve (2s,5s)-2-((Benzyloxy)methyl)-5-(5-methoxy-2-(4-methyl-1-penten-1-yl)phenyl)-1,3-dioxane (20-10) (6.60 g, 21.27 mmol) and p-toluenesulfonic acid (18.00 g, 106.35 mmol) in methanol (150 ml), and stir the reaction at room temperature overnight. After the reaction is completed, add water and stir, extract with ethyl acetate three times, wash with ice water, concentrate, and purify by column chromatography to obtain colorless oil 22-1 (5.10 g, yield: 90.0%).

[0581] m / z: 267.25 [M+1].

[0582] Step 2: Ethyl 5-(5-methoxy-2-(4-methylpentane)benzene-1,3-dioxane-2-carboxylate (22-2)

[0583] Dissolve 2-(5-Methoxy-2-(4-methylpentane)phenyl)-1,3-propanediol (22-1) (3.49 g, 13.14 mmol) and ethyl glyoxylate (2.68 g, 13.14 mmol) in acetonitrile (35 ml), add boron trifluoride diethyl etherate (3.73 g, 26.28 mmol), and stir the reaction at room temperature overnight. After the reaction is completed, add water and stir, extract with ethyl acetate three times, wash with ice water, concentrate, and purify by column chromatography to obtain colorless oil 22-2 (607 mg, yield: 13.2%).

[0584] m / z: 351.25 [M+1], 723.55 [2M+Na].

[0585] Step 3: 5-(5-Methoxy-2-(4-methylpentane)phenyl)-1,3-dioxane-2-carboxylic acid (22-3)

[0586] Dissolve ethyl 5-(5-methoxy-2-(4-methylpentane)benzene-1,3-dioxane-2-carboxylate (607 mg, 1.734 mmol) in tetrahydrofuran (6 ml) and water (6 ml), add sodium hydroxide solid (312 mg, 7.803 mmol), and stir the reaction at room temperature for 1 h. After the reaction is completed, concentrate, adjust the pH value to 5.0 - 6.0 with 1 mol / L citric acid, extract with ethyl acetate (10 ml) three times, wash with brine (10 ml), concentrate, and purify to obtain white solid 22-3 (600 mg, yield: 100%).

[0587] Step 4: (S)-3-Cyclopropyl-3-(3-((5-(5-methoxy-2-(4-methylpentyl)phenyl)-1,3-dioxan-2-carbonyl)oxy)phenyl)propanoic acid (22-4)

[0588] Dissolve 5-(5-methoxy-2-(4-methylpentyl)phenyl)-1,3-dioxane-2-carboxylic acid (22-3) (600 mg, 1.734 mmol) in dichloromethane (12 ml), add dicyclohexylcarbodiimide (536 mg, 2.601 mmol), 4-dimethylaminopyridine (106 mg, 0.867 mmol), (S)-3-cyclopropyl-3-(3- benzyl 3-(3-hydroxyphenyl)propionate (565 mg, 1.907 mmol), Stir the reaction at room temperature overnight. Monitor the reaction After completion, add water and stir, extract with ethyl acetate three times, wash with ice water, concentrate, and obtain a colorless oil 22-4 (619 mg, yield: 44.5%) after purification.

[0589] m / z: 623.45 [M+Na].

[0590] Step 5: (S)-3-Cyclopropyl-3-(3-((5-(5-methoxy-2-(4-methylpentyl)phenyl)-1,3-dioxan-2-carbonyl)oxy)phenyl)propanoic acid (Compound 22)

[0591] Dissolve benzyl (S)-3-cyclopropyl-3-(3-((5-(5-methoxy-2-(4-methylpentyl)phenyl)-1,3-dioxan-2-carbonyl)oxy)phenyl)propanoate (300 mg) in tetrahydrofuran (3 ml), add 10% palladium on carbon (60 mg), hydrogen, and stir at room temperature for 4 h. After monitoring the completion of the reaction, filter, concentrate, and prepare a colorless oil (153 mg, yield 60%) on a thin-layer silica gel plate.

[0592] 11H NMR (400 MHz, CDCl3): δ 7.36 - 7.32 (t, J = 8.0 Hz, 1H), 7.05 (d, 2H), 6.77 - 6.74 (d, J = 4.0 Hz, 2H), 6.86 - 6.84 (m, 1H), 6.75 - 6.73 (m, 1H), 5.35 (s, 1H), 4.35 - 4.31 (dd, J = 8.0 Hz, 2H), 4.02 - 3.97 (t, J = 12 Hz, 2H), 3.80 (s, 3H), 3.69 - 3.62 (m, 1H), 2.84 - 2.75 (m, 2H), 2.64 - 2.59 (m, 2H), 2.44 - 2.37 (m, 1H), 1.60 - 1.49 (m, 3H), 1.29 - 1.26 (m, 2H), 1.08 - 1.04 (m, 1H), 0.89 - 0.87 (m, 6H), 0.64 - 0.55 (m, 1H), 0.48 - 0.41 (m, 1H), 0.34 - 0.28 (m, 1H), 0.19 - 0.12 (m, 1H). m / z: 511.40 [M+1]. ee value: 99.8%.

[0593] Example 23: Preparation of Compound 23

[0594]

[0595] Compound 23 was prepared according to a synthetic method similar to that of Examples 13 and 22.

[0596] Yield: 60%. 1 1H NMR (400 MHz, CDCl3): δ 7.36 - 7.32 (t, J = 8.0 Hz, 1H), 7.05 (d, 2H), 6.77 - 6.74 (d, J = 4.0 Hz, 2H), 6.86 - 6.84 (m, 1H), 6.75 - 6.73 (m, 1H), 5.35 (s, 1H), 4.35 - 4.31 (dd, J = 8.0 Hz, 2H), 4.02 - 3.97 (t, J = 12 Hz, 2H), 3.80 (s, 3H), 3.69 - 3.62 (m, 1H), 2.84 - 2.75 (m, 2H), 2.64 - 2.59 (m, 2H), 2.44 - 2.37 (m, 1H), 1.60 - 1.49 (m, 3H), 1.29 - 1.26 (m, 2H), 1.08 - 1.04 (m, 1H), 0.89 - 0.87 (m, 6H), 0.64 - 0.55 (m, 1H), 0.48 - 0.41 (m, 1H), 0.34 - 0.28 (m, 1H), 0.19 - 0.12 (m, 1H). m / z: 509.40 [M+1].

[0597] Example 24:

[0598]

[0599] According to a synthetic method similar to that of Example 16, after replacing ethyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate with ethyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)-2-methylpropionate, Compound 24 was prepared.

[0600] (2R,3R)-3-Cyclopropyl-3-(2-((5-(5-fluoro-2-methoxypyridin-4-yl)-1,3-dioxan-2-yl)methoxy)pyridin-4-yl)-2-methylpropanoic acid (Compound 24)

[0601] 1 H NMR (400 MHz, CDCl3): δ 8.09 - 8.06 (m, 1H), 7.96 - 7.94 (m, 1H), 7.47 (d, 1H), 6.82 - 6.76 (m, 1H), 6.50 - 6.49 (m, 1H), 5.11 - 5.01 (m, 1H), 4.30 - 4.25 (m, 2H), 3.93 - 3.88 (m, 4H), 3.62 - 3.51 (m, 1H), 2.84 - 2.72 (m, 2H), 1.09 - 1.17 (d, 3H), 1.04 - 0.93 (m, 1H), 0.67 - 0.57 (m, 1H), 0.49 - 0.42 (m, 1H), 0.35 - 0.28 (m, 1H), 0.21 - 0.14 (m, 1H). m / z: 447.20 [M + H]. ee value: 100%.

[0602] Reference Example 1: SCO-267 (Ref01)

[0603] Lit1: [Journal of Medicinal Chemistry, 2020, vol. 63, #18, p. 10352 - 10379]

[0604]

[0605] Reference Example 2: TAK-875 (Ref02)

[0606] Lit2: [ACS Med.Chem.Lett. 2010, 1, 290–294]

[0607]

[0608] Test Experiment 1: GPR40 Assay Activity Test This experiment aims to verify the agonist activity of the compounds of the present invention against the GPR40 receptor.

[0609] cell line

[0610] GPR40 / CHO

[0611] medium

[0612] F12, Gibco (Cat#11765 - 047) DFBS, Biological Industries (Cat#04-011-1A) Geneticin, Invitrogen (Cat#10131-027)

[0613] Main reagents

[0614]

[0615] Main equipment

[0616] 384-well plate, Greiner #781090 Vi-cell XR Cell Viability Analyzer, Beckman Coulter, No.2785631 FLIPR, Molecular Devices, No.668115 Incubator, Thermo, No.1153447

[0617] Test method Reference substances and compound plates: The reference substances are diluted 10-fold in buffer in a 1:3 sequence, and the test substances are diluted in buffer in a 1:4 sequence. Then, 750 nL of the compounds are transferred to the destination plate. 30 μL of the assay buffer is added to each well.

[0618] 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 2X Fluo-4 DirectTM wash-free loading buffer into a 384-well cell culture plate.

[0619] b) Incubate at 37 °C in 5% CO2 for 50 minutes and then at room temperature for 10 minutes.

[0620] 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.

[0621] d) Compound plate (agonist assay):

[0622] 1) Run the protocol on the FLIPR TETRA

[0623] 2) Transfer 10 μL of the compound to the cell plate.

[0624] 3) Read the fluorescence signal

[0625] 4) Calculate "Max - Min" from Read 0 to the Maximum allowed.

[0626] e) Analyze the data using Prism.

[0627] The specific test data are shown in the following table.

[0628] Compound EC50, (nM) Compound EC50, (nM) Compound EC50, (nM) 1 22.75 2 100 3 17.79 4 2.67 5 41.10 6 >210 7 145.6 8 >210 9 >210 10 201.8 11 1.048 12 42.89 13 >210 14 >210 15 >210 16 1.082 17 >210 18 0.879 19 18.86 20 2.688 21 1.864 22 50.68 23 100.50 24 >210 Ref0l 3.736 Ref02 210

[0629] Conclusion: Most of the compounds in the present invention showed good GPR40 receptor agonist activity.

[0630] Test Example 2: Pharmacokinetics Evaluation in Rats Using rats as the test animals, the drug concentrations in plasma at different time points 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 the LC-MS / MS analysis method, and the lower limit of quantification of the method was 20 ng / mL. The concentration data in plasma were statistically analyzed using the pharmacokinetic data analysis software WinNonlin 7.0, and the pharmacokinetic parameters were calculated using the non-compartmental model method (NCA), as shown in Table 2 below.

[0631] Experimental protocol :

[0632] Experimental drugs: The compounds of the present invention and control compounds.

[0633] Drug preparation:

[0634] Intravenous group: The test article with a final concentration of 0.1 mg / mL was used for intravenous administration, and the preparation solvent was 5% DMSO + 45% PEG400 + 50% aqueous solution. After preparation, all were clear and transparent solutions.

[0635] Oral group: The test article with a final concentration of 0.3 mg / mL was used for oral administration, and the preparation solvent was 0.5% CMC aqueous solution. After preparation, all were clear and transparent solutions.

[0636] Drug administration: After the rats were fasted overnight (12 h), they were given intragastric administration at a dose of 3 mg / kg.

[0637] Operation: The rats were given intragastric administration. Blood was collected from the tail vein before 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 4°C and 3500 rpm for 10 minutes to separate plasma, stored at -20°C, and allowed to eat 2 h after administration.

[0638] Determination of the content of the compound to be measured in the plasma of rats after intragastric administration of the drug: After the plasma samples were thawed at room temperature, 300 μL (terfenadine 200 ng / mL, acetonitrile) internal standard was added respectively. After vortex mixing for 1 min, centrifugation was carried out at 4°C and 15400 rpm for 10 min. The supernatant was diluted 20 times with 80% acetonitrile water and then injected for analysis by LC / MS / MS analysis.

[0639] The drug metabolism data of rats are shown in the following table:

[0640]

[0641] Conclusion: Compared with the control compound Ref0l, after oral administration, the compounds of the present invention have less drug entering the blood and lower drug exposure in the blood, which may help reduce the potential risk of liver toxicity.

Claims

1. A compound represented by the following 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; or R 6 and R 7 together are oxo or thio; R 8 is halogen or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 9 C 1-6 Alkyl, -COOR 9-1 、-CON(R 10 R 11 ), halogen or R 9-2 A substituted 5-10 membered heterocycloalkyl group, wherein the heteroatom in the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of the heteroatom is 1 to 4; R 9-1 C 1-6 Alkyl or R 9-1-1 Substituted C 1-6 alkyl; R 9-2 C 1-6 Alkyl or C substituted by 1-3 halogen atoms 1-6 alkyl; R 9-1-1 C 1-6 Alkoxy; R 10 is optionally substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 A 5-10 membered heterocyclic aryl group substituted with a cycloalkyl group; R 11 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; X1, X2, X3 are independently N or CH; Y1 and Y3 are O, Y2 and Y4 are CH2 or Y2 and Y4 are CH2, Y1 and Y3 are O.

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 halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Alkoxy substitution; 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 with one or more halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Alkoxy substitution; the heteroatoms in the 5-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4; the heteroatoms in the 5-6 membered heterocyclic aromatic group are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4; 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 are independently H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy; R 6 , R 7 are independently halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; R 6 and R 7 together are oxo or thio; said C 1-6 Alkyl and C 3-6 The cycloalkyl radicals are each optionally substituted with one or more H, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Alkoxy substitution; R 8 are independently 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 halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Alkoxy substitution; R 9 Independently for C 1-6 Alkyl, -COOR 9-1 、-CON(R 10 R 11 ), halogen or R 9-2 A substituted 5-10 membered heterocycloalkyl group, wherein the heteroatom in the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of the heteroatom is 1 to 4; R 9-1 Independently for C 1-6 Alkyl or R 9-1-1 Substituted C 1-6 alkyl; R 9-2 Independently for C 1-6 Alkyl or C substituted by 1-3 halogen atoms 1-6 alkyl; R 9-1-1 Independently for C 1-6 Alkoxy; R 10 Optionally, one or more halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 A 5-10-membered heterocyclic aromatic group substituted with a cycloalkyl group; the heteroatom in the 5-10-membered heterocyclic aromatic group is selected from one or more of N, O and S, and the number of the heteroatoms is 1 to 4; R 11 Optionally, one or more 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; the C 4-8 The heteroatoms in the heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 4; X1, X2, X3 are independently N or CH; Y1 and Y3 are O, Y2 and Y4 are CH2 or Y2 and Y4 are CH2, Y1 and Y3 are O.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 and R 2 C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl; (2)R 3 and R 4 C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably ethyl; (3)R 3 and R 4 C 2-6 The alkenyl groups are independently C 3-5 Alkenyl, preferably allyl, propenyl, n-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, more preferably 2-methylpropenyl; (4)R 3 and R 4 C 2-6 Alkynyl is independently ethynyl, propynyl, butynyl, pentynyl, 2-methylpropynyl, 3-methylbutynyl, preferably propynyl; (5)R 3 and R 4 C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, preferably cyclopropyl; (6)R 6 and R 7 The oxo group in (7)R 8 C 1-6 The alkoxy groups are independently C 1-4 Alkoxy, preferably methoxy, ethoxy, propoxy, butoxy or isopropoxy, more preferably methoxy; (8)R 9 C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl or neohexyl, and is further preferably neohexyl, for example, 2-methylpentyl; (9)R 9 The halogen in is independently F, Cl, Br, I, preferably F; (10)R 9-1 C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably isopropyl; (11)R 9-1-1 C 1-6 The alkoxy groups are independently C 1-4 Alkoxy, preferably methoxy, ethoxy, propoxy, butoxy or isopropoxy, more preferably isopropoxy; (12) R 9-2 The 5-10-membered heterocycloalkyl in the substituted 5-10-membered heterocycloalkyl is a 5-6-membered heterocycloalkyl, for example, a 6-membered heterocycloalkyl; (13) R 9-2 The heteroatom in the substituted 5-10 membered heterocycloalkyl is N, O, S, preferably N; (14) R 9-2 The number of heteroatoms in the substituted 5-10 membered heterocycloalkyl group is 1 to 4, preferably 1, 2, 3 or 4, and more preferably 1; (15) R 9-2 The substituted 5-10 membered heterocycloalkyl is piperidinyl, for example (16)R 9-2 In the case of C substituted by 1-3 halogen atoms 1-6 The halogen atoms in the alkyl group are independently F, Cl, Br, I, preferably F; (17)R 9-2 In the case of C substituted by 1-3 halogen atoms 1-6 The number of halogen atoms in the alkyl group is independently 1, 2 or 3, preferably 3; (18)R 9-2 In the case of C substituted by 1-3 halogen atoms 1-6 C in the alkyl group 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably ethyl; (19)R 10 and R 11 C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or neopentyl, and is more preferably neopentyl; (20)R 10 The 5-10-membered heterocyclic aromatic group is a 5-6-membered heterocyclic aromatic group, for example, a 6-membered heterocyclic aromatic group; (21)R 10 The heteroatom in the 5-10 membered heterocyclic aromatic group is N, O, or S, preferably N; (22)R 10 The number of heteroatoms in the 5-10 membered heterocyclic aromatic group is 1 to 4, preferably 1, 2, 3 or 4, and more preferably 1; (23)R 10 The 5-10 membered heterocyclic aromatic group in is pyridyl; for example 4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 and R 2 independently H or C 1-6 alkyl; (2)R 3 and R 4 Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl; (3)R 6 and R 7 H independently or together (4)R 8 Independently for C 1-6 Alkoxy; (5)R 10 Independently for C 1-6 An alkyl-substituted 5-10-membered heterocyclic aromatic group; the heteroatom in the 5-10-membered heterocyclic aromatic group is selected from one or more of N, O and S, and the number of the heteroatoms is 1 to 4; (6)R 11 Independently for C 1-6 alkyl; (7) X1 is N or CH; (8) X2 is N or CH, and X3 is CH.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 and R 2 One of them is H and the other is H or C 1-6 Alkyl; for example, all are H; (2)R 3 and R 4 One of them is H and the other is C 3-6 Cycloalkyl; (3)R 9 Independently for C 1-6 Alkyl, -COOR 9-1 , halogen or R 9-2 A substituted 5-10 membered heterocycloalkyl group, wherein the heteroatom in the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of the heteroatom is 1 to 4; (4)R 9-1 Independently for C 1-6 alkyl.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 9 Independently -COOR 9-1 , the R 9-1 Independently for R 9-1-1 Substituted C 1-6 When alkyl, R 9-1 is isopropoxy-ethyl; (2)R 9 Independently for R 9-2 Substituted 5-10 membered heterocycloalkyl, wherein the 5-10 membered heterocycloalkyl is The R 9-2 are independently trifluoroethyl; (3)R 9 Independently -CON(R 10 R 11 ), R 10 Middle C 1-6 The 5-10 membered heterocyclic aromatic group substituted by an alkyl group is C 1-4 Alkyl-substituted 6-membered pyridyl; for example, methyl-substituted pyridyl; for example (4)R 10 , R 11 C 1-6 Alkyl groups, such as neopentyl; (5)R 11 Independently for C 1-6 Alkyl, R 10 For C 1-6 Alkyl-substituted 5-10 membered heterocyclic aryl.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 and R 2 is H or methyl; (2) R 3 and R 4 for H, ethyl, (3) for (4) R 5 is hydrogen; (5) R 6 and R 7 H or together (6) R 8 is methoxy; (7) R 9 For F, 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound or its pharmaceutically acceptable salt has the structure of the following formula (II): in, 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 6 , R 7 Each independently is H or R 6 and R 7 together are oxo or thio; R 8 is optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 9 C 1-6 Alkyl, -COOR 9-1 、-CON(R 10 R 11 ), halogen or R 9-2 A substituted 5-10 membered heterocycloalkyl group, wherein the heteroatom in the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of the heteroatom is 1 to 4; R 9-1 C 1-6 Alkyl or R 9-1-1 Substituted C 1-6 alkyl; R 9-2 C 1-6 Alkyl or C substituted by 1-3 halogen atoms 1-6 alkyl; R 9-1-1 C 1-6 Alkoxy; 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 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; X1, X2, and X3 are independently N or CH.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound or a pharmaceutically acceptable salt thereof has the structure of the following formula (III): in, 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 6 , R 7 Each independently is H or R 6 and R 7 together are oxo or thio; R 8 is optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 9 C 1-6 Alkyl, -COOR 9-1 、-CON(R 10 R 11 ), halogen or R 9-2 A substituted 5-10 membered heterocycloalkyl group, wherein the heteroatom in the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of the heteroatom is 1 to 4; R 9-1 C 1-6 Alkyl or R 9-1-1 Substituted C 1-6 alkyl; R 9-2 C 1-6 Alkyl or C substituted by 1-3 halogen atoms 1-6 alkyl; R 9-1-1 C 1-6 Alkoxy; 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 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; X1, X2, and X3 are independently N or CH.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 , R 2 are each independently H, methyl; R 3 , R 4 Each independently is H, C 1-6 Alkyl, C 2-6 Olefin group, C 2-6 Alkynyl, C 3-6 Cycloalkyl; R 6 , R 7 Each independently is H or R 6 and R 7 Together they are an oxo group; R 8 C 1-6 Alkoxy; R 9 C 1-6 Alkyl, -COOR 9-1 、-CON(R 10 R 11 ), halogen or R 9-2 A substituted 5-10 membered heterocycloalkyl group, wherein the heteroatom in the 5-10 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of the heteroatom is 1 to 4; R 9-1 C 1-6 Alkyl or R 9-1-1 Substituted C 1-6 alkyl; R 9-2 C 1-6 Alkyl or C substituted by 1-3 halogen atoms 1-6 alkyl; R 9-1-1 C 1-6 Alkoxy; 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 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; X1, X2, X3 are independently N or CH; Preferably, R 1 , R 2 Each independently is H; R 3 , R 4 Each independently is H or C 3-6 Cycloalkyl; R 8 is methoxy; R 9 C 1-6 Alkyl; or -COOC 1-6 Alkyl; or R 9 For R 9-2 Replaced The R 9-2 C substituted with halogen 1-6 Alkyl; or R 9 -CON(R 10 R 11 ), the R 10 is optionally substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl-substituted pyridyl, wherein R 11 C 1-6 alkyl; Further preferably, any of the following schemes is used; Scenario 1: R 3 , R 4 Each is independently H or cyclopropyl; R 9 C 1-6 Alkyl or -COOC 1-6 alkyl; Scenario 2: R 3 , R 4 Each is independently H or cyclopropyl; R 9 For R 9-2 Replaced The R 9-2 is trifluoroethyl; Scenario 3: R 3 , R 4 Each is independently H or cyclopropyl; R 9 -CON(R 10 R 11 ), the R 10 for The R 11 It is neopentyl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is selected from one of the following compounds:

12. A compound represented by formula (Ia), or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 9-1 , R 9-2 , R 9-1-1 , X1, X2, X3, Y2, Y3, Y4, Y1 are as defined in the above formula (Ⅰ); R is C 1-6 Alkyl or benzyl; Preferably, C in R 1-6 The alkyl groups are independently C 1-4 The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, and is further preferably an ethyl group; Preferably, the present invention has the following structural compounds 1a-24a:

13. A method for preparing a compound represented by formula (I), comprising the following steps: (1) When R is C 1-6 When the alkyl group is present, compound (Ia) is subjected to a deprotection reaction in a solvent in the presence of a base to obtain compound (I); The solvent is a mixed solvent of tetrahydrofuran and methanol; The alkali is sodium hydroxide solution; The concentration of the base is 1-3 mol / L, preferably 2 mol / L; The reaction temperature is 40-80°C, preferably 60°C; The progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC-Ms or NMR) is used for detection, and the reaction endpoint is generally when the carbonyl compound represented by formula (Ia) disappears or no longer reacts, or the product no longer increases; the reaction time is 0.5h-5h, preferably 0.5h; In the reaction, the ratio of compound (Ia) to base is 1:1-6, preferably 1:4; The ratio of compound (Ia) to solvent in the reaction is 30-80 mg / mL, preferably 55.75 mg / mL; The organic solvent in the reaction is an aprotic solvent, preferably ethyl acetate; The pH regulator is citric acid; The pH regulator concentration is 0.5-2 mol / L, preferably 1 mol / L; (2) When R is benzyl, compound (Ia) is subjected to a debenzylation reaction in a solvent under 10% Pd / C and hydrogen atmosphere to obtain compound (I); The reaction temperature is 10-25°C, preferably 25°C; The reaction time is 3-8h, preferably 5h; in, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 9-1 , R 9-2 , R 9-1-1 , X1, X2, X3, Y2, Y3, Y4, and Y1 are as defined in the above formula (I).

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.

15. A compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutical preparation thereof The acceptable salt or The pharmaceutical composition of claim 14 is used in the preparation of GPR40 receptor Use in agonists or medicines; 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, cirrhosis, lethargy and the like; 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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