Sulfur-containing aromatic propionic acid derivative as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a sulfur-containing 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 a sulfur-containing aromatic propionic acid derivative, a preparation method thereof, a pharmaceutical composition and an application thereof. Background Art

[0002] GPR40 (FFAR1 or FFA1) belongs to the GPCR family and is a G protein-coupled receptor, which is mainly expressed in pancreatic islet β cells, intestinal endocrine cells and the brain. When GPR40 is activated by its endogenous ligand (medium / long-chain fatty acids), 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 promote the secretion of intestinal hormones such as GLP-1 and achieve weight loss by inhibiting central nervous appetite, which 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, etc. of Eli Lilly and Company.

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

[0004] Therefore, new molecules are needed to improve the properties of compounds to reduce potential toxicity and the like.

[0005] More and more experimental and clinical evidence shows that changes / lesions in the intestinal environment are involved in the disease pathological processes of more extensive tissues in the body and even play a key role. These diseases include but are not limited to diabetes, obesity, non-alcoholic steatohepatitis, chronic kidney disease and neurodegenerative diseases, etc. Therefore, drugs acting locally in the intestine may not only be a safer treatment method, but also may curb the occurrence of multiple diseases at the source. GPR40 plays a hypoglycemic and weight loss role mainly through the following aspects.

[0006] 1. The GPR40 gene is expressed in multiple parts of the body, with the highest expression level in pancreatic tissue, which indicates that the pancreas pancreas It has a specific transcriptional regulator of the GPR40 gene. Research has found that in the complete genomic sequence from the end of the CD22 gene to the GPR40 gene, the HR2 region 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 the effect of reducing blood sugar by regulating islet β-cells.

[0007] The GPR40 protein is mainly distributed in pancreatic tissues. After being activated by binding to an appropriate ligand, it affects the function of islet cells. Research shows that free fatty acids can enhance the insulin secretion response of islet β-cells under glucose stimulation.

[0008] 2. GPR40 is also generally expressed in intestinal endocrine cells. Endogenous medium- and long-chain fatty acids can activate downstream pathways by binding to GPR40 to promote the secretion of GLP-1 and PYY by intestinal endocrine L-cells, the secretion of GIP by intestinal endocrine K-cells, and the secretion of CCK by intestinal endocrine I-cells. Therefore, the GPR40 receptor can be used as a therapeutic target for obesity and diabetes. When GPR40 agonists have no or very little blood system exposure, it may be possible to reduce the potential toxicity caused by systemic exposure. It can be foreseen that if these GPR40 agonist drugs can be highly enriched in intestinal tissues with a large number of GPR40 receptors, they can not only exert their pharmacological functions for the treatment of diabetes or obesity, but also reduce the side effects caused by potential high systemic exposure.

[0009] The compound of the present invention has greatly improved intestinal targeting through structural modification, enabling the drug to be enriched in intestinal tissues and exert its pharmacological effect. At the same time, it reduces oral absorption, resulting in extremely low drug concentration in the blood, which helps to reduce the side effects caused by systemic exposure. Summary of the Invention

[0010] Aiming at the deficiencies of current GPR40 series agonists in aspects such as drug metabolism, bioavailability, and compound toxicity, the present invention provides a class of compounds with GPR40 receptor agonist activity, which have one or more advantages such as good activity, high targeting, and low toxicity.

[0011] The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof,

[0012]

[0013] wherein,

[0014] R 1 , R 2 are each independently H, halogen, optionally substituted: C 1-6 alkyl, C1-6 an alkoxy group or C 3-6 cycloalkyl;

[0015] 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, a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl;

[0016] or R 3 and R 4 together with the adjacent carbon atoms form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group;

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

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

[0019] R 8 is H, optionally substituted: C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0020] R 9 is optionally substituted by R 9-1 substituents independently selected from: halogen, hydroxy and C 1-6 alkyl, C 3-6 cycloalkyl, C 1-10 alkoxy or C 2-10 heteroalkyl, said R 9-1 substituents independently selected from: halogen, hydroxy and C 1-6 alkoxy;

[0021] X is CH or N;

[0022] Y is CH or N;

[0023] Ring A is an optionally substituted aryl or heteroaryl, aryl or heteroaryl and a 5- to 12-membered heterocyclic group;

[0024] Ring B is an optionally substituted C 6-10 aryl or a 5- to 12-membered heteroaryl;

[0025] When the number of the substitutions selected from a plurality of them, they are independently the same or different;

[0026] The carbon atom with "*" indicates that when selected from chiral carbon atoms, it is in the S configuration, R configuration and a mixture of any ratio thereof.

[0027] Preferably, R 1 , R 2 are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are each optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halo C 3-6 cycloalkyl and halo C 1-6 alkoxy;

[0028] R 3 , R 4 are each independently H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- or 6-membered heterocyclic group or 5- or 6-membered heteroaryl group; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- or 6-membered heterocyclic group and 5- or 6-membered heteroaryl group are each optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halo C 3-6 cycloalkyl and halo C 1-6 alkoxy;

[0029] Or R 3 , R 4 together with the adjacent carbon atoms form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl;

[0030] R 5 is H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;

[0031] R 6 ,R 7 each independently is H, halogen, C 1-6 alkyl or C 3-6 cycloalkyl; the C 1-6 alkyl and C 3-6 cycloalkyl are each optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halo C3-6 substituted by a cycloalkyl group and a halogenated C 1-6 alkoxy substituent;

[0032] R 8 is H, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are each optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 3-6 cycloalkyl and halogenated C 1-6 alkoxy substituent;

[0033] R 9 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-10 alkoxy or C 2-10 heteroalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-10 alkoxy and C 2-10 heteroalkyl are each optionally substituted by one or more R 9-1 substituents;

[0034] R 9-1 is independently selected from halogen, hydroxy and C 1-6 alkoxy;

[0035] X is CH or N;

[0036] Y is CH or N;

[0037] Ring A is C 6-10 aryl, 5- to 12-membered heteroaryl, or C 6-10 aryl-fused 5- to 12-membered heterocyclic group; the C 6-10 aryl and 5- to 12-membered heteroaryl are each optionally substituted by one or more A 1 substituents; the C 6-10 aryl-fused 5- to 12-membered heterocyclic group is optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 3-6 cycloalkyl and halogenated C 1-10 alkoxy substituent, wherein C 6-10 aryl is linked to the amide bond;

[0038] A 1 is independently selected from C 1-6Alkoxy, 5-12 membered heterocyclic group, 5-12 membered heteroaryl and C 3-6 Cycloalkyl; said A 1 Optionally substituted by one or more A 1-1 Substituted;

[0039] A 1-1 Independently selected from hydroxy, C 1-6 Alkyl and C 1-6 Alkoxy;

[0040] Ring B is C 6-10 Aryl or 5-12 membered heteroaryl; said ring B is optionally substituted by 1 or more substituents selected from halogen, cyano, C 1-6 Alkyl, halo C 1-6 Alkyl, halo C 3-6 Cycloalkyl and halo C 1-10 Alkoxy substituted.

[0041] In certain preferred embodiments of the present invention, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is defined as follows, and the groups not mentioned are the same as those described in any embodiment of the present application.

[0042] In some embodiments, the compound of formula (I), wherein R 1 , R 2 Are each independently selected from H and C 1-6 Alkyl; preferably one is selected from H and the other is selected from H and C 1-6 Alkyl; more preferably both are selected from H and methyl.

[0043] In some embodiments, the compound of formula (I), wherein R 3 , R 4 Are each independently selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and halo C 1-6 Alkyl.

[0044] In some embodiments, the compound of formula (I), wherein R 3 , R 4 Are each independently selected from H, C 2-6 Alkyn Base, C 3-6 Naphthenyl and halogenated C 1-6 alkyl; for example H, C 2-6 alkynyl and C 3-6 naphthenyl; again for example H and C 3-6 ring Alkyl.

[0045] In some embodiments, the compound of formula (I), wherein R 3 Is selected from H, R 4 Is selected from C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and halo C 1-6 Alkyl; for example C2-6 Alkynyl, C 3-6 Cycloalkyl and halogenated C 1-6 Alkyl; preferably selected from C 2-6 Alkynyl and C 3-6 Cycloalkyl; for example C 3-6 Cycloalkyl.

[0046] In some embodiments, the compound of formula (I), wherein R 5 is selected from H.

[0047] In some embodiments, the compound of formula (I), wherein R 6 , R 7 are each independently selected from H.

[0048] In some embodiments, the compound of formula (I), wherein R 8 is selected from C 1-6 Alkyl.

[0049] In some embodiments, the compound of formula (I), wherein R 9 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and C 2-10 Heteroalkyl; the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 2-10 Heteroalkyl is optionally substituted with one or more R 9-1 ; for example, optionally substituted C 9-1 Alkyl substituted with one or more R 1-6 ; for example C 1-6 Alkyl.

[0050] In some embodiments, the compound of formula (I), wherein R 9-1 is selected from hydroxy.

[0051] In some embodiments, the compound of formula (I), wherein X is selected from CH.

[0052] In some embodiments, the compound of formula (I), wherein Y is selected from CH.

[0053] In some embodiments, the compound of formula (I), wherein A 1-1 is selected from hydroxy and C 1-6 Alkyl.

[0054] In some embodiments, the compound of formula (I), wherein A 1 is selected from C 1-6 Alkoxy, 5-12 membered heterocyclic group and C 3-6 Cycloalkyl; the C 1-6Alkoxy, 5- to 12-membered heterocyclic group, and C 3-6 Cycloalkyl is optionally substituted with one or more A 1-1 Substituted; for example, optionally substituted with one or more A 1-1 Substituted C 1-6 Alkoxy; and for another example, C 1-6 Alkoxy.

[0055] In some embodiments, the compound of formula (I) wherein ring B is selected from 5- to 12-membered heteroaryl.

[0056] In some embodiments, the compound of formula (I) wherein the number of substitutions is selected from 1, 2, and 3; when selected from 2 and 3, they are independently the same or different.

[0057] In some embodiments, when the compound of formula (I) contains a chiral center, the compound of formula (I) is selected from each stereoisomer and mixtures thereof; for example, when containing 1 chiral center, the compound of formula (I) is in the R configuration and / or the S configuration.

[0058] In some embodiments, each halogen is independently selected from fluorine, chlorine, bromine, and iodine.

[0059] In some embodiments, each C 1-6 Alkyl is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl; for example, methyl.

[0060] In some embodiments, each C 1-6 alkoxy is independently selected from -O-methyl, -O-ethyl, -O-n-propyl, -O -Isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl, -O-sec-butyl, and -O-pentyl; for example, methoxy.

[0061] In some embodiments, each C 1-10 Alkoxy is independently selected from C 1-6 Alkoxy.

[0062] In some embodiments, each C 1-10 Alkoxy is independently selected from -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl, -O-sec-butyl, and -O-pentyl; for example, methoxy.

[0063] In some embodiments, each C 3-6 Cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; for example, cyclopropyl.

[0064] In some embodiments, each halo is independently selected from fluoro, chloro, bromo, and iodo; for example, fluoro.

[0065] In some embodiments, the number of each halogen is independently selected from 1, 2, and 3; for example, 3.

[0066] In some embodiments, each C 2-6 alkenyl is independently selected from vinyl, propenyl, isopropenyl, butenyl, and pentenyl.

[0067] In some embodiments, each C 2-6 alkynyl is independently selected from ethynyl, propynyl, propargyl, butynyl, and pentynyl; for example, propynyl.

[0068] In some embodiments, the heteroatoms in each 5- to 6-membered heterocyclic group are independently selected from N, O, and S, and the number of heteroatoms is independently selected from 1, 2, and 3; preferably, the heteroatoms in each 5- to 6-membered heterocyclic group are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2.

[0069] In some embodiments, the heteroatoms in each 5- to 6-membered heteroaryl group are independently selected from N, O, and S, and the number of heteroatoms is independently selected from 1, 2, and 3; preferably, the heteroatoms in each 5- to 6-membered heteroaryl group are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2.

[0070] In some embodiments, each 3- to 6-membered cycloalkyl group is independently selected from saturated 3- to 6-membered cycloalkyl groups; for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0071] In some embodiments, each 3- to 6-membered cycloalkyl group is independently selected from partially unsaturated 3- to 6-membered cycloalkyl groups; for example, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

[0072] In some embodiments, the heteroatoms in each 3- to 6-membered heterocyclic group are independently selected from N, O, and S, and the number of heteroatoms is independently selected from 1, 2, and 3; preferably, the heteroatoms in each 3- to 6-membered heterocyclic group are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2.

[0073] In some embodiments, each C 2-10 heteroalkyl has heteroatoms independently selected from N, O, and S, and the number of number Independently selected from 1, 2, and 3; preferably, each C 2-10 The heteroatoms in the heteroalkyl are independently selected from O and S, and the hetero heteroatoms is independently selected from 2 and 3; more preferably, each C 2-10 heteroalkyl has heteroatoms independently selected from O, and the number of heteroatoms is independently selected from 2.

[0074] In some embodiments, each C 2-10 heteroalkyl is independently selected from C 2-8 oxyalkyl.

[0075] In some embodiments, each C2-10 The heteroalkyl is independently selected from C 1-3 alkyl-O-C 1-3 alkyl-O-C 1-3 alkyl; for example

[0076] In some embodiments, in A 1 Among them, the heteroatoms in the 5- to 12-membered heterocyclic group are independently selected from N, O, and S, and the number of heteroatoms is independently selected from 1, 2, and 3; preferably, the heteroatoms in the 5- to 12-membered heterocyclic group are independently selected from N and O, and the number of heteroatoms is independently selected from 2 and 3; more preferably, the heteroatoms in the 5- to 12-membered heterocyclic group are independently selected from N and O, and the number of heteroatoms is independently selected from 2.

[0077] In some embodiments, in A 1 Among them, the 5- to 12-membered heterocyclic group is selected from 3- to 6-membered heterocyclic groups.

[0078] In some embodiments, in A 1 Among them, the 5- to 12-membered heterocyclic group is Preferably

[0079] In some embodiments, in ring A, the C 6-10 aryl is independently selected from phenyl and naphthyl; for example, phenyl.

[0080] In some embodiments, in ring A, the heteroatoms in the 5- to 12-membered heteroaryl are independently selected from N, O, and S, and the number of heteroatoms is independently selected from 1, 2, and 3; preferably, the heteroatoms in the 5- to 12-membered heteroaryl are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2; more preferably, the heteroatoms in the 5- to 12-membered heteroaryl are independently selected from N, and the number of heteroatoms is independently selected from 1.

[0081] In some embodiments, in ring A, the 5- to 12-membered heteroaryl is selected from 5- to 6-membered heteroaryl groups.

[0082] In some embodiments, in ring A, the 5- to 12-membered heteroaryl is selected from pyridyl; preferably selected from

[0083] In some embodiments, in ring A, the C 6-10 aryl-fused 5- to 12-membered heterocyclic group, the aryl is selected from phenyl and naphthyl; preferably phenyl.

[0084] In some embodiments, in ring A, the C 6-10The heteroatoms in the aryl-fused 5- to 12-membered heterocycle are independently selected from N, O, and S, and the number of heteroatoms is independently selected from 1, 2, and 3; preferably, the C 6-10 The heteroatoms in the aryl-fused 5- to 12-membered heterocycle are independently selected from N and O, and the number of heteroatoms is selected from 1 and 2; more preferably, the C 6-10 The heteroatoms in the aryl-fused 5- to 12-membered heterocycle are independently selected from O, and the number of heteroatoms is selected from 1 and 2.

[0085] In some embodiments, in ring A, the C 6-10 The 5- to 12-membered heterocyclic group in the aryl-fused 5- to 12-membered heterocyclic group is selected from 5- to 6-membered heterocyclic groups.

[0086] In some embodiments, in ring A, the C 6-10 The 5- to 12-membered heterocyclic group in the aryl-fused 5- to 12-membered heterocyclic group is selected from Preferably selected from

[0087] In some embodiments, in ring B, the C 6-10 The aryl is independently selected from phenyl and naphthyl, such as phenyl.

[0088] In some embodiments, in ring B, the heteroatoms in the 5- to 12-membered heteroaryl are independently selected from N, O, and S, and the number of heteroatoms is independently selected from 1, 2, and 3; preferably, the heteroatoms in the 5- to 12-membered heteroaryl are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2; more preferably, the heteroatoms in the 5- to 12-membered heteroaryl are independently selected from N, and the number of heteroatoms is independently selected from 1.

[0089] In some embodiments, in ring B, the 5- to 12-membered heteroaryl is selected from 5- to 10-membered heteroaryl; preferably selected from 5- to 6-membered heteroaryl.

[0090] In some embodiments, in ring B, the 5- to 12-membered heteroaryl is selected from pyridyl; preferably selected from

[0091] In some embodiments, for the compound represented by formula (I), wherein R 9 Is selected from C1-6 Alkyl, C 3-6 Cycloalkyl, C 2-8 Oxaalkyl and hydroxy-substituted C 1-6 Alkyl; such as C 1-6 Alkyl.

[0092] In some embodiments, for the compound represented by formula (I), wherein A 1-1 Is selected from hydroxy and methyl.

[0093] In some embodiments, the compound of formula (I), wherein A 1 is selected from C 1-6 alkoxy, hydroxy-substituted C 1-6 alkoxy, 3- to 6-membered heterocyclic group, C 3-6 cycloalkyl and methyl-substituted 3- to 6-membered heterocyclic group; for example, C 1-6 alkoxy.

[0094] In some embodiments, the compound of formula (I), wherein ring A is selected from phenyl, 5- to 6-membered heteroaryl, and phenyl-fused 5- to 6-membered heterocyclic group.

[0095] In some embodiments, the compound of formula (I), wherein

[0096] R 1 and R 2 are each independently selected from H;

[0097] R 3 and R 4 are each independently selected from H and C 3-6 cycloalkyl;

[0098] R 5 is selected from H;

[0099] R 6 and R 7 are each selected from H;

[0100] R 8 is selected from C 1-6 alkyl;

[0101] R 9 is selected from C 1-6 alkyl;

[0102] Ring A is selected from phenyl and phenyl-fused 5- to 6-membered heterocyclic group;

[0103] A 1 is selected from C 1-6 alkoxy;

[0104] Ring B is selected from 5- to 6-membered heteroaryl.

[0105] In some embodiments, the compound of formula (I), wherein R 1 and R 2 are each independently selected from H and CH3; for example, R 1 is selected from H, and R 2 is selected from H and CH3.

[0106] In some embodiments, the compound of formula (I), wherein R 3 and R 4 are each independently selected from H, -CH 3、 and CF3; for example, R 3 is selected from H, R 4 is selected from

[0107] In some embodiments, the compound of formula (I), wherein, when R 3 , R 4 the carbon atom connected to is a chiral carbon atom, is selected from

[0108] In some embodiments, the compound of formula (I), wherein, R 8 is selected from

[0109] In some embodiments, the compound of formula (I), wherein, R 9 is selected from -CH3, -CH2CH2OH and -CH2CH2OCH2CH2OCH2CH2OH.

[0110] In some embodiments, the compound of formula (I), wherein, is selected from

[0111] In some embodiments, the compound of formula (I), wherein, is selected from

[0112]

[0113] In some embodiments, the compound of formula (I), wherein, A 1 is selected from methoxy, -OCH2CH2OH, cyclopropyl,

[0114] In some embodiments, the compound of formula (I), wherein ring A is selected from

[0115]

[0116] For example, the a end is connected to connected.

[0117] Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure shown in the following formula (II):

[0118]

[0119] Wherein, R 1 , R 2 , R 3, R 4 , R 5 , R 8 , R 9 , X, Y, * and ring A are as described in any of the compounds of formula (I) of the present invention. Preferably, R 1 , R 2 are each independently H, halogen or optionally substituted C 1-6 alkyl;

[0120] 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 or C 1-6 alkyl-substituted five-membered heteroaryl;

[0121] R 5 is H;

[0122] R 8 is optionally substituted: C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0123] R 9 is optionally substituted by R 9-1 : C 1-6 alkyl, C 3-6 cycloalkyl or C 1-10 alkoxy; the R 9-1 substituent is hydroxyl;

[0124] X is CH or N;

[0125] Y is CH or N;

[0126] A is optionally substituted: phenyl, pyridine or benzo 5-6-membered heterocyclic group.

[0127] Further preferably, in the compound of formula II or its pharmaceutically acceptable salt, the R 1 , R 2 are each independently H or methyl;

[0128] R 3 , R 4 are each independently H, C 2-6 alkynyl, C 3-6 cycloalkyl or CF3;

[0129] R 8 is C 1-6 alkyl;

[0130] R9 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, hydroxy-substituted C 2-10 alkyl or hydroxy-substituted C 2-10 alkoxy;

[0131] Y is CH;

[0132] A is optionally substituted: phenyl, pyridine, The substituents are selected from: C 1-6 alkyl, C 3-6 cycloalkyl, C 1-10 alkoxy, optionally substituted 5-12 membered heterocycloalkyl, halogen and hydroxy-substituted C 1-6 alkoxy.

[0133] More preferably, the R 1 , R 2 are each independently H; R 3 , R 4 are each independently H or C 3-6 cycloalkyl; R 9 is methyl, ethyl or cyclopropyl; A is optionally substituted: phenyl, pyridine, The substituents are selected from: C 1-10 alkoxy and 4-8 membered heterocycloalkyl optionally substituted by C 1-6 alkyl.

[0134] More preferably, R 3 , R 4 are each independently H or cyclopropyl; R 9 is methyl; A is phenyl or pyridine optionally substituted by C 1-10 alkoxy.

[0135] More preferably, the compound represented by formula (I) of the present invention is selected from one of the following compounds:

[0136]

[0137] The present invention also provides a compound represented by formula (IA), or a pharmaceutically acceptable salt thereof,

[0138]

[0139] wherein, R is C 1-6 alkyl; preferably, R is methyl or ethyl; more preferably, R is ethyl; and

[0140] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 、R 8 、R 9 、X, Y, ring A, ring B, and * are defined as in any one of the embodiments of formula (I).

[0141] In some embodiments, the compound of formula (IA) or a pharmaceutically acceptable salt thereof according to the present invention may be the compound of formula (IIA) or a pharmaceutically acceptable salt thereof.

[0142]

[0143] wherein R, R 1 、R 2 、R 3 、R 4 、R 5 、R 8 、R 9 、X, Y, ring A, and * are defined as in any one of the embodiments of formula (IA).

[0144] In some embodiments, the compound of formula (IA) according to the present invention has any of the following structures:

[0145]

[0146] The present invention also provides a method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

[0147] In an organic solvent, the compound of formula (IA) is subjected to a hydrolysis reaction with a basic reagent to obtain the compound of formula (I);

[0148]

[0149] wherein,

[0150] R is C 1-6 alkyl; preferably, R is methyl or ethyl; more preferably, R is ethyl; and

[0151] R 1 ,R 2 、R 3 ,R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、X, Y, *, ring A, and ring B are defined as in any one of the embodiments of the compound of formula (I);

[0152] Preferably, the preparation method satisfies one or more of the following conditions:

[0153] The organic solvent may be a mixture of an ether solvent and an alcohol solvent, preferably a mixed solvent of tetrahydrofuran and methanol;

[0154] The basic reagent may be an organic strong base, preferably a sodium hydroxide solution;

[0155] The concentration of the basic reagent may be 1 - 3 mol / L, preferably 2 mol / L;

[0156] The molar ratio of the compound shown by formula (IA) to the base may be 0.1 - 0.5:1, preferably 0.2:1;

[0157] The molar volume ratio of the compound shown by formula (IA) to the solvent may be 0.08 - 0.12 mol / L, preferably 0.09 mol / L;

[0158] The temperature of the reaction may be 40 - 60 °C, preferably 50 °C;

[0159] The progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR). Generally, the disappearance or no longer reaction of the compound shown by formula (IA), or when the product no longer increases, is taken as the end point of the reaction. The reaction time may be 0.5 - 4 h, preferably 0.5 h;

[0160] After the reaction, post - treatment is also included. The post - treatment includes the following steps: concentration, pH adjustment, extraction, washing with ice water, concentration, and purification.

[0161] The organic solvent used for extraction in the post - treatment may be an ester solvent, preferably ethyl acetate;

[0162] The pH regulator in the post - treatment may be an organic weak acid, preferably citric acid;

[0163] The concentration of the pH regulator in the post - treatment may be 0.5 - 2 mol / L, preferably 1 mol / L.

[0164] In some embodiments, the method for preparing the compound shown by general formula (II) or a pharmaceutically acceptable salt thereof includes the following steps:

[0165] In an organic solvent, the compound shown by formula (IIA) reacts with a basic reagent to undergo a hydrolysis reaction to obtain the compound shown by formula (II);

[0166]

[0167] Among them,

[0168] R is C 1-6 alkyl; preferably, R is methyl or ethyl; more preferably, R is ethyl; and

[0169] R 1 ,R 2 、R 3 ,R 4 、R 5 、R 8 、R 9 、X, Y, *, and ring A are defined as in any embodiment of the compound of formula (II), and the reaction conditions are defined as in any embodiment of the compound of formula (IA).

[0170] The present invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) the compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof (as an active ingredient), and a pharmaceutically acceptable excipient.

[0171] 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 drug.

[0172] 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 GPR40 receptor agonist.

[0173] In the above-mentioned use, the GPR40 receptor agonist can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as providing comparison as a standard sample or a control sample, or being made into a kit according to conventional methods in the art to provide a rapid detection of the agonist effect of the GPR40 receptor.

[0174] 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 drug for preventing and / or treating metabolic-related diseases.

[0175] 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 drug for preventing and / or treating metabolic-related diseases by activating the GPR40 receptor.

[0176] 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, cirrhosis, and somnolence. The metabolic-related diseases can 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.

[0177] The metabolic-related diseases can also be selected from hypertriglyceridemia.

[0178] The present invention will be described in detail below. Before the description, it should be understood that the terms used in this specification and the appended claims should not be construed as being limited to their general and dictionary meanings, but should be based on the principle that allows the inventor to appropriately define the terms for the best interpretation, and according to the meanings corresponding to the technical aspects of the present invention and general concept is explained. Therefore, the descriptions presented here are merely preferred examples for illustrative purposes and are not intended limit the scope of the present invention, so 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.

[0179] When used alone or in combination with other groups in this application, the term "alkyl" refers to an alkyl group containing 1 to a certain number of carbon atoms. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or pentyl, isopentyl, neopentyl, hexyl. The alkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point.

[0180] When used alone or in combination with other groups in this application, the term "alkenyl" refers to a straight-chain or branched-chain, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (for example, C 2-6 ) and having a carbon-carbon sp 2 double bond. Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point.

[0181] When used alone or in combination with other groups in this application, the term "alkynyl" refers to a straight-chain or branched-chain, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (for example, C 2-6 ) and having a carbon-carbon sp triple bond. Alkynyl groups include, but are not limited to: etc.

[0182] When used alone or in combination with other groups in this application, the term "alkoxy" means that an oxygen atom is connected to the alkyl group as described above in the parent molecular moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, pentyloxy, etc.

[0183] When used alone or in combination with other groups in this application, the term "cycloalkyl group" refers to a saturated or partially unsaturated all-carbon ring, preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group). The "cycloalkyl group" can be saturated, such as "cycloalkyl"; or, the "cycloalkyl group" can be partially unsaturated, such as "cycloalkenyl". For example, in a certain embodiment, a monocyclic cycloalkyl group is preferred.

[0184] The cycloalkyl groups mentioned above, non-limiting examples of which include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0185] In one embodiment, a monocyclic cycloalkenyl group is preferred. The monocyclic cycloalkenyl groups, non-limiting examples of which include: cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.

[0186] When used alone or in combination with other groups in the present application, the term "heterocyclic group" refers to a saturated and partially unsaturated non-aromatic cyclic group containing at least one heteroatom selected from N, O, and S as a ring member. Preferably, the number of heteroatoms is 1, 2, 3, or 4. More preferably, the heteroatom is N or O, and the number of heteroatoms is 1, 2, or 3. The heterocyclic group can be monocyclic or polycyclic, and the polycyclic can be a fused ring, spiro ring, and bridged ring structure. For example, a 3- to 6-membered heterocyclic group. In addition, the heterocyclic group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point. When used alone or in combination with other groups in the present application, the term "heteroalkyl" means that one or more carbon atoms in the alkyl group (referring to non-terminal carbon atoms, or carbon atoms at the position directly connected to other groups) are replaced by heteroatoms; preferably, the heteroatoms are independently selected from N, O, and S, and the number of heteroatoms is selected from 1, 2, and 3; more preferably, the heteroatoms are independently selected from O and S, and the number of heteroatoms is selected from 1, 2, and 3. For example, C2-8 oxaalkyl refers to a group containing 1-3 heteroatoms and 2-8 carbon atoms, and the heteroatoms are located in the middle of the heteroalkyl group.

[0187] The term "aryl group" refers to an aromatic system, including an aryl group or a heteroaryl group; in the heteroaryl group, the number of heteroatoms is 1, 2, 3, or 4, and the types of heteroatoms are selected from N, O, or S. Among them, aryl groups include but are not limited to: phenyl, naphthyl. Heteroaryl groups include but are not limited to: thiazolyl, thienyl, pyridyl, pyrimidinyl.

[0188] In the present application, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0189] In the present application, the term "hydroxyl" refers to -OH.

[0190] In the present application, the term "cyano" refers to -CN.

[0191] When used alone or in combination with other groups in the present application, the term "substituted by a halogen atom" means that one or more hydrogen atoms are replaced by a halogen. For example, the term "halogenated C1-6 alkyl" refers to a C1-6 alkyl optionally substituted by one or more (such as 1-3) halogens. Those skilled in the art should 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 halogenated alkyls are, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0192] As used in the present application, the term "each independently" means that at least two groups (or segments) with the same or similar value ranges present in the structure can have the same or different meanings in a specific situation. For example, if substituents A and B are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl, then when substituent A is hydrogen, substituent B can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl; similarly, when substituent B is hydrogen, substituent A can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.

[0193] The term "one (kind) or more (kinds)" or a similar expression "at least one (kind)" can represent, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0194] As used in the present application, the term "substituted" and its other variant forms herein mean that one or more (such as 1, 2, 3 or 4) atoms or atomic groups (such as hydrogen atoms) on the specified atom are replaced by other equivalents, provided that the normal valence of the specified atom or atomic group in the current situation is not exceeded and a stable compound can be formed. If an atom or atomic group is described as "optionally substituted by...", it can be either substituted or unsubstituted. Unless otherwise specified, the connection site of the substituent herein can be from any suitable position of the substituent. When the connecting bond in the substituent is shown as a chemical bond passing between two interconnected atoms in the ring system, it means that the substituent can be connected to any ring-forming atom in the ring system.

[0195] In the present application, a solid line ( ) or a solid wedge or a dashed wedge 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 all possible stereoisomers at that carbon atom are included (e.g., a specific enantiomer, a racemic mixture, etc.). Using a solid or dashed wedge to depict a bond attached to an asymmetric carbon atom is intended to indicate that the stereoisomer shown exists. When present in a racemic mixture, a solid and a dashed wedge are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise specified, the compounds of the present invention may 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 may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs).

[0196] In the present application, is used to indicate that this position is connected to other groups.

[0197] The compounds represented by formula (I), the compounds represented by formula (II), and the compounds represented by 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 a suitable sterilized device for injection or infusion.

[0198] The various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to the conventional preparation methods in the pharmaceutical field. For example, the unit dose of its formulation contains 0.1-1000 mg of the compounds represented by formula (I), the compounds represented by formula (II), and the compounds represented by formula 1-24. Preferably, the unit dose of the formulation contains 1 mg-500 mg of the compounds represented by formula (I), the compounds represented by formula (II), and the compounds represented by formula 1-24.

[0199] The compounds represented by formula (I) of the present invention and the pharmaceutical compositions 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.

[0200] In the present invention, the term "(therapeutically) effective amount" may 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. A person of ordinary skill in the art can determine the effective amount of a specific compound empirically without undue experimentation.

[0201] Typical formulations are prepared by mixing the compound of formula (I) of the present invention with carriers, diluents or excipients. Suitable carriers, diluents or excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc.

[0202] 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 buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavor enhancers or other known additives to make the drug in an acceptable form for manufacture or use.

[0203] When the compound of formula (I) of 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) of the present invention or the pharmaceutical composition can be administered to a subject separately or together in any known oral, intravenous injection, rectal administration, vaginal administration, transdermal absorption, other local or systemic administration forms.

[0204] The pharmaceutical composition may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavor enhancers or other known additives to make the pharmaceutical composition in an acceptable form for manufacture or use.

[0205] The drug of the present invention preferably uses an oral administration route. Solid dosage forms for oral administration may include capsules, tablets, powders Or a granule preparation. 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, certain complex silicates, sodium carbonate, etc.; solution blockers such as paraffin, etc.; absorption promoters such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules, using lactose and high molecular weight polyethylene glycol, etc. as excipients.

[0206] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compound or its pharmaceutical composition of the present invention, the liquid dosage form 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.

[0207] 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.

[0208] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0209] The reagents and raw materials used in the present invention are all commercially available.

[0210] 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 intestinal targeting properties.

[0211] According to the present invention, unless otherwise specified, all terms cited herein have the same meaning as those understood by those skilled in the art for the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0212] Figure 1 It is the graph of the change of blood glucose over time and the area under the curve after administration in the OGTT experiment of wild-type mice.

[0213] Figure 2 It is the graph of the change of blood glucose over time and the area under the curve after administration in the OGTT experiment of diabetic db / db mice.

[0214] Figure 3 It is the graph of the change of rat body weight over time after administration in the weight loss experiment of DIO rats. Specific implementation manners

[0215] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0216] The present invention will be further described in detail below in combination with specific examples, but the present invention is not limited to the following examples. The examples are for better explaining some 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.

[0217] Column chromatography or purification generally uses silica gel with 200 - 300 mesh as the carrier.

[0218] In the examples, without special instructions, the reaction temperature is room temperature, which is 20 - 30 degrees.

[0219] The elution machine system for column chromatography adopted 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 compounds.

[0220] Example 1:

[0221] Compound 1, 3 - cyclopropyl - 3 - (2 - ((1 - (6 - ((6 - (methylthio)pyridin - 2 - yl)pivalanilide)benzene[d][1,3]dioxolan - 5 - yl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid

[0222]

[0223] Compound 1 was prepared according to the following route.

[0224]

[0225] Step 1: N - (6 - bromopyridin - 2 - yl)pivalamide (1 - 2)

[0226] 2-Amino-6-bromopyridine (1-1) (1 g, 5.81 mmol) was added to dichloromethane (9 ml), and diisopropylethylamine (2.0 ml, 11.85 mmol, 2.05 eq) was added. Pivaloyl chloride (0.75 ml, 6.0 mmol, 1.05 eq) was added dropwise, and the reaction was carried out at room temperature for 4 hours. The reaction was complete. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain white solid 1-2 (1.3 g, yield: 85%).

[0227] 1 1H NMR (400 MHz, CDCl3): δ 8.21 (dd, 1H), 7.98 (s, 1H), 7.54 (m, 1H), 7.19 (dd, 1H), 1.28 (s, 9H). m / z 255.15 [M+H].

[0228] Step 2: N-(6-(Methylthio)pyridin-2-yl)pivalamide (1-3)

[0229] N-(6-Bromopyridin-2-yl)pivalamide (1-2) (1.2 g, 4.7 mmol) was dissolved in N,N-dimethylformamide (10 ml), sodium methanethiolate (333 mg, 4.7 mmol, 0.9 eq) was added, and cesium carbonate (3.1 g, 9.2 mmol) was added. The reaction was heated to 80 °C for 16 hours. The reaction was complete. Water (30 ml) was added to the reaction solution, and after stirring for 10 minutes, ethyl acetate (30 ml × 3) was added for extraction. The organic phases were combined, washed with water, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness and purified by column chromatography to obtain colorless liquid 1-3 (1.1 g, yield 92.0%).

[0230] 1 1H NMR (400 MHz, CDCl3): δ 8.21 - 8.33 (br, 1H), 7.98 - 7.96 (d, 1H), 7.55 - 7.51 (m, 1H), 7.01 - 6.99 (d, 1H), 2.71 (s, 3H), 1.33 (s, 9H). m / z 225.15 [M+H].

[0231] Step 3: 6-(Methylthio)-N-pivalylpyridin-2-amine (1-4)

[0232] Dissolve N-(6-(methylthio)pyridin-2-yl)pivalamide (1-3) (1.0 g, 3.9 mmol) in tetrahydrofuran (12 ml), cool down to about -10 °C, and add lithium aluminum hydride (0.45 g, 11.7 mmol) portionwise. After addition, heat to 60 °C and react for 2 hours. The reaction is complete. Let the reaction solution cool naturally to room temperature, slowly add water (12 ml) with stirring, adjust the pH value to alkaline with saturated sodium bicarbonate, extract with ethyl acetate (30 ml × 3), combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain colorless liquid 1-4 (722 mg, yield 88.0%).

[0233] 1 1H NMR (400 MHz, DMSO-d6): δ 8.15 - 8.05 (br, 1H), 7.38 - 7.36 (d, 1H), 7.05 - 6.99 (m, 1H), 6.65 - 6.63 (d, 1H), 3.03 - 3.01 (d, J = 8, 2H), 2.74 (s, 3H), 1.03 (s, 9H). m / z 211.15 [M + H].

[0234] Step 4: 6-Fluoro-N-(6-(methylthio)pyridin-2-yl)-N-pivalylbenzo[d][1,3]dioxole-5-carboxamide (1-6)

[0235] Under nitrogen atmosphere, add 6-fluorobenzo[d][1,3]dioxole-5-carboxylic acid (1-5) (940 mg, 5.1 mmol) to tetrahydrofuran (15 ml), stir, add oxalyl chloride (647 mg, 5.08 mmol), and then dropwise add N,N-dimethylformamide (2 drops). React at room temperature for 1 hour. After the reaction is complete, concentrate to dryness, and dissolve the solid with tetrahydrofuran (3 ml).

[0236] Dissolve 6-(methylthio)-N-pivalylpyridin-2-amine (1-4) (700 mg, 3.33 mmol) in tetrahydrofuran (5 ml), add triethylamine (1.0 g, 9.98 mmol), protect with nitrogen, add the above acyl chloride solution, and react at room temperature for 16 hours. After the reaction is complete, concentrate the reaction solution, dissolve it with ethyl acetate (30 ml), wash with water (30 ml), extract the aqueous phase with ethyl acetate (30 ml × 2), combine the organic phases, wash with brine (60 ml), and dry over anhydrous sodium sulfate. Purify by column chromatography to obtain colorless liquid 1-6 (998 mg, yield 80.0%).

[0237] 11H NMR (400 MHz, CDCl3): δ 7.50 - 7.46 (d, 1H), 7.35 - 7.30 (m, 2H), 7.21 - 7.19 (d, 1H), 6.91 - 6.89 (m, 1H), 6.82 (m, 1H), 6.84 - 6.82 (m, 1H), 4.23 (s, 2H), 3.85 (s, 3H), 2.72 (s, 3H), 1.01 (s, 9H). m / z 363.15 [M + H].

[0238] Step 5: 5-(3-Hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1-8)

[0239] m-Hydroxybenzaldehyde (1-7) (15 g, 0.122 mol) was added to water (120 ml), and the mixture was heated to 85 °C until the reaction system became clear. Isopropylidene malonate (17.7 g, 0.122 mol) was added portionwise. After addition, the reaction solution was heated to 85 °C and stirred for 16 h. Monitoring showed that the raw materials were completely reacted. 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 1-8 (15.2 g, yield: 50.0%).

[0240] 1 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]

[0241] Step 6: 5-(Cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1-9)

[0242] 5-(3-Hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1-8) (11 g, 0.048 mol, 1.0 eq) was added to tetrahydrofuran (50 ml), and the temperature was cooled to -10 °C. 1 mol / L cyclopropylmagnesium bromide (220 ml, 3.0 eq) was added dropwise, and the reaction was carried out at room temperature for 1.5 h. Monitoring showed that the raw materials were completely reacted. The reaction solution was quenched with 1 mol / L hydrochloric acid, and the pH value was adjusted to 2.0 - 3.0. The mixture was extracted with ethyl acetate (100 * 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 1-9 (11.5 g, yield: 81%).

[0243] 1 1H NMR (400 MHz, CDCl3) δ: 9.30 (s, 1H); 7.18 - 7.14 (t, J = 8.0 Hz, 1H); 6.75 (s, 1H); 6.69 - 6.67 (d, 1H); 6.70 - 6.95 (m, 1H); 4.56 (s, 1H); 2.69 - 2.66 (m, 1H); 1.75 (s, 3H); 1.74 - 1.72 (m, 1H); 1.44 (s, 3H); 0.60 - 0.56 (m, 2H); 0.37 - 0.35 (m, 1H); 0.13 - 0.10 (m, 1H)

[0244] Step 7: Ethyl 3 - cyclopropyl - 3-(3 - hydroxyphenyl)propionate (1 - 10)

[0245] Under nitrogen atmosphere, dissolve 5-(cyclopropyl(3 - hydroxyphenyl)methyl)-2,2 - dimethyl - 1,3 - dioxane - 4,6 - dione (1 - 9) (11.5 g, 0.039 mol) in N,N - dimethylformamide (12 ml) and ethanol (6 ml), stir, and heat the reaction solution to 100 °C for reaction for 5 hours. Monitor the completion of the reaction. Concentrate the solvent, add ethyl acetate (50 ml) to dissolve, wash with saturated brine (50 ml), dry over anhydrous sodium sulfate, and purify the organic phase by column chromatography to obtain colorless liquid 1 - 10 (5 g, yield: 53.8%).

[0246] 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]

[0247] Step 8: tert - Butyl 4 - ((3-(1 - cyclopropyl - 3 - ethoxy - 3 - propionyl)phenoxy)methyl)piperidine - 1 - carboxylate (1 - 11)

[0248] Under nitrogen atmosphere, ethyl 3-cyclopropyl-3-(3-hydroxyphenyl)propionate (1-10) (5 g, 0.021 mol) was dissolved in acetone (50 ml), then N-Boc-4-piperidinemethanol (4.59 g, 0.021 mmol), cyanomethylenetributylphosphorane (10.14, 0.042 mmol) were added. The mixture was heated to 100 °C and reacted for 1 hour, and the reaction was monitored until completion. After cooling, the reaction solution was concentrated and purified by column chromatography to obtain colorless liquid 1-11 (6.7 g, yield: 73.2%).

[0249] Step 9: Ethyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (1-12)

[0250] tert-Butyl 4-((3-(1-cyclopropyl-3-ethoxy-3-oxopropyl)phenoxy)methyl)piperidine-1-carboxylate (1-11) (6.7 g, 0.0155 mol) was dissolved in isopropanol (10 ml), then hydrogen chloride isopropanol solution (20 ml, 4 mol / L, 0.021 mmol) was added. The mixture was stirred at room temperature for 4 hours and the reaction was monitored until completion. The reaction solution was concentrated, dispersed in ethyl acetate (20 ml), then neutralized with saturated sodium carbonate, and separated. The organic phase was dried over anhydrous sodium sulfate for 12 hours, filtered, and the organic phase was concentrated to obtain an oily substance 1-12 (4.37 g, yield: 85.0%).

[0251] Step 10: Ethyl 3-cyclopropyl-3-(2-((1-(6-((6-(methylthio)pyridin-2-yl)pivalanilino)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (1-13)

[0252] Under nitrogen atmosphere, 6-fluoro-N-(6-(methylthio)pyridin-2-yl)-N-pivalylbenzo[d][1,3]dioxole-5-carboxamide (1-6) (4.80 g, 12.67 mmol) was added to ethyl 3-cyclopropyl-3-(2-(piperidin-4-ylmethoxy)pyridin-4-yl)propionate (1-12) (6.32 g, 19.0 mmol), then cesium carbonate (8.2 g, 25.34 mmol) was added. The temperature was raised to 130 °C and the mixture was stirred overnight. After completion of the reaction, it was cooled, ethyl acetate (20 ml) was added and stirred, then filtered. The filter cake was washed with ethyl acetate, and the organic phase was purified by column chromatography to obtain a colorless oily substance 1-13 (3.48 g, yield: 40.0%).

[0253] 11H NMR (400 MHz, CDCl3): δ: 7.80 - 7.78 (d, J = 8 Hz, 1H), 7.64 - 7.60 (t, J = 8 Hz, 1H), 7.34~7.32 (m, 2H), 7.22 - 7.18 (m, 1H), 7.02 - 6.98 (m, 2H), 6.78 - 6.73 (m, 1H), 6.55 - 6.45 (m, 2H), 4.35 - 4.32 (t, J = 8 Hz, 1H), 4.25 (m, 1H), 4.21 - 4.18 (m, 2H), 3.79 (s, 3H), 2.56~2.53 (m, 1H), 2.53 (s, 3H), 2.29 - 2.28 (m, 2H), 1.79 - 1.68 (m, 3H), 1.30 - 1.21 (m, 2H), 1.18 - 1.14 (t, J = 8.0 Hz, 3H), 1.04 - 0.89 (m, 2H), 0.87 - 0.82 (m, 9H), 0.61~0.58 (m, 1H), 0.49~0.46 (m, 1H), 0.33~0.30 (m, 1H), 0.19~0.17 (m, 1H). m / z 688.35 [M + H].

[0254] Step 11: 3 - cyclopropyl - 3 - (2 - ((1 - (6 - ((6 - (methylthio)pyridin - 2 - yl)pivalanilide)benzo[d][1,3]dioxol - 5 - yl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 1)

[0255] Dissolve 3 - cyclopropyl - 3 - (2 - ((1 - (6 - ((6 - (methylthio)pyridin - 2 - yl)pivalanilide)benzo[d][1,3]dioxol - 5 - yl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid (1 - 13) (1.22 g, 1.78 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml), add 2 mol / L sodium hydroxide solution (6.25 ml, 8.9 mmol), and stir the reaction at 50 °C for 4 hours. When. Monitoring shows that after the reaction ends, it is concentrated, 1 mol / L citric acid is added to adjust the pH value to 5 - 6, and extracted with ethyl acetate Wash with ice - water for 3 times, concentrate, and after purification, obtain white solid Compound 1 (1017 mg, yield: 86.5%).

[0256] 11H NMR (400 MHz, CDCl3): δ 8.07 - 8.05 (d, J = 8.0 Hz, 1H), 7.06 - 7.03 (m, 1H), 6.76 (s, 1H), 6.78 - 6.76 (m, 2H), 6.63 (s, 1H), 6.33 (s, 1H), 5.95 - 5.89 (d, 2H), 4.23 (s, 1H), 4.16 - 4.12 (m, 2H), 3.26 - 3.25 (m, 1H), 2.78 - 2.72 (m, 2H), 2.57 - 2.51 (m, 4H), 2.43 (s, 3H), 2.34 - 2.32 (m, 2H), 1.76 - 1.72 (m, 3H), 1.51 - 1.49 (m, 1H), 1.29 - 1.21 (m, 2H), 1.01 - 0.99 (m, 1H), 0.85 (s, 9H), 0.62 - 0.61 (m, 1H), 0.45 - 0.44 (m, 1H), 0.32 - 0.30 (m, 1H), 0.18 - 0.16 (m, 1H). m / z: 661.45 [M+1].

[0257] Example 2:

[0258] Compound 2,3 - cyclopropyl - 3 - (3 - ((1 - (6 - ((6 - (methylthio)pyridin - 2 - yl)pivalanilide)benzene[d][1,3]dioxol - 5 - yl)piperidin - 4 - yl)methoxy)phenyl)propanoic acid

[0259]

[0260] Compound 2 was prepared according to the following route.

[0261]

[0262] Step 1: Cyclopropyl(2 - methoxypyridin - 4 - yl)methanol (2 - 2)

[0263] 2 - Methoxy - 4 - pyridinecarbaldehyde (2 - 1) (10.0 g, 7.29 mmol, 1.0 eq) was added to tetrahydrofuran (80 mL). A 1 mol / L solution of cyclopropylmagnesium bromide in tetrahydrofuran (213 mL, 0.213 mol, 3.0 eq) was added dropwise under an ice - water bath. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried and concentrated, and purified by column chromatography to obtain the product 2 - 2 (11.4 g, 87%).

[0264] 11H 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]

[0265] Step 2: Cyclopropyl(2-methylpyridin-4-yl)methanone (2-3)

[0266] Dissolve cyclopropyl(2-methoxypyridin-4-yl)methanol (2-2) (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 batches and stir at room temperature for 10 minutes. The reaction is complete. Add water (200 ml) to the reaction solution and stir. Extract with ethyl acetate (200 ml × 2). Combine the organic phases, wash with water and saturated brine, and purify by column chromatography to obtain a pale yellow liquid 2-3 (6.50 g, 64%).

[0267] 1 1H NMR (400 MHz, DMSO-d6): δ 8.37 - 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].

[0268] Step 3: Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)acrylate (2-4)

[0269] Sodium hydride (2.94 g, 0.0734 mol, 2.0 eq) was dissolved in tetrahydrofuran (35 ml) under nitrogen protection. The temperature was lowered to 0 °C, and ethyl phosphonoacetate (16.47 g, 0.0734 mol, 2.0 eq) was added dropwise. After addition, the mixture was stirred at 0 °C for 30 minutes. Then, cyclopropyl(2-methylpyridin-4-yl)methanone (2-3) (6.5 g, 0.0367 mol, 1.0 eq) dissolved in tetrahydrofuran (35 ml) was added dropwise. Subsequently, the mixture was slowly warmed to room temperature and then heated to 80 °C for reflux reaction for 3 hours until the reaction was completed. The reaction solution was cooled to room temperature and then quenched by pouring it into ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate (35 ml × 2), and the organic phases were combined, washed with water, washed with saturated sodium chloride, and purified by column chromatography to obtain a pale yellow oil 2-4 (9.45 g, 100%).

[0270] 1 H NMR (400 MHz, DMSO-d6): δ 7.64 - 7.63 (d, J = 8.0 Hz, 1H), 6.81 - 6.80 (s, 1H), 6.22 - 6.20 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 4.27 - 4.19 (q, J = 4.0 Hz 2H), 1.42 - 1.40 (m, 1H), 1.25 - 1.23 (t, J = 4.0 Hz, 3H), 0.55 - 0.51 (m, 2H), 0.25 - 0.22 (m, 2H). m / z: 248.20 [M + 1]

[0271] Step 4: Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (2-5)

[0272] Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)acrylate (2-4) (9.45 g, 0.0383 mol, 1.0 eq) was dissolved in acetic acid (45 ml). Zinc powder (14.93 g, 0.230 mol, 6.0 eq) was added in portions, and there was a slight exothermic phenomenon. The mixture was stirred at room temperature for 30 minutes until the reaction was completed. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (45 ml × 2). The filtrate was concentrated to dryness, dissolved in ethyl acetate (45 ml), washed with saturated sodium bicarbonate solution until the system was alkaline, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a yellow oil 2-5 (9.85 g, 100%). It was directly used for the next step.

[0273] 11H 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]

[0274] Step 5: Ethyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate (2-6)

[0275] Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (2-5) (7.5 g, 30 mmol, 1.0 eq) was added to N,N-dimethylformamide (75 ml), pyridine hydrochloride (34.8 g, 30 mmol, 1.00 eq) was added, the system was purged with nitrogen, heated to 120 °C and reacted for 1.0 h. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (75 ml) to obtain the organic phase. The organic phase was dried and concentrated, and purified by column chromatography to obtain a colorless oil 2-6 (7.0 g, 90%).

[0276] 1 1H 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].

[0277] Step 6: tert-Butyl 4-(((4-(1-cyclopropyl-3-ethoxy-3-propionylpyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (2-7)

[0278] Under nitrogen atmosphere, ethyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate (2-6) (4.70 g, 20 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (4.33 g, 20 mmol) were added to toluene (40 ml). The mixture was stirred, and cyanomethylenetributylphosphine (9.70 g, 40 mmol) was added. The temperature was raised to 100 °C and the reaction was carried out for 3 hours. The reaction was stopped and the product was purified by column chromatography to obtain a foamy solid 2-7 (3.00 g, yield: 86.1%).

[0279] 1 H NMR (400 MHz, CDCl3): δ 8.09 - 8.08 (1H, d, J = 4.0 Hz), 6.77 - 6.76 (1H, d, J = 4.0 Hz), 6.63 (1H, s), 4.15 - 4.13 (2H, d, J = 8.0 Hz), 4.17 - 4.05 (2H, m), 3.20 - 3.17 (2H, d, J = 12.0 Hz), 2.79 - 2.61 (4H, m), 2.33 - 2.24 (1H, m), 2.03 - 1.89 (1H, m), 1.85 (2H, d, J = 12.0 Hz), 1.49 (s, 9H), 1.45 - 1.26 (2H, m), 1.18 - 1.16 (3H, t, J = 8.0 Hz), 1.07 - 0.88 (1H, m), 0.66 - 0.55 (1H, m), 0.55 - 0.40 (1H, m), 0.35 - 0.29 (1H, m), 0.22 - 0.15 (1H, m), m / z: 333.25 [M - CO2 - C3H6].

[0280] Step 7: Ethyl 3-cyclopropyl-3-(2-(piperidin-4-yloxy)pyridin-4-yl)propionate (2-8)

[0281] tert-Butyl 4-(((4-(1-cyclopropyl-3-ethoxy-3-propionylpyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (2-7) (2.5 g, 5.78 mmol) was added to dichloromethane (15 ml). The mixture was stirred until dissolved, and trifluoroacetic acid (0.66 g, 5.8 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, saturated sodium bicarbonate solution was added for washing, followed by brine washing, and then dried over sodium sulfate to obtain a white solid 2-8 (1.87 g, yield: 97.0%).

[0282] 11H NMR (400 MHz, CDCl3): δ 8.05 - 8.04 (1H, d, J = 4.0 Hz), 6.75 - 6.74 (1H, d, J = 4.0 Hz), 6.61 (1H, s), 4.12 - 4.10 (2H, d, J = 8.0 Hz), 4.13 - 3.99 (2H, m), 3.17 - 3.14 (2H, d, J = 12.0 Hz), 2.79 - 2.61 (4H, m), 2.33 - 2.24 (1H, m), 2.03 - 1.89 (1H, m), 1.85 - 1.82 (2H, d, J = 12.0 Hz), 1.45 - 1.26 (2H, m), 1.18 - 1.16 (3H, t, J = 8.0 Hz), 1.05 - 0.86 (1H, m), 0.66 - 0.55 (1H, m), 0.51 - 0.38 (1H, m), 0.35 - 0.24 (1H, m), 0.20 - 0.07 (1H, m), m / z: 333.25 [M+1].

[0283] In a synthetic manner similar to Example 1, replace ethyl 3 - cyclopropyl - 3-(3-(piperidin - 4 - ylmethoxy)phenyl)propionate with ethyl 3 - cyclopropyl - 3-(2-(piperidin - 4 - methoxypyridin - 4 - yl)propionate to prepare Compound 2.

[0284] 3 - Cyclopropyl - 3-(3 - ((1-(6 - ((6 - (methylthio)pyridin - 2 - yl)pivalanilide)benzene[d][1,3]dioxol - 5 - yl)piperidin - 4 - yl)methoxy)phenyl)propionic acid (Compound 2)

[0285] Yield: 84.3%. 1 1H NMR (400 MHz, CDCl3): 7.56 - 7.50 (m, 1H), 7.35 (s, 1H), 7.22 - 7.18 (m, 3H), 6.99 - 6.90 (m, 2H), 6.78 - 6.60 (m, 2H), 6.06 (s, 2H), 4.25 - 4.15 (m, 2H), 3.85 (m, 2H), 3.35 - 3.15 (m, 4H), 2.95 (s, 2H), 2.56 - 2.45 (m, 2H), 2.54 (s, 3H), 2.15 - 2.10 (m, 1H), 1.60 - 1.45 (m, 2H), 1.28 - 1.26 (m, 2H), 1.03 - 0.99 (m, 1H), 0.85 (s, 9H), 0.60 (s, 1H), 0.45 (s, 1H), 0.35 (s, 1H), 0.15 (s, 1H). m / z: 660.35 [M+1].

[0286] Example 3:

[0287] Compound 3,3-cyclopropyl-3-(2-((1-(5-((6-(methylthio)pyridin-2-yl)pivalanilide)benzo[d][1,3]dioxol-4-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0288]

[0289] According to a synthetic method similar to that of Example 2, using the raw material 4-fluorobenzo[d][1,3]dioxole-5-carboxylic acid to replace 6-fluorobenzo[d][1,3]dioxole-5-carboxylic acid, Compound 3 was prepared.

[0290] Yield: 83.9%. 1 H NMR(400MHz,CDCl3):8.06 - 8.05(d,J = 4Hz,1H),6.81(s,1H),6.75 - 6.70(m,3H),6.46(s,1H),6.31 - 6.30(d,J = 4Hz,1H),5.86 - 5.78(d,2H),4.29 - 4.10(m,4H),3.26 - 3.22(m,1H),3.02 - 3.00(m,1H),2.82 - 2.55(m,4H),2.51(s,3H),2.33 - 2.27(m,1H),1.82 - 1.71(m,3H),1.46 - 1.37(m,2H),1.01 - 0.97(m,1H),0.83(s,3H),0.64 - 0.57(s,1H),0.50 - 0.41(m,1H),0.36 - 0.28(m,1H),0.21 - 0.12(m,1H).m / z:661.35[M + 1].[[]END]]

[0291] Example 4:

[0292] Compound 4,3-cyclopropyl-3-(2-((1-(7-((6-(methylthio)pyridin-2-yl)pivalanilide)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0293]

[0294] According to a synthetic method similar to that of Example 2, using the raw material 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid to replace 6-fluorobenzo[d][1,3]dioxole-5-carboxylic acid, Compound 4 was prepared.

[0295] Yield: 60.0%. 11H NMR (400 MHz, CDCl3): δ 8.32 - 8.31 (m, 1H), 7.51 (s, 1H), 7.30 - 7.20 (m, 1H), 7.01 (s, 2H), 6.87 (s, 1H), 6.55 - 6.48 (m, 2H), 4.47 (m, 5H), 4.38 (s, 2H), 3.73 (s, 1H), 3.50 (s, 1H), 3.02 (s, 2H), 2.75 (s, 3H), 2.57 (s, 2H), 2.00 (s, 3H), 1.76 (s, 1H), 1.50 (s, 2H), 1.23 (s, 1H), 1.07 (m, 9H), 0.85 (s, 1H), 0.72 (s, 1H), 0.57 (s, 1H), 0.42 (s, 1H). m / z: 675.45 [M+1].

[0296] Example 5:

[0297] Compound 5, 3 - cyclopropyl - 2 - methyl - 3 - (3 - ((1 - (6 - ((6 - (methylthio)pyridin - 2 - yl)pivalanilide)benzo[d][1,3]dioxol - 5 - yl)piperidin - 4 - yl)methoxy)phenyl)propanoic acid

[0298]

[0299] Compound 5 was prepared according to the following route.

[0300]

[0301] Step 1: Methyl 3 - cyclopropyl - 2 - methyl - 3 - oxopropionate (5 - 2)

[0302] Methyl 3 - cyclopropyl - 3 - oxopropionate (5 - 1) (25.00 g, 0.176 mol, 1.0 eq) was added to tetrahydrofuran (160 ml), and then cesium carbonate (85.95 g, 0.264 mol, 1.5 eq) was added. The mixture was stirred at room temperature for 30 minutes, potassium iodide (27.50 g, 0.193 mol, 1.1 eq) was added dropwise, and the reaction was heated to 40 °C for 3 hours until the reaction was complete. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed twice with ethyl acetate, and the filtrate was concentrated to dryness to obtain white solid 5 - 2 (32.50 g). The crude product was directly used in the next step.

[0303] 11H 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].

[0304] Step 2: Methyl 3-cyclopropyl-2-methyl-3-(p-toluenesulfonyl)acrylate (5-3)

[0305] Methyl 3-cyclopropyl-2-methyl-3-oxopropionate (5-2) (15.00 g, 0.096 mol, 1.0 eq) was added to tetrahydrofuran (100 ml), and the temperature was lowered 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 * 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%).

[0306] 1 1H NMR (400 MHz, CDCl3): δ 7.85 - 7.80 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 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].

[0307] Step 3: Methyl 3-(3-(benzyloxy)phenyl)-3-cyclopropyl-2-methylacrylate (5-4)

[0308] Dissolve methyl 3-cyclopropyl-2-methyl-3-(p-toluenesulfonyl)acrylate (5-3) (10.00 g, 0.032 mol, 1.0 eq) in dioxane (50 ml) and water (5 ml), then add 3-benzyloxybenzeneboronic acid (8.10 g, 0.035 mol, 1.1 eq), cesium carbonate (11.56 g, 0.035 mol, 1.1 eq), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (1.18 g, 0.05%). Heat the reaction mixture to 100 °C under nitrogen protection and react for 2 hours. Monitor the completion of the reaction. Add water (100 ml), extract with ethyl acetate (50 ml × 3), combine the organic phases, wash with saturated brine (150 ml), and dry over anhydrous sodium sulfate. Purify by column chromatography to obtain colorless liquid 5-4 (6 g, yield 57.7%).

[0309] 1 H 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). LC-MS m / z 323.1 [M+1].

[0310] Step 4: Methyl 3-cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropionate (5-5)

[0311] Dissolve methyl 3-(3-(benzyloxy)phenyl)-3-cyclopropyl-2-methylacrylate (5-4) (6.00 g, 0.018 mmol, 1.0 eq) in a mixed solvent of methanol / tetrahydrofuran (30 ml), add 10% palladium on carbon (1.20 g, 20%), displace with hydrogen five times, and react at room temperature for 16 hours. Monitor the completion of the reaction. Filter the reaction solution through diatomaceous earth, wash the filter cake with ethyl acetate twice, concentrate the filtrate, and purify by column chromatography to obtain colorless liquid 5-5 (2.10 g, yield 48.1%).

[0312] 1 H 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].

[0313] According to a synthetic method similar to that of Example 1, methyl 3-cyclopropyl-3-(3-hydroxyphenyl)-2-methylpropionate was used to replace ethyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate, and Compound 5 was prepared.

[0314] 3-Cyclopropyl-2-methyl-3-(3-((1-(6-((6-(methylthio)pyridin-2-yl)pivaloyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)phenyl)propanoic acid (Compound 5)

[0315] Yield: 64.3%. 1 H NMR (400 MHz, CDCl3): 7.45 (s, 1H), 7.31 - 7.18 (m, 4H), 7.01 - 6.96 (m, 2H), 6.78 - 6.76 (m, 1H), 6.15 - 6.14 (d, 1H), 6.06 (s, 2H), 3.86 (m, 2H), 3.25 - 3.15 (m, 4H), 3.06 (s, 2H), 2.84 - 2.79 (m, 2H), 2.54 (s, 3H), 2.17 - 2.12 (m, 1H), 1.62 - 1.55 (m, 2H), 1.31 - 1.29 (m, 2H), 1.15 - 1.10 (m, 3H), 1.08 - 1.04 (m, 1H), 0.90 (s, 9H), 0.61 (s, 1H), 0.48 (s, 1H), 0.38 (s, 1H), 0.21 (s, 1H). m / z: 674.35 [M+1].

[0316] Example 6:

[0317] Compound 6, 3-Cyclopropyl-3-(2-((1-(6-((6-(cyclopropylthio)pyridin-2-yl)(pivaloyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)phenyl)propanoic acid

[0318]

[0319] According to a synthetic method similar to those of Example 1 and Example 2, sodium cyclopropylthiolate was used to replace sodium methanethiolate, and Compound 6 was prepared.

[0320] Yield: 50.3%. 11H NMR (400 MHz, CDCl3): δ 7.45 - 7.42 (m, 1H), 7.31 (s, 1H), 7.23 - 6.96 (m, 3H), 6.78 - 6.60 (m, 1H), 6.55 - 6.45 (m, 2H), 6.07 (s, 2H), 4.25 - 4.15 (m, 2H), 3.86 (m, 2H), 3.36 - 3.15 (m, 4H), 2.96 (s, 2H), 2.56 - 2.45 (m, 2H), 2.15 - 2.10 (m, 1H), 1.60 - 1.45 (m, 3H), 1.28 - 1.26 (m, 2H), 1.12 (s, 2H), 1.03 - 0.99 (m, 1H), 0.88 (s, 2H), 0.86 (s, 9H), 0.62 (s, 1H), 0.47 (s, 1H), 0.36 (s, 1H), 0.17 (s, 1H). m / z: 687.35 [M+1].

[0321] Example 7:

[0322] Compound 7, 3-cyclopropyl-3-(2-((1-(2-methoxy-5-((6-(methylthio)pyridin-2-yl)(pivalyl)carbamoyl)pyridin-4-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0323]

[0324] According to a synthetic method similar to that of Example 1 and Example 2, replacing 6-fluorobenzo[d][1,3]dioxole-5-carboxylic acid with 2-fluoro-4-methoxypyridine-4-carboxylic acid as the raw material, Compound 7 was prepared.

[0325] Yield: 89.0%. 11H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.13 - 7.10 (t, J = 4.0 Hz, 1H), 6.76 - 6.82 (dd, J = 16.0, 8.0 Hz, 2H), 6.62 (s, 1H), 6.26 (s, 1H), 5.80 (s, 1H), 4.20 - 4.13 (m, 4H), 3.89 (m, 3H), 3.32 (s, 1H), 2.99 (s, 1H), 2.79 - 2.75 (m, 3H), 2.50 (m, 3H), 2.32 - 2.30 (m, 1H), 1.87 - 1.75 (m, 3H), 1.42 - 1.37 (m, 2H), 1.00 - 0.95 (m, 2H), 0.83 (s, 9H), 0.63 - 0.60 (m, 1H), 0.48 - 0.46 (m, 1H), 0.32 - 0.31 (m, 1H), 0.19 - 0.17 (s, 1H). m / z: 648.45 [M+1], 670.40 [M+Na].

[0326] Example 8:

[0327] Compound 8: 3 - cyclopropyl - 3-(2 - ((1-(5 - methoxy - 2 - ((6-(methylthio)pyridin - 2 - yl)(neopentyl)carbamoyl)phenyl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid

[0328]

[0329] Compound 8 was prepared according to the following route.

[0330]

[0331] Step 1: 2 - fluoro - 4 - methoxy - N-(6-(methylthio)pyridin - 2 - yl)-N - neopentylbenzamide (8 - 2)

[0332] Under nitrogen atmosphere, 2 - fluoro - 4 - methoxybenzoic acid (8 - 1) (1.16 g, 5.1 mmol) was added to tetrahydrofuran (15 ml), stirred, oxalyl chloride (647 mg, 5.08 mmol) was added, and then N,N - dimethylformamide (2 drops) was dropped in. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, it was concentrated to dryness, and the solid was dissolved in tetrahydrofuran (3 ml).

[0333] Under nitrogen atmosphere, 6-(methylthio)-N-neopentylpyridin-2-amine (1-4) (700 mg, 3.33 mmol) was dissolved in tetrahydrofuran (5 ml), triethylamine (1.00 g, 9.98 mmol) was added, and the above acyl chloride solution was added. The reaction was carried out at room temperature for 16 hours until completion. The reaction solution was concentrated, dissolved in ethyl acetate (30 ml), washed with water (30 ml), and the aqueous phase was extracted with ethyl acetate (30 ml * 2). The organic phases were combined, washed with brine (60 ml), and dried over anhydrous sodium sulfate. Column chromatography gave a colorless liquid 8-2 (604 mg, yield 50.1%).

[0334] 1 H NMR (400 MHz, CDCl3): δ 7.50 - 7.46 (d, 1H), 7.35 - 7.30 (m, 2H), 7.21 - 7.19 (d, 1H), 6.91 - 6.89 (m, 1H), 6.82 (m, 1H), 6.84 - 6.82 (m, 1H), 4.23 (s, 2H), 3.85 (s, 3H), 2.72 (s, 3H), 1.01 (s, 9H). m / z 363.15 [M + H].

[0335] Step 2: Ethyl 3-cyclopropyl-3-(2-((1-(5-methoxy-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propionate (8-3)

[0336] Under nitrogen atmosphere, 2-fluoro-4-methoxy-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (8-2) (507 mg, 1.40 mmol) was added to ethyl 3-cyclopropyl-3-(2-(piperidin-4-yloxy)pyridin-4-yl)propionate (2-8) (698 mg, 2.1 mmol), and then cesium carbonate (912 mg, 2.8 mmol, 2.0 eq) was added. The temperature was raised to 130 °C and the reaction was stirred overnight until completion. After cooling, ethyl acetate (20 ml) was added and stirred. The mixture was filtered, and the filter cake was washed with ethyl acetate. The organic phase was purified by column chromatography to give a colorless oil 8-3 (463 mg, yield: 49.0%).

[0337] 11H NMR (400 MHz, CDCl3): δ 8.09 - 8.07 (d, J = 8 Hz, 1H), 7.37 - 7.35 (d, J = 8 Hz, 1H), 7.03 - 6.99 (t, J = 8 Hz, 1H), 6.79 - 6.75 (m, 2H), 6.68 (s, 1H), 6.54 - 6.51 (m, 1H), 6.19 (m, 2H), 4.35 - 4.32 (t, J = 8 Hz, 1H), 4.25 (m, 1H), 4.21 - 4.18 (m, 2H), 3.79 (s, 3H), 2.56 - 2.53 (m, 1H), 2.53 (s, 3H), 2.29 - 2.28 (m, 2H), 1.79 - 1.68 (m, 3H), 1.30 - 1.21 (m, 2H), 1.18 - 1.14 (t, J = 8.0 Hz, 3H), 1.04 - 0.89 (m, 2H), 0.87 - 0.82 (m, 9H), 0.61 - 0.58 (m, 1H), 0.49 - 0.46 (m, 1H), 0.33 - 0.30 (m, 1H), 0.19 - 0.17 (m, 1H). m / z 675.35 [M + H].

[0338] Step 3: 3 - Cyclopropyl - 3-(2 - ((1-(5 - methoxy - 2 - ((6-(methylthio)pyridin - 2 - yl)(neopentyl)carbamoyl)phenyl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid (Compound 8)

[0339] Ethyl 3 - cyclopropyl - 3-(2 - ((1-(5 - methoxy - 2 - ((6-(methylthio)pyridin - 2 - yl)(neopentyl)carbamoyl)phenyl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoate (8 - 3) (450 mg, 0.62 mmol) was added to a mixed solvent of tetrahydrofuran (4 ml) / methanol (4 ml), stirred, 2 mol / L sodium hydroxide solution (4 ml) was added, heated to 50 °C, and reacted for 4 hours. After the reaction was completed, the reaction solution was concentrated to dryness, water (10 ml) was added, stirred, the pH value was adjusted to 5.0 - 6.0 with 1 mol / L citric acid, extracted with ethyl acetate (20 ml × 3), the organic phases were combined, washed with brine, the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel to obtain white solid Compound 8 (341 mg, yield: 85%).

[0340] 11H NMR (400 MHz, CDCl3): δ 8.06 - 8.04 (d, J = 8 Hz, 1H), 7.35 - 7.33 (d, J = 8 Hz, 1H), 7.02 - 6.98 (t, J = 8 Hz, 1H), 6.76 - 6.73 (m, 2H), 6.62 (s, 1H), 6.52 - 6.50 (m, 1H), 6.17 (m, 2H), 4.29 - 4.27 (t, J = 8 Hz, 1H), 4.22 (m, 1H), 3.76 (s, 3H), 2.54 - 2.51 (m, 1H), 2.51 (s, 3H), 2.29 - 2.28 (m, 2H), 1.79 - 1.68 (m, 3H), 1.30 - 1.21 (m, 2H), 1.00 - 0.82 (m, 2H), 0.86 - 0.82 (m, 9H), 0.61 - 0.58 (m, 1H), 0.48 - 0.44 (m, 1H), 0.31 - 0.29 (m, 1H), 0.16 - 0.13 (m, 1H), m / z: 647.55 [M+1].

[0341] Example 9:

[0342] Compound 9: 3-Cyclopropyl-3-(3-((1-(5-methoxy-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)phenyl)propanoic acid

[0343]

[0344] According to the synthesis method of Example 8, replace ethyl 3-cyclopropyl-3-(2-(piperidin-4-ylmethoxy)pyridin-4-yl)propionate (2-8) with ethyl 3-cyclopropyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (1-12) as the raw material to prepare Compound 9.

[0345] 11H NMR (400 MHz, CDCl3): δ: 7.81 - 7.79 (d, J = 8 Hz, 1H), 7.65 - 7.61 (t, J = 8 Hz, 1H), 7.35 - 7.33 (m, 2H), 7.22 (m, 1H), 7.02 - 6.98 (m, 2H), 6.78 - 6.73 (m, 1H), 6.55 - 6.45 (m, 2H), 4.26 - 4.26 (t, J = 8 Hz, 1H), 4.25 (m, 1H), 3.78 (s, 3H), 2.55 - 2.52 (m, 1H), 2.53 (s, 3H), 2.29 - 2.27 (m, 2H), 1.79 - 1.69 (m, 3H), 1.32 - 1.23 (m, 2H), 1.03 - 0.85 (m, 2H), 0.89 - 0.87 (m, 9H), 0.62 - 0.59 (m, 1H), 0.49 - 0.46 (m, 1H), 0.33 - 0.29 (m, 1H), 0.19 - 0.15 (m, 1H),

[0346] m / z: 646.35 [M + H], 668.35 [M + Na]

[0347] Example 10:

[0348] Compound 10: 3-(3-((1-(5-methoxy-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)phenyl)-4-octynoic acid

[0349]

[0350] Compound 10 was prepared according to the following route.

[0351]

[0352] Step 1: 5-(3-benzylidene)-2-dimethyl-1,3-dioxane-4,6-dione (10-3)

[0353] m-Hydroxybenzaldehyde (10-2) (10.00 g, 82 mmol) was dissolved in water (82 ml). Isopropylidene malonate (10-1) (12.39 g, 86 mmol) was added portionwise at 75 °C, and the mixture was stirred for 2 hours. After cooling to room temperature, the mixture was filtered. The filter cake was washed with ice water and n-hexane respectively, and then dried to obtain yellow solid 10-3 (17.2 g, yield 85%).

[0354] 11H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.52 - 7.68 (t, J = 16 Hz, 1H), 7.26 (dt, J = 16.0, 4.0 Hz, 1H), 6.97 (dt, J = 18, 4 Hz, 2H), 4.74 (s, 1H), 1.65 (s, 6H). m / z: 249.15 [M+1]

[0355] Step 2: 5-(1-(3-Hydroxyphenyl)-2-butyn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-one (10-4)

[0356] Dissolve 5-(3-Benzylidene)-2-dimethyl-1,3-dioxane-4,6-dione (10-3) (10 g, 40.3 mmol) in tetrahydrofuran. Under ice bath, drop it into a tetrahydrofuran solution of 1-propynylmagnesium bromide (80 ml, 80.6 mmol, 1 mol / L). The dropping is completed in 30 minutes, and the reaction is carried out at room temperature for 30 minutes. Dilute with ammonium chloride solution, adjust the pH value to 2.0 with potassium bisulfate solution, extract three times with ethyl acetate, wash with saturated brine, combine the organic phases, evaporate the solvent under reduced pressure, and obtain a pale yellow oily substance 10-4 (9.75 g, yield 84.1%) by column chromatography.

[0357] 1 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 4.86 - 4.82 (m, 1H), 3.87 (d, J = 2.8 Hz, 1H), 1.89 (d, J = 2.5 Hz, 3H), 1.73 (s, 3H), 1.64 (s, 3H). m / z: 289.50 [M+1]

[0358] Step 3: 3-(3-Hydroxyphenyl)-4-hexynoic acid (10-5)

[0359] Dissolve 5-(1-(3-Hydroxyphenyl)-2-butyn-1-yl)-2,2-dimethyl-1,3-dioxolan-4-one (10-4) (9.3 g, 32.3 mmol) in N,N-dimethylformamide (100 mL) and water (10 ml), and react overnight at 90 °C. Add water, adjust the pH value to 3.0 with 2 mol / L hydrochloric acid aqueous solution, extract three times with ethyl acetate, wash with saturated brine, combine the organic phases, dry, evaporate the solvent under reduced pressure, and obtain a pale yellow oily substance 10-5 (6.10 g, yield 92.7%).

[0360] m / z: 205.15 [M+H].[[]END]]

[0361] Step 4: Methyl 3-(3-hydroxyphenyl)-4-hexynoate (10-6)

[0362] Dissolve 3-(3-hydroxyphenyl)-4-hexynoic acid (10-5) (6.30 g, 30.9 mmol) in methanol (80 ml), add concentrated sulfuric acid (123.6 mmol), reflux at 75 °C for 2 hours, rotary evaporate the solvent, add water, extract with ethyl acetate three times, wash with saturated brine, combine the organic phases, evaporate the solvent under reduced pressure, and obtain colorless oil 10-6 (6.00 g, 90.9%) by column chromatography.

[0363] 1 H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 4.07 - 4.00 (m, 1H), 3.67 (s, 3H), 2.77 (dd, J = 16, 8.0 Hz, 1H), 2.67 (dd, J = 16, 8.0 Hz, 1H), 1.80 (d, J = 2.4 Hz, 3H), MS (ESI, m / z): 219 [M + H].[[]END]]

[0364] Step 5: 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (10-7)

[0365] Mix 2-fluoro-4-methoxy-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (7-2) (2.96 g, 8.15 mmol), 4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine (2.51 g, 11.41 mmol, 1.4 eq), and cesium carbonate (0.67 g, 20.38 mmol) evenly, heat without solvent to 130 °C and react overnight. After the reaction is completed, cool to room temperature, add ethyl acetate (15 ml), filter through diatomaceous earth to obtain the filtrate, dry and concentrate, and purify to obtain product 10-7 (2.56 g, 55.0%).

[0366] m / z: 572.35 [M + 1].[[]END]]

[0367] Step 6: 2-(4-(Hydroxymethyl)piperidin-1-yl)-4-methoxy-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (10-8)

[0368] 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (10-7) (2.07 g, 3.62 mmol), methanol (15 ml), and tetrabutylammonium fluoride (2.37 g, 9.05 mmol, 2.5 eq) were stirred and reacted at 75 °C for 4 h. After the reaction was completed, it was concentrated and purified by column chromatography to obtain product 10-8 (1.49 g, 90.1%).

[0369] m / z: 458.25 [M+1].

[0370] Step 7: Methyl 3-(3-((1-(5-methoxy-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)phenyl)-4-octynoate (10-9)

[0371] Under nitrogen, 2-(4-(hydroxymethyl)piperidin-1-yl)-4-methoxy-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (10-8) (1391 mg, 3.04 mmol), methyl 3-(3-hydroxyphenyl)-4-hexynoate (663 mg, 3.04 mmol), and toluene (50 ml) were added to a flask. Cyano-methyltributylphosphine (1475 mg, 6.08 mmol) was added and stirred overnight. After the reaction was completed, water was added for washing, and liquid separation was performed. The organic phase was dried by rotation and purified by column chromatography to obtain solid 10-9 (680 mg, yield: 34%).

[0372] 1 H NMR (400 MHz, CDCl3): 7.60 - 7.58 (t, J = 8.0 Hz, 1H), 7.38 - 7.26 (m, 3H), 6.96 - 6.58 (m, 5H), 6.49 - 6.40 (m, 2H), 4.40 - 4.25 (m, 1H), 3.45 (m, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 3.38 - 3.15 (m, 4H), 2.87 (s, 2H), 2.79 - 2.73 (m, 1H), 2.56 - 2.52 (m, 1H), 2.54 (s, 3H), 2.35 - 2.32 (m, 1H), 1.89 (s, 3H), 1.58 - 1.39 (m, 4H), 1.09 (s, 9H)..m / z: 658.90 [M+1].

[0373] Step 8: 3-(3-((1-(5-methoxy-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)phenyl)-4-octynoic acid (Compound 10)

[0374] Dissolve methyl 3-(3-((1-(5-methoxy-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)phenyl)-4-octynoate (10-9) (364 mg, 0.552 mmol, 1.0 eq) in methanol (5 ml) and tetrahydrofuran (5 mL), add 2 mol / L sodium hydroxide solution (20 ml), and react at 50 °C for 4 hours. After the reaction is completed, concentrate the reaction solution to remove methanol, adjust the pH value to 4.0 with 1 mol / L citric acid, extract twice with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride, and obtain the solid compound 10 (329 mg, yield: 90%) by column chromatography.

[0375] 1 H NMR (400 MHz, CDCl3): 7.59 - 7.57 (t, J = 8.0 Hz, 1H), 7.35 - 7.20 (m, 3H), 6.90 - 6.53 (m, 5H), 6.46 - 6.35 (m, 2H), 4.28 - 4.17 (m, 1H), 3.89 (m, 2H), 3.78 (s, 3H), 3.31 - 3.10 (m, 4H), 2.83 (s, 2H), 2.79 - 2.74 (m, 1H), 2.56 - 2.51 (m, 1H), 2.45 (s, 3H), 2.32 - 2.29 (m, 1H), 1.88 (s, 3H), 1.57 - 1.312 (m, 4H), 0.99 (s, 9H). m / z: 644.35 [M+1], 666.35 [M+Na].

[0376] Example 11:

[0377]

[0378] Compound 11: 3-cyclopropyl-3-(2-((1-(5-methoxy-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)-2-methylpropanoic acid

[0379] According to the synthesis method of Example 8, use the raw material methyl 3-cyclopropyl-2-methyl-3-(3-(piperidin-4-ylmethoxy)phenyl)propionate (5-7) to replace ethyl 3-cyclopropyl-3-(2-(piperidin-4-ylmethoxy)pyridin-4-yl)propionate (2-8) to prepare Compound 11.

[0380] Yield: 76.0%. 11H NMR (400 MHz, CDCl3): δ 7.81 - 7.79 (d, J = 8.0 Hz, 1H), 7.63 - 7.61 (t, J = 8.0 Hz, 1H), 7.35 - 7.20 (m, 3H), 7.05 - 6.98 (m, 2H), 6.78 - 6.74 (m, 1H), 6.65 - 6.45 (m, 2H), 3.89 (s, 3H), 3.86 - 3.84 (m, 2H), 3.31 - 3.15 (m, 2H), 3.06 - 3.00 (m, 4H), 2.84 - 2.80 (m, 1H), 2.75 - 2.70 (m, 1H), 2.54 (s, 3H), 2.10 - 2.08 (m, 1H), 1.57 - 1.45 (m, 2H), 1.28 - 1.26 (m, 2H), 1.10 - 1.08 (m, 3H), 1.04 - 0.96 (m, 1H), 0.94 (s, 9H), 0.60 - 0.64 (m, 1H), 0.44 - 0.39 (m, 1H), 0.21 - 0.19 (m, 1H), 0.15 - 0.13 (m, 1H). m / z: 660.35 [M+1], 682.35 [M+Na]

[0381] Example 12:

[0382] Compound 12: 3-Cyclopropyl-3-(2-((1-(5-(2-hydroxyethyl)-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0383]

[0384] Compound 12 was prepared according to the following route.

[0385]

[0386] Step 1: Phenyl 3-fluoro-4-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)acetate (12-2)

[0387] Dissolve 4-acetoxy-2-fluorobenzoic acid (12-1) (1 g, 5.05 mmol) in tetrahydrofuran (10 ml), under nitrogen protection, add oxalyl chloride (624 mg, 4.92 mmol), then dropwise add N,N-dimethylformamide (0.01 ml), and react at room temperature for 1 hour. Monitor that the raw material reaction is complete, concentrate to dryness, and dissolve with tetrahydrofuran (1 ml). Dissolve 6-(methylthio)-N-neopentylpyridin-2-amine (1-4) (530 mg, 2.52 mmol, 0.5 eq) in tetrahydrofuran (5 ml), add triethylamine (1.53 g, 15.15 mmol), under nitrogen protection, add the above acyl chloride solution, and react at room temperature for 1 hour. Concentrate the reaction solution to dryness, add water (20 ml) and stir, extract with ethyl acetate (20 * 3), combine the organic phases, wash with saturated brine (60 ml), dry over anhydrous sodium sulfate, and perform column chromatography on the organic phase to obtain colorless liquid 12-2 (500 mg, yield 25.3%).

[0388] 1 H NMR (400 MHz, CDMO-d6): 7.28 - 7.23 (t, J = 8.0 Hz, 2H), 6.90 - 6.88 (d, J = 8 Hz, 1H), 6.81 - 6.79 (d, J = 8 Hz, 1H), 6.72 - 6.70 (d, 1H), 6.61 - 6.59 (d, 1H), 4.08 (s, 2H), 2.39 (s, 1H), 2.25 (s, 1H), 0.88 (s, 1H). m / z: 391.15 [M+1].

[0389] Step 2: 3-Fluoro-4-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenol (12-3)

[0390] Dissolve 3-fluoro-4-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl acetate (12-2) (450 mg, 1.15 mmol) in a mixed solvent of tetrahydrofuran (10 ml) / methanol (10 ml), add 2 mol / L sodium hydroxide solution (2.5 ml), and heat to 60 °C for reaction for 2 hours. Monitor that the reaction is complete. Concentrate the system to dryness, adjust the pH value to about 4.0 with 1 mol / L HCl, extract with ethyl acetate (20 ml * 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain colorless liquid 12-3 (420 mg, yield 92%).

[0391] m / z 349.15 [M+1].

[0392] Step 3: 4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-2-fluoro-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (12-4)

[0393] Dissolve 3-fluoro-4-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenol (12-3) (400 mg, 1.15 mmol) in 10 ml of DMF, add (2-bromoethoxy)-tert-butyldimethylsilane (0.33 g, 1.38 mmol), then add cesium carbonate (0.75 g, 2.3 mmol), and heat to 50 °C for reaction for 16 hours. Monitor the completion of the reaction. Cool the reaction solution to room temperature, add water (20 ml) and stir, extract with ethyl acetate (20 ml * 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrate by column chromatography to obtain a colorless liquid 12-4 (560 mg, yield 96%).

[0394] m / z 507.40 [M+1].

[0395] The subsequent steps are carried out according to the steps of Example 2 to obtain Compound 12.

[0396] Yield: 84.0%. 1 H NMR (400 MHz, CDCl3): 8.06 - 8.05 (d, J = 4.0 Hz, 1H), 7.35 - 7.33 (d, J = 8 Hz, 1H), 7.04 - 7.00 (t, J = 8 Hz, 1H), 6.76 - 6.74 (m, 2H), 6.63 (s, 1H), 6.51 - 6.49 (d, J = 8 Hz, 1H), 6.21 - 6.13 (m, 2H), 4.27 - 4.24 (m, 2H), 4.13 - 4.11 (m, 2H), 4.03 - 4.01 (m, 2H), 3.94 (s, 2H), 3.31 - 3.28 (m, 1H), 2.79 - 2.75 (m, 2H), 2.51 - 2.42 (m, 4H), 2.32 - 2.30 (m, 2H), 1.78 - 1.75 (m, 3H), 1.56 - 1.52 (m, 1H), 1.29 - 1.26 (m, 4H), 0.99 - 0.96 (m, 1H), 0.83 (s, 9H), 0.61 - 0.60 (m, 1H), 0.48 - 0.46 (m, 1H), 0.32 - 0.30 (m, 1H), 0.18 - 0.17 (m, 1H). m / z: 677.45 [M+1].

[0397] Example 13:

[0398] Compound 13: 3-cyclopropyl-3-(2-((1-(2-((6-((2-hydroxyethyl)thio)pyridin-2-yl)(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0399]

[0400] According to a synthesis method similar to that of Example 1, using sodium tert-butyldimethylsilylethyl mercaptan as a raw material to replace sodium methanethiol, compound 13 was prepared.

[0401] 1 H NMR(400MHz,CDCl3):7.87-7.86(d,J=4Hz,1H),7.05~7.03(d,J=8Hz,2H),6.74-6.70(t,J=8Hz,2H),6.54(s,1H),6.41~6.38(m,1H),6.10~6.04(m,2H),5.58(s,1H),4.04~3.94(m,4H),3.42-3.41(d,3H),3.42-3.41(m,2H),3.23~3.20(m,2H),3.05~3.02(m,4-3H),2.83~2.81(m,1H),2.33(s,3H),2.22-2.19(m,1H),2.16-2.08(m,1H),1.55-1.29(m,3H),0.82-0.80(m,1H),0.61(s,9H),0.34~0.33(m,1H),0.18~0.16(m,1H),0.11~0.09(m,1H),0.03-0.01(m,1H).

[0402] Example 14:

[0403] Compound 14: 3-cyclopropyl-3-(2-((1-(2-((6-((2-(2-(2-hydroxyethyl)ethoxy)ethyl)thio)pyridin-2-yl)(neopentyl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0404]

[0405] According to a synthesis method similar to that of Example 14, using sodium 2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecane-12-thiol as a raw material to replace sodium methanethiol, compound 14 was prepared.

[0406] 11H NMR (400 MHz, CDCl3): δ 8.09 - 8.08 (d, J = 4 Hz, 1H), 7.38 - 7.35 (d, J = 8 Hz, 2H), 7.01 - 6.99 (t, J = 8 Hz, 1H), 6.75 - 6.74 (m, 2H), 6.64 - 6.62 (s, 1H), 6.55 - 6.53 (m, 1H), 6.19 - 6.04 (m, 2H), 4.23 (s, 2H), 4.13 - 4.10 (m, 3H), 3.78 (s, 3H), 3.73 - 3.49 (m, 11H), 3.34 - 3.31 (m, 1H), 3.18 - 3.16 (m, 1H), 2.56 - 2.47 (m, 2H), 2.40 - 2.32 (m, 1H), 2.26 - 2.23 (m, 1H), 2.05 (s, 1H), 1.76 (m, 3H), 1.52 - 1.50 (m, 1H), 1.20 - 1.18 (t, J = 8 Hz, 1H), 1.18 - 1.15 (m, 1H), 1.03 - 1.00 (m, 1H), 0.83 (s, 9H), 0.59 - 0.57 (m, 1H), 0.44 - 0.42 (m, 1H), 0.28 - 0.26 (m, 1H), 0.16 - 0.13 (m, 1H).

[0407] m / z: 765.55 [M+1].

[0408] Example 15:

[0409] Compound 15: 3-Cyclopropyl-3-(2-((1-(2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)-5-morpholinophenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0410]

[0411] Compound 15 was prepared according to the following route.

[0412]

[0413] Step 1: 4-Bromo-2-fluoro-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (15-2)

[0414] Oxalyl chloride (1.44 ml, 16.8 mmol) was dissolved in tetrahydrofuran (30 ml), N,N-dimethylformamide (0.05 ml) was added, and 2-fluoro-4-bromobenzoic acid (15-1) (3.23 g, 15.3 mmol) was added. The reaction was stirred at room temperature for 10 minutes, and then concentrated for use as acyl chloride. 6-(Methylthio)-N-neopentylpyridin-2-amine (1.93 g, 9.18 mmol) and triethylamine (6.37 ml, 45.9 mmol) were dissolved in tetrahydrofuran (30 ml), and the prepared acyl chloride was added. The reaction was stirred at room temperature for 16 hours. After monitoring the completion of the reaction, the reaction solution was concentrated and purified by column chromatography to obtain a colorless oil 15-2 (1.97 g, yield: 35%).

[0415] 1 H NMR (400 MHz, DMSO-d6): 7.30 - 7.28 (d, J = 8.0 Hz, 1H), 7.13 - 7.06 (m, 3H), 6.92 - 6.90 (d, J = 8.0 Hz, 1H), 6.60 - 6.58 (d, J = 8.0 Hz, 1H), 4.06 (s, 2H), 2.39 (s, 3H), 0.88 (s, 9H). m / z: 410.10, 413.10 [M+1].

[0416] Step 2: 2-Fluoro-N-(6-(methylthio)pyridin-2-yl)-4-morpholino-N-neopentylbenzamide (15-3)

[0417] 4-Bromo-2-fluoro-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (15-2) (1 g, 2.44 mmol), morpholine (234 mg, 2.68 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (300 mg), cesium carbonate (955 mg, 2.93 mmol), chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), second-generation RuPhos precatalyst (130 mg) were added to 1,4-dioxane (10 ml), and the reaction was stirred at 100 °C for 4 hours. After monitoring the completion of the reaction, it was filtered, concentrated, and purified by column chromatography to obtain a colorless oil 15-3 (406 mg, yield: 39.8%).

[0418] 11H NMR (400 MHz, CDCl3): δ 7.24 - 7.15 (m, 2H), 6.87 - 6.86 (d, 1H), 6.53 - 6.50 (m, 2H), 6.31 - 6.28 (d, m, 1H), 4.10 (s, 2H), 3.81 - 3.79 (m, 4H), 3.13 - 3.11 (m, 4H), 2.44 (s, 9H), 0.87 (s, 9H). m / z: 418.25 [M+1]

[0419] The subsequent steps were carried out according to the steps of Example 2 to obtain Compound 15.

[0420] 3-Cyclopropyl-3-(2-((1-(2-((6-(Methylthio)pyridin-2-yl)(neopentyl)carbamoyl)-5-morpholinophenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 15)

[0421] Yield: 81.1%. 1 1H NMR (400 MHz, DMSO-d6): δ 8.03 - 8.02 (d, J = 4.0 Hz, 1H), 7.23 - 7.19 (t, J = 16 Hz, 1H), 7.14 - 7.12 (dd, J = 8 Hz, 1H), 6.90 - 6.85 (m, 2H), 6.68 (s, 1H), 6.28 - 6.26 (d, J = 8 Hz, 1H), 6.16 (s, 1H), 4.22 - 4.03 (m, 5H), 3.68 (s, 4H), 3.16 (s, 2H), 3.07 - 3.05 (m, 4H), 2.67 - 2.66 (m, 2H), 2.44 (s, 3H), 2.40 m, 1H), 2.29 - 2.19 (m, 1H), 1.72 - 1.53 (m, 3H), 1.41 - 1.39 (m, 1H), 1.19 - 1.13 (m, 1H), 1.07 - 0.93 (m, 1H), 0.75 (s, 9H), 0.55 - 0.52 (m, 1H), 0.37 - 0.33 (m, 1H), 0.21 - 0.19 (m, 1H), 0.11 - 0.07 (m, 1H). m / z: 702.65 [M+1].

[0422] Example 16:

[0423] Compound 16: 3-Cyclopropyl-3-(3-((1-(2-((6-(Methylthio)pyridin-2-yl)(neopentyl)carbamoyl)-5-morpholinophenyl)piperidin-4-yl)methoxy)phenyl)propanoic acid

[0424]

[0425] Following a synthetic method similar to that of Example 15, the starting material 2-fluoro-N-(6-(methylthio)pyridin-2-yl)-4-morpholino-N-neopentylbenzamide (15-3) was used to replace 6-fluoro-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzo[d][1,3]dioxole-5-carboxamide (1-6) to prepare Compound 16.

[0426] Yield: 75.0%. 1 H NMR (400 MHz, DMSO-d6): 8.09 - 8.07 (d, J = 8.0 Hz, 1H), 7.75 - 7.53 (m, 2H), 7.25 - 7.20 (m, 2H), 6.96 - 6.94 (m, 1H), 6.40 - 6.38 (m, 1H), 6.14 - 6.08 (m, 2H), 3.86 (m, 2H), 3.79 - 3.73 (m, 4H), 3.37 - 3.20 (m, 4H), 3.15 - 3.09 (m, 2H), 3.06 - 2.90 (m, 5H), 2.63 - 2.60 (m, 1H), 2.54 (s, 3H), 2.38 - 2.34 (m, 1H), 2.08 - 2.00 (m, 1H), 1.64 - 1.56 (m, 2H), 1.40 - 1.35 (m, 2H), 1.03 - 0.96 (m, 1H), 0.96 (s, 9H), 0.55 - 0.52 (m, 1H), 0.33 - 0.31 (m, 1H), 0.17 - 0.15 (m, 1H), 0.11 - 0.08 (m, 1H). m / z: 701.35 [M+1]

[0427] Example 17:

[0428] Compound 17: 3-cyclopropyl-3-(2-((1-(5-cyclopropyl-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0429]

[0430] Following a synthetic method similar to that of Example 15, cyclopropylboronic acid was used as the starting material instead of morpholine, and tetrakis(triphenylphosphine)palladium and potassium phosphate were used to replace the second-generation RuPhos precatalyst to prepare Compound 17.

[0431] Yield: 57.0%. 11H NMR (400 MHz, CDCl3): δ 8.09 - 8.08 (d, J = 4.0 Hz, 1H), 7.30 - 7.28 (m, 1H), 7.02 (s, 1H), 6.78 - 6.76 (m, 2H), 6.65 - 6.64 (m, 2H), 6.44 (s, 1H), 6.17 (s, 1H), 4.28 - 4.14 (m, 4H), 3.49 (s, 2H), 3.35 - 3.32 (m, 1H), 2.79 - 2.74 (m, 2H), 2.67 - 2.65 (m, 1H), 2.51 (s, 3H), 2.34 (s, 1H), 2.32 - 2.30 (m, 1H), 1.84 - 1.73 (m, 4H), 1.59 - 1.55 (m, 1H), 1.32 - 1.26 (m, 1H), 1.22 - 1.20 (m, 1H), 0.96 - 0.94 (m, 2H), 0.85 (s, 9H), 0.64 - 0.62 (m, 1H), 0.46 - 0.43 (m, 1H), 0.32 - 0.21 (m, 1H), 0.20 - 0.17 (m, 1H). m / z: 657.55 [M+1].

[0432] Example 18

[0433] Compound 18: 3 - Cyclopropyl - 3-(2 - ((1-(2 - ((6-(Methylthio)pyridin - 2 - yl)(neopentyl)carbamoyl)-5-(oxetan - 3 - yl)phenyl)piperidin - 4 - yl)methoxy)pyridin - 4 - yl)propanoic acid

[0434]

[0435] According to a synthetic method similar to that of Example 15, replacing morphine with potassium 3 - oxetane trifluoroborate as the raw material, Compound 18 was prepared.

[0436] Yield: 27.0%. 11H NMR (400 MHz, DMSO-d6): δ 8.09 - 8.07 (d, J = 8.0 Hz, 1H), 7.85 - 7.53 (m, 2H), 7.25 - 7.20 (m, 3H), 6.96 - 6.84 (m, 2H), 6.14 - 6.08 (m, 1H), 5.14 - 4.89 (m, 4H), 4.00 - 3.96 (m, 1H), 3.86 - 3.81 (m, 2H), 3.14 - 3.09 (m, 2H), 3.06 - 2.90 (m, 5H), 2.63 - 2.61 (m, 1H), 2.54 (s, 3H), 2.39 - 2.36 (m, 1H), 2.08 - 2.00 (m, 1H), 1.64 - 1.56 (m, 2H), 1.36 - 1.31 (m, 2H), 1.03 - 1.00 (m, 1H), 0.95 (s, 9H), 0.58 - 0.55 (m, 1H), 0.36 - 0.33 (m, 1H), 0.19 - 0.17 (m, 1H), 0.12 - 0.10 (m, 1H). m / z: 673.35 [M+1].

[0437] Example 19:

[0438] Compound 19: 3-Cyclopropyl-3-(2-((1-(5-(4-methylpiperazin-1-yl)-2-((6-(methylthio)pyridin-2-yl)(pivaloyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0439]

[0440] According to a synthetic method similar to that of Example 15, using the raw material cyclo-N-methylpiperazine to replace morphine, Compound 19 was prepared.

[0441] Yield: 40.0%. 11H NMR (400 MHz, DMSO-d6): δ 8.09 - 8.07 (d, J = 8.0 Hz, 1H), 7.75 - 7.53 (m, 2H), 7.25 - 7.20 (m, 2H), 6.96 - 6.94 (m, 1H), 6.40 - 6.38 (m, 1H), 6.14 - 6.08 (m, 2H), 3.86 (m, 2H), 3.49 - 3.43 (m, 4H), 3.16 - 3.10 (m, 2H), 3.06 - 2.90 (m, 5H), 2.63 - 2.60 (m, 1H), 2.59 (s, 3H), 2.37 - 2.20 (m, 5H), 2.20 (s, 3H), 2.07 - 2.01 (m, 1H), 1.64 - 1.56 (m, 2H), 1.40 - 1.35 (m, 2H), 1.03 - 0.96 (m, 1H), 0.96 (s, 9H), 0.55 - 0.52 (m, 1H), 0.33 - 0.31 (m, 1H), 0.17 - 0.15 (m, 1H), 0.11 - 0.07 (m, 1H). m / z: 715.40 [M+1].

[0442] Example 20:

[0443] Compound 20: (S)-3-Cyclopropyl-3-(2-((1-(6-((6-(Methylthio)pyridin-2-yl)pivalanilide)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid

[0444]

[0445] Compound 20 was prepared according to the following route.

[0446]

[0447] Step 1: 3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (20-1)

[0448] Ethyl 3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoate (2-5) (14.50 g, 58.2 mmol, 1.0 eq) was dissolved in methanol (100 ml), and 2 mol / L sodium hydroxide (116 ml, 232 mmol, 4.0 eq) solution was added. The system was turbid. Tetrahydrofuran (100 ml) was added, and the system became clear. The reaction was carried out at room temperature for 2 hours and then completed. The reaction solution was concentrated to dryness Remove methanol, add 1 mol / L citric acid solution to adjust the pH value to 4.0, add ethyl acetate (100 ml) for extraction, and the organic The organic phase was washed with saturated brine to obtain a crystalline solid (12.50 g, 97%).

[0449] 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]

[0450] Step 2: 3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid.(S)-1-(p-tolyl)ethylamine salt (20-2)

[0451] Dissolve 3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (20-1) (12.50 g, 56 mmol, 1.0 eq) in absolute ethanol (280 ml), add (S)-1-(p-tolyl)ethylamine (7.63 g, 56 mmol, 1.0 eq) dissolved in ethyl acetate (560 ml). 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 (4.90 g). Dissolve the white solid in absolute ethanol (96 ml), heat to 70 °C, stir to dissolve, control the temperature at 50 - 60 °C, slowly add n-heptane (144 ml), stir at 50 °C for 1.5 hours, and then at room temperature overnight. Cool to 0 °C in an ice bath and stir for 1 hour. Filter, wash the filter cake once with n-heptane, drain, and dry the filter cake to obtain white solid 20-2 (3.74 g, yield: 19%). ee value: 99.6%.

[0452] Chiral purity test conditions:

[0453] Analyticals FC conditions Instrument: UPOC (Waters)

[0454] Column: OJ-3 4.6*100 mm 3um

[0455] Column temperature: 40 °C

[0456] Mobile phase: CO2 / EtOH [1% NH3 (7M in MeOH)] = 90 / 10

[0457] Flow: 3.0 ml / min

[0458] Back Pressure: 2000psi - njection

[0459] Volume: 1ul

[0460] Step 3: (S)-3-Cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (20-3)

[0461] Dissolve 3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid.(S)-1-(p-tolyl)ethylamine salt (20-2) (3.74 g, 0.0105 mol, 1.0 eq) in ethyl acetate, cool the temperature to 0 - 10 °C, add 1 mol / L hydrochloric acid (37.4 ml), stir for 10 minutes at this temperature, and the reaction is completed. Add ethyl acetate (60 ml * 2) for washing, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain solid 20-3 (2.30 g, 100%).

[0462] 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%.

[0463] Chiral purity liquid phase conditions: same as those of 20-2.

[0464] Step 4: Ethyl (S)-3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoate (20-4)

[0465] Add (S)-3-cyclopropyl-3-(2-methylpyridin-4-yl)propanoic acid (20-3) (2.3 g, 0.0104 mol, 1.0 eq) to ethanol (40 ml), add concentrated sulfuric acid (6.0 ml), displace with nitrogen, heat to 80 °C and react for 1.0 hour. After the reaction is completed, cool to room temperature, adjust the pH value to alkaline with saturated sodium bicarbonate solution, extract with ethyl acetate to obtain the organic phase, dry and concentrate to obtain a colorless oily substance 20-4 (2.50 g, 96%).

[0466] 11H 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].

[0467] Step 5: Ethyl (S)-3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate (20-5)

[0468] Ethyl (S)-3-cyclopropyl-3-(2-methylpyridin-4-yl)propionate (20-4) (2.50 g, 0.010 mol, 1.0 eq) was added to N,N-dimethylformamide (25 ml), pyridinium hydrochloride (11.60 g, 0.10 mol, 1.00 eq) was added, the system was purged with nitrogen, heated to 120 °C and reacted for 1.0 h. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (25 ml) to obtain an organic phase. The organic phase was dried and concentrated, and purified by column chromatography to obtain a colorless oil 20-5 (2.20 g, 85%).

[0469] 1 1H 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].

[0470] Step 6: tert-Butyl (S)-4-(((4-(1-cyclopropyl-3-ethoxy-3-propionylpyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (20-6)

[0471] Under nitrogen atmosphere, ethyl (S)-3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propionate (20-5) (1.88 g, 8 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.73 g, 8 mmol) were added to toluene (15 ml), stirred, and then cyanomethylenetributylphosphorane (3.87 g, 16 mmol) was added. The temperature was raised to 100 °C and the reaction was carried out for 3 hours. After stopping the reaction, the product was purified by column chromatography to obtain a foamy solid 20-6 (2.77 g, yield: 80.0%).

[0472] 1 H NMR (400 MHz, CDCl3): δ 8.09 - 8.08 (1H, d, J = 4.0 Hz), 6.77 - 6.76 (1H, d, J = 4.0 Hz), 6.63 (1H, s), 4.15 - 4.13 (2H, d, J = 8.0 Hz), 4.17 - 4.05 (2H, m), 3.20 - 3.17 (2H, d, J = 12.0 Hz), 2.79 - 2.61 (4H, m), 2.33 - 2.24 (1H, m), 2.03 - 1.89 (1H, m), 1.85 (2H, d, J = 12.0 Hz), 1.49 (s, 9H), 1.45 - 1.26 (2H, m), 1.18 - 1.16 (3H, t, J = 8.0 Hz), 1.07 - 0.88 (1H, m), 0.66 - 0.55 (1H, m), 0.55 - 0.40 (1H, m), 0.35 - 0.29 (1H, m), 0.22 - 0.15 (1H, m), m / z: 333.25 [M - CO2 - C3H6].

[0473] Step 7: Ethyl (S)-3-cyclopropyl-3-(2-(piperidin-4-yloxy)pyridin-4-yl)propionate (20-7)

[0474] Ethyl (S)-4-(((4-(1-cyclopropyl-3-ethoxy-3-propionylpyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (20-6) (2.16 g, 5 mmol) was added to dichloromethane (10 ml), stirred until dissolved, and then trifluoroacetic acid (0.57 g, 5 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, it was washed with saturated sodium bicarbonate solution, brine, and dried over sodium sulfate to obtain a white solid 20-7 (1.59 g, yield: 96.0%).

[0475] 11H NMR (400 MHz, CDCl3): δ 8.05 - 8.04 (1H, d, J = 4.0 Hz), 6.75 - 6.74 (1H, d, J = 4.0 Hz), 6.61 (1H, s), 4.12 - 4.10 (2H, d, J = 8.0 Hz), 4.13 - 3.99 (2H, m), 3.17 - 3.14 (2H, d, J = 12.0 Hz), 2.79 - 2.61 (4H, m), 2.33 - 2.24 (1H, m), 2.03 - 1.89 (1H, m), 1.85 - 1.82 (2H, d, J = 12.0 Hz), 1.45 - 1.26 (2H, m), 1.18 - 1.16 (3H, t, J = 8.0 Hz), 1.05 - 0.86 (1H, m), 0.66 - 0.55 (1H, m), 0.51 - 0.38 (1H, m), 0.35 - 0.24 (1H, m), 0.20 - 0.07 (1H, m), m / z: 333.25 [M+1].

[0476] According to a synthetic method similar to that of Example 2, ethyl (S)-3-cyclopropyl-3-(2-(piperidin-4-yloxy)pyridin-4-yl)propionate (20-7) was used to replace ethyl 3-cyclopropyl-3-(2-(piperidin-4-yloxy)pyridin-4-yl)propionate (2-8) to prepare Compound 20.

[0477] (S)-3-Cyclopropyl-3-(2-((1-(6-((6-(methylthio)pyridin-2-yl)neopentyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 20)

[0478] Yield: 54.0%. 1 HNMR (400 MHz, CDCl3): 8.07 - 8.06 (d, J = 4.0 Hz, 1H), 7.06 - 7.04 (m, 1H), 6.76 (s, 1H), 6.78 - 6.76 (m, 2H), 6.62 (s, 1H), 6.33 (s, 1H), 5.95 - 5.89 (d, 2H), 4.23 (s, 1H), 4.16 - 4.12 (m, 2H), 3.26 - 3.24 (m, 1H), 2.78 - 2.72 (m, 2H), 2.57 - 2.51 (m, 4H), 2.43 (s, 3H), 2.34 - 2.32 (m, 2H), 1.76 - 1.72 (m, 3H), 1.51 - 1.49 (m, 1H), 1.29 - 1.20 (m, 2H), 1.01 - 0.99 (m, 1H), 0.83 (s, 9H), 0.62 - 0.59 (m, 1H), 0.47 - 0.44 (m, 1H), 0.33 - 0.30 (m, 1H), 0.20 - 0.16 (m, 1H). m / z: 661.30 [M+1], 683.25 [M+Na], ee value: 99.8%.

[0479] Example 21:

[0480] Compound 21: (S)-3-Cyclopropyl-3-(3-((1-(6-((6-(Methylthio)pyridin-2-yl)pivalanilino)benzene[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)phenyl)propanoic acid

[0481]

[0482] Compound 21 was prepared according to a synthetic method similar to that of Example 1 and Example 6.

[0483] Yield: 78.0%. 1 H NMR (400 MHz, CDCl3): 7.05 - 6.97 (m, 2H), 6.87 - 6.61 (m, 5H), 6.16 (s, 2H), 5.74 (s, 2H), 4.07 (s, 2H), 3.64 (s, 2H), 3.07 (s, 1H), 2.61 (s, 2H), 2.33 (s, 3H), 2.18 (s, 2H), 1.58 (s, 3H), 1.34 (s, 1H), 1.10 (s, 3H), 0.85 (s, 1H), 0.67 (s, 9H), 0.58 (s, 1H), 0.41 (s, 1H), 0.26 (s, 1H), 0.12 (s, 1H). m / z: 660.30 [M+1], 682.25 [M+Na], ee value: 99.8%.

[0484] Example 22: Preparation of Compound 22

[0485]

[0486] According to a synthetic method similar to that of Example 20, 2-fluoro-4-methoxy-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzamide (8-2) was used to replace 6-fluoro-N-(6-(methylthio)pyridin-2-yl)-N-neopentylbenzo[d][1,3]dioxole-5-carboxamide (1-6) to prepare Compound 22.

[0487] (S)-3-cyclopropyl-3-(2-((1-(5-methoxy-2-((6-(methylthio)pyridin-2-yl)(neopentyl)carbamoyl)phenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 22)

[0488] Yield: 87.0%. 1 H NMR (400 MHz, CDCl3): δ 8.07 - 8.06 (m, 1H), 7.36 - 7.34 (d, J = 8.0 Hz, 1H), 7.01 - 6.99 (m, 1H), 6.76 - 6.74 (m, 2H), 6.62 (s, 1H), 6.53 - 6.50 (d, J = 12.0 Hz, 1H), 6.18 - 6.13 (m, 2H), 4.28 - 4.14 (m, 4H), 3.77 (s, 2H), 3.34 - 3.31 (m, 1H), 2.79 - 2.72 (m, 2H), 2.52 - 2.46 (m, 1H), 2.42 (s, 3H), 2.40 - 2.39 (m, 1H), 2.32 - 2.30 (m, 1H), 1.82 - 1.77 (m, 3H), 1.71 - 1.49 (m, 2H), 1.26 - 1.19 (m, 2H), 0.98 - 0.95 (m, 1H), 0.83 (s, 9H), 0.62 (s, 1H), 0.48 (s, 1H), 0.31 (s, 1H), 0.19 (s, 1H). m / z: 647.40 [M+1], 685.30 [M+Na], ee value: 99.8%.

[0489] Example 23:

[0490] Compound 23: (S)-3-cyclopropyl-3-(2-((1-(6-((4-methylpentane)(6-(methylthio)pyridin-2-yl)carbamoyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (Compound 23)

[0491]

[0492] According to a synthetic method similar to that of Example 1 and Example 20, Compound 23 was prepared.

[0493] Yield: 71.0%. 1 1H NMR (400 MHz, CDCl3): δ 8.04 - 8.02 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.95 (s, 1H), 6.82 - 6.81 (d, J = 8 Hz, 2H), 6.77 - 6.76 (d, J = 4 Hz, 1H), 6.62 (s, 1H), 6.37 (s, 2H), 5.96 - 5.92 (d, J = 16 Hz, 2H), 4.13 - 4.02 (m, 4H), 3.16 (s, 1H), 2.83 - 2.71 (m, 2H), 2.49 (m, 5H), 2.34 - 2.28 (m, 1H), 1.75 - 1.73 (m, 5H), 1.52 - 1.51 (m, 2H), 1.29 - 1.18 (m, 4H), 1.00 - 0.97 (m, 1H), 0.85 - 0.83 (m, 7H), 0.63 - 0.58 (m, 1H), 0.48 - 0.45 (m, 1H), 0.33 - 0.30 (m, 1H), 0.19 - 0.16 (m, 1H). m / z: 675.40 [M+1], 697.40 [M+Na], ee value: 99.8%.

[0494] Example 24:

[0495] Compound 24: (R)-4,4,4-trifluoro-3-(3-((1-(6-((6-(methylthio)pyridin-2-yl)(pivaloyl)carbamoyl)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)phenyl)propanoic acid

[0496]

[0497] Compound 9 was prepared in a similar synthetic manner to Example 1 and the literature ACS Med. Chem. Lett. 2012, 3, 726 - 730.

[0498] Yield: 45.0%. 11H NMR (400 MHz, CDCl3): δ 7.50 - 7.48 (m, 1H), 7.35 (s, 1H), 7.22 - 7.18 (m, 3H), 7.01 - 6.95 (m, 2H), 6.79 - 6.77 (d, J = 8 Hz, 1H), 6.80 - 6.55 (m, 2H), 6.10 (s, 2H), 5.40 - 5.35 (m, J = 16 Hz, 1H), 4.05 - 3.98 (m, 2H), 3.16 - 3.14 (m, 2H), 3.06 - 3.03 (m, 4H), 2.71 - 2.62 (m, 1H), 2.54 (m, 3H), 2.42 - 2.39 (m, 1H), 2.24 - 2.20 (m, 1H), 1.56 - 1.53 (m, 2H), 1.31 - 1.28 (m, 2H), 0.90 (m, 9H). m / z: 688.30 [M+1], 700.40 [M+Na], ee value: 99.8%.

[0499] Reference Example 1: SCO-267 (Ref01)

[0500] Lit1: [Journal of Medicinal Chemistry, 2020, vol.63, #18, p.10352 - 10379]

[0501]

[0502] Reference Example 2: TAK-875 (Ref02)

[0503] Lit2: [ACS Med.Chem.Lett. 2010, 1, 290–294]

[0504]

[0505] Reference Example 3:

[0506] Compound Ref03: 3-Cyclopropyl-3-(3-((1-(6-((6-methylpyridin-2-yl)pivalanilide)benzene[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)phenyl)propanoic acid

[0507]

[0508] The compound Ref03 was prepared according to the following route.

[0509]

[0510] Step 1: (Ref03-2)

[0511] Dissolve Ref03-1 (5.00 g, 0.0272 mol, 1.0 eq) in dichloromethane (30 ml) under nitrogen protection. Cool the solution to -70 °C and slowly add boron tribromide (81 ml, 0.081 mol, 3.0 eq, 1 mol / L) while maintaining the temperature below -65 °C. After the addition, transfer the reaction mixture to room temperature and stir overnight. After the reaction is complete, cool the mixture to 0 °C, add methanol (33 ml), concentrate to dryness, add methanol (40 ml) again, concentrate to dryness, dissolve in dichloromethane, and purify by column chromatography to obtain the product as a yellow solid Ref03-2 (4.15 g, 98.8%).

[0512] Step 2: (Ref03-3)

[0513] Add compound 2 (4.15 g, 0.026 mol, 1.0 eq) to N,N-dimethylformamide (40.0 ml), add potassium carbonate (9.2 g, 0.066 mol, 2.5 eq), and dibromomethane (5.1 g, 0.029 mol, 1.1 eq). React under nitrogen protection at 80 °C overnight. After the reaction is complete, add water, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, concentrate the organic phase, and purify by column chromatography to obtain the product as a white solid Ref03-3 (3.5 g, 78%).

[0514] 1 1H NMR (400 MHz, CDCl3): 10.18 (s, 1H), 7.23 - 7.21 (d, J = 8.0 Hz, 1H), 6.65 - 6.63 (d, J = 8.0 Hz, 1H), 6.08 (s, 2H). m / z: 169.05 [M+1].

[0515] Step 3: (Ref03-4)

[0516] Add Ref03-4 (3.50 g, 20 mmol, 1.0 eq) to tert-butanol (80 ml), 80% aqueous sodium chlorite solution (4.7 g, 41 mmol, 2.0 eq, 42 ml), sodium dihydrogen phosphate dihydrate (14.3 g, 104 mmol, 5.0 eq), and 2-methyl-2-butene (11.7 g, 167 mmol, 8.0 eq). React at room temperature for 0.5 h. After the reaction is complete, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate the organic phase by rotary evaporation, and purify to obtain a pale white solid Ref03-4 (3.60 g, 94%).

[0517] 11H NMR (400 MHz, CDCl3): δ 7.30 - 7.29 (d, J = 4.0 Hz, 1H), 6.75 - 6.72 (d, J = 12.0 Hz, 1H), 6.08 (s, 2H). m / z: 185.05 [M+1].

[0518] Step 4: Ref03-6

[0519] Add Ref03-4 (1.6 g, 8.6 mmol, 1.0 eq) to dichloromethane (20 ml), add N,N-dimethylformamide (0.05 ml), oxalyl chloride (2.2 g, 17 mmol, 2.0 eq), and react at room temperature for 3.0 h. After the reaction is complete, evaporate the solvent under reduced pressure, then dissolve the residue in dichloromethane (10 ml), and dropwise add it to a mixed solution of dichloromethane (10 ml) containing Ref03-5 (1.3 g, 6.9 mmol, 0.8 eq) and triethylamine (2.63 g, 26 mmol, 3.0 eq). After addition, react at room temperature for 16 h. After the reaction is completed, add water (10 mL), stir, separate the layers, evaporate the organic phase under reduced pressure, and obtain the product Ref03-6 as a white solid (2.0 g, 67%) by column chromatography.

[0520] 1 1H NMR (400 MHz, CDCl3): δ 7.34 - 7.30 (m, 1H), 6.88 - 6.86 (d, J = 8.0 Hz, 1H), 6.67 - 6.65 (m, 2H), 6.37 - 6.35 (d, J = 8.0 Hz, 1H), 5.93 (s, 2H), 4.10 (s, 2H), 2.47 (s, 3H), 0.85 (s, 9H). m / z: 345.15 [M+1]

[0521] The subsequent steps are carried out in a similar synthetic manner to Example 20, replacing 1-6 with Ref03-6 to prepare compound Ref03.

[0522] 3-Cyclopropyl-3-(3-((1-(6-((6-Methylpyridin-2-yl)pivalanilide)benzo[d][1,3]dioxol-5-yl)piperidin-4-yl)methoxy)phenyl)propanoic acid (Compound Ref03)

[0523] 11H NMR (400 MHz, CDCl3): δ 8.08 - 8.06 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 6.78 - 6.75 (m, 3H), 6.64 (s, 1H), 6.47 - 6.35 (m, 2H), 5.92 - 5.87 (d, J = 20.0 Hz, 2H), 4.27 - 4.24 (m, 1H), 4.16 - 4.15 (m, 2H), 3.31 - 3.29 (m, 1H), 2.77 - 2.75 (m, 2H), 2.71 - 2.56 (m, 1H), 2.43 (s, 3H), 2.31 - 2.29 (m, 2H), 1.78 - 1.76 (m, 3H), 1.37 - 1.29 (m, 3H), 0.98 - 0.91 (m, 1H), 0.90 - 0.87 (m, 1H), 0.82 (s, 9H), 0.60 - 0.58 (m, 1H), 0.46 - 0.47 (m, 1H), 0.33 - 0.31 (m, 1H), 0.18 - 0.17 (m, 1H). m / z: 629.45 [M+1], 651.40 [M+Na]

[0524] Test Example 1: GPR40 Assay Activity Test

[0525] This experiment aims to verify the agonist activity of the compounds of the present invention against the GPR40 receptor.

[0526] Cell line:

[0527] GPR40 / CHO

[0528] Medium:

[0529] F12, Gibco (Cat#11765-047) DFBS, Biological Industiries (Cat#04-011-1A) Geneticin, Invitrogen (Cat#10131-027)

[0530] Main reagents:

[0531] Fluo-4 Direct, (Invitrogen, Cat#F10471) Assay buffer: 1X HBSS:1M HEPES = 49:1, with 0.2% fatty acids free BSA 1X HBSS, (Gibco, Cat#14025-076) BSA, (Sigma, Cat#SRE0098-50G)

[0532] Main equipment:

[0533] 384 well plate, Greiner#781090 Vi-cell XR Cell Viability Analyzer, Beckman Coulter, No.2785631 FLIPR, Molecular Devices, No.668115 Incubator, Thermo, No.1153447

[0534] Test method:

[0535] Control and compound plates: The control was diluted 10-fold in buffer in a 1:3 order, and the test compound was diluted in buffer in a 1:4 order. Then 750 μl of the compound was transferred to the destination plate. 30 μl of the assay buffer was added to each well.

[0536] a) Remove the cell plate from the incubator, discard the culture medium, and gently pipette 20 μl of experimental buffer and 20 μl of 2X Fluo-4 DirectTM wash-free loading buffer into the 384-well cell culture plate.

[0537] b) Incubate at 37 °C in 5% CO2 for 50 minutes and then at room temperature for 10 minutes.

[0538] c) Remove the cell plate from the incubator and place it in the FLIPR. Place the compound plate and tip box in the flir.

[0539] d) Compound plate (agonist test):

[0540] 1) Run the protocol on the FLIPR TETRA;

[0541] 2) Transfer 10 μl of the compound to the cell plate;

[0542] 3) Read the fluorescence signal;

[0543] 4) Calculate "Max - Min" from Read 0 to the Maximum allowed.

[0544] e) Analyze the data using Prism.

[0545] The specific test data are shown in the following table.

[0546] Compound EC50, (nM) Compound EC50, (nM) Compound EC50, (nM) 1 0.940 2 45.950 3 49.950 4 20.620 5 8.535 6 62.435 7 25.060 8 2.867 9 3.900 10 6.245 11 5.567 12 2.593 13 25.060 14 21.000 15 6768 16 5050 17 33.50 18 101 19 8088 20 2.466 21 4.695 22 1.814 23 2.460 24 20.650 Ref01 3.736 Ref02 207.600 Ref03 4.878

[0547] Conclusion: The compounds in the present invention show good GPR40 receptor agonist activity.

[0548] Test Example 2: Evaluation of the distribution of rat pharmacokinetics in intestine and blood:

[0549] Using rats as the test animals, SD male rats with similar body weights were selected, 3 rats in each group. The test drug of the example with a dose of 1.5 mg / kg was orally administered once, and blood and intestinal (small intestine segment) tissues were collected respectively. The LC-MS / MS analysis method was used to detect the content of the analyte in plasma and intestinal (small intestine segment) tissues.

[0550] Test drugs: The compounds of the present invention and the control compound.

[0551] Drug preparation:

[0552] Oral group: The test articles with final concentrations of 0.3 mg / mL were prepared for oral administration. The preparation solvent was 5% DMSO + 95% (20% HP-β-CD) aqueous solution, and the prepared preparations were all in a clear solution state.

[0553] Administration: After fasting the rats overnight (12 hours), administer the drug by gavage at a dose of 1.5 mg / kg.

[0554] After collecting the blood samples, place them in labeled ice-bath centrifuge tubes, and quickly centrifuge to separate the plasma. Centrifugation conditions: 4000 revolutions per minute, 10 minutes, 4 degrees. Store the plasma at -40 degrees or below for further testing.

[0555] After collecting the tissue samples, wash the surface with normal saline, dry with medical gauze, place them in labeled homogenization tubes, homogenize with 1 g of tissue: 4 mL of 50% methanol-water, and store at -70 degrees or below for further testing.

[0556] Sampling time: 1 / 4 / 8h

[0557] Liquid phase analysis conditions:

[0558] HPLC: LC-20A, SHIMADZU

[0559] Liquid phase pump: LC-20AD

[0560] Column oven: CTO-20A

[0561] Autosampler: SIL-20AC

[0562] Controller: CBM-20A

[0563] Degasser: DGU-20A3R

[0564] Chromatographic column: ZORBAX Eclipse Plus C18, 2.1*50mm, 5μm, Agilent

[0565] Pre-column: Security Guard Cartridges C18 4*2.00mm, Phenomenex

[0566] Mobile phase: A: 0.1% formic acid & 5 mM ammonium acetate aqueous solution

[0567] B: Acetonitrile

[0568] Autosampler needle washing solution: 80% methanol-water (containing 0.5% formic acid)

[0569] Autosampler needle washing program: Rinse Mode: Before and after aspiration

[0570] Mobile phase gradient:

[0571]

[0572] Flow rate: 0.70 mL / min

[0573] Autosampler temperature: 4 °C

[0574] Column temperature: 40 °C

[0575] Injection volume: 1.00 μL

[0576] Run time: 2.5 min

[0577] Mass spectrometry analysis conditions:

[0578] API 4000 with ESI source, positive ion MRM scan was used.

[0579] Source parameters:

[0580]

[0581] The test data are as follows:

[0582]

[0583]

[0584] Conclusion: 1) The compound of the present invention has intestinal restriction characteristics, which helps to reduce the distribution of the drug in other organs of the body, thereby reducing potential systemic toxicity. For example, the comparative compound TAK-875 (Reference Example 2) can cause liver toxicity.

[0585] 2) On the other hand, the compound of the present invention has very good intestinal targeting, the concentration in intestinal tissue is much higher than that in blood, and the intestinal-blood ratio coefficient is much higher than that of the control compound Ref01, indicating that the introduction of a sulfur atom can bring better intestinal targeting.

[0586] Test Example 3: Evaluation of OGTT experiment in wild-type mice

[0587] Experimental purpose: To detect the pharmacodynamic effect of the drug on OGTT using wild-type mice.

[0588] Experimental drugs: The compound of the present invention and control compounds, namely SCO-267 (Ref01), Reference Example 3 (Ref03), Compound 20, Compound 21 and Compound 22.

[0589] Drug preparation:

[0590] Oral group: Drug concentration 1.5 mg / kg;

[0591] Drug preparation concentration 100 mM: First, centrifuge the powder of the drug in Example briefly, then take 37.83 μL of DMSO and dissolve the powder in the tube of Example, and store at -20 °C;

[0592] Configure glucose: concentration 2 g / kg. (Normal saline)

[0593] The average weight of the mice is 22 g, the gavage volume is 0.4 mL / mouse, and there are 4 mice in each group. Configure the corresponding drug requirements according to the number of groups.

[0594] Solvent configuration: 2% Tween-80 + 98% (0.5% W / V) methylcellulose (MC methylcellulose)

[0595] Steps for configuring MC: Weigh 0.5 g of methylcellulose (Alfa Aesar part number 036718) into a 100 mL glass bottle, add an appropriate amount of ultrapure water to make up to 100 mL and dissolve. Mix well on a magnetic stirrer with a small magnetic stirrer rotor at room temperature and store at 4 °C;

[0596] Steps: After cutting the tip of a 1 mL pipette at an oblique angle, take 2 mL of Tween 80 (Aladdin part number T104866) and add it to 98 mL of methylcellulose. Mix well on a magnetic stirrer with a small magnetic stirrer rotor at room temperature and store at 4 °C;

[0597] Animal preparation:

[0598] Group and label the mice, and group them according to the number of drugs in the examples, with 4 mice in each group.

[0599] Measure the weight of the mice and group them: Configure the drugs and Glucose according to the average weight of each group;

[0600] Prepare the drug buffer: 0.5% MC: Methyl cellulose is used as a protective dispersant, stabilizer and emulsifier.

[0601] Drug administration time: After the mice are fasted overnight, there are 4 mice in each group, (the gavage volume is 0.4 mL);

[0602] Experimental procedure:

[0603] 1. After the mice are fasted overnight, measure the blood glucose of the mice, and immediately administer drugs by gavage to each group after measurement;

[0604] 2. Measure the blood glucose after 30 min, and immediately administer glucose (2 g / kg) by gavage after measuring the blood glucose;

[0605] 3. Measure the blood glucose at 15, 30, 45, 60, 90 and 120 min after administering glucose;

[0606] 4. Statistical analysis.

[0607] Conclusion: According to the test results ( Figure 1 ), the compound of the present invention has a significant blood glucose lowering effect.

[0608] Test Example 4: Evaluation of OGTT Experiment in Diabetic db / db Mice

[0609] Experimental Purpose: To detect the pharmacodynamic effect of drugs on OGTT using diabetic db / db model mice.

[0610] Experimental Drugs: The compounds of the present invention and control compounds, namely SCO-267 (Ref01), Reference Example 3 (Ref03), Compound 20, Compound 21 and Compound 22.

[0611] Drug Preparation:

[0612] Drug Concentration 3mg / kg;

[0613] Drug Preparation Concentration 100mM: First, centrifuge the powder of the drug in Example briefly, then take 37.83 μL of DMSO and dissolve the powder in the tube of Example. Mark the information such as time and concentration on the tube body and store it at -20 °C;

[0614] Glucose Preparation: Concentration 2g / kg. (Normal saline)

[0615] The average body weight of the mice is 45g, the gavage volume is 0.4mL / animal, and there are 4 mice in each group. Configure the corresponding drug requirements according to the number of groups.

[0616] Solvent Preparation: 2% Tween-80 + 98% (0.5% W / V) methyl cellulose (MC methylcellulose)

[0617] Steps for Preparing MC: Weigh 0.5g of methyl cellulose (Alfa Aesar product number 036718) into a 100mL glass bottle, add an appropriate amount of ultrapure water to make up to 100mL and dissolve. Mix evenly with a small magnetic stirring rotor on a magnetic stirrer at room temperature (1500rpm for about 4.5h), and store at 4 °C;

[0618] Steps: After cutting the tip of a 1mL pipette obliquely, take 2mL of Tween 80 (Aladdin product number T104866) and add it to 98mL of methyl cellulose. Mix evenly with a small magnetic stirring rotor on a magnetic stirrer at room temperature (1500rpm for about 4h), and store at 4 °C;

[0619] Animal Preparation:

[0620] Grouping and Marking of Mice. Group the mice according to the number of drugs in the example, with 4 mice in each group.

[0621] Measure the body weight of the mice and group them: Configure the drugs and Glucose according to the average body weight of each group;

[0622] Preparation of pharmaceutical buffer: 0.5% MC: Methyl cellulose is used as a protective dispersant, stabilizer and emulsifier.

[0623] Administration time: After the mice are fasted overnight, 4 mice in each group (the gavage volume is 0.4 mL);

[0624] Experimental procedure:

[0625] 1. After the mice are fasted overnight, measure the blood glucose of the mice, and immediately perform gavage administration for each group after measurement;

[0626] 2. Measure the blood glucose after 30 min, and immediately perform gavage administration of glucose (2 g / kg) after measuring the blood glucose;

[0627] 3. Measure the blood glucose at 15, 30, 45, 60, 90 and 120 min after administering glucose;

[0628] 4. Statistical analysis.

[0629] Conclusion: According to the test results ( Figure 2 ), the compound of the present invention has a significant blood glucose lowering effect.

[0630] Test Example 5: Evaluation of weight loss experiment in DIO rats

[0631] Experimental purpose: Use DIO rats to detect the pharmacodynamic effect of drug weight loss.

[0632] Experimental drugs: The compound of the present invention and control compounds, namely SCO-267 (Ref01), TAK875 (Ref02), Liraglutide as positive control, compound 21 and compound 22.

[0633] Drug preparation:

[0634] Oral group: The drug concentration is prepared at 10 mg / kg with solvent;

[0635] Subcutaneous injection group: Liraglutide is prepared with PBS, the drug concentration is 0.3 mg / kg, and the injection volume is 1.5 mL;

[0636] The average body weight of the rats is 610 g, the gavage volume is 1.5 mL / rat, 3 rats in each group, and the corresponding drug demand is configured according to the number of groups.

[0637] Solvent preparation: 2% Tween-80 + 98% (0.5% W / V) methyl cellulose (MC methylcellulose)

[0638] Configuration of MC procedure: Weigh 0.5 g of methylcellulose (Alfa Aesar part number 036718) into a 100 mL glass bottle, add an appropriate amount of ultrapure water to make up to 100 mL and dissolve. Mix well on a magnetic stirrer with a small magnetic stirring rotor at room temperature (1500 rpm for about 4.5 h), and store at 4 °C;

[0639] Procedure: After cutting the tip of a 1 mL pipette at an oblique angle, take 2 mL of Tween 80 (Aladdin part number T104866) and add it to 98 mL of methylcellulose. Mix well on a magnetic stirrer with a small magnetic stirring rotor at room temperature (1500 rpm for about 4 h), and store at 4 °C;

[0640] Animal preparation:

[0641] Grouping and labeling of rats. Group the rats according to the number of drugs in the examples, with 3 rats in each group.

[0642] Measure the body weight of the rats and group them: Prepare the drugs according to the average body weight of each group;

[0643] Experimental procedure:

[0644] 1. Place the DIO rats in a SPF-class animal room for 2 weeks for adaptation and adjustment. Start grouping when the diet is relatively stable.

[0645] 2. Start drug administration after grouping, by oral or subcutaneous injection, BID.

[0646] 3. Record the diet and body weight every day.

[0647] 4. Administer the drug continuously for 14 days, and statistically analyze the weight loss results.

[0648] Conclusion: According to the test results ( Figure 3 ), the compound of the present invention has a significant weight loss effect.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 Each independently is H, halogen, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 3 , R 4 Each independently represents H, halogen, cyano, optionally substituted: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl; or R 3 , R 4 Together with the adjacent carbon atoms, it forms a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl group; R 5 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy; R 6 , R 7 Each independently is H, halogen, optionally substituted: C 1-6 Alkyl or C 3-6 Cycloalkyl; R 8 is H, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 9 For optional R 9-1 Replaces: C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-10 Alkoxy or C 2-10 Heteroalkyl, the R 9-1 The substituents are independently selected from: halogen, hydroxyl and C 1-6 Alkoxy; X is CH or N; Y is CH or N; Ring A is an optionally substituted aryl or heteroaryl group, an aryl or heteroaryl group and a 5-12-membered heterocyclic group; Ring B is optionally substituted C 6-10 Aryl or 5-12 membered heteroaryl; When the number of substitutions is selected from a plurality, they are independently the same and different; The carbon atom with "*" indicates that when selected from chiral carbon atoms, it is in S configuration, R configuration or a mixture thereof in any ratio.

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 by one or more groups selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Substitution of alkoxy groups; R 3 , R 4 are independently H, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Substitution of alkoxy groups; or R 3 , R 4 Together with the adjacent carbon atoms, it forms a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; R 5 H, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Alkoxy; R 6 , R 7 are independently H, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; said C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted by one or more groups selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Substitution of alkoxy groups; R 8 H, 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 by one or more groups selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 Substitution of alkoxy groups; R 9 C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-10 Alkoxy or C 2-10 Heteroalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-10 Alkoxy and C 2-10 The heteroalkyl group is optionally substituted with one or more R 9-1 replace; R 9-1 are independently selected from halogen, hydroxyl and C 1-6 Alkoxy; X is CH or N; Y is CH or N; Ring A is C 6-10 Aryl, 5-12 membered heteroaryl, or C 6-10 Aryl and 5-12 membered heterocyclic group; said C 6-10 Aryl and 5-12 membered heteroaryl are each optionally substituted by one or more A 1 Replacement; said C 6-10 The aryl and 5-12 membered heterocyclic groups are optionally substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 The substituents of the alkoxy group are substituted, wherein C 6-10 The aromatic group is attached to the amide bond; A 1 Independently selected from C 1-6 Alkoxy, 5-12 membered heterocyclic, 5-12 membered heteroaryl and C 3-6 Cycloalkyl; said A 1 Optionally one or more A 1-1 replace; A 1-1 Independently selected from hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy; Ring B is C 6-10 Aryl or 5-12 membered heteroaryl; the ring B is optionally substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl and halogenated C 1-6 The substituents of the alkoxy group are substituted.

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 , R 2 Each independently selected from H and C 1-6 Alkyl; preferably one of them is selected from H and the other is selected from H and C 1-6 Alkyl; more preferably all selected from H and methyl; (2)R 3 , R 4 Each independently selected from H, C 2-6 Alkynyl, C 3-6 Cycloalkyl and halogenated C 1-6 Alkyl; such as H, C 2-6 Alkynyl and C 3-6 Cycloalkyl; for example H and C 3-6 Cycloalkyl; (3)R 5 Selected from H; (4)R 6 , R 7 are each independently selected from H; (5)R 8 Selected from C 1-6 alkyl; (6)R 9 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and C 2-10 Heteroalkyl; said C 1-6 Alkyl, C 3-6 Cycloalkyl and C 2-10 The heteroalkyl group is optionally substituted with one or more R 9-1 substituted; for example, optionally with one or more R 9-1 Substituted C 1-6 Alkyl; for example, C 1-6 alkyl; (7)R 9-1 Selected from hydroxyl group; (8) X is selected from CH; (9) Y is selected from CH; (10)A 1-1 Selected from hydroxyl and C 1-6 alkyl; (11)A 1 Selected from C 1-6 Alkoxy, 5-12 membered heterocyclic group and C 3-6 Cycloalkyl; the C 1-6 Alkoxy, 5-12 membered heterocyclic group and C 3-6 The cycloalkyl group is optionally substituted with one or more A 1-1 substituted; for example, optionally by one or more A 1-1 Substituted C 1-6 Alkoxy; for example, C 1-6 Alkoxy; (12) Ring B is selected from 5-12 membered heteroaryl groups; (13) The number of substitutions is selected from 1, 2 and 3; when selected from 2 and 3, they are independently the same and different; and (14) When the compound represented by formula (I) contains a chiral center, the compound represented by formula (I) is selected from various stereoisomers and mixtures thereof. For example, when it contains one chiral center, the compound represented by formula (I) is in R configuration and / or S configuration.

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) each halogen is independently selected from fluorine, chlorine, bromine and iodine; (2) Each C 1-6 The alkyl groups are independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl; for example, methyl; (3) Each C 1-6 Alkoxy is independently selected from -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl, -O-sec-butyl and -O-pentyl; for example, methoxy; (4) Each C 1-10 Alkoxy is independently selected from C 1-6 Alkoxy; preferably, each C 1-10 Alkoxy is independently selected from -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl, -O-sec-butyl and -O-pentyl; for example, methoxy; (5) Each C 3-6 Cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for example, cyclopropyl; (6) each halo is independently selected from fluoro, chloro, bromo and iodo; for example, fluoro; (7) The number of each halogenated group is independently selected from 1, 2 and 3; for example, 3; (8) Each C 2-6 Alkenyl is independently selected from ethenyl, propenyl, isopropenyl, butenyl and pentenyl; (9) Each C 2-6 Alkynyl is independently selected from ethynyl, propynyl, propargyl, butynyl and pentynyl; for example, propynyl; (10) The heteroatoms in each 5-6 membered heterocyclic group are independently selected from N, O and S, and the number of heteroatoms is independently selected from 1, 2 and 3; preferably, the heteroatoms in each 5-6 membered heterocyclic group are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2; (11) The heteroatoms in each 5-6 membered heteroaryl group are independently selected from N, O and S, and the number of heteroatoms is independently selected from 1, 2 and 3; preferably, the heteroatoms in each 5-6 membered heteroaryl group are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2; (12) Each 3-6 membered cyclic hydrocarbon group is independently selected from saturated 3-6 membered cyclic hydrocarbon groups; for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; (12) each 3-6 membered cyclic hydrocarbon group is independently selected from a partially unsaturated 3-6 membered cyclic hydrocarbon group; for example, cyclopentenyl, cyclohexenyl and cyclohexadienyl; (13) The heteroatoms in each 3-6 membered heterocyclic group are independently selected from N, O and S, and the number of heteroatoms is independently selected from 1, 2 and 3; preferably, the heteroatoms in each 3-6 membered heterocyclic group are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2; (14) Each C 2-10 The heteroatoms in the heteroalkyl group are independently selected from N, O and S, and the number of heteroatoms is independently selected from 1, 2 and 3; preferably, each C 2-10 The heteroatoms in the heteroalkyl group are independently selected from O and S, and the number of heteroatoms is independently selected from 2 and 3; further preferably, each C 2-10 The heteroatoms in the heteroalkyl group are independently selected from O, and the number of heteroatoms is independently selected from 2; for example, each C 2-10 The heteroalkyl group is selected from C 1-3 Alkyl-OC 1-3 Alkyl-OC 1-3 Alkyl; for example (15) In A 1 In the 5-12 membered heterocyclic group, the heteroatoms are independently selected from N, O and S, and the number of heteroatoms is independently selected from 1, 2 and 3; preferably, the heteroatoms are independently selected from N and O, and the number of heteroatoms is independently selected from 2 and 3; further preferably, the heteroatoms are independently selected from N and O, and the number of heteroatoms is independently selected from 2; Preferably, the 5-12 membered heterocyclic group is selected from a 3-6 membered heterocyclic group; For example, the 5-12 membered heterocyclic group is Preferably (16) In ring A, the C 6-10 Aryl is independently selected from phenyl and naphthyl; for example, phenyl; (17) In ring A, the heteroatoms in the 5-12 membered heteroaryl group are independently selected from N, O and S, and the number of heteroatoms is independently selected from 1, 2 and 3; preferably, the heteroatoms in the 5-12 membered heteroaryl group are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2; more preferably, the heteroatoms in the 5-12 membered heteroaryl group are independently selected from N, and the number of heteroatoms is independently selected from 1; Preferably, the 5-12 membered heteroaryl group is selected from a 5-6 membered heteroaryl group; For example, the 5-12 membered heteroaryl group is selected from pyridyl; preferably selected from (18) In ring A, the C 6-10 The aryl group in the 5- to 12-membered heterocyclic group is selected from phenyl and naphthyl; preferably phenyl; (19) In ring A, the C 6-10 The heteroatoms in the 5-12 membered heterocyclic ring of the aryl group are independently selected from N, O and S, and the number of heteroatoms is independently selected from 1, 2 and 3; preferably, the C 6-10 The heteroatoms in the 5-12 membered heterocyclic ring of the aryl group are independently selected from N and O, and the number of the heteroatoms is selected from 1 and 2; further preferably, the C 6-10 The heteroatoms in the aryl 5-12 membered heterocyclic ring are independently selected from O, and the number of the heteroatoms is selected from 1 and 2; Preferably, the C 6-10 The 5-12-membered heterocyclic group in the aryl and 5-12-membered heterocyclic group is selected from a 5-6-membered heterocyclic group; For example, the C 6-10 The 5-12 membered heterocyclic group in the aryl and 5-12 membered heterocyclic group is selected from Preferably selected from (20) In ring B, the C 6-10 Aryl is independently selected from phenyl and naphthyl, for example phenyl; and (21) In ring B, the heteroatoms in the 5-12 membered heteroaryl group are independently selected from N, O and S, and the number of heteroatoms is independently selected from 1, 2 and 3; preferably, the heteroatoms in the 5-12 membered heteroaryl group are independently selected from N and O, and the number of heteroatoms is independently selected from 1 and 2; further preferably, the heteroatoms in the 5-12 membered heteroaryl group are independently selected from N, and the number of heteroatoms is independently selected from 1; Preferably, the 5-12 membered heteroaryl is selected from a 5-10 membered heteroaryl; preferably selected from a 5-6 membered heteroaryl; For example, selected from pyridyl; preferably selected from 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 , R 2 Each is independently selected from H and CH3; for example, R 1 Selected from H, R 2 is selected from H and CH3; (2)R 3 , R 4 Each independently selected from H, -CH3, and CF3; for example, R 3 Selected from H, R 4 Selected from (3) When R 3 , R 4 When the connected carbon is a chiral carbon, Selected from (4)R 8 Selected from (5)R 9 Selected from -CH3, -CH2CH2OH and -CH2CH2OCH2CH2OCH2CH2OH; (6) Selected from (7) Selected from (8)A 1 Selected from methoxy, -OCH2CH2OH, Cyclopropyl, (9) Ring A is selected from For example, end A and connect.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The compound represented by formula (I) has a structure represented by the following formula (II): in, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , X, Y, * and ring A are as defined in any one of claims 1-5.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that: R 1 , R 2 are each independently H, halogen or 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 or C 1-6 Alkyl-substituted five-membered heteroaryl; R 5 is H; R 8 is optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 9 For optional R 9-1 Replaces: C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-10 Alkoxy; said R 9-1 The substituent is hydroxyl; X is CH or N; Y is CH or N; A is optionally substituted: phenyl, pyridine or benzo 5-6 membered heterocyclic group.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that: R 1 , R 2 are each independently H or methyl; R 3 , R 4 Each independently is H, C 2-6 Alkynyl, C 3-6 Cycloalkyl or CF3; R 8 C 1-6 alkyl; R 9 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, hydroxyl substituted C 2-10 Alkyl or hydroxy substituted C 2-10 Alkoxy; Y is CH; A is optionally substituted: phenyl, pyridine, The substituent is selected from: 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-10 Alkoxy, optionally substituted 5-12 membered heterocycloalkyl, halogen and hydroxy substituted C 1-6 Alkoxy.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, characterized in that: R 1 , R 2 Each independently is H; R 3 , R 4 Each independently is H or C 3-6 Cycloalkyl; R 9 is methyl, ethyl or cyclopropyl; A is optionally substituted: phenyl, pyridine, The substituent is selected from: 1-10 Alkoxy and C 1-6 Alkyl-substituted 4- to 8-membered heterocycloalkyl.

10. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 9, characterized in that: R 3 , R 4 Each is independently H or cyclopropyl; R 9 is methyl; A is accessible by C 1-10 Alkoxy substituted: phenyl or pyridine.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, 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 is C 1-6 alkyl; preferably, R is methyl or ethyl; more preferably, R is ethyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, Y, ring A, ring B and * are defined as any one of claims 1-11; Preferably, the compound represented by formula (IA) is a compound represented by formula (IIA), Among them, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , X, Y, ring A and * are defined as in any one of claims 1-11; The compound represented by formula (IA) is more preferably any of the following structures:

13. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11, comprising the following steps: In an organic solvent, the compound represented by formula (IA) is subjected to a hydrolysis reaction with an alkaline reagent to obtain a compound represented by formula (I); in, R is C 1-6 alkyl; preferably, R is methyl or ethyl; more preferably, R is ethyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, Y, *, ring A and ring B as described in any one of claims 1-11; Preferably, the preparation method satisfies one or more of the following conditions: The organic solvent is a mixed solution of ether and alcohol solvents, preferably a mixed solvent of tetrahydrofuran and methanol; The alkaline agent is an organic strong base, preferably a sodium hydroxide solution; The concentration of the alkaline agent is 1-3 mol / L, preferably 2 mol / L; The molar ratio of the compound represented by formula (IA) to the base is 0.1-0.5:1, preferably 0.2:1; The molar volume ratio of the compound represented by formula (IA) to the solvent is 0.08-0.12 mol / L, preferably 0.09 mol / L; The reaction temperature is 40-60 degrees, preferably 50 degrees; After the reaction is completed, post-processing is also included, and the post-processing includes the following steps: concentration, pH adjustment, extraction, ice water washing, concentration, and purification; The organic solvent used for extraction in the post-treatment is an ester solvent, preferably ethyl acetate; The pH regulator in the post-treatment is an organic weak acid, preferably citric acid; The concentration of the pH regulator in the post-treatment is 0.5-2 mol / L, preferably 1 mol / L; Preferably, the method for preparing the compound represented by formula (II) or a pharmaceutically acceptable salt thereof comprises the following steps: In an organic solvent, the compound represented by formula (IIA) undergoes a hydrolysis reaction with an alkaline reagent to obtain a compound represented by formula (II); in, R is C 1-6 alkyl; preferably, R is methyl or ethyl; more preferably, R is ethyl; and R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , X, Y, * and ring A are as described in any one of claims 1 to 11, and the reaction conditions are the same as defined for the compound represented by formula (IA).

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. Use of the compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 14 in the preparation of a GPR40 receptor agonist or a drug; Preferably, the drug is used for preventing and / or treating metabolic-related diseases by activating the GPR40 receptor; or The drug is a drug for treating and / or curing a metabolic-related disease; the metabolic-related disease is selected from any one of glucose intolerance, dyslipidemia, syndrome X, insulin resistance, arteriosclerosis, hypertension, obesity, non-alcoholic fatty liver disease, cirrhosis and narcolepsy; 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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