Small molecule inhibitors of β-catenin / BCL9 protein-protein interaction and their applications

Abstract

This invention discloses a small molecule inhibitor of β-catenin / BCL9 protein-protein interaction and its application. Specifically, it provides a compound as shown in formula (I), or an isomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug thereof; wherein rings A, X, and R... 1 R 2 and R 3 The definition is as described in the specification. The compound shown in formula (I) has good affinity for β-catenin / BCL9 protein-protein, good antitumor activity, and broad application prospects.

Description

Technical Field

[0001] This invention relates to the field of antitumor drug technology, and in particular to a small molecule inhibitor of β-catenin / BCL9 protein-protein interaction, its preparation method, pharmaceutical composition and its antitumor application. Background Technology

[0002] Studies have identified 19 Wnt proteins in humans and other mammals, which share 27%–83% amino acid sequence homology and conserved sequences of 23 or 24 cysteine ​​residues. Wnt signaling is transmitted through at least three distinct intracellular pathways: (1) the Wnt / β-catenin signaling pathway; (2) the Wnt / Ca... 2+ Signaling pathways; (3) Wnt / pcp (planar cell polarity) signaling pathway. Among them, the Wnt / β-catenin signaling pathway has been the most extensively studied. This pathway is also known as the classical Wnt pathway or the β-catenin-dependent Wnt pathway.

[0003] Studies show that the Wnt / β-catenin signaling pathway promotes embryonic development and maintains homeostasis by regulating cell proliferation, migration, differentiation, survival, adhesion, and stem cell regeneration. The Wnt / β-catenin signaling pathway plays a crucial role in life activities, and its abnormal activation primarily leads to cancer-related diseases. Therefore, developing drugs targeting the Wnt / β-catenin signaling pathway is of great significance for tumor treatment. Currently, several small molecule compounds targeting the Wnt / β-catenin signaling pathway have been reported for cancer-related diseases. These inhibitors mainly act on upstream components of the Wnt / β-catenin pathway. Since β-catenin protein is an effector in the Wnt pathway, these inhibitors affect the adhesion of β-catenin protein between cells, leading to a series of side effects. Inhibitors that act on nuclear proteins can effectively avoid these side effects.

[0004] In the Wnt / β-catenin signaling pathway, nuclear proteins exist in a form that interacts with β-catenin. BCL9, a nuclear transcriptional coactivator composed of 1350 amino acids, is one such protein. Studies have shown that knocking out BCL9 in mice with colon cancer, liver cancer, or multiple myeloma significantly inhibits tumor growth and prolongs survival. Simultaneously, downstream genes Myc, Ccnd1, Cd44, and Vegfa are also suppressed without affecting the growth of normal cells. The crystal structure of the β-catenin / BCL9 complex shows that the binding surface of the two proteins reaches [a certain value]. With an affinity of 0.5 μM, it is suitable for small molecule retention. The above studies all indicate that the β-catenin / BCL9 protein-protein interaction can serve as a novel anti-tumor target for inhibiting the Wnt pathway.

[0005] Based on their structural type, β-catenin / BCL9 protein inhibitors are classified into peptides and small molecules. Peptide inhibitors are difficult to prepare and have poor oral absorption, while small molecule inhibitors are easy to prepare, can be absorbed orally, and have high targeting specificity, making them the current focus of β-catenin / BCL9 PPI inhibitor research.

[0006] There are few reports on small molecule inhibitors of β-catenin / BCL9 in existing studies. Compound a (J Am ChemSoc, 2015, 137, 12249-60) has a protein affinity of Ki = 0.41 μM and selectivity = 125, but this compound has many rigid skeletal fragments and poor drug-like properties.

[0007]

[0008] Compound b (Nat Commun, 2012, 3, 680) and compound c (Anal Biochem, 2015, 469, 43-53), small molecule inhibitors of β-catenin / BCL9, were obtained through in vitro screening. Compound b contains a hydroquinone structure, which may lead to false positives. Compound c was obtained through high-throughput screening and can be used to block β-catenin / BCL9 protein-protein interactions, but it showed no activity in cell experiments (Journal of Medicinal Chemistry, 2021, 64(9)), suggesting that it may have difficulty crossing the cell membrane to exert its effects.

[0009]

[0010] There is an urgent need for a small molecule inhibitor of β-catenin / BCL9 protein-protein interaction with high targeting affinity and good cell membrane permeability. Summary of the Invention

[0011] The present invention provides a compound of formula (I), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;

[0012]

[0013] in,

[0014] Ring A is a saturated aliphatic ring group, aryl ring group, or heteroaryl group;

[0015] X is -C(=O)-(CH2)n -、-C(=O)-NH-(CH2) n -, -CH(OH)-(CH2) n -, -SO2-(CH2) n -, -SO2-NH-(CH2) n -、-C(=O)-(CH=CH) m -(CH2) n -or-(CH2) n - where each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;

[0016] R 1 and R 2 Independently, each of the following groups is a hydrogen group, saturated or unsaturated alkyl group, alkoxy group, alkoxycarbonyl group, hydroxyl group, halogen group, amino group, alkylamine group, nitro group, cyano group, carboxyl group, acyl group, amide group, haloalkyl group, haloalkoxy group, haloalkylthio group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, -OR group. a Substituted or unsubstituted heteroaryl groups or substituted or unsubstituted saturated or unsaturated heterocycles;

[0017] R a It is a 4- to 6-membered heterocyclic alkyl group;

[0018] R 3 It can be alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amino, alkylamino, carboxyl,

[0019] Among them, R 4 It is a hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, nitro, amino, alkylamine, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted alkylamine, substituted or unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle;

[0020] Compounds with the general structural formula shown in formula (I) are not:

[0021]

[0022]

[0023] Preferably, the isomer is an enantiomer or diastereomer of the compound shown in formula (I).

[0024] In one embodiment, certain groups in the compound represented by formula (I), or its isomers, or pharmaceutically acceptable salts, esters, or prodrugs, have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment"):

[0025] The present invention provides a small molecule inhibitor that interacts with β-catenin / BCL9 protein, which is a compound of formula (I), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof.

[0026] In one embodiment, the small molecule inhibitor that interacts with the β-catenin / BCL9 protein is a compound with the general structural formula shown in formula (I-1), or an isomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug thereof;

[0027]

[0028] in,

[0029] Ring A is a saturated aliphatic ring, aromatic ring, or heteroaromatic ring;

[0030] X is -C(=O)-(CH2) n -、-C(=O)-NH-(CH2) n -, -CH(OH)-(CH2) n -, -SO2-(CH2) n -, -SO2-NH-(CH2) n -or-(CH2) n - where n is 0, 1, 2, 3 or 4;

[0031] R 1 R 2 Independently, they are hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, amino, alkylamine, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated or unsaturated heterocycles;

[0032] R 3 It can be alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amino, alkylamino, carboxyl,

[0033] Among them, R 4It is a hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, nitro, amino, alkylamine, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonamide, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle.

[0034] Preferably, the compound represented by formula (I-1) is a compound represented by general formula (II), or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;

[0035]

[0036] in,

[0037] X, R 1 and R 2 The definition is shown in equation (I-1);

[0038] R 4 It is a hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, nitro, amino, alkylamine, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonamide, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle.

[0039] Preferably, the aliphatic ring or cycloalkyl group is an cycloalkyl group containing 5 or more carbon atoms independently;

[0040] Preferably, the aryl / aromatic ring or aromatic heterol / heteroaromatic ring is independently phenyl, biphenyl, naphthyl, anthracene, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, morpholinyl, piperidinyl or piperazinyl, thiophene, benzothiophene, pyrazolyl, benzopyrazolyl, indolyl, dioxolane, benzo[1,3]dioxolane, oxazolyl, benzooxazolyl, furanyl, benzofuranyl, thiazolyl or benzothiazolyl, which may optionally be substituted;

[0041] Preferably, the halogen or halogen in the halogenation is independently fluorine, chlorine or bromine;

[0042] Preferably, the alkyl group is an alkyl group containing 1-6 carbon atoms;

[0043] Preferably, the heterocycle or heterocyclic group is independently a five-membered or six-membered ring containing at least one O, N, or S.

[0044] Preferably, the pharmaceutically acceptable salt comprises an acid addition salt formed by the small molecule inhibitor with one or more of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, and mandelic acid.

[0045] More preferably, it includes the following compounds:

[0046] 2-(3-(1-((3',4'-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0047] 2-(3-(1-(3-(3',4'-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0048] 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0049] 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0050] 2-(3-(1-(3-(benzo[b]thiophene-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0051] 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0052] 2-Methyl-2-(3-(1-(3-(thien-3-yl)benzoyl)piperidin-3-yl)phenoxy)propionic acid;

[0053] 2-Methyl-2-(3-(1-(3-(thien-2-yl)benzoyl)piperidin-3-yl)phenoxy)propionic acid;

[0054] 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0055] 2-(3-(1-(4'-isopropyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0056] 2-(3-(1-([1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0057] 2-(3-(1-([1,1'-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0058] 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0059] 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0060] 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0061] 2-Methyl-2-(3-(1-((3-(thien-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionic acid;

[0062] 2-(3-(1-([1,1'-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0063] 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0064] 2-Methyl-2-(3-(1-((3-(thien-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionic acid;

[0065] 2-(3-(1-((3-(benzo[b]thiophene-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0066] 2-(3-(1-((3'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0067] 2-(3-(1-((4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0068] 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0069] 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid;

[0070] (3S)-3-((5-(3-(3-((2-carboxypropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-3',4'-difluoro-[1,1'-biphenyl]-2-yl)oxy)pyrrolidine-1-ammonium chloride;

[0071] (3S)-3-(4-(3-(3-((2-carboxypropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-cyclohexylphenoxy)pyrrolidine-1-ammonium chloride;

[0072] 4-(2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-ammonium chloride;

[0073] 4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-ammonium chloride;

[0074] 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(benzenesulfonyl)propionamide;

[0075] 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(benzenesulfonyl)propionamide;

[0076] 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(benzenesulfonyl)propionamide.

[0077] In one embodiment, the small molecule inhibitor that interacts with the β-catenin / BCL9 protein has the general structural formula shown in formula (I-1), or an isomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0078] Ring A is a saturated aliphatic ring, aromatic ring, or heteroaromatic ring;

[0079] The ring A can be cyclohexane, benzene, biphenyl, naphthalene, or quinoline.

[0080] In one particular scheme, X is -C(=O)-(CH2). n -、-C(=O)-NH-(CH2) n -, -CH(OH)-(CH2) n -, -SO2-(CH2) n -, -SO2-NH-(CH2) n -or-(CH2) n- where n is 0, 1, 2, 3 or 4.

[0081] In one scheme, X can be -C(=O)-, -C(=O)-(CH2)2-, -SO2-, -CH2- or -(CH2)3-, or it can be without X (i.e. -(CH2)0-).

[0082] In one of the schemes, R 1 and R 2 Independently, each of the following groups is hydrogen, saturated or unsaturated alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, nitro, amino, alkylamine, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle; R 1 R 2 They can be the same or different.

[0083] In one of the schemes, R 1 R 2 It can be independently selected from hydrogen, halogen, C1-C4 alkyl, alkoxy, thienyl, benzothienyl, pyrazolyl, haloaryl and Any two of them; more preferably, the R 1 R 2 The possible combinations are shown in the table below:

[0084]

[0085]

[0086] R 3 It can be alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amino, alkylamino, carboxyl,

[0087] In one of the schemes, R 4 It can be hydrogen, amino, amide, carboxyl,

[0088] In one of the schemes, R 5 It is a hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, amino, alkylamine, nitro, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonamide, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle.

[0089] In one of the schemes, R 5 It can be hydrogen, alkyl, piperazine or benzenesulfonyl.

[0090] In one embodiment, the compound represented by formula (II), or an isomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein X, R 1 and R 2 The definition is shown in equation (I-1);

[0091] R 4 It is a hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, nitro, amino, alkylamine, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted sulfonamide, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycle.

[0092] In a certain scheme, R 4 It can be hydroxyl, alkoxy, alkylamine or benzenesulfonyl.

[0093] In one embodiment, the alkyl group is a C1-C6 alkyl group.

[0094] In one embodiment, the pharmaceutically acceptable salt comprises an acid addition salt formed by the small molecule inhibitor that interacts with the β-catenin / BCL9 protein and one or more of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, and mandelic acid.

[0095] In one embodiment, the compound shown in formula (I) is the same as the compound shown in formula (III).

[0096]

[0097] in,

[0098] Ring A can be a saturated aliphatic ring group, an aromatic ring group, or a heteroaryl group.

[0099] The saturated aliphatic cyclic group is a 4- to 6-membered cycloalkyl group.

[0100] The aromatic ring group is a 6- to 14-membered aryl group.

[0101] The heteroaryl group is a 5- to 12-membered heteroaryl group;

[0102] X is -C(=O)-(CH2) n -、-C(=O)-NH-(CH2) n -, -CH(OH)-(CH2) n -, -SO2-(CH2) n -, -SO2-NH-(CH2) n -、-C(=O)-(CH=CH) m-(CH2) n -or-(CH2) n - where each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;

[0103] R 1 and R 2 Independently, each of the following groups is a hydrogen group, saturated or unsaturated alkyl group, alkoxy group, alkoxycarbonyl group, hydroxyl group, halogen group, amino group, alkylamine group, nitro group, cyano group, carboxyl group, acyl group, amide group, haloalkyl group, haloalkoxy group, haloalkylthio group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, -OR group. a Substituted or unsubstituted heteroaryl groups or substituted or unsubstituted saturated or unsaturated heterocycles

[0104] The saturated or unsaturated alkyl group is a C1-C6 alkyl group.

[0105] The alkoxy group is a C1-C6 alkoxy group.

[0106] The alkoxycarbonyl group is a C1-C6 alkyl-OC(=O)-.

[0107] The alkylamine group is C1-C6 alkyl-NH-.

[0108] The acyl group is C1-C6 alkyl-C(=O)-, C1-C6 alkyl-SO2-, or benzenesulfonyl.

[0109] The amide group is C1-C6 alkyl-C(=O)NH-, C1-C6 alkyl-SO2NH-, or benzenesulfonamide.

[0110] The haloalkyl group is a C1-C6 alkyl group substituted with one or more halogens.

[0111] The haloalkoxy group is a C1-C6 alkoxy group substituted with one or more halogens.

[0112] The haloalkylthio group is a C1-C6 alkylthio group substituted with one or more halogens.

[0113] The substituted or unsubstituted cycloalkyl group is a 3- to 6-membered cycloalkyl group.

[0114] The substituted or unsubstituted aryl group is a 6- to 14-membered aryl group, wherein the substituted aryl group is a group with one or more R groups. b Substituted 6-14 aryl groups,

[0115] The substituted or unsubstituted heteroaryl group is a 5- to 12-membered heteroaryl group, wherein the substituted heteroaryl group is dominated by one or more R groups. f Substituted 5- to 12-membered heteroaryl groups,

[0116] The heterocycle in the substituted or unsaturated or unsaturated heterocycle is a 4- to 6-membered heterocyclic alkyl group;

[0117] R a It is a 4- to 6-membered heterocyclic alkyl group;

[0118] Each R b and R f It is independently a halogen or a C1-C6 alkyl group;

[0119] R 3 It can be alkoxy, substituted or unsubstituted alkyl, halogen, nitro, amino, alkylamino, carboxyl,

[0120] The alkoxy group is a C1-C6 alkoxy group.

[0121] The substituted or unsubstituted alkyl group is a C1-C6 alkyl group.

[0122] The alkylamine group is C1-C6 alkyl-NH-;

[0123] R 4 It can be hydrogen, alkyl, alkoxy, alkoxycarbonyl, hydroxyl, halogen, nitro, amino, alkylamine, cyano, carboxyl, acyl, amide, haloalkyl, haloalkoxy, haloalkylthio, substituted or unsubstituted alkylamine, substituted or unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted saturated or unsaturated heterocycles.

[0124] The alkyl group is a C1-C6 alkyl group.

[0125] The alkoxy group is a C1-C6 alkoxy group.

[0126] The alkoxycarbonyl group is a C1-C6 alkyl-OC(=O)-.

[0127] The alkylamine group is a C1-C6 alkyl-NH-.

[0128] The acyl group is C1-C6 alkyl-C(=O)-, C1-C6 alkyl-SO2-, or benzenesulfonyl.

[0129] The amide group is C1-C6 alkyl-C(=O)NH-, C1-C6 alkyl-SO2NH-, or benzenesulfonamide.

[0130] The haloalkyl group is a C1-C6 alkyl group substituted with one or more halogens.

[0131] The haloalkoxy group is a C1-C6 alkoxy group substituted with one or more halogens.

[0132] The haloalkylthio group is a C1-C6 alkylthio group substituted with one or more halogens.

[0133] The alkylamine group in the substituted or unsubstituted alkylamine group is -NH-(CH2). k In this case, the substituted alkylamine group is -NH-(CH2). k -R d k is 1, 2, 3 or 4.

[0134] The substituted amino group is -NH-(CH2). k -R d k is 0

[0135] The substituted sulfonamide is -NH-(SO2)-R c ,

[0136] The substituted or unsubstituted aryl group has 6- to 14-membered aryl groups.

[0137] The substituted or unsubstituted heteroaryl group is a 5- to 12-membered heteroaryl group.

[0138] The substituted or unsubstituted saturated or unsaturated heterocycle is a 4- to 10-membered heterocyclic alkyl group, wherein the substituted saturated or unsaturated heterocycle is a ring formed by one or more R groups. e Substituted 4- to 10-membered heterocyclic alkyl groups;

[0139] R c It is hydrogen, 6-14 aryl, 4-6 heterocyclic alkyl, 5-12 heteroaryl, and is surrounded by one or more R c-1 The substituted 6- to 14-membered aryl group or the group containing one or more R c-2 Substituted 5- to 12-membered heteroaryl groups;

[0140] R d It is hydrogen, 6-14 aryl, 5-12 heteroaryl, or 4-6 heterocyclic alkyl;

[0141] Each R c-1 and R c-2 Independently hydroxyl, cyano, C1-C6 alkyl, or with one or more R c-1-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, nitro, halogen, or with one or more R c-1-2 Substituted C1-C6 alkoxy or -NHC(=O)-R c-1-3 ;

[0142] Each R e It can be an oxo group (C=O), a hydroxyl group, or an amino group independently;

[0143] Each R c-1-1 and R c-1-2 Halogens are independent of each other;

[0144] R c-1-3 It is a C1-C6 alkyl group;

[0145] In each of the 5- to 12-membered heteroaryl groups, 4- to 6-membered heterocyclic alkyl groups, and 4- to 10-membered heterocyclic alkyl groups, the heteroatom is selected from N, O, or S, and the number of heteroatoms is 1, 2, or 3.

[0146] In one scheme, ring A is a 6- to 14-membered aryl group.

[0147] In one of the schemes, R 1 and R 2 Each of the following is independently hydrogen, C1-C6 alkyl, 5-12 heteroaryl, 3-6 cycloalkyl, 6-14 aryl, -OR a Or by one or more R b Substituted 6- to 14 aryl groups.

[0148] In one of the schemes, R 1 It is a 5-12-membered heteroaryl, a 3-6-membered cycloalkyl, a 6-14-membered aryl, or is surrounded by one or more R groups. b Substituted 6- to 14 aryl groups.

[0149] In one of the schemes, R 1 and R 2 Each is independently hydrogen, 5-12-membered heteroaryl, 3-6-membered cycloalkyl, 6-14-membered aryl, -OR a Or by one or more R b Substituted 6- to 14 aryl groups.

[0150] In one particular scheme, X is -C(=O)-(CH2). n -、-C(=O)-NH-(CH2) n -, -SO2-(CH2) n -, -SO2-NH-(CH2) n -、-C(=O)-(CH=CH) m -(CH2) n -or-(CH2) n -

[0151] In one particular scheme, X is -C(=O)- or -SO2-(CH2). n -, -SO2-NH-(CH2) n -、-C(=O)-(CH=CH) m -(CH2) n -or-(CH2) n -

[0152] In one scheme, X is a carbonyl group, and the compound shown in formula (III) is not:

[0153]

[0154] In one particular scheme, X is -SO2-(CH2). n -, -SO2-NH-(CH2) n -、-C(=O)-(CH=CH) m -(CH2) n -or-(CH2) n -

[0155] In a certain scheme, each n is independently 0, 1, or 3.

[0156] In a certain scheme, each m is independently equal to 1.

[0157] In one of the schemes, R 3 for For example

[0158] In one of the schemes, R 4 It is a hydroxyl group, a C1-C6 alkyl group, a 4- to 10-membered heterocyclic alkyl group, or a -NH-(SO2)-R group. c -NH-(CH2) k -R d Or by one or more R e Substituted 4- to 10-membered heterocyclic alkyl groups, for example, R 4 It is a hydroxyl group, a 4- to 10-membered heterocyclic alkyl group, or -NH-(SO2)-R. c Or -NH-(CH2) k -R d For example, R 4 It is a hydroxyl group, a 4- to 10-membered heterocyclic alkyl group, or -NH-(SO2)-R. c -NH-(CH2) k -R d Or by one or more R e Substituted 4- to 10-membered heterocyclic alkyl groups.

[0159] In one scheme, k is either 0 or 1.

[0160] In one of the schemes, R c It is a 6-14 aryl group, surrounded by one or more R groups. c-1 Substituted 6-14 aryl or 5-12 heteroaryl.

[0161] In one of the schemes, R d It is a 6- to 14-membered aryl or a 4- to 6-membered heterocyclic alkyl, for example, R d It is a 4- to 6-membered heterocyclic alkyl group, such as R d It consists of 6- to 14 aryl groups.

[0162] In a certain scheme, each R c-1 Independently cyano, with one or more R c-1-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, nitro, halogen, or with one or more R c-1-2 Substituted C1-C6 alkoxy or -NHC(=O)-R c-1-3 Or, each R c-1 Independently hydroxyl, by one or more R c-1-1 Substituted C1-C6 alkyl or C1-C6 alkoxy.

[0163] In one embodiment, the 4- to 6-membered cycloalkyl group in ring A is cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0164] In one embodiment, the 6-14 aryl group in ring A is phenyl or naphthyl, for example, phenyl.

[0165] In one embodiment, in ring A, the heteroatom in the 5-12 member heteroaryl group is N, S or O, and the number of heteroatoms is 1 or 2, preferably a 6-member nitrogen-containing heteroaryl group.

[0166] In one of the schemes, R 1 and R 2 In the C1-C6 alkyl, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-NH-, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-C(=O)NH- and C1-C6 alkyl substituted with one or more halogens, the C1-C6 alkyl is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example methyl or isopropyl.

[0167] In one of the schemes, R 1 and R 2 In the C1-C6 alkoxy group and the C1-C6 alkoxy group substituted with one or more halogens, the C1-C6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, or isobutoxy.

[0168] In one of the schemes, R 1 and R 2 In this context, the halogen, the C1-C6 alkyl group substituted with one or more halogens, the C1-C6 alkoxy group substituted with one or more halogens, and the C1-C6 alkylthio group substituted with one or more halogens are fluorine, chlorine, bromine, or iodine.

[0169] In one of the schemes, R 1 and R 2In the above, the C1-C6 alkylthio group substituted with one or more halogens is methylthio, ethylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, tert-butylthio, or isobutylthio.

[0170] In one of the schemes, R 1 and R 2 In this context, the 3- to 6-membered cycloalkyl group is cyclopropane, cyclobutane, cyclopentane, or cyclohexane, for example, cyclohexane.

[0171] In one of the schemes, R 1 and R 2 In the case of the 6-14 aryl group and one or more R groups b In the substituted 6- to 14-membered aryl groups, the 6- to 14-membered aryl groups are phenyl or naphthyl, for example, phenyl.

[0172] In one of the schemes, R 1 and R 2 In this context, the 5-12 membered heteroaryl group and one or more R groups are... f The substituted 5- to 12-membered heteroaryl group is a 5- to 10-membered heteroaryl group. Preferably, the heteroatom in the 5- to 10-membered heteroaryl group is N, O, or S, and the number of heteroatoms is one or two, such as thienyl, pyrazole, or benzothienyl.

[0173] In one of the schemes, R 1 and R 2 In the 4- to 6-membered heterocyclic alkyl group, the heteroatom is N, S or O, and the number of heteroatoms is 1 or 2, preferably a 6-membered nitrogen-containing heterocyclohexyl group.

[0174] In one of the schemes, R a In this context, the 4-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group. Preferably, the heteroatom in the 5-6 membered heterocyclic alkyl group is N, O, or S, and the number of heteroatoms is 1, such as azircyclopentane.

[0175] In one of the schemes, R b and R f In this context, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine.

[0176] In one of the schemes, R b and R f In this context, the C1-C6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, or isobutyl, for example, methyl, isopropyl, or tert-butyl.

[0177] In one of the schemes, R 3 In this context, the C1-C6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, or isobutoxy.

[0178] In one of the schemes, R 3 In the C1-C6 alkyl group and C1-C6 alkyl-NH-, the C1-C6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, or isobutyl.

[0179] In one of the schemes, R 3 In this context, the halogen is fluorine, chlorine, bromine, or iodine.

[0180] In one of the schemes, R 4 In the C1-C6 alkyl, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-NH-, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-SO2-, C1-C6 alkyl-C(=O)NH-, C1-C6 alkyl-SO2NH- and C1-C6 alkyl substituted with one or more halogens, the C1-C6 alkyl is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl or isobutyl, for example methyl.

[0181] In one of the schemes, R 4 In the C1-C6 alkoxy group and the C1-C6 alkoxy group substituted with one or more halogens, the C1-C6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, or isobutoxy.

[0182] In one of the schemes, R 4 In this context, the halogen, the C1-C6 alkyl group substituted with one or more halogens, the C1-C6 alkoxy group substituted with one or more halogens, and the C1-C6 alkylthio group substituted with one or more halogens are fluorine, chlorine, bromine, or iodine.

[0183] In one of the schemes, R 4 In the above, the C1-C6 alkylthio group substituted with one or more halogens is methylthio, ethylthio, isopropylthio, n-propylthio, n-butylthio, sec-butylthio, tert-butylthio, or isobutylthio.

[0184] In one of the schemes, R 4 In the above, the 6-14 aryl group is phenyl or naphthyl.

[0185] In one of the schemes, R 4 In the 5-12 member heteroaryl group, the 5-12 member heteroaryl group is a 5-10 member heteroaryl group. Preferably, the heteroatom in the 5-10 member heteroaryl group is N, O or S, and the number of heteroatoms is 1 or 2.

[0186] In one of the schemes, R 4 In this context, the 4- to 10-membered heterocyclic alkyl group and the one or more R eThe substituted 4- to 10-membered heterocyclic alkyl group is a 4- to 7-membered heterocyclic alkyl group. Preferably, the heteroatom in the 4- to 7-membered heterocyclic alkyl group is O or N. More preferably, the number of heteroatoms in the 4- to 7-membered heterocyclic alkyl group is one or two. For example...

[0187] In one of the schemes, R c In the case of the 6-14 aryl group and one or more R groups c-1 The 6- to 14-membered aryl groups are phenyl or naphthyl, for example, phenyl or naphthyl.

[0188] In one of the schemes, R c In this context, the 4-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group. Preferably, the heteroatom in the 5-6 membered heterocyclic alkyl group is N. More preferably, the number of heteroatoms in the 5-6 membered heterocyclic alkyl group is 1.

[0189] In one of the schemes, R c In this context, the 5-12 membered heteroaryl group and one or more R groups are... c-2 The substituted 5- to 12-membered heteroaryl group is a 5- to 10-membered heteroaryl group. Preferably, the heteroatom in the 5- to 10-membered heteroaryl group is S or O. More preferably, the number of heteroatoms in the 5- to 10-membered heteroaryl group is 1. For example, the 5- to 10-membered heteroaryl group is thiophene.

[0190] In one of the schemes, R d In this context, the 6-14 aryl groups are phenyl or naphthyl, such as phenyl.

[0191] In one of the schemes, R d In this context, the 5-12 member heteroaryl group is a 5-6 member heteroaryl group. Preferably, the heteroatom in the 5-6 member heteroaryl group is N, S, or O. More preferably, the number of heteroatoms in the 5-6 member heteroaryl group is 1.

[0192] In one of the schemes, R d In this context, the 4-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group. Preferably, the heteroatom in the 5-6 membered heterocyclic alkyl group is N. More preferably, the number of heteroatoms in the 5-6 membered heterocyclic alkyl group is 1, such as azircyclohexane.

[0193] In one of the schemes, R c-1 and R c-2 In the case of C1-C6 alkyl groups and one or more R c-1-1 The substituted C1-C6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, or isobutyl, for example, methyl.

[0194] In one of the schemes, R c-1and R c-2 In this context, the C1-C6 alkoxy group and the group with one or more R c-1-2 The C1-C6 alkoxy group in the substituted C1-C6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, or isobutoxy, such as methoxy.

[0195] In one of the schemes, R c-1 and R c-2 In this context, the halogen is fluorine, chlorine, bromine, or iodine, such as fluorine or chlorine.

[0196] In one of the schemes, R c-1-1 and R c-1-2 In this context, the halogen is fluorine, chlorine, bromine, or iodine, such as fluorine.

[0197] In one of the schemes, R c-1-3 In this context, the C1-C6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, or isobutyl, such as methyl.

[0198] In one embodiment, the compound with the general structural formula shown in formula (III) is a compound with the general structural formula shown in formula (III-1).

[0199]

[0200] Among them, R 1 It is a 5-12-membered heteroaryl, a 3-6-membered cycloalkyl, a 6-14-membered aryl, or is surrounded by one or more R groups. b Substituted 6- to 14-membered aryl groups;

[0201] Each R b It is independently a halogen or a C1-C6 alkyl group;

[0202] R 4 It is a hydroxyl group, a 4- to 10-membered heterocyclic alkyl group, or -NH-(SO2)-R. c Or -NH-(CH2) k -R d k can be 0, 1, 2, 3, or 4;

[0203] R c It is a 6-14 aryl group, surrounded by one or more R groups. c-1 Substituted 6-14 aryl or 5-12 heteroaryl;

[0204] R d It consists of 6-14 aryl groups;

[0205] Each R c-1 Independently cyano, with one or more R c-1-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, nitro, halogen, or with one or more Rc-1-2 Substituted C1-C6 alkoxy or -NHC(=O)-R c-1-3 ;

[0206] Each R c-1-1 and R c-1-2 Halogens are independent of each other;

[0207] R c-1-3 It is a C1-C6 alkyl group;

[0208] The heteroatoms in each of the 5- to 12-membered heteroaryl groups and the 4- to 10-membered heterocyclic alkyl groups are selected from N, O, or S, and the number of heteroatoms is 1, 2, or 3.

[0209] In one embodiment, the compound with the general structural formula shown in formula (III) is a compound with the general structural formula shown in formula (III-2).

[0210]

[0211] R 1 and R 2 Each is independently hydrogen, 5-12-membered heteroaryl, 3-6-membered cycloalkyl, 6-14-membered aryl, -OR a Or by one or more R b Substituted 6- to 14-membered aryl groups;

[0212] R a It is a 4- to 6-membered heterocyclic alkyl group;

[0213] Each R b It is independently a halogen or a C1-C6 alkyl group;

[0214] R 4 It is a hydroxyl group, a 4- to 10-membered heterocyclic alkyl group, or -NH-(SO2)-R. c -NH-(CH2) k -R d Or by one or more R e Substituted 4- to 10-membered heterocyclic alkyl groups; k is 0, 1, 2, 3, or 4;

[0215] R c It is a 6-14 aryl group, surrounded by one or more R groups. c-1 Substituted 6-14 aryl or 5-12 heteroaryl;

[0216] R d It is a 4- to 6-membered heterocyclic alkyl group;

[0217] Each R c-1 Independently hydroxyl, by one or more R c-1-1 Substituted C1-C6 alkyl or C1-C6 alkoxy;

[0218] Each Re It can be an oxo group (C=O), a hydroxyl group, or an amino group independently;

[0219] Each R c-1-1 and R c-1-2 Halogens are independent of each other;

[0220] In each of the 5- to 12-membered heteroaryl groups, 4- to 6-membered heterocyclic alkyl groups, and 4- to 10-membered heterocyclic alkyl groups, the heteroatom is selected from N, O, or S, and the number of heteroatoms is 1, 2, or 3.

[0221] In one embodiment, the compound with the general structural formula shown in formula (III), or a pharmaceutically acceptable salt thereof,

[0222] R 1 and R 2 Each of the following is independently hydrogen, C1-C6 alkyl, 5-12 heteroaryl, 3-6 cycloalkyl, 6-14 aryl, -OR a Or by one or more R b Substituted 6- to 14-membered aryl groups;

[0223] R a It is a 4- to 6-membered heterocyclic alkyl group;

[0224] Each R b It is independently a halogen or a C1-C6 alkyl group;

[0225] X is -C(=O)-(CH2) n -、-C(=O)-NH-(CH2) n -, -SO2-(CH2) n -, -SO2-NH-(CH2) n -、-C(=O)-(CH=CH) m -(CH2) n -or-(CH2) n - where each n is independently 0, 1, 2, 3 or 4; m is 0, 1 or 2;

[0226] R 4 It is a hydroxyl group, a C1-C6 alkyl group, a 4- to 10-membered heterocyclic alkyl group, or a -NH-(SO2)-R group. c -NH-(CH2) k -R d Or by one or more R e Substituted 4- to 10-membered heterocyclic alkyl groups; k is 0, 1, 2, 3, or 4;

[0227] R c It is a 6-14 aryl group, surrounded by one or more R groups. c-1 Substituted 6-14 aryl or 5-12 heteroaryl;

[0228] R d It is a 6-14 membered aryl or a 4-6 membered heterocyclic alkyl;

[0229] Each R c-1 Independently hydroxyl, cyano, C1-C6 alkyl, or with one or more R c-1-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, nitro, halogen, or with one or more R c-1-2 Substituted C1-C6 alkoxy or -NHC(=O)-R c-1-3 ;

[0230] Each R e It can be an oxo group (C=O), a hydroxyl group, or an amino group independently;

[0231] Each R c-1-1 and R c-1-2 Halogens are independent of each other;

[0232] R c-1-3 It is a C1-C6 alkyl group;

[0233] In each of the 5- to 12-membered heteroaryl groups, 4- to 6-membered heterocyclic alkyl groups, and 4- to 10-membered heterocyclic alkyl groups, the heteroatom is selected from N, O, or S, and the number of heteroatoms is 1, 2, or 3.

[0234] In one of the schemes, R a The compound is a 4- to 6-membered heterocyclic alkyl group. Hydrochloric acid is combined with the N atom in the 4- to 6-membered heterocyclic alkyl group to obtain the hydrochloride salt of the compound shown in formula (III).

[0235] In one of the schemes, R e The amino group is formed by the combination of hydrochloric acid and the amino group to obtain the hydrochloride salt of the compound with the general structural formula shown in formula (III).

[0236] In one embodiment, the pharmaceutically acceptable salt of the compound represented by formula (III) is preferably a hydrochloride salt.

[0237] In one of the schemes, X is Chemical bonds, methyl groups

[0238] In one of the schemes, R 1 and R 2 Each independently consists of hydrogen, methyl,

[0239] In one of the schemes, R 3 for

[0240] In one of the schemes, R 4 for

[0241] In one embodiment, the compound represented by formula (III), or a pharmaceutically acceptable salt thereof, is any of the following compounds:

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of substance A and a pharmaceutical excipient; wherein substance A is the compound shown in formula (I) above, or an isomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof;

[0249] Preferably, substance A is the compound shown in formula (III) above or a pharmaceutically acceptable salt thereof.

[0250] The present invention also provides the use of substance A in the preparation of a drug for treating and / or preventing tumors, wherein substance A is a compound of formula (I), its isomer, its pharmaceutically acceptable salt, ester or prodrug;

[0251]

[0252] Among them, R 1 R 2 X and R 3 As described in any one of the present invention;

[0253] Preferably, the tumor is breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, leukemia, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor, or skin cancer. More preferably, the tumor is breast cancer, colon cancer, or liver cancer.

[0254] In one embodiment, in the application, substance A is the compound shown in formula (III) above or a pharmaceutically acceptable salt thereof.

[0255] The present invention also provides a method for treating and / or preventing tumors, comprising administering to a patient a therapeutically effective amount of substance A, said substance A being a compound of formula (I), its isomers, its pharmaceutically acceptable salts, esters, or prodrugs thereof;

[0256]

[0257] Among them, R 1 R 2 X and R 3 As described in any one of the present invention;

[0258] Preferably, the tumor is breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, leukemia, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor, or skin cancer. More preferably, the tumor is breast cancer, colon cancer, or liver cancer.

[0259] In one embodiment, in the method, substance A is the compound shown in formula (III) above or a pharmaceutically acceptable salt thereof.

[0260] The present invention also provides a pharmaceutical composition comprising substance A and an immune checkpoint inhibitor (ICI), wherein substance A is a compound of formula (I), an isomer thereof, a pharmaceutically acceptable salt thereof, an ester thereof, or a prodrug thereof; preferably, the immune checkpoint inhibitor is PD-1, and more preferably, substance A is a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0261] The present invention also provides a pharmaceutical composition comprising at least one active component and one or more pharmaceutically acceptable carriers or excipients; the active component comprising any one or more of the small molecule inhibitors that interact with β-catenin / BCL9 protein as described in the foregoing technical solutions or small molecule inhibitors that interact with β-catenin / BCL9 protein prepared by the methods described in the foregoing technical solutions, and isomers, pharmaceutically acceptable salts or esters of the above small molecule inhibitors.

[0262] In this invention, the active component in the pharmaceutical composition may also be combined with other effective components that have therapeutic effects or enhance therapeutic effects, reduce toxic side effects, or prolong metabolic time to form a pharmaceutical composition.

[0263] The present invention also provides the use of the small molecule inhibitor that interacts with β-catenin / BCL9 protein, the small molecule inhibitor that interacts with β-catenin / BCL9 protein prepared by the method described in the foregoing technical solutions, or the pharmaceutical composition described in the foregoing technical solutions in the preparation of antitumor drugs.

[0264] Preferably, the tumors mentioned in this invention include breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, leukemia, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, gastrointestinal stromal tumor, and skin cancer.

[0265] This invention demonstrates through experiments that the small molecule inhibitor that interacts with β-catenin / BCL9 protein has an anti-proliferative inhibitory effect on tumor cell lines such as human breast cancer cells MDA-MB-231, human breast cancer cells MDA-MB-468, human colon cancer cells HCT-116, and human liver cancer cells HepG2. It can be applied in drugs for the treatment of human or animal cell proliferation-related solid tumors or hematological malignancies.

[0266] The present invention also provides a method for preparing the compound shown in formula (I) above, which can be prepared by any of the following schemes:

[0267] Scheme (1): In a solvent, under the action of a catalyst, the compound shown in formula (III-4) undergoes the hydrolysis reaction shown below to obtain the compound shown in formula (III-3).

[0268]

[0269] Among them, rings A and R 1 R 2 X and R 4 As described in any one of the present invention;

[0270] Scheme (2): In a solvent, under the action of a catalyst, the compound shown in formula (III-3) is reacted with NH2-R g The amidation reaction shown below yields the compound represented by formula (III-5);

[0271]

[0272] Among them, R g -(CH2) k -R d or -(SO2)-R c ;

[0273] Rings A, K, R 1 R 2 X, R d and R c As described in any one of the present invention;

[0274] Scheme (3): In a solvent, under the action of a catalyst, the compound shown in formula (III-3) is reacted with HR. 4 The acylation reaction shown below yields the compound represented by formula (III-6);

[0275]

[0276] Among them, R 4 It is a 4- to 10-membered heterocyclic alkyl group or is composed of one or more R groups. e Substituted 4- to 10-membered heterocyclic alkyl groups;

[0277] Rings A and R 1 R 2 R e X, 4- to 10-membered heterocyclic alkyl groups as described in any one of the present invention.

[0278] In one embodiment, in the preparation method, in embodiment (1), the solvent is a conventional solvent for such reactions in the art, such as one or more of tetrahydrofuran, methanol and water, preferably a mixed solvent of tetrahydrofuran / methanol / water = 3:1:1.

[0279] In one embodiment, in the preparation method, in embodiment (1), the catalyst is a conventional catalyst for such reactions in the art, such as lithium hydroxide.

[0280] In one embodiment, in the preparation method, in embodiment (1), after the hydrolysis reaction is completed, Brønsted acid, such as hydrochloric acid, is added, and the pH of the system is 3-4 after the addition of Brønsted acid.

[0281] In one embodiment, in the preparation method, in embodiment (1), the compound shown in formula (III-3) can further undergo a salt formation reaction in a dioxane solution of hydrochloric acid.

[0282] In one embodiment, in the preparation method, in embodiment (2), the solvent is a conventional solvent for such reactions in the art, such as DCM.

[0283] In one embodiment, in the preparation method, in embodiment (2), the catalyst is a conventional catalyst for such reactions in the art, such as 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and / or 4-dimethylaminopyridine.

[0284] In one embodiment, in the preparation method, in embodiment (3), the solvent is a conventional solvent for such reactions in the art, such as dichloromethane and / or DMF.

[0285] In one embodiment, in the preparation method, in embodiment (3), the catalyst is a conventional catalyst for such reactions in the art, such as triethylamine and / or HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate).

[0286] In one embodiment, in the preparation method, in embodiment (3), the compound of formula (III-6) obtained can further undergo a salt formation reaction in a dioxane solution of hydrochloric acid.

[0287] This invention provides a compound represented by formula (III-4).

[0288]

[0289] Among them, R 4 It is a C1-C6 alkoxy group, with rings A, X, and R. 1 and R 2 As described in any one of the present invention.

[0290] In one embodiment, in the compound represented by formula (III-4), R 4 In this context, the C1-C6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, or isobutoxy, such as methoxy.

[0291] In one embodiment, the compound represented by formula (III-4) is any of the following compounds:

[0292] 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester;

[0293] 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester;

[0294] 2-(3-(1-(3-(benzo[b]thiophene-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0295] 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0296] 2-Methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propionate;

[0297] 2-Methyl-2-(3-(1-(3-(thien-2-yl)benzoyl)piperidin-3-yl)phenoxy)propionate;

[0298] 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0299] 2-(3-(1-(4'-isopropyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester;

[0300] 2-(3-(1-([1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0301] 2-(3-(1-([1,1'-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0302] 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester;

[0303] 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester;

[0304] 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0305] 2-Methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)methyl propionate;

[0306] 2-(3-(1-([1,1'-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0307] 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0308] 2-Methyl-2-(3-(1-((3-(thien-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)methyl propionate;

[0309] 2-(3-(1-((3-(benzo[b]thiophene-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;

[0310] 2-(3-(1-((3'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0311] 2-(3-(1-((4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;

[0312] Methyl 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-propionate;

[0313] 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester;

[0314] 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0315] 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropionate;

[0316] 2-(3-(1-2-(4-isopropylphenylacetyl)piperidin-3-ylphenoxy)-2-methylpropionate;

[0317] 3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy-2-methylpropionate methyl ester;

[0318] 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropionate;

[0319] 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropionate;

[0320] 2-(3-1-Biphenyl)-4-carbonylpiperidine-3-phenoxy-2-methylpropionate methyl ester;

[0321] 2-(3-1-(3'-isopropylbiphenyl)-3-sulfonylpiperidin-3-ylphenoxy-2-methylpropionate;

[0322] 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidine-2-methylpropionate methyl ester;

[0323] 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate.

[0324] This invention also provides a method for preparing the small molecule inhibitor that interacts with β-catenin / BCL9 protein as described in the above technical solution, comprising the following steps:

[0325] The compound of formula (V) is coupled with the compound of formula (VI) to obtain the intermediate compound of formula (VII);

[0326] The coupling reagent is selected from one or more of triethylamine, dichloromethane, HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), DMF, palladium on carbon, and Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene);

[0327]

[0328] in,

[0329] Cycle A' is selected from cyclic A or a precursor compound of cyclic A;

[0330] Y is selected from X or a precursor group of X;

[0331] R 5 Selected from R 3 Or R 3 The precursor group, or may be R 3 Or R 3 The precursor group is substituted with halogen, hydroxyl, carboxyl, amino, acyl, amide, alkoxy, alkylamine, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl, or heterocyclic groups;

[0332] R8 is a group that can react with 1-NH in the piperidine ring;

[0333] R6 and R7 are independently selected from the precursor groups of R6 / R7 or R6 / R7, or halogen, hydroxyl, carboxyl, amino, acyl, amide, alkoxy, alkylamine, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl, or heterocyclic groups that can be substituted by the precursor groups of R6 / R7 or R6 / R7.

[0334] Preferably, the method for preparing the compound of formula (V) includes:

[0335] 5-Pyridineboronic acid reacts with compound (III) in a first reaction to give compound (IV);

[0336] Compound (Ⅳ) undergoes a second reaction to yield compound (Ⅴ);

[0337] The conditions for the first reaction include heating the reactants under alkaline conditions;

[0338] The second reaction is a catalytic hydrogenation reaction, and the catalyst is selected from Pt, Pd or Ni-based catalysts;

[0339]

[0340] Preferably, the method for preparing compound (II) includes the following steps:

[0341] The compound of formula (VIII) is coupled with the compound of formula (VI) to obtain the intermediate compound of formula (IX);

[0342] The coupling reaction reagent is selected from one or more of triethylamine, dichloromethane, HATU, DMF, palladium on carbon, and Xantphos;

[0343]

[0344] in,

[0345] "Ring A" is selected from substituted or unsubstituted benzene or its precursor group;

[0346] R9 is selected from R4 or the precursor group of R4, or a halogen, hydroxyl, carboxyl, amino, acyl, amide, alkoxy, alkylamine, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl, or heterocyclic group that can be replaced by the precursor group of R4 or R4.

[0347] Preferably, the preparation method of compound (VIII) includes:

[0348] 5-Pyridineboronic acid undergoes a third reaction with compound (X) to give compound (XI);

[0349] Compound (XI) undergoes a fourth reaction with methyl 2-bromoisobutyrate to give compound (XII);

[0350] Compound (XII) undergoes a fifth reaction to yield compound (VIII);

[0351] The conditions for the third reaction include heating the reactants under alkaline conditions;

[0352] The conditions for the fourth reaction include heating the reactants under alkaline conditions;

[0353] The fifth reaction is a catalytic hydrogenation reaction, and the catalyst is selected from Pt, Pd or Ni-based catalysts;

[0354]

[0355] in,

[0356] R10 is selected from a group that can undergo a substitution reaction with methyl 2-bromoisobutyrate;

[0357] R9 is selected from R4 or the precursor group of R4, or a halogen, hydroxyl, carboxyl, amino, acyl, amide, alkoxy, alkylamine, mercapto, sulfonyl, hydrocarbon, aryl, heteroaryl, or heterocyclic group that can be replaced by the precursor group of R4 or R4.

[0358] Terminology Explanation:

[0359] Unless otherwise stated, the terms used in this invention are defined as follows:

[0360] The term "isomer" includes, but is not limited to, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, tautomers, mixtures of racemic mixtures and diastereomers, and their pharmaceutically acceptable salts. Unless otherwise stated, when the isomer component is not specifically specified, all possible isomers are included.

[0361] The term "pharmaceutically acceptable salt" refers to compounds modified by forming the acidic or basic salt of the small molecule inhibitors that interact with the β-catenin / BCL9 protein as described in this invention, including but not limited to salts of inorganic acids selected, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromic acids, sulfates, sulfites, and nitrates; and salts of organic salts selected, for example, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkylates such as acetates, and salts of HOOC-(CH2)n-COOH, where n is selected from 0-4. If the compound is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acidic salt. Conversely, if the product is a free base, the addition salt (e.g., a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with acid, consistent with the conventional process for preparing acid addition salts from basic compounds. Those skilled in the art will understand the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation. See, for example, the Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition), for details on hydrochloride salts.

[0362] The term "pharmaceutically acceptable ester" refers to an ester derivative formed by the formation of the small molecule inhibitor described in this invention, such as a methyl ester derivative obtained by the esterification of a small molecule inhibitor with methanol.

[0363] The term "pharmaceuticalally acceptable prodrug" refers to a precursor compound that forms the small molecule inhibitor described in this invention in vivo and in vitro.

[0364] The term "aromatic ring" or "aryl" refers to an all-carbon monocyclic or fused polycyclic group with 5-12 carbon atoms and a fully conjugated π-electron system. Non-limiting examples of aromatic rings include benzene rings, biphenyl rings, naphthalene rings, and anthracene rings.

[0365] The term "heteroaromatic ring" or "heteroaryl" refers to an unsaturated carbon ring of 5-12 ring atoms, in which one or more carbon atoms are replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc. Heteroaromatic rings can be monocyclic or bicyclic, formed by the fusion of two rings. Specific heterocyclic aryl groups can be: pyrrole, pyrazolyl, imidazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyrrole, morpholinyl, piperidinyl or piperazinyl, thiophene, benzothiophene, pyrazolyl, benzopyrazolyl, indolyl, dioxopentyl, benzo[1,3]dioxopentyl, oxazolyl, benzooxazolyl, furanyl, benzofuranyl, thiazolyl or benzothiazolyl, etc.

[0366] The terms "alicylic ring" or "cycloalkyl" refer to a saturated monocyclic carbon ring having 3 or more carbon atoms, unless a different number of atoms and degree of saturation are specified. "Alicylic ring" or "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0367] The term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above. Examples of "alkoxy" as used in this invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy.

[0368] The term "halogen" or "halogenated" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0369] The terms "heterocyclic," "heterocyclic," or "heterocyclic group" refer to a saturated or partially unsaturated 4- to 12-membered monocyclic, bicyclic, and tricyclic ring containing at least one carbon atom in addition to one, two, three, or four heteroatoms selected from oxygen, sulfur, and nitrogen. "Heterocyclic," "heterocyclic," or "heterocyclic group" also refers to a 5- to 7-membered heterocycle fused with a 5, 6, and / or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring and containing at least one heteroatom selected from N, O, and S, provided that the connection point is on the heterocycle when fused with a carbocyclic aromatic or heteroaromatic ring, and on the cycloalkyl or heterocycle when fused with a cycloalkyl ring. "Heterocyclic," "heterocyclic," or "heterocyclic group" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, provided that the connection point is on the heterocycle. The connection point can be a carbon atom or a heteroatom in the heterocycle. A heterocycle is not a heteroaryl group as defined herein.

[0370] The term "fused ring" refers to a polycyclic system, such as a bicyclic or tricyclic system, in which the two rings share only two ring atoms and one bond. Examples of fused rings can include fused bicyclic alkyl rings, such as bicyclic rings composed of 7-12 ring atoms selected from the above-described [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems; fused bicyclic aryl rings, such as the above-described 7-12 membered bicyclic aryl ring systems; fused tricyclic aryl rings, such as the above-described 10-15 membered tricyclic aryl ring systems; fused bicyclic heteroaryl rings, such as the above-described 8-12 membered bicyclic heteroaryl rings; fused tricyclic heteroaryl rings, such as the above-described 11-14 membered tricyclic heteroaryl rings; and the above-described fused bicyclic or tricyclic heterocyclic rings.

[0371] The term "-" indicates that the group is attached to the rest of the molecule through that site. For example, "CH3O-" refers to an alkoxy group.

[0372] the term This means that the structural segment is connected to the rest of the molecule through this site.

[0373] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0374] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the *Pharmacopoeia of the People's Republic of China (2020 Edition)* and *Handbook of Pharmaceutical Excipients* (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0375] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0376] The term "prevention" refers to reducing the risk of developing a disease.

[0377] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0378] The term "therapeutic effective amount" refers to the amount of compound administered to a patient that is sufficient to effectively treat the disease. Therapeutic effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0379] The expression "a group B substituted by one or more groups A" means that one or more hydrogen atoms in group B are independently substituted by group A. When multiple groups A appear simultaneously, unless otherwise specified, their definitions are independent and do not affect each other.

[0380] The term "oxo" refers to =O, where an oxygen atom replaces two hydrogen atoms on the same atom. For example, methylene (-(CH2-)) becomes carbonyl (-C(=O)-) after being oxidized.

[0381] The term "alkyl" refers to a saturated monovalent hydrocarbon group that has a specified number of carbon atoms, is straight-chain or branched. For example, C1-C6 alkyl groups (C 1-6 Alkyl) or C4-C 20 Alkyl (C) 4-20 Alkyl), preferably C1-C4 alkyl (C 1-4 Alkyl) or C9-C 15 Alkyl (C) 1-6 Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0382] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0383] The reagents and raw materials used in this invention are all commercially available.

[0384] The positive and progressive effects of this invention are as follows:

[0385] 1. The small molecule inhibitor that interacts with β-catenin / BCL9 protein described in this invention is a novel phenylpiperidine compound with a novel structure, high pharmacological activity, and good safety profile, possessing one or more of the following advantages:

[0386] (1) It has a high affinity for β-catenin / BCL9 protein-protein, which can block the activation of Wnt pathway and inhibit tumor cells through the cell membrane;

[0387] (2) It has a selective inhibitory effect on tumor cells. In in vitro experiments, it showed high inhibitory activity against human breast cancer cells, human colon cancer cells and human liver cancer cells, but low inhibitory activity against normal human cells, showing low toxic side effects.

[0388] (3) It has a high inhibitory concentration on hERG potassium channels and low potential cardiotoxicity;

[0389] (4) Liver microsomal metabolism is stable;

[0390] (5) It has shown a significant inhibitory effect on tumor growth in animal experiments and can inhibit a variety of tumor cells.

[0391] 2. The method for preparing small molecule inhibitors that interact with β-catenin / BCL9 protein provided by this invention has simple conditions, readily available raw materials, and low preparation cost. Attached Figure Description

[0392] Figure 1 This is a comparison of the in vivo efficacy of different compounds in the colon cancer mouse model in Example 36.

[0393] Figure 2 Changes in tumor volume after drug administration in a mouse model of colon cancer.

[0394] Figure 3 Changes in body weight after drug administration in a mouse model of colon cancer. Detailed Implementation

[0395] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0396] Example 1 Preparation of 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-1

[0397]

[0398] Step a: Preparation of 3-(pyridin-3-yl)phenol, compound 3

[0399] Compound 1 (200 mg, 1.16 mmol) and compound 2 (171 mg, 1.39 mmol) were dissolved in an ethanol / toluene solution (1:2, 30 mL), followed by the addition of 5 mL of 2 M sodium carbonate solution. The reaction mixture was reacted at 110 °C for 5 h under nitrogen protection. The reaction solution was filtered, concentrated under reduced pressure, and repeatedly extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1-3:1) to give 120 mg of a pale yellow solid, with a yield of 60%.

[0400] Step b: Preparation of methyl 2-methyl-2-(3-(pyridin-3-yl)phenoxy)propionate, compound 5

[0401] Compound 3 (2.5 g, 14.6 mmol) and compound 4 (3.2 g, 17.5 mmol) were dissolved in acetonitrile (50 mL) solution, followed by the addition of potassium carbonate (4 g, 29.2 mmol). The reaction was carried out at 90 °C for 20 h. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1-4:1) to give 2.5 g of a pale yellow oil, with a yield of 64%.

[0402] Step c: Preparation of methyl 2-methyl-2-(3-(piperidin-3-yl)phenoxy)propionate, compound 6

[0403] A methanol (30 mL) solution of compound 5 (2.7 g, 9.9 mmol) was added to a 1 N hydrochloric acid solution (10 mL), followed by 200 mg of platinum dioxide as a catalyst. The reaction was carried out at a hydrogen pressure of 50 psi for 5 h. The reaction solution was filtered to remove platinum dioxide. The pH of the reaction solution was adjusted to alkaline by adding saturated sodium bicarbonate aqueous solution. The solution was repeatedly extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:1-100:5) to obtain 1.3 g of a pale yellow oil, with a yield of 47%.

[0404] Step d: Preparation of methyl 3',4'-dimethyl-[1,1'-biphenyl]-3-carboxylic acid, compound 9

[0405] Compound 7 (800 mg, 3.7 mmol) and compound 8 (669 mg, 4.5 mmol) were dissolved in a toluene / methanol / 2M sodium carbonate solution (2:1:1, 30 mL). Tetraphenylphosphine palladium (129 mg, 0.11 mmol) was added. The mixture was reacted at 110 °C for 3 h under nitrogen protection. After filtration, the reaction solution was evaporated to dryness under reduced pressure. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 870 mg of a colorless oil, with a yield of 98%.

[0406] Step e: Preparation of 3',4'-dimethyl-[1,1'-biphenyl]-3-carboxylic acid, compound 10

[0407] Compound 9 (868 mg, 3.6 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (758 mg, 18 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-6:1) to give 760 mg of white solid, with a yield of 86%.

[0408] Step f: Preparation of methyl 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate, compound 11: Compound 6 (500 mg, 1.8 mmol) was dissolved in N,N-dimethylformamide (25 mL) solution, and compound 9 (316 mg, 1.4 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (836 g, 1.2 mmol) and triethylamine (364 mg, 3.6 mmol) were added, respectively. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain crude product, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-6:1) to obtain 648 mg of colorless oil, yield 98%.

[0409] Step g: Preparation of 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-1

[0410] Methyl 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate (671 mg, 1.4 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (290 mg, 6.9 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution. The solution was filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-1:1) to give 201 mg of white solid, yield 32%.

[0411] 1H NMR(400MHz,MeOD)δ7.79–7.60(m,2H),7.52(dd,J=15.7,7.9Hz,1H),7.46–7.28(m,3H), 7.17(dt,J=15.4,10.0Hz,2H),7.02–6.86(m,1H),6.77(dd,J=20.9,11.6Hz,1H),6.71(s ,1H),4.70(d,J=10.4Hz,1H),3.80(t,J=12.0Hz,1H),3.16(dd,J=27.0,13.6Hz,1H),2.8 8(dd,J=34.1,22.1Hz,2H),2.33(d,J=13.0Hz,6H),2.15–1.67(m,4H),1.60–1.46(m,6H).

[0412] Example 2

[0413] Preparation of 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-2

[0414]

[0415] Methyl 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate was obtained according to Example 1.

[0416] Methyl 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate (660 mg, 1.3 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (279 mg, 6.6 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution. The solution was filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-2:1) to give 50 mg of white solid, yield 8%.

[0417] 1H NMR(400MHz,MeOD)δ7.76–7.49(m,4H),7.47–7.27(m,3H),7.15(dt,J=51.3, 7.8Hz,1H),7.01–6.85(m,1H),6.74(dd,J=21.6,13.1Hz,1H),6.67(s,1H),4 .68(d,J=11.9Hz,1H),3.88–3.63(m,1H),3.16(dd,J=26.3,13.6Hz,1H),2.9 8–2.69(m,2H),2.02(t,J=15.5Hz,1H),1.88–1.70(m,2H),1.66–1.41(m,7H).

[0418] Example 3

[0419] Preparation of 2-(3-(1-(3-(benzo[b]thiophene-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-3

[0420]

[0421] Referring to Example 1, intermediate methyl 2-(3-(1-(3-(benzo[b]thiophene-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained.

[0422] The intermediate methyl 2-(3-(1-(3-(benzo[b]thiophene-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate (660 mg, 1.2 mmol) was dissolved in a solution of tetrahydrofuran / methanol / water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (245 mg, 5.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1-1:1) to give 130 mg of white solid, yield 22%.

[0423] 1H NMR(400MHz,MeOD)δ8.16(d,J=15.1Hz,1H),8.00–7.85(m,1H),7.88–7.44(m,5H),7.3 9(s,2H),7.15(dt,J=53.2,7.7Hz,1H),7.00–6.83(m,1H),6.85–6.61(m,2H),4.69(d,J =12.0Hz,1H),3.79(t,J=14.9Hz,1H),3.16(dd,J=26.5,13.6Hz,1H),2.84(dt,J=21.9, 11.4Hz, 2H), 2.02 (d, J = 11.3Hz, 1H), 1.98–1.72 (m, 2H), 1.54 (dd, J = 47.5, 26.4Hz, 7H).

[0424] Example 4

[0425] Preparation of 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-4

[0426]

[0427] The intermediate methyl 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained according to Example 1.

[0428] The intermediate methyl 22-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate (530 mg, 1.1 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (240 mg, 5.7 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1-1:1) to give 180 mg of white solid, yield 34%.

[0429] 1 H NMR (400MHz, MeOD) δ7.44–7.07(m,5H),6.92(dd,J=48.8,20.5Hz,1H),6.77(dd,J=24.1,15.9Hz ,2H),4.69(s,1H),3.85–3.60(m,1H),3.25–2.98(m,1H),2.99–2.47(m,3H),2.12–1.37(m,20H).

[0430] Example 5

[0431] Preparation of 2-methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propionic acid, compound II-5

[0432]

[0433] The intermediate methyl 2-methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propionate was obtained according to Example 1.

[0434] The intermediate methyl 2-methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propionate (600 mg, 1.3 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (272 mg, 6.5 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1-1:1) to give 230 mg of white solid, yield 38%.

[0435] 1 H NMR (600MHz, MeOD) δ7.80–7.69(m,3H),7.53–7.47(m,3H),7.34(d,J=5.4Hz,1H),7.26–7.07(m,1H),7.01–6.87(m,1H),6.78(dd,J=31.3,7.4Hz ,1H),6.70(s,1H),4.70(d,J=11.7Hz,1H),3.91–3.60(m,1H),3.22–3.0 5(m,1H),3.00–2.63(m,2H),1.97–1.68(m,3H),1.54(d,J=61.5Hz,7H).

[0436] Example 6

[0437] Preparation of 2-methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propionic acid, compound II-6

[0438]

[0439] The intermediate methyl 2-methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propionate was obtained according to Example 1.

[0440] The intermediate methyl 2-methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)propionate (510 mg, 1.1 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (231 mg, 5.5 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 135 mg of white solid, yield 27%.

[0441] 1 H NMR(400MHz,MeOD)δ7.80–7.66(m,2H),7.48(dd,J=24.4,12.8Hz,3H),7.34(d ,J=7.2Hz,1H),7.21(dd,J=30.9,23.0Hz,2H),7.02–6.86(m,1H),6.77(dd,J= 25.1,13.9Hz,2H),4.69(d,J=11.3Hz,1H),3.76(t,J=12.2Hz,1H),3.14(dd,J =26.5,13.3Hz,1H),2.95–2.64(m,2H),2.03-1.93(m,1H),2.01–1.41(m,9H).

[0442] Example 7

[0443] Preparation of 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-7

[0444]

[0445] Referring to Example 1, intermediate methyl 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained.

[0446] The intermediate methyl 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate (200 mg, 0.45 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (93 mg, 2.2 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution. The solution was filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 25 mg of white solid, with a yield of 10%.

[0447] 1 H NMR(400MHz,MeOD)δ7.81–7.45(m,5H),7.42–7.24(m,3H),7.28–7.03(m,1H),7.00–6.86(m,1H),6.77(dd,J=30.9,7.9Hz,2H) ,4.69(d,J=11.7Hz,1H),3.78(t,J=11.0Hz,1H),3.21–3.03(m,1H),3.03–2.62(m,3H),2.15–1.96(m,1H),1.77–1.34(m,8H).

[0448] Example 8

[0449] Preparation of 2-(3-(1-(4'-isopropyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-8

[0450]

[0451] Methyl 2-(3-(1-(4'-isopropyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate was obtained according to Example 1.

[0452] The intermediate methyl 2-(3-(1-(4'-isopropyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate (400 mg, 0.66 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (182 mg, 4.3 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 150 mg of white solid, yield 46%.

[0453] 1 H NMR(400MHz,MeOD)δ7.76–7.62(m,2H),7.54(dt,J=19.8,7.8Hz,3H),7.43–7.28(m,3H ),7.26–7.04(m,1H),7.06–6.86(m,1H),6.77(dd,J=30.9,7.9Hz,2H),4.69(d,J=11.7 Hz,1H),3.78(t,J=11.0Hz,1H),3.24–3.09(m,1H),3.01–2.68(m,3H),2.01(t,J=19.8 Hz, 1H), 1.73 (dd, J = 38.7, 20.3Hz, 2H), 1.53 (d, J = 36.2Hz, 6H), 1.29 (t, J = 6.3Hz, 6H).

[0454] Example 9

[0455] Preparation of 2-(3-(1-([1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-9

[0456]

[0457] The intermediate methyl 2-(3-(1-([1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained according to Example 1.

[0458] The intermediate methyl 2-(3-(1-([1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionate (425 mg, 0.92 mmol) was dissolved in a solution of tetrahydrofuran / methanol / water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (195 mg, 4.65 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 126 mg of white solid, yield 30%.

[0459] 1H NMR (400MHz, MeOD) δ7.80–7.33(m,9H),7.20(dd,J=34.3,26.4Hz,1H),6.93(dd,J=42.9,15.1Hz,1H),6.86–6.62(m,2H),4.70 (d,J=11.5Hz,1H),3.80(d,J=10.9Hz,1H),3.15(dd,J=23.8,11.7Hz,1H),2.93-2.79(m,2H),2.03(s,1H),1.98–1.46(m,9H).

[0460] Example 10

[0461] Preparation of 2-(3-(1-([1,1'-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-10

[0462]

[0463] The intermediate methyl 2-(3-(1-([1,1'-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained according to Example 1.

[0464] The intermediate methyl 2-(3-(1-([1,1'-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionate (350 mg, 0.76 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (159 mg, 3.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 177 mg of white solid, yield 35%.

[0465] 1 H NMR(400MHz,MeOD)δ7.68(d,J=26.9Hz,4H),7.55–7.34(m,5H),7.18(d,J=4 2.5Hz,1H),7.03–6.87(m,1H),6.76(d,J=30.5Hz,2H),4.69(d,J=10.1Hz,1H ),3.80(s,1H),3.14(dd,J=25.8,12.9Hz,1H),2.86(dd,J=35.0,23.3Hz,2H ), 2.03 (t, J = 10.0Hz, 1H), 1.81 (dd, J = 43.4, 32.2Hz, 2H), 1.66–1.45 (m, 7H).

[0466] Example 11

[0467] Preparation of 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-11

[0468]

[0469] Step a: Preparation of methyl 2-(3-(1-((3-bromophenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate, compound 13

[0470] Compound 6 (1 g, 3.6 mmol) was dissolved in dichloromethane solution, and triethylamine (540 mg, 5.4 mmol) was added and stirred for 10 min. Under nitrogen protection, compound 12 (1.1 g, 4.3 mmol) was added, and the mixture was reacted at room temperature for 24 h. The reaction solution was directly evaporated to dryness and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 1.06 g of white solid, yield 62%.

[0471] Step b: Methyl 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate was obtained according to Example 1.

[0472] Step c: Preparation of 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-11

[0473] Intermediate 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid (1.1 g, 2.0 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (428 mg, 10.2 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution. The solution was filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 500 mg of white solid, yield 48%.

[0474] 1H NMR(400MHz,MeOD)δ7.94–7.80(m,2H),7.72–7.59(m,2H),7.38(s,1H),7.36–7.29( m,1H),7.22–7.16(m,1H),7.16–7.07(m,1H),6.81(d,J=7.7Hz,1H),6.72(dd,J=4.1 ,2.1Hz,2H),3.85–3.70(m,2H),2.73(ddd,J=11.5,8.2,3.5Hz,1H),2.40–2.20(m,8 H),1.86–1.71(m,2H),1.71–1.56(m,1H),1.48(t,J=11.5Hz,6H),1.46–1.34(m,1H).

[0475] Example 12

[0476] Preparation of 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-12

[0477]

[0478] Methyl 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate was obtained with reference to Example 11.

[0479] Methyl 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate (377 mg, 0.71 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (149 mg, 3.6 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 148 mg of white solid, yield 39%.

[0480] 1 H NMR (400MHz, DMSO-d) 6)δ13.04(s,1H),8.03(dt,J=7.3,1.6Hz,1H),7.95(d,J=1.5Hz,1H),7.91–7. 80(m,1H),7.82–7.65(m,2H),7.64–7.43(m,2H),7.21–7.08(m,1H),6.84(d,J =7.7Hz,1H),6.70(d,J=1.5Hz,1H),6.64(dd,J=8.1,2.1Hz,1H),3.69(dt,J= 20.0,14.2Hz,2H),2.81–2.64(m,1H),2.41–2.30(m,2H),1.80–1.26(m,10H).

[0481] Example 13

[0482] Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-13

[0483]

[0484] Referring to Example 11, intermediate methyl 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained.

[0485] The intermediate methyl 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate (330 mg, 0.61 mmol) was dissolved in a solution of tetrahydrofuran / methanol / water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (129 mg, 3.1 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 101 mg of white solid, yield 32%.

[0486] 1H NMR(400MHz,MeOD)δ7.80–7.66(m,2H),7.48(dd,J=24.4,12.8Hz,3H),7.34(d,J =7.2Hz,1H),7.21(dd,J=30.9,23.0Hz,2H),7.02–6.86(m,1H),6.77(dd,J=25.1 ,13.9Hz,2H),4.69(d,J=11.3Hz,1H),3.76(t,J=12.2Hz,1H),3.14(dd,J=26.5, 13.3Hz, 1H), 2.95–2.64 (m, 2H), 1.99 (dd, J=34.5, 7.5Hz, 1H), 2.01–1.41 (m, 9H).

[0487] Example 14

[0488] Preparation of 2-methyl-2-(3-(1-((3-(thien-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionic acid, compound II-14

[0489]

[0490] Referring to Example 11, intermediate methyl 2-methyl-2-(3-(1-((3-(thien-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionate was obtained.

[0491] The intermediate methyl 2-methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionate (280 mg, 0.56 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (94 mg, 2.2 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 115 mg of white solid, yield 46%.

[0492] 1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),8.12–8.02(m,2H),7.98(s,1H),7.66(dtd, J=6.4,5.1,2.1Hz,4H),7.16(t,J=7.9Hz,1H),6.83(d,J=7.7Hz,1H),6.71(d,J=1 .9Hz,1H),6.64(dd,J=8.1,2.0Hz,1H),3.91–3.54(m,2H),2.79–2.66(m,1H),2.4 0–2.28(m,2H),1.77(dd,J=8.4,4.9Hz,2H),1.67–1.51(m,1H),1.51–1.36(m,7H).

[0493] Example 15

[0494] Preparation of 2-(3-(1-([1,1'-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-15

[0495]

[0496] Referring to Example 11, intermediate methyl 2-(3-(1-([1,1'-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained.

[0497] The intermediate methyl 2-(3-(1-([1,1'-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate (420 mg, 0.85 mmol) was dissolved in a solution of tetrahydrofuran / methanol / water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (178 mg, 4.2 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 101 mg of white solid, yield 24%.

[0498] 1H NMR(600MHz,DMSO-d6)δ13.06(s,1H),8.02(d,J=6.7Hz,1H),7.93(s,1H),7.74(dd,J= 12.2,7.7Hz,4H),7.56–7.46(m,2H),7.44(t,J=7.2Hz,1H),7.17(t,J=7.8Hz,1H),6.85 (d,J=7.4Hz,1H),6.70(d,J=32.4Hz,1H),6.65(d,J=7.9Hz,1H),3.80–3.56(m,2H),2.7 4(t,J=11.0Hz,1H),2.48(d,J=37.5Hz,1H),2.39(t,J=9.0Hz,1H),1.82–1.40(m,10H).

[0499] Example 16

[0500] Preparation of 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-16

[0501]

[0502] Referring to Example 11, intermediate methyl 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained.

[0503] The intermediate methyl 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate (190 mg, 0.38 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (71 mg, 1.7 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 110 mg of white solid, with a yield of 30%.

[0504] 1 H NMR(600MHz, DMSO-d6)δ7.10(t,J=7.9Hz,1H),6.76(d,J=7.6Hz,1H),6.69–6.52(m,2H),3.58(dd, J=31.0,9.9Hz,2H),2.71–2.48(m,2H),2.25–2.13(m,2H),1.77–1.57(m,7H),1.55–1.18(m,13H).

[0505] Example 17

[0506] Preparation of 2-methyl-2-(3-(1-((3-(thien-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionic acid, compound II-17

[0507]

[0508] Referring to Example 11, intermediate methyl 2-methyl-2-(3-(1-((3-(thien-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionate was obtained.

[0509] The intermediate methyl 2-methyl-2-(3-(1-((3-(thiophen-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionate (190 mg, 0.38 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (71 mg, 1.7 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 110 mg of white solid, yield 30%.

[0510] 1 H NMR (600MHz, DMSO-d6) δ8.00(d,J=5.9Hz,1H),7.90(s,1H),7.72–7.63(m,4H),7.23–7.14(m,2H),6.85(d,J=7.6Hz,1H),6.72(s,1H),6.65(d, J=8.1Hz,1H),3.70(dd,J=36.0,10.2Hz,2H),2.73(dd,J=15.3,7.3Hz,1H),2.44–2.26(m,2H),1.77(dd,J=17.2,7.0Hz,2H),1.67–1.40(m,8H).

[0511] Example 18

[0512] Preparation of 2-(3-(1-((3-(benzo[b]thiophene-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-18

[0513]

[0514] Referring to Example 11, intermediate methyl 2-(3-(1-((3-(benzo[b]thiophene-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate was obtained.

[0515] Methyl 2-(3-(1-((3-(benzo[b]thiophene-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-propanoate (310 mg, 0.57 mmol) was dissolved in a solution of tetrahydrofuran / methanol / water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (119 mg, 2.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 123 mg of white solid, yield 24%.

[0516] 1 H NMR(400MHz,MeOD)δ8.18(s,1H),8.08–7.88(m,3H),7.82–7.56(m,4H),7.40(d,J=5.4Hz,1H),7.21–7.12(m,1H),6.83 (d,J=7.7Hz,1H),6.79–6.68(m,2H),3.83(d,J=11.3Hz,2H),2.87–2.63(m,1H),2.49–2.21(m,2H),1.92–1.45(m,10H).

[0517] Example 19

[0518] Preparation of 2-(3-(1-((3'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-19

[0519]

[0520] Referring to Example 11, intermediate methyl 2-(3-(1-((3'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained.

[0521] The intermediate methyl 2-(3-(1-((3'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate (400 mg, 0.75 mmol) was dissolved in a solution of tetrahydrofuran / methanol / water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (57 mg, 3.8 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution. The solution was filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 201 mg of white solid, with a yield of 56%.

[0522] 1 H NMR (400MHz, DMSO-d6) δ8.05–7.93(m,1H),7.89(s,1H),7.79–7.65(m,2H),7.55–7.47(m,2H),7.41( t,J=7.6Hz,1H),7.30(d,J=7.6Hz,1H),7.10(t,J=7.8Hz,1H),6.76(t,J=12.2Hz,1H),6.67(dd,J=13 .5,5.3Hz,2H),3.68(dt,J=19.9,11.1Hz,2H),2.97(hept,J=6.8Hz,1H),2.71(dd,J=15.2,7.3Hz,1H ), 2.35(t,J=11.2Hz,2H),1.74(s,2H),1.63–1.49(m,1H),1.50–1.35(m,7H),1.23(d,J=6.9Hz,6H).

[0523] Example 20

[0524] Preparation of 2-(3-(1-((4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-20

[0525]

[0526] Referring to Example 11, intermediate methyl 2-(3-(1-((4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate was obtained.

[0527] Methyl 2-(3-(1-((4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propanoate (300 mg, 0.55 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (115 mg, 2.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 121 mg of white solid, yield 46%.

[0528] 1 H NMR(400MHz,DMSO-d6)δ8.06–7.94(m,1H),7.89(s,1H),7.76–7.67(m,2H),7.69–7.60(m,2H),7 .51(d,J=8.5Hz,2H),7.15(t,J=7.9Hz,1H),6.83(d,J=7.7Hz,1H),6.68(d,J=15.1Hz,1H),6.64 (dd,J=8.1,2.1Hz,1H),3.77–3.66(m,2H),2.71(dt,J=22.4,7.4Hz,1H),2.41–2.26(m,2H),1.7 6(dd,J=8.3,4.9Hz,2H),1.58(dt,J=13.2,7.9Hz,1H),1.49–1.38(m,7H),1.30(d,J=6.4Hz,9H).

[0529] Example 21

[0530] Preparation of 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-21

[0531]

[0532] Step a: Preparation of methyl 2-(3-(1-(3-bromophenyl)piperidin-3-yl)phenoxy)-2-methylpropionate, compound 17

[0533] Compound 6 (1 g, 3.6 mmol) and compound 16 (1 g, 4.3 mmol) were dissolved in toluene (50 mL). Palladium acetate (20 mg, 0.07 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (80 mg, 0.14 mmol), and cesium carbonate (1.63 g, 5 mmol) were added, respectively. The mixture was reacted overnight at 80 °C under nitrogen protection. After filtration, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 100:2-100:3) to give 101 mg of white solid, yield 24%.

[0534] Step b: Methyl 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-propionate was obtained according to Example 1.

[0535] Step c: Preparation of 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-21

[0536] The intermediate methyl 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-propionate (160 g, 0.35 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (73 mg, 1.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution. The solution was filtered and dried to obtain 120 mg of white solid, with a yield of 77%.

[0537] 1 H NMR (400MHz, MeOD) δ7.31(d,J=12.6Hz,1H),7.29–7.21(m,2H),7.22–7.10(m,3H),7.05(d,J=7.6Hz,1H),6.95(dd,J=11.0,5.0Hz,2H),6.86( s,1H),6.75(dd,J=8.1,2.2Hz,1H),3.73(t,J=13.4Hz,2H),2.95–2.69(m,3H),2.28(d,J=12.1Hz,6H),2.07–1.77(m,3H),1.73–1.43(m,7H).

[0538] Example 22

[0539] Preparation of 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-22

[0540]

[0541] Step a: Preparation of methyl 2-(3-(1-(3-bromobenzyl)piperidin-3-yl)phenoxy)-2-methylpropionate, compound 21

[0542] Compounds 6 (1 g, 3.6 mmol) and 20 (666 mg, 3.6 mmol) were dissolved in 1,2-dichloromethane (50 mL) and stirred at room temperature for 2 h. Then, sodium trifluoroacetylborohydride (1.5 g, 7.2 mmol) was added and stirred at room temperature overnight. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give 310 mg of a colorless oil, with a yield of 19%.

[0543] Step b: Methyl 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-propionate was obtained according to Example 1.

[0544] Step c: Preparation of 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-22

[0545] The intermediate methyl 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-propionate (300 g, 0.69 mmol) was dissolved in a solution of tetrahydrofuran / methanol / water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (145 mg, 3.5 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution. The solution was filtered and dried to obtain 18 mg of white solid, with a yield of 6%.

[0546] 1H NMR (400MHz, MeOD) δ7.77(d,J=16.8Hz,1H),7.72(d,J=7.6Hz,1H),7.67–7.43(m,4H),7.36(dd,J=18.8,8.5Hz,1H),7.16(t,J=8.2Hz,1H),6.79(d,J=7 .5Hz,3H),4.35(q,J=13.0Hz,2H),3.45(t,J=13.0Hz,2H),3.10–2.90(m,3H ),1.92–1.77(m,1H),1.71(dd,J=25.2,11.1Hz,1H),1.53(d,J=4.1Hz,6H).

[0547] Example 23

[0548] Preparation of (3S)-3-((5-(3-(3-((2-carboxypropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-3',4'-difluoro-[1,1'-biphenyl]-2-yl)oxy)pyrrolidine-1-ammonium chloride, compound II-23

[0549]

[0550] Step a; Preparation of (S)-3-(2-bromo-4-(methoxycarbonyl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester, compound 26

[0551] Compound 24 (1 g, 4.33 mmol), compound 25 (811 mg, 4.3 mmol), and triphenylphosphine (1.4 mmol, 5.2 mmol) were dissolved in toluene (50 mL). Under nitrogen protection, diisopropyl azodicarbonate (1.0 g, 5.2 mmol) was added at 0 °C, and the mixture was gradually cooled to room temperature for 5 h. A 10% sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-7:1) to give 1.7 mg of a colorless oil, with a yield of 94%.

[0552] Step b: Referring to Example 1, (S)-3-((3',4'-difluoro-5-(methoxycarbonyl)-[1,1'-biphenyl]-2-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester was obtained.

[0553] Step c: (S)-6-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)-3',4'-difluoro-[1,1'-biphenyl]-3-carboxylic acid was obtained according to Example 1.

[0554] Step d: Referring to Example 1, tert-butyl(3S)-3-((3',4'-difluoro-5-(3-(3-(((1-methoxy-2-methyl-1-oxopropane-2-yl)oxy)phenyl)piperidin-1-carbonyl)-[1,1'-biphenyl]-2-yl)oxy)pyrrolidine-1-carboxylate was obtained.

[0555] Step e: 2-(3-(1-(6-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)-3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid was obtained according to Example 1.

[0556] Step f: Preparation of (3S)-3-((5-(3-(3-((2-carboxypropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-3',4'-difluoro-[1,1'-biphenyl]-2-yl)oxy)pyrrolidine-1-ammonium chloride, compound II-23

[0557] The intermediate 2-(3-(1-(6-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)-3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid (100 mg, 0.15 mmol) was dissolved in 4 M dioxane hydrochloride solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to give 77 mg of white solid, yield 85%.

[0558] 1 H NMR (400MHz, MeOD) δ7.31(d,J=12.6Hz,1H),7.29–7.21(m,2H),7.22–7.10(m,3H),7.05(d,J=7.6Hz,1H),6.95(dd,J=11.0,5.0Hz,2H),6.86( s,1H),6.75(dd,J=8.1,2.2Hz,1H),3.73(t,J=13.4Hz,2H),2.95–2.69(m,3H),2.28(d,J=12.1Hz,6H),2.07–1.77(m,3H),1.73–1.43(m,7H).

[0559] Example 24

[0560] Preparation of (3S)-3-(4-(3-(3-(((2-carboxypropane-2-yl)oxy)phenyl)piperidine-1-carbonyl)-2-cyclohexylphenoxy)pyrrolidine-1-ammonium chloride, compound II-24

[0561]

[0562] Referring to Example 23, intermediate 2-(3-(1-(4-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)-3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid was obtained.

[0563] The intermediate 2-(3-(1-(4-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)-3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid (125 mg, 0.20 mmol) was dissolved in 4M dioxane hydrochloride solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to give 85 mg of white solid, yield 74%.

[0564] 1 H NMR(400MHz,MeOD)δ7.38–7.07(m,3H),7.04–6.89(m,1H),6.89–6.60(m,2H),5.24(s,1H),4.63(s,1H),3.82– 3.42(m,5H),3.26–2.66(m,4H),2.29-2.26(m,2H),2.10–2.00(m,1H),1.94–1.66(m,7H),1.57–1.19(m,11H).

[0565] Example 25

[0566] Preparation of Compound II-25: 4-(2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-ammonium chloride

[0567]

[0568] Step a: Following Example 1, tert-butyl 4-(2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-carboxylic acid ester was obtained.

[0569] Step b: The intermediate tert-butyl 4-(2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-carboxylic acid ester (230 mg, 0.34 mmol) was dissolved in 15 mL of 4 M dioxane hydrochloride solution and reacted at room temperature for 2 h. The reaction solution was evaporated to dryness to give 130 mg of white solid, yield 63%.

[0570] 1H NMR(400MHz, DMSO-d6)δ9.42(s,2H),7.97(dd,J=5.5,2.9Hz,1H),7.88(s,1H),7.75–7.63( m,2H),7.49(s,1H),7.43(d,J=5.7Hz,1H),7.32–7.18(m,2H),6.89(d,J=7.5Hz,1H),6.64( dd,J=11.6,3.4Hz,2H),3.95(s,1H),3.73–3.64(m,4H),3.54–3.45(m,1H),2.93(s,2H),2. 72(dd,J=28.2,16.9Hz,3H),2.41–2.20(m,8H),1.74(t,J=18.9Hz,2H),1.62–1.39(m,8H).

[0571] Example 26

[0572] Preparation of 4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-ammonium chloride, compound II-26

[0573]

[0574] Referring to Example 25, intermediate 4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-carboxylic acid tert-butyl ester was obtained.

[0575] The intermediate tert-butyl 4-(2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.19 mmol) was dissolved in 15 mL of 4 M dioxane hydrochloride solution and reacted at room temperature for 2 h. The reaction solution was evaporated to dryness to give 60 mg of white solid, with a yield of 57%.

[0576] 1 H NMR (400MHz, MeOD) δ7.31(d,J=12.6Hz,1H),7.29–7.21(m,2H),7.22–7.10(m,3H),7.05(d,J=7.6Hz,1H),6.95(dd,J=11.0,5.0Hz,2H),6.86( s,1H),6.75(dd,J=8.1,2.2Hz,1H),3.73(t,J=13.4Hz,2H),2.95–2.69(m,3H),2.28(d,J=12.1Hz,6H),2.07–1.77(m,3H),1.73–1.43(m,7H).

[0577] Example 27

[0578] Preparation of 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(benzenesulfonyl))propionamide, compound II-27

[0579]

[0580] Step a: Compound II-11 (200 mg, 0.39 mmol) and compound 34 (61 mg, 0.39 mmol) were dissolved in dichloromethane (15 mL) solution. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.59 mmol) and 4-dimethylaminopyridine (95 mg, 0.78 mmol) were added, respectively. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 50 mg of white solid, yield 20%.

[0581] 1 H NMR(400MHz,DMSO-d6)δ12.17(d,J=147.9Hz,1H),7.89(dd,J=27.4,21.5Hz,4 H),7.76–7.36(m,7H),7.24(d,J=7.8Hz,1H),7.03(t,J=7.8Hz,1H),6.84(d,J= 7.3Hz,1H),6.62(s,1H),6.45(d,J=7.9Hz,1H),3.68(dd,J=34.6,10.2Hz,2H) ,2.61(t,J=8Hz,1H),2.42–2.18(m,8H),1.78-1.56(m,3H),1.49–1.28(m,7H).

[0582] Example 28

[0583] Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(benzenesulfonyl)propionamide, compound II-28

[0584]

[0585] II-13 (50 mg, 0.09 mmol) and compound 34 (14 mg, 0.09 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (27 mg, 0.14 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 30 mg of white solid, yield 22%.

[0586] 1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.02–7.93(m,1H),7.90–7.66(m,5H),7.59 (dd,J=31.4,19.7Hz,5H),7.36(d,J=8.2Hz,2H),6.99(t,J=7.8Hz,1H),6.79(d,J =6.4Hz,1H),6.59(s,1H),6.43(dd,J=8.1,2.0Hz,1H),3.67(dd,J=39.1,11.3Hz, 2H),3.01–2.83(m,1H),2.67–2.53(m,1H),2.41–2.26(m,2H),1.80–1.16(m,18H).

[0587] Example 29

[0588] Preparation of 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(benzenesulfonyl)propionamide, compound II-29

[0589]

[0590] II-2 (580 mg, 1.2 mmol) and compound 34 (171 mg, 1.1 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.8 mmol) and 4-dimethylaminopyridine (296 mg, 2.4 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 177 mg of white solid, yield 25%. 1H NMR (400MHz, MeOD) δ8.01(dd,J=22.3,7.5Hz,2H),7.65(ddd,J=23.3,21.5,7.5Hz,7H),7.53–7.26(m,3H),7.14–6.42(m,4H),4.69(dd,J=21. 5,13.1Hz,1H),3.74(dd,J=38.0,12.6Hz,1H),3.23–3.06(m,1H),2.99 –2.78(m,1H),2.80–2.57(m,1H),2.08–1.55(m,4H),1.49–1.31(m,6H).

[0591] Example 30 Preparation of Compound I-1 of 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid

[0592]

[0593] The intermediate methyl 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained according to Example 1.

[0594] The intermediate methyl 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropionate (700 mg, 1.6 mmol) was dissolved in a solution of tetrahydrofuran / methanol / water (3:1:1, 25 mL), followed by the addition of lithium hydroxide (335 mg, 8.0 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1-2:1) to give 280 mg of white solid, yield 40%.

[0595] 1 H NMR (400MHz, DMSO-d) 6)δ13.05(s,1H),7.19(t,J=7.9Hz,1H),7.08–6.97(m,3H),6.96(d,J=7.6H z,1H),6.88(d,J=7.7Hz,1H),6.74(s,1H),6.64(dd,J=8.1,2.1Hz,1H),4. 13(t,J=16.4Hz,2H),4.05(d,J=4.4Hz,1H),2.75–2.61(m,2H),2.18(d,J= 5.9Hz, 6H), 1.87 (d, J = 11.7Hz, 1H), 1.77–1.51 (m, 2H), 1.54–1.38 (m, 7H).

[0596] Example 31 Preparation of 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound I-2

[0597]

[0598] Methyl 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained according to Example 1. Methyl 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropionate (625 mg, 1.5 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (310 mg, 7.4 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution. The solution was filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using silica gel column chromatography (dichloromethane / methanol = 100:5-100:10) to give 270 mg of a white solid, with a yield of 45%.

[0599] 1 H NMR (600MHz, DMSO-d) 6 )δ7.12(t,J=7.9Hz,1H),7.00(d,J=7.6Hz,1H),6.94(s,1H),6.88(d,J=7.1Hz,1H),6.75(t,J=9.6Hz,1H),6.72(s,1H),6.64(dd,J=8.2,2. 2Hz,1H),3.05(t,J=11.5Hz,2H),2.76(dd,J=15.7,7.5Hz,1H),2.50–2.42(m,4H),2.30–2.09(m,8H),1.80-1.67(m,4H),1.58–1.40(m,8H).

[0600] Example 32 Preparation of 2-(3-(1-(2-(4-isopropylphenyl)acetyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-30

[0601]

[0602] The intermediate methyl 2-(3-(1-2-(4-isopropylphenylacetyl)piperidin-3-ylphenoxy)-2-methylpropionate was obtained according to Example 1.

[0603] The intermediate methyl 2-(3-(1-2-(4-isopropylphenylacetyl)piperidin-3-ylphenoxy)-2-methylpropionate (360 mg, 0.82 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (172 mg, 4.1 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 130 mg of white solid, yield 51%.

[0604] 1 H NMR (400MHz, CD3OD) δ7.06-7.24(m,5H),6.70-6.89(m,2H),6.50-6.54(m,1H),4.54-4.63(m,1H),3.87-4.02(m,1H),3.66-3. 81(m,2H),2.84-3.09(m,2H),2.52-2.70(m,1H),1.99-2.12(m,1H),1.63-1.93(m,3H),1.53-1.54(m,7H),1.22-1.28(m,6H). 13C NMR (100MHz, CD3OD) δ178.75,178.51,172.18,171.98,157.14,157.09,148.87,148.70,145 .77,145.31,133.87,133.80,130.18,129.96,129.65,129.54,128.04,127.77,124.94,121 .84,119.55,119.30,118.58,118.22,80.35,80.25,54.38,47.96,44.47,43.64,43.57,41. 85,41.26,35.07,35.00,32.60,32.33,26.86,26.29,25.79-25.90(m),24.56,24.52,24.45.

[0605] Example 33 Preparation of 3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy)-2-methylpropionic acid, compound II-31

[0606]

[0607] The intermediate methyl 3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy-2-methylpropionate was obtained according to Example 1.

[0608] The intermediate methyl 3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy-2-methylpropionate (318 mg, 0.75 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (157 mg, 3.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 60 mg of white solid, yield 23%.

[0609] 1H NMR(600MHz,CD3OD)δ7.49-7.58(m,3H),7.18-7.27(m,3H),7.04-7.13(m,1H),6.9 2(d,1H,J=7.8Hz),6.85(s,1H),6.77(d,1H,J=7.8Hz),4.65(t,1H,J=12.0Hz),4.21 -4.30(m,1H),3.16-3.24(m,1H),2.87-2.93(m,1H),2.62-2.80(m,1H),2.00-2.01( m,2H),1.84-1.90(m,1H),1.73-1.77(m,1H),1.52-1.62(m,7H),1.22-1.25(m,6H). 13 C NMR (150MHz, CD3OD) δ177.93,167.82,167.81,157.11,152.29,145.94,145.67,144.23,134.18,134.10,130.33,130.24,129.17,127.97,122. 04,119.40,118.62,117.44,117.27,80.17,53.68,50.20,47.58,45.01 ,44.05,43.91,35.27,33.09,32.88,30.76,27.59,26.36,25.79,24.23.

[0610] Example 34 Preparation of 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropionic acid, compound II-32

[0611]

[0612] The intermediate methyl 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropionate was obtained according to Example 1.

[0613] The intermediate methyl 2-(3-(1-(4-isopropylbenzoyl)piperidin-3-ylphenoxy)-2-methylpropionate (410 mg, 0.96 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (157 mg, 4.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 75 mg of white solid, yield 19%.

[0614] 1 H NMR(600MHz,CD3OD)δ7.33-7.35(m,4H),7.12-7.21(m,1H),6.88-6.96(m,1H),6.70-6.78(m,2H),4.66(s,1H),3.7 7(t,1H,J=13.8Hz),3.06-3.13(m,1H),2.73-2.94(m,3H),2.01-2.04(m,1H),1.51-1.90(m,9H),1.24-1.30(m,6H). 13 C NMR (150MHz, CD3OD) δ178.13,178.03,172.64,157.14,152.33,145.84,145.26,134.59,134.49,130.27,128.06,127.96,127.70,121. 98,121.64,119.38,118.62,80.19,55.78,49.92,44.86,43.77,35.28,32.76,32.61,27.26,26.32,26.32,26.01,25.82,25.54,24.25.

[0615] Example 35 Preparation of 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropionic acid, compound II-33

[0616]

[0617] The intermediate methyl 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropionate was obtained according to Example 1.

[0618] The intermediate methyl 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropionate (400 mg, 0.88 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (185 mg, 4.4 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 113 mg of white solid, yield 31%.

[0619] 1H NMR (600MHz, DMSO-d6) δ13.10 (s, 1H), 7.15-7.20 (m, 5H), 7.06 (t, 1H, J = 6.0Hz), 6. 87(d,1H,J=7.2Hz),6.75(s,1H),6.65(dd,1H,J1=1.8Hz,J2=7.8Hz),4.19(d,2H,J =6.0Hz),4.03-4.06(m,2H),2.82-2.87(m,1H),2.65-2.72(m,2H),2.51-2.56(m,1 H),1.87-1.89(m,1H),1.66-1.68(m,1H),1.47-1.59(m,8H),1.18(d,6H,J=7.2Hz). 13 C NMR(150MHz,DMSO-d6)δ175.18,157.23,155.42,146.48,145.23,138.59,128.97,127.09,125.95 ,120.29,117.37,115.71,78.23,50.14,43.74,43.32,41.97,33.13,31.56,25.13,25.07,23.99.

[0620] Example 36 Preparation of 2-(3-1-biphenyl)-4-carbonylpiperidine-3-phenoxy)-2-methylpropionic acid, compound II-34

[0621]

[0622] The intermediate methyl 2-(3-1-biphenyl)-4-carbonylpiperidine-3-phenoxy-2-methylpropionate was obtained according to Example 1.

[0623] The intermediate methyl 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropionate (350 mg, 0.76 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (159 mg, 3.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 177 mg of white solid, yield 53%.

[0624] 1H NMR (400MHz, CD3OD) δ7.63-7.70(m,4H),7.36-7.50(m,5H),7.11-7.21(m,1H),6.88-6.96(m,1H),6.70-6.78(m,2H),4.6 7(d,1H,J=10.0Hz),3.78(t,1H,J=10.8Hz),3.08-3.17(m,1H),2.75-2.90(m,2H),1.99-2.04(m,1H),1.47-1.91(m,9H). 13 C NMR(100MHz,CD3OD)δ178.14,178.01,172.27,157.10,145.81,145.20,14 4.07,141.29,135.83,130.30,130.00,128.94,128.52,128.42,128.20,1 28.07,122.01,121.66,119.40,119.23,118.62,80.20,55.84,49.92,44. 84,43.76,32.74,32.51,30.77,30.72,27.25,26.30,25.98,25.82,25.50.

[0625] Example 37 Preparation of compound II-35: 2-(3-1-3'-isopropylbiphenyl)-3-sulfonylpiperidine-3-ylphenoxy)-2-methylpropionic acid

[0626]

[0627] Referring to Example 11, intermediate methyl 2-(3-1-(3'-isopropylbiphenyl)-3-sulfonylpiperidine-3-ylphenoxy-2-methylpropionate was obtained.

[0628] The intermediate methyl 2-(3-1-(3'-isopropylbiphenyl)-3-sulfonylpiperidin-3-ylphenoxy-2-methylpropionate (400 mg, 0.76 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (157 mg, 3.8 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1 N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 288 mg of white solid, with a yield of 61%.

[0629] 1H NMR(400MHz,DMSO-d6)δ7.98-8.01(m,1H),7.90(s,1H),7.70-7.73(m,2H),7.49-7.5 3(m,2H),7.41(t,1H,J=7.6Hz),7.30(d,1H,J=7.6Hz),7.11(t,1H,J=7.6Hz),6.78(d, 1H,J=7.6Hz),6.66-6.70(m,2H),3.66-3.74(m,2H),2.92-3.02(m,1H),2.69-2.74(m ,1H),2.33-2.38(m,2H),1.74-1.76(m,2H),1.38-1.60(m,8H),1.23(d,6H,J=6.4Hz). 13 CNMR(100MHz,DMSO-d6)δ175.99,155.82,149.40,143.82,141.66,138.54,136.59,131.47,130.16,129.19,128.87,126.2 1,125.16,125.01,124.60,119.66,117.54,116.02,78.80,51.88,45.94,41.47,33.48,29.82,25.41,25.25,24.50,23.84.

[0630] Example 38 Preparation of compound II-36: 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidin-3-ylphenoxy)-2-methylpropionic acid

[0631]

[0632] The intermediate methyl 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidine-2-methylpropionate was obtained according to Example 11.

[0633] The intermediate methyl 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidine-2-methylpropionate (300 mg, 0.55 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (115 mg, 2.75 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 120 mg of white solid, yield 48%.

[0634] 1H NMR (400MHz, DMSO-d6) δ7.97-8.00 (m, 1H), 7.89 (s, 1H), 7.72 (d, 2H, J = 5.2Hz), 7. 64(d,2H,J=8.4Hz), 7.52(d,2H,J=8.8Hz), 7.16(t,1H,J=8.0Hz), 6.83(d,1H,J=7. 6Hz),6.70(s,1H),6.64(dd,1H,J1=2.0Hz,J2=8.0Hz),3.65-3.73(m,2H),2.70-2 .75(m,1H),2.32-2.39(m,2H),1.75-1.78(m,2H),1.41-1.63(m,8H),1.31(s,9H). 13 C NMR(100MHz,DMSO-d6)δ175.15,155.51,150.91,144.09,141.22,136.60,135.60,131.14,130.21,129.15,126.70,12 6.05,125.99,124.79,120.24,117.50,115.99,78.33,51.83,45.98,41.44,34.34,31.05,29.83,25.24,24.97,24.48.

[0635] Example 39 Preparation of N-((4-cyanophenyl)sulfonyl)-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methylpropionamide, compound II-37

[0636]

[0637] II-13 (100 mg, 0.19 mmol) and a derivative of compound 34 (34 mg, 0.17 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (55 mg, 0.28 mmol) and 4-dimethylaminopyridine (46 mg, 0.38 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 72 mg of a white solid, yield 65%.

[0638] 1H NMR (400MHz, CD3OD) δ8.05 (t, 2H, J = 4.8Hz), 7.91 (t, 1H, J = 1.2Hz), 7.83-7.88 (m, 3H), 7.60- 7.70(m,2H),7.52(d,2H,J=8.4Hz),7.29(d,2H,J=8.4Hz),6.98(t,1H,J=8.0Hz),6.75(d,1H J=7.6Hz),6.62(s,1H),6.49(dd,1H,J1=2.0Hz,J2=8.0Hz),3.73-3.80(m,2H),2.86-2.92(m,6.9Hz,1H),2.60- 2.66(m,1H),2.28-2.38(m,2H),1.74-1.80(m,2H),1.60-1.69(m,1H),1.33-1.42(m,7H),1.22(d,6H,J=7.2Hz). 13 C NMR (100MHz, CD3OD) δ177.48,156.42,150.37,145.80,145.45,143.49,138.17,137.81,133.72,132.29,130.98,130.32,129.83,128. 24,128.07,127.11,126.45,122.16,119.03,118.50,118.31,117.45,81.59,53.57,47.54,43.31,34.98,31.50,26.04,25.09,24.36.

[0639] Example 40: Preparation of N-benzyl-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropionamide, compound II-38

[0640]

[0641] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (32 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 151 mg of a white solid, yield 65%.

[0642] 1 H NMR (400MHz, DMSO-d6) δ8.62 (t, 1H, J = 6.0Hz), 7.97-8.00 (m, 1H), 7.89 (s, 1H), 7.68-7.73 (m,2H),7.63(d,2H,J=8.4Hz),7.36(d,2H,J=8.4Hz),7.12-7.25(m,6H),6.88(d,1H,J=7.6 Hz),6.69-6.73(m,2H),4.26-4.28(m,2H),3.63-3.74(m,2H),2.90-2.97(m,1H),2.67-2. 72(m,1H),2.28-2.38(m,2H),1.69-1.77(m,2H),1.42-1.63(m,8H),1.22(d,6H,J=7.2Hz). 13 C NMR(100MHz,DMSO-d6)δ173.47,154.87,148.67,143.91,141.30,139.54,136.56,135.96,131.11,130.15,129.08,128.07,127.18,127.1 1,126.92,126.59,125.96,124.74,120.96,118.72,117.97,80.07,5 1.79,45.93,42.24,41.36,33.11,29.71,25.13,24.97,24.44,23.75.

[0643] Example 41 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propionamide, compound II-39

[0644]

[0645] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (76 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 65 mg of a white solid, yield 59%.

[0646] 1H NMR (600MHz, CD3OD) δ8.08 (d, 2H, J = 8.4Hz), 7.92 (t, 1H, J = 1.8Hz), 7.87-7.88 (m, 1H), 7.79 (d, 2H, J = 8.4Hz), 7. 69-7.71(m,1H),7.64(t,1H,J=7.8Hz),7.54(d,2H,J=8.4Hz),7.31(d,2H,J=7.8Hz),6.95(t,1H,J=7.8Hz),6.75 (d,1H,J=7.8Hz),6.66(s,1H),6.47(dd,1H,J1=2.4Hz,J2=8.4Hz),3.75-3.81(m,2H),2.85-2.98(m,1H),2.65- 2.70(m,1H),2.31-2.39(m,2H),1.78-1.82(m,2H),1.63-1.69(m,1H),1.39-1.43(m,7H),1.24(d,6H,J=6.6Hz). 13 C NMR (150MHz, CD3OD) δ156.77,150.41,146.49,145.36,143.59,138.26,137.92,132.31,130.98,130.13,129.70,128.24,128.08,127 .11,126.67,126.64,125.88,124.08,121.77,119.01,118.08,81.72,53.67,47.57,43.39,35.03,31.52,26.05,25.39,25.36,24.34.

[0647] Example 42 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-((3-(trifluoromethyl)phenyl)sulfonyl)propionamide, compound II-40

[0648]

[0649] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (76 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 95 mg of a white solid, yield 62%.

[0650] 1 H NMR (600MHz, DMSO-d6) δ12.62 (s, 1H), 8.08-8.10 (m, 2H), 7.98 (d, 2H, J = 3.0Hz), 7.89 (s, 1H), 7.78-7.8 0(m,1H),7.71-7.72(m,2H),7.62(d,2H,J=7.8Hz),7.35(d,2H,J=7.8Hz),6.96(t,1H,J=7.8Hz),6.78(d ,1H,J=6.6Hz),6.60(s,1H),6.40(d,1H,J=7.8Hz),3.64-3.73(m,2H),2.90-2.95(m,1H),2.63-2.66(m, 1H),2.31-2.37(m,2H),1.68-1.77(m,2H),1.56-1.58(m,1H),1.33-1.43(m,7H),1.21(d,6H,J=6.6Hz). 13 C NMR(150MHz,DMSO-d6)δ175.16,155.12,148.64,143.92,141.28,136.59,136.00,131.19,131.09,130.16,128.76,127.09 ,126.94,126.01,124.77,123.84,120.19,117.74,116.05,80.13,51.75,45.94,41.39,33.11,29.76,24.61,24.48,23.74.

[0651] Example 43 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-N-((4-methoxyphenyl)sulfonyl)-2-methylpropionamide, compound II-41

[0652]

[0653] II-13 (205 mg, 0.39 mmol) and a derivative of compound 34 (71 mg, 0.35 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (111 mg, 0.58 mmol) and 4-dimethylaminopyridine (95 mg, 0.78 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 82 mg of a white solid, yield 61%.

[0654] 1 H NMR (600MHz, DMSO-d6) δ12.18(s,1H),7.98-8.00(m,1H),7.89(s,1H),7.81(d,2H,J=9.0Hz),7.71(d,2H,J=4.8 Hz), 7.63 (d, 2H, J = 8.4Hz), 7.36 (d, 2H, J = 8.4Hz), 7.12 (d, 2H, J = 9.0Hz), 7.06 (t, 1H, J = 7.8Hz), 6.88 (d, 1H, J = 7. 2Hz),6.65(s,1H),6.45(dd,1H,J1=2.4Hz,J2=8.4Hz),3.86(s,3H),3.64-3.73(m,2H),2.91-2.95(m,1H),2.64- 2.69(m,1H),2.32-2.38(m,2H),1.69-1.78(m,2H),1.57-1.59(m,1H),1.32-1.42(m,7H),1.22(d,6H,J=7.2Hz). 13 C NMR(150MHz,DMSO-d6)δ173.06,163.05,154.54,148.67,144.14,141.30,136.56,135.99,131.11,130.18,129.99,129.16,127.11 ,126.94,125.99,124.77,121.19,118.35,116.97,114.11,79.94,55.76,51.71,45.95,41.33,33.11,29.73,24.43,23.94,23.75.

[0655] Example 44 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methyl-N-((4-nitrophenyl)sulfonyl)propionamide, compound II-42

[0656]

[0657] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (69 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 82 mg of a white solid, yield 61%.

[0658] 1 H NMR (600MHz, DMSO-d6) δ12.73 (s, 1H), 8.30 (d, 2H, J = 8.4Hz), 7.97-8.02 (m, 3H), 7.89 (s, 1H), 7.71 ( d,2H,J=4.8Hz),7.62(d,2H,J=8.4Hz),7.35(d,2H,J=7.8Hz),6.98(t,1H,J=7.8Hz),6.75(d,1H,J=6 .6Hz),6.62(s,1H),6.43(d,1H,J=8.4Hz),3.63-3.73(m,2H),2.90-2.95(m,1H),2.62-2.66(m,1H) ,2.31-2.37(m,2H),1.68-1.76(m,2H),1.55-1.57(m,1H),1.34-1.46(m,7H),1.22(d,6H,J=7.2Hz). 13 CNMR(150MHz,DMSO-d6)δ155.42,148.91,148.63,143.77,141.27,136.60,136.00,131.09,130.18,128.76,128.63,127.1 0,126.94,126.01,124.75,123.58,117.46,116.03,80.23,51.83,45.94,41.44,33.11,29.72,24.92,24.49,23.76,23.75.

[0659] Example 45: Preparation of Compound II-43, N-((4-fluorophenyl)sulfonyl)-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropionamide

[0660]

[0661] II-13 (190 mg, 0.36 mmol) and a derivative of compound 34 (56 mg, 0.32 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) and 4-dimethylaminopyridine (88 mg, 0.72 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 79 mg of a white solid, yield 65%.

[0662] 1 H NMR (600MHz, CD3OD) δ7.99-8.01(m,2H),7.92(s,1H),7.88(d,1H,J=7.8Hz),7.70(d,1H,J=7.8Hz),7.64(t,1H ,J=7.8Hz),7.54(d,2H,J=7.8Hz),7.31(d,2H,J=7.8Hz),7.25(t,2H,J=8.4Hz),7.01(t,1H,J=7.8Hz),6.80(d ,1H,J=7.2Hz),6.61(s,1H),6.49(dd,1H,J1=1.8Hz,J2=7.8Hz),3.75-3.81(m,2H),2.89-2.94(m,1H),2.63-2 .67(m,1H),2.29-2.38(m,2H),1.76-1.81(m,2H),1.63-1.70(m,1H),1.35-1.39(m,7H),1.25(d,6H,J=7.2Hz). 13 C NMR (150MHz, CD3OD) δ176.05,166.88,156.31,150.43,145.59,143.61,138.27,137.93,137.18,132.42,132.35,132.32,130.98,130.41,128 .25,128.10,127.13,126.50,122.44,119.10,118.50,117.01,116.86, 81.48,53.59,47.56,43.36,35.05,31.56,26.04,24.89,24.86,24.35.

[0663] Example 46 Preparation of N-((3-fluorophenyl)sulfonyl)-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropionamide, compound II-44

[0664]

[0665] II-13 (190 mg, 0.36 mmol) and a derivative of compound 34 (56 mg, 0.32 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) and 4-dimethylaminopyridine (88 mg, 0.72 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 75 mg of a white solid, yield 63%.

[0666] 1 H NMR(600MHz,CD3OD)δ7.92(t,1H,J=1.8Hz),7.87-7.88(m,1H),7.75-7.76(m,1H),7.69-7.71(m,1H),7.63- 7.66(m,2H),7.53-7.58(m,3H),7.39-7.42(m,1H),7.31(d,2H,J=7.8Hz),7.00(t,1H,J=8.4Hz),6.79(d,1H, J=7.8Hz),6.61(s,1H),6.49(dd,1H,J1=1.8Hz,J2=7.8Hz),3.74-3.81(m,2H),2.89-2.94(m,1H),2.64-2.6 5(m,1H),2.30-2.38(m,2H),1.77-1.82(m,2H),1.64-1.69(m,1H),1.35-1.40(m,7H),1.25(d,6H,J=7.2Hz). 13CNMR(150MHz,CD3OD)δ163.34,156.35,150.42,145.59,143.63,143.26,13 8.26,137.93,132.32,132.04,131.98,130.97,130.39,128.24,128.09,127 .11,126.52,125.11,122.34,121.61,121.48,119.05,118.32,116.41,116.25,81.50,53.55,47.57,43.37,35.05,31.64,26.07,24.97,24.89,24.35.

[0667] Example 47 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methyl-N-((3-nitrophenyl)sulfonyl)propionamide, Compound II-45

[0668]

[0669] II-13 (195 mg, 0.37 mmol) and a derivative of compound 34 (67 mg, 0.33 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and 4-dimethylaminopyridine (90 mg, 0.74 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 82 mg of a white solid, yield 66%.

[0670] 1H NMR (600MHz, CD3OD) δ8.65(t,1H,J=1.8Hz),8.39-8.40(m,1H),8.25(d,1H,J=7.8Hz),7.92(s,1H),7.88(d,1H,J=7 .8Hz),7.70-7.75(m,2H),7.65(t,1H,J=7.2Hz),7.54(d,2H,J=7.8Hz),7.30(d,2H,J=7.8Hz),6.89(t,1H,J=8.4Hz ),6.68(d,1H,J=7.2Hz),6.62(s,1H),6.43(dd,1H,J1=1.8Hz,J2=7.8Hz),3.74-3.81(m,2H),2.88-2.93(m,1H),2. 59-2.64(m,1H),2.29-2.37(m,2H),1.76-1.81(m,2H),1.62-1.68(m,1H),1.36-1.44(m,7H),1.24(d,6H,J=6.9Hz). 13 C NMR (150MHz, CD3OD) δ179.82,156.93,150.38,149.16,145.31,145.02,143.60,138.25,137.92,134.57,132.30,131.10,130.96,130.01, 128.21,128.08,127.72,127.12,126.52,123.95,121.38,118.82,11 7.65,81.73,53.63,47.57,43.45,35.03,31.59,26.11,25.54,24.33.

[0671] Example 48 Preparation of N-((3-cyanophenyl)sulfonyl)-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropionamide, compound II-46

[0672]

[0673] II-13 (208 mg, 0.42 mmol) and a derivative of compound 34 (70 mg, 0.38 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 75 mg of a white solid, yield 67%.

[0674] 1 H NMR (600MHz, CD3OD) δ8.18-8.19(m,2H),7.97(d,1H,J=7.8Hz),7.93(s,1H),7.87-7.88(m,1H),7.69-7.72( m,2H),7.64(t,1H,J=7.8Hz),7.54(d,2H,J=8.4Hz),7.30(d,2H,J=8.4Hz),6.97(t,1H,J=7.8Hz),6.77(d,1H ,J=7.8Hz),6.62(s,1H),6.45(dd,1H,J1=1.8Hz,J2=7.8Hz),3.75-3.81(m,2H),2.88-2.93(m,1H),2.62-2.6 4(m,1H),2.31-2.37(m,2H),1.78-1.82(m,2H),1.64-1.70(m,1H),1.36-1.41(m,7H),1.24(d,6H,J=7.2Hz). 13 C NMR(150MHz,CD3OD)δ177.40,156.48,150.40,145.55,143.59,143.09,1 38.23,137.90,137.46,133.35,132.84,132.31,131.15,130.96,130.31, 128.24,128.10,127.13,126.52,122.11,118.94,118.37,117.92,114.0 8,81.52,53.55,47.58,43.39,35.03,31.65,26.09,25.10,25.05,24.35.

[0675] Example 49 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methyl-N-(thiophene-2-ylsulfonyl)propionamide, compound II-47

[0676]

[0677] II-13 (200 mg, 0.40 mmol) and a derivative of compound 34 (58 mg, 0.36 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and 4-dimethylaminopyridine (121 mg, 0.80 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 69 mg of a white solid, yield 63%.

[0678] 1 H NMR (600MHz, CD3OD) δ7.92 (s, 1H), 7.88 (d, 1H, J = 7.8Hz), 7.84 (d, 1H, J = 4.2Hz), 7.78 (d, 1H, J = 3.0Hz), 7.68 -7.71(m,1H),7.65(t,1H,J=7.2Hz),7.54(d,2H,J=8.4Hz),7.32(d,2H,J=8.4Hz),7.13(t,1H,J=4.8Hz),7.0 3(t,1H,J=7.8Hz),6.78(d,1H,J=7.8Hz),6.52-6.55(m,2H),3.74-3.81(m,2H),2.90-2.94(m,1H),2.58-2.6 2(m,1H),2.27-2.37(m,2H),1.75-1.81(m,2H),1.62-1.68(m,1H),1.39-1.44(m,6H),1.25(d,6H,J=6.6Hz). 13 C NMR (150MHz, CD3OD) δ176.17,156.31,150.44,145.56,143.62,141.16,138.22,137.92,135.50,135.01,132.34,131.01,130.49,128.27,128.2 4,128.10,127.12,126.50,122.35,118.99,118.71,81.47,53.55,48.86 ,48.71,48.57,47.56,43.40,35.06,31.66,26.07,25.05,24.73,24.36.

[0679] Example 50 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methyl-N-((4-(trifluoromethoxy)phenyl)sulfonyl)propionamide, compound II-48

[0680]

[0681] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (82 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 58 mg of a white solid, yield 56%.

[0682] 1 H NMR (600MHz, CD3OD) δ8.00(d,2H,J=9.0Hz,),7.92(s,1H),7.88(d,1H,J=7.8Hz),7.70(d,1H,J=7.8Hz),7.64(t ,1H,J=7.2Hz),7.55(d,2H,J=7.8Hz),7.36(d,2H,J=8.4Hz),7.32(d,2H,J=8.4Hz),6.95(t,1H,J=7.8Hz),6.73 (d,1H,J=7.2Hz),6.65(s,1H),6.47(dd,1H,J1=1.8Hz,J2=8.4Hz),3.76-3.81(m,2H),2.90-2.94(m,1H),2.64- 2.68(m,1H),2.30-2.39(m,2H),1.78-1.82(m,2H),1.63-1.69(m,1H),1.39-1.44(m,7H),1.25(d,6H,J=7.2Hz). 13C NMR (150MHz, CD3OD) δ179.96,156.97,152.83,150.41,145.27,143.61,142.02,138.32,137.95,132.30,131.19,130.96,130.04,128.24, 128.09,127.10,126.49,122.57,121.52,120.87,119.02,118.06,81 .82,53.71,47.56,43.45,35.05,31.54,26.08,25.61,25.56,24.34.

[0683] Example 51: Preparation of N-((4-acetamidophenyl)sulfonyl)-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methylpropionamide, compound II-49

[0684]

[0685] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (72 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 75 mg of a white solid, yield 68%.

[0686] 1H NMR (600MHz, CD3OD) δ7.92 (s, 1H), 7.87 (d, 3H, J = 9.0Hz), 7.75 (d, 2H, J = 8.4Hz), 7.69 (d, 1H, J = 7.8Hz), 7. 64(t,1H,J=7.8Hz),7.53(d,2H,J=7.8Hz),7.30(d,2H,J=8.4Hz),7.01(t,1H,J=7.8Hz),6.79(d,1H,J=7. 2Hz),6.57(s,1H),6.48(d,1H,J=7.8Hz),3.72-3.79(m,2H),2.89-2.93(m,1H),2.59-2.63(m,1H),2.27- 2.37(m,2H),2.17(s,3H),1.74-1.79(m,2H),1.61-1.67(m,1H),1.33-1.38(m,7H),1.24(d,6H,J=7.2Hz). 13 CNMR(150MHz,CD3OD)δ175.44,172.01,156.20,150.41,145.61,145.05,143.62,138.18,137.91,134.53,132.33,130.98,130.56,130.51,12 8.24,128.10,127.13,126.52,122.54,119.97,119.04,118.61,81.43, 53.52,47.58,43.25,35.04,31.62,26.01,24.85,24.72,24.36,24.16.

[0687] Example 52 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-(naphthalene-2-ylsulfonyl)propionamide, compound II-50

[0688]

[0689] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (70 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 78 mg of a white solid, yield 69%.

[0690] 1 H NMR (600MHz, CD3OD) δ8.54 (s, 1H), 7.97 (t, 3H, J = 9.0Hz), 7.87-7.92 (m, 3H), 7.60-7.70 (m, 4H ),7.55(d,2H,J=8.4Hz),7.30(d,2H,J=7.8Hz),6.84(t,1H,J=8.4Hz),6.70(d,1H,J=7.8Hz), 6.52(s,1H),6.46(dd,1H,J1=1.8Hz,J2=7.8Hz),3.70-3.74(m,2H),2.88-2.92(m,1H),2.46- 2.50(m,1H),2.22-2.26(m,2H),1.60-1.66(m,2H),1.34-1.51(m,8H),1.23(d,6H,J=6.6Hz). 13 C NMR (150MHz, CD3OD) δ156.35,150.46,145.49,143.65,138.23,137.96,136 .61,133.26,132.34,131.06,131.00,130.53,130.37,130.34,130.08,129 .11,128.72,128.27,128.11,127.14,126.52,124.00,122.30,118.71,118.54,81.48,53.51,47.50,43.19,35.06,31.52,25.93,25.14,24.67,24.34.

[0691] Example 53 Preparation of 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-N-((3-methoxyphenyl)sulfonyl)-2-methylpropionamide, compound II-51

[0692]

[0693] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (68 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 81 mg of a white solid, yield 70%.

[0694] 1 H NMR (600MHz, CD3OD) δ7.92 (s, 1H), 7.87 (d, 1H, J = 7.2Hz), 7.70 (d, 1H, J = 7.8Hz), 7.64 (t, 1H, J = 7.8Hz), 7.50 -7.54(m,3H),7.41-7.46(m,2H),7.31(d,2H,J=7.8Hz),7.18-7.20(m,1H),6.98(t,1H,J=7.8Hz),6.78(d,1H ,J=7.8Hz),6.58(s,1H),6.45(dd,1H,J1=1.8Hz,J2=7.8Hz),3.74-3.80(m,5H),2.89-2.93(m,1H),2.60-2.6 4(m,1H),2.28-2.37(m,2H),1.74-1.80(m,2H),1.62-1.68(m,1H),1.32-1.44(m,7H),1.24(d,6H,J=6.6Hz). 13 C NMR(150MHz,CD3OD)δ175.91,161.03,156.30,150.44,145.58,143.62,1 42.00,138.26,137.92,132.32,131.02,130.99,130.42,128.26,128.10 ,127.12,126.51,122.32,121.14,120.80,119.02,118.37,114.04,81.4 5,56.16,53.54,47.56,43.29,35.05,31.61,26.05,24.94,24.81,24.36.

[0695] Example 54 Preparation of N-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-ylphenoxy)-2-methylpropionamide, compound II-52

[0696]

[0697] II-13 (200 mg, 0.38 mmol) and a derivative of compound 34 (88 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 67 mg of a white solid, yield 60%.

[0698] 1 H NMR (600MHz, CD3OD) δ8.28 (d, 1H, J = 8.4Hz), 7.93 (s, 1H), 7.88 (d, 1H, J = 7.8Hz), 7.80 (s, 1H), 7.63-7. 72(m,3H),7.55(d,2H,J=8.4Hz),7.31(d,2H,J=8.4Hz),7.03(t,1H,J=7.8Hz),6.77(d,1H,J=7.2Hz),6 .70(s,1H),6.63(dd,1H,J1=1.8Hz,J2=7.8Hz),3.79-3.83(m,2H),2.89-2.94(m,1H),2.70-7.74(m,1 H),2.34-2.41(m,2H),1.81-1.83(m,2H),1.64-1.71(m,1H),1.43-1.45(m,7H),1.24(d,6H,J=7.2Hz). 13 C NMR (150MHz, CD3OD) δ156.98,150.40,145.34,143.59,138.32,137.94,135.79,134.26,133.88,132.29,130.98,130.16,129.32,128.24,128 .10,127.15,126.49,125.13,124.70,123.33,121.74,118.77,118.39, 81.70,53.70,47.59,43.56,35.04,31.62,26.14,25.56,25.48,24.33.

[0699] Example 55 Preparation of 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionic acid, compound II-53

[0700]

[0701] The intermediate methyl 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate was obtained according to Example 1.

[0702] The intermediate methyl 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate (380 mg, 0.93 mmol) was dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 25 mL), followed by the addition of lithium hydroxide (195 mg, 4.6 mmol). The mixture was stirred at room temperature for 16 h, and the reaction solution was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 3-4 using an appropriate amount of 1N hydrochloric acid solution, filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 200 mg of white solid, yield 72%.

[0703] 1 H NMR (600MHz, CD3OD) δ7.29-7.38(m,3H),7.10-7.22(m,2H),6.88-6.97(m,1H),6.70-6.79(m,2H),4.66-4.67(m,1H),3.67-3. 74(m,1H),3.05-3.15(m,1H),2.85-2.97(m,2H),2.72-2.77(m,1H),2.01-2.05(m,1H),1.50-1.93(m,9H),1.25-1.28(m,6H). 13 C NMR (150MHz, CD3OD) δ178.00,177.87,172.76,157.14,157.08,150.80,145.85,145.2 8,137.20,137.15,130.26,129.79,129.73,129.10,125.82,125.60,125.24,125.10, 122.03,121.74,119.42,119.34,118.63,118.59,80.17,80.13,55.71,49.83,44.88,43.77,43.68,35.29,32.78,32.62,27.24,26.33,25.88,25.81,25.61,24.37,24.30.

[0704] Example 56 Preparation of 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(thiophene-2-ylsulfonyl)propionamide, compound II-54

[0705]

[0706] II-2 (200 mg, 0.42 mmol) and derivative of compound 34 (60 mg, 0.37 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 177 mg of white solid, yield 82%.

[0707] 1 H NMR (400MHz, CD3OD) δ7.77-7.82(m,2H),7.54-7.71(m,4H),7.27-7.44(m,3H),6.48-7.15(m,5H),4.63-4. 70(m,1H),3.66-3.77(m,1H),3.08-3.18(m,1H),2.65-2.87(m,2H),1.72-2.00(m,4H),1.36-1.46(m,6H). 13 C NMR(100MHz,CD3OD)δ176.73,171.91,156.43,152.80,150.44,145.94,145.28,141.70,140.76 ,138.77,138.04,137.86,135.15,135.04,134.62,134.50,130.48,130.42,129.40,128.11,127 .14,127.03,126.30,124.54-124.64(m),122.34,121.88,118.65-119.04(m),118.53,117.09,1 16.91,81.54,81.47,55.62,44.84,43.64,32.59-32.80(m),27.21,26.27,25.42,25.02,24.49.

[0708] Example 57 Preparation of 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propionamide, compound II-55

[0709]

[0710] II-2 (200 mg, 0.42 mmol) and derivative of compound 34 (83 mg, 0.37 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 217 mg of white solid, 90% yield.

[0711] 1 H NMR (400MHz, CD3OD) δ8.11-8.20(m,2H),7.84-7.91(m,2H),7.64-7.71(m,2H),7.25-7.43(m,5H),6.84-7.07(m,2H),6.64-6.76(m,1H),6.42-6. 51(m,1H),4.65-4.72(m,1H),3.70-3.78(m,1H),3.12-3.15(m,1H),2.8 5-2.91(m,1H),2.71-2.74(m,1H),1.61-1.99(m,4H),1.34-1.44(m,6H). 13C NMR (100MHz, CD3OD) δ175.84,175.78,171.96,156.21,152.81,150.36,146.13,145.53,144.43,140.76, 138.77,138.01,137.91,136.37,136.04,135.71,135.39,130.45,130.42,130.17,129.40,128.84,127. 10,126.32,126.28,126.14,124.51-124.61(m),123.43,122.67,122.25,119.38,118.88,118.72,118.2 0,117.10,116.91,81.48,81.37,55.59,44.79,43.72,32.66,27.17,26.23,24.97,24.84,24.70,24.38.

[0712] Example 58 Preparation of 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(naphthalene-2-ylsulfonyl)propionamide, compound II-56

[0713]

[0714] II-2 (200 mg, 0.42 mmol) and derivative of compound 34 (77 mg, 0.37 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 201 mg of white solid, yield 86%.

[0715] 1H NMR (400MHz, CD3OD) δ8.56-8.61(m,1H),7.86-7.99(m,4H),7.45-7.68(m,6H),7.24-7.40(m,3H),6.73-6.90(m,2H),6.40-6.65(m,2H) ,4.59-4.63(m,1H),3.59-3.69(m,1H),2.96-3.00(m,1H),2.72-2.78(m,1H),2.48-2.60(m,1H),1.56-1.82(m,4H),1.26-1.41(m,6H). 13 C NMR(100MHz,CD3OD)δ175.59,175.44,171.82,156.19,150.33,145.92,145.26,140.73,138.73,137.97,1 37.81,137.41,136.66,133.21,131.27,130.54,130.45,130.14,130.09,129.38,129.03,128.79,127.16 ,126.93,126.33,126.23,124.51-124.60(m),123.97,122.58,122.03,118.89,118.72,118.44,117.08,1 16.90,81.42,81.32,55.64,44.62,43.63,43.44,32.52,32.30,27.09,26.17,25.22,24.85,24.74,24.21.

[0716] Example 59 Preparation of 1-(2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazin-4-one, compound II-57

[0717]

[0718] Compound II-2 (200 mg, 0.42 mmol) was dissolved in dichloromethane (25 mL), and 4-piperidinone (316 mg, 1.4 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (836 g, 1.2 mmol), and triethylamine (364 mg, 3.6 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-6:1) to give 112 mg of white solid, yield 75%.

[0719] 1 H NMR(600MHz,CD3OD)δ7.66-7.71(m,2H),7.53-7.56(m,2H),7.42-7.43(m,2H ),7.33-7.34(m,1H),7.09-7.25(m,1H),6.73-6.96(m,2H),6.62-6.68(m,1H) ,4.64-4.69(m,1H),3.59-3.91(m,5H),3.14-3.19(m,1H),2.85-2.92(m,1H) ,2.78-2.80(m,1H),2.25-2.41(m,1H),1.75-2.02(m,4H),1.55-1.73(m,9H). 13 C NMR(150MHz,CD3OD)δ208.59,208.37,173.97,173.77,173.35,173.16,171.93,157.12,152.42,150.78,145.66-146.43(m),140.75,1 38.80,137.92-138.06(m),130.85,130.70,130.50,130.45,129.42,127.14,127.10,126.33,126.23,124.56-124.62(m),121.24-121 .69(m),118.90,118.78,117.10,116.98,116.26-116.85(m),96.13,96.02,81.82,81.72,55.64,55.55,49.85,49.42,44.86-45.10(m) ),44.26,44.18,43.75,41.93,41.84,41.66,41.56,41.19,41.12,38.87,36.77,36.52,36.13,32.86,32.77,27.20,26.25-26.58(m).

[0720] Example 60 Preparation of 4-(2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-1-ammonium chloride, compound II-58

[0721]

[0722] Referring to Example 25, the intermediate 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-1-(piperazin-1-yl)prop-1-one was obtained.

[0723] The intermediate 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-1-(piperazin-1-yl)prop-1-one (225 mg, 0.41 mmol) was dissolved in 15 mL of 4 M dioxane hydrochloride solution and reacted at room temperature for 2 h. The reaction solution was evaporated to dryness to give 75 mg of white solid, with a yield of 61%.

[0724] 1 H NMR (600MHz, CD3OD) δ7.57-7.73(m,4H),7.27-7.46(m,4H),7.00-7.15(m,1H),6.65-6.84(m,2H),4.65-4. 67(m,1H),3.60-4.18(m,5H),2.73-3.23(m,7H),1.94-2.06(m,1H),1.76-1.80(m,2H),1.57-1.66(m,6H). 13 C NMR (150MHz, CD3OD) δ173.64,173.50,172.01,171.89,156.71,156.64,152.41,150.77,146. 64,146.07,140.77,138.79,137.96,130.98,130.51,129.46,127.15,127.07,126.30,126.2 2,124.58-124.64(m),121.89,121.77,118.94,118.82,117.07,117.02,116.95,116.33,116 .17,81.84,55.61,49.90,49.43,49.29,43.80-44.72(m),40.81,32.72,27.19,26.46,26.25.

[0725] Example 61 Preparation of 1-(2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)piperazine-4-ammonium chloride, compound II-59

[0726]

[0727] Referring to Example 25, the intermediate 1-(4-aminopiperidin-1-yl)-2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropane-1-one was obtained.

[0728] The intermediate 1-(4-aminopiperidin-1-yl)-2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropane-1-one (150 mg, 0.27 mmol) was dissolved in 15 mL of 4 M dioxane hydrochloride solution and reacted at room temperature for 2 h. The reaction solution was evaporated to dryness to give 61 mg of white solid, yield 53%.

[0729] 1 H NMR (600MHz, CD3OD) δ7.57-7.73(m,4H),7.23-7.44(m,4H),6.97-7.12(m,1H),6.61-6.83(m,2H),4.58-4. 78(m,2H),3.71-3.79(m,1H),2.64-3.23(m,6H),1.93-2.05(m,3H),1.34-1.87(m,11H),1.19-1.24(m,1H). 13 C NMR (150MHz, CD3OD) δ173.71,173.56,171.88,156.91,156.81,152.42,150.78,146.31,145.75,14 0.78,140.69,138.79,137.95,130.79,130.52,129.46,127.16,126.30,124.58-124.65(m),121.75 ,121.59,118.94,118.82,117.37,117.07,116.95,116.78,116.37,81.79,55.63,50.08,49.83,44. 67-44.93(m),43.78,42.55,42.45,32.87,32.63,32.52,31.46,30.87,27.20,26.61,26.39,26.20.

[0730] Example 62 Preparation of 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-1-morpholinoprop-1-one, compound II-60

[0731]

[0732] Compound II-2 (200 mg, 0.42 mmol) was dissolved in dichloromethane (25 mL). Morpholine (40 mg, 0.46 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (239 g, 0.63 mmol), and N,N-diisopropylethylamine (108 mg, 0.84 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-6:1) to give 108 mg of white solid, yield 65%.

[0733] 1 H NMR(400MHz,CD3OD)δ7.53-7.71(m,4H),7.32-7.44(m,3H),6.81-7.26(m,2H),6.61-6.77(m,2H) ,4.68-4.70(m,1H),3.36-3.87(m,7H),2.80-3.21(m,5H),1.92-2.04(m,3H),1.56-1.75(m,7H).

[0734] 13 C NMR(100MHz,CD3OD)δ173.46,173.25,171.95,171.90,156.85,152.83,150.38,146.32,145.82 ,140.74,138.79,138.02,130.77,130.47,129.41,127.14,126.33,126.23,124.53-124.63(m), 121.59,121.31,118.93,118.76,117.12,116.94,116.68,116.36,81.72,67.35-67.73(m),55. 59,49.87,48.17,44.89,44.67,44.58,43.80,43.72,32.93,32.85,27.20,26.44,26.36,26.25.

[0735] Example 63 Preparation of 4-(2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionamide)piperidin-1-ammonium chloride, compound II-61

[0736]

[0737] Referring to Example 25, the intermediate 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(piperidin-4-yl)propionamide was obtained.

[0738] The intermediate 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methyl-N-(piperidin-4-yl)propionamide (240 mg, 0.43 mmol) was dissolved in 15 mL of 4 M dioxane hydrochloride solution and reacted at room temperature for 2 h. The reaction solution was evaporated to dryness to give 72 mg of white solid, yield 57%.

[0739] 1 H NMR (400MHz, CD3OD) δ7.56-7.73(m,4H),7.24-7.44(m,4H),7.01-7.14(m,1H),6.72-6.89(m,2H),4.66-4.74(m,1H) ,4.01-4.04(m,1H),3.65-3.79(m,1H),3.36-3.39(m,2H),2.77-3.23(m,5H),1.80-2.06(m,8H),1.40-1.68(m,6H). 13 C NMR (100MHz, CD3OD) δ176.77,176.65,171.96,171.91,156.34,156.18,152.82,150.34,145. 84,145.40,140.75,138.75,138.02,130.50,130.36,129.42,127.13,126.68,126.16,124.5 5-124.65(m),122.33,120.48,120.17,119.65,117.08,116.90,81.47,64.38,64.27,55.64, 49.91,45.84,45.77,44.76,44.34,43.81,32.66,29.21,27.20,26.25,26.00,25.66,25.26.

[0740] Example 64 Preparation of 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-N-((4-hydroxyphenyl)sulfonyl)-2-methylpropionamide, compound II-62

[0741]

[0742] II-2 (200 mg, 0.42 mmol) and derivative of compound 34 (64 mg, 0.37 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 80 mg of white solid, yield 32%.

[0743] 1 H NMR (400MHz, CD3OD) δ7.88-7.96(m,2H),7.62-7.70(m,2H),7.26-7.58(m,6H),7.00-7.20(m,3H),6.74-6.92(m,2H) ,4.65-4.68(m,1H),3.69-3.75(m,1H),3.10-3.15(m,1H),2.75-2.85(m,2H),1.88-2.00(m,2H),1.57-1.75(m,8H). 13 C NMR(100MHz,CD3OD)δ173.76,173.57,171.98,171.92,157.01,154.59,152.80,150.34,146.17,145.67, 142.88,140.72,138.76,137.98,137.84,130.66,130.45,129.41,128.97,128.92,127.14,127.00,126. 31,126.42,124.53-124.63(m),123.11,123.03,122.43,122.18,119.25,119.17,118.90,118.72,118.5 2,118.19,117.09,116.91,80.53,55.63,49.83,44.73,43.71,32.70,27.15,26.19,25.94,25.82,25.68.

[0744] Example 65 Preparation of compound II-63: 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-1-(4-hydroxypiperidin-1-yl)-2-methylprop-1-one

[0745]

[0746] The compound II-57 (88 mg, 0.15 mmol) was dissolved in methanol (10 mL), and sodium borohydride (11 mg, 0.30 mmol) was slowly added. The mixture was reacted overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-3:1) to give 55 mg of white solid, yield 75%.

[0747] 1 H NMR (400MHz, CD3OD) δ7.66-7.72(m,2H),7.54-7.57(m,2H),7.31-7.44(m,3H),7.08-7.24(m,1H),6.81-6.95(m,1H) ,6.61-6.74(m,2H),4.67-4.70(m,1H),3.34-4.31(m,5H),2.78-3.18(m,4H),1.92-2.05(m,1H),1.39-1.94(m,13H). 13 C NMR (100MHz, CD3OD) δ173.40,173.22,171.94,157.09,152.84,150.38,146.18,145.63,140.76 ,138.82,138.05,137.94,130.68,130.47,129.42,127.14,126.31,124.54,124.64,124.54-124 .64(m),121.55,121.31,118.93,118.76,117.13,116.95,116.34-116.79(m),81.72,67.46,55. 62,49.88,44.86,44.22,43.80,41.92,35.28,35.28,35.18,32.84,27.22,26.56,26.45,26.26.

[0748] Example 66 Preparation of (S)-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propionamide, compound II-64

[0749]

[0750] (S)-II-13 (219 mg, 0.42 mmol) and a derivative of compound 34 (85 mg, 0.38 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and 4-dimethylaminopyridine (103 mg, 0.84 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 150 mg of a white solid, yield 65%.

[0751] 1 H NMR (400MHz, CD3OD) δ8.12 (d, 2H, J = 8.0Hz), 7.92 (s, 1H), 7.73-7.85 (m, 3H), 7.60-7.70 (m, 2H) ,7.53(d,2H,J=8.0Hz),7.29(d,2H,J=8.0Hz),6.97(t,1H,J=7.6Hz),6.80(d,1H,J=7.6Hz),6. 68(s,1H),6.46(d,1H,J=7.6Hz),3.75-3.80(m,2H),2.86-2.93(m,1H),2.66-2.72(m,1H),2.3 0-2.39(m,2H),1.77-1.80(m,2H),1.60-1.66(m,1H),1.33-1.38(m,7H),1.22(d,6H,J=6.8Hz). 13 C NMR (100MHz, CD3OD) δ175.68,156.13,150.40,145.70,144.33,143.56,138.22,137.88,135.85,132.29,130.97,130.40,130.16,128.24,128 .08,127.12,127.08,126.48,126.12,123.41,122.66,119.23,118.25, 81.43,53.55,47.56,43.29,35.01,31.54,26.00,24.72,24.70,24.34.

[0752] Example 67 Preparation of (1R,4R)-5-(2-(3-(3-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)-2,5-diazabicyclo[2.2.1]hept-2-ammonium chloride, compound II-65

[0753]

[0754] Referring to Example 25, intermediate 1-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropane-1-one was obtained.

[0755] The intermediate 1-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropane-1-one (200 mg, 0.36 mmol) was dissolved in 4 M dioxane hydrochloride solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to give 84 mg of white solid, yield 55%.

[0756] 1 H NMR (600MHz, CD3OD) δ7.66-7.73(m,2H),7.57-7.60(m,2H),7.43-7.46(m,2H),7.34-7.38(m,1H),7.15-7.28(m,1H),6.64-6.86(m,3H),5.33-5. 44(m,1H),4.60-4.70(m,1H),4.35-4.43(m,1H),3.50-3.77(m,3H),3.1 9-3.23(m,2H),2.69-2.93(m,3H),1.78-2.05(m,5H),1.56-1.64(m,6H). 13 C NMR (150MHz, CD3OD) δ173.37,172.03,156.62,152.60,152.23,150.97,150.59,146.70,140. 79,138.80,137.94,130.96,130.53,129.46,127.11,126.27,124.60,122.04,118.94,118.9 2,117.54,117.07,116.95,116.52,81.62,81.35,59.97,58.29,57.87,56.78,55.57,52.74,50.88,49.84,44.79,43.66,37.43,35.03,32.64,27.18,26.49,26.22,25.33,25.15,24.03.

[0757] Example 68 Preparation of (1S,4S)-5-(2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionyl)-2,5-diazabicyclo[2.2.1]heptane-2-ammonium chloride, compound II-66

[0758]

[0759] Referring to Example 25, intermediate 1-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylprop-1-one was obtained.

[0760] The intermediate 1-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylprop-1-one (200 mg, 0.36 mmol) was dissolved in 4M dioxane hydrochloride solution (15 mL), reacted at room temperature for 2 h, and the reaction solution was evaporated to dryness to give 92 mg of white solid, yield 56%.

[0761] 1 H NMR (600MHz, CD3OD) δ7.66-7.72(m,2H),7.44-7.57(m,4H),7.35-7.38(m,1H),7.15-7.28(m,1H),6.64-6.85(m,3H),5.33-5. 44(m,1H),4.65-4.68(m,1H),4.34-4.43(m,1H),3.41-3.73(m,4H),2.71-3.21(m,5H),1.80-2.05(m,5H),1.53-1.64(m,6H). 13C NMR(150MHz,CD3OD)δ173.38,172.05,156.62,152.58,152.29,150.98,150.64,140.81,13 8.81,137.94,130.97,130.53,129.47,127.11,126.27,124.62,122.02,118.94,118.82,11 7.53,117.017,116.95,116.57,81.63,81.36,59.96,58.30,57.86,56.79,55.58,52.73,50.87,49.77,44.81,43.77,37.41,34.95,32.64,27.18,26.38,26.22,25.33,25.13,23.98.

[0762] Example 69 Preparation of (R)-2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl(phenoxy)-2-methyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propionamide, compound II-67

[0763]

[0764] (R)-II-13 (270 mg, 0.51 mmol) and a derivative of compound 34 (105 mg, 0.47 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (146 mg, 0.76 mmol) and 4-dimethylaminopyridine (124 mg, 1.0 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 120 mg of a white solid, yield 58%.

[0765] 1H NMR (400MHz, CD3OD) δ8.13 (d, 2H, J = 8.4Hz), 7.93 (t, 1H, J = 2.4Hz), 7.83-7.89 (m, 3H), 7.69-7.72 (m, 1 H),7.62-7.66(m,1H),7.53-7.56(m,2H),7.30(d,2H,J=8.4Hz),6.98(t,1H,J=8.0Hz),6.80(d,1H,J=7 .6Hz),6.68(t,1H,J=2.0Hz),6.45-6.48(m,1H),3.75-3.81(m,2H),2.88-2.94(m,1H),2.66-2.73(m,1 H),2.31-2.41(m,2H),1.79-1.82(m,2H),1.62-1.71(m,1H),1.37-1.40(m,7H),1.24(d,6H,J=7.2Hz). 13 C NMR (100MHz, CD3OD) δ176.14,156.26,150.43,145.68,144.65,143.60,138.26,137.93,135.89,135.56,132.31,130.98,130.37,1 30.11,128.25,128.10,127.14,127.03,126.50,122.56,119.16,118.24,81.47,53.60,43.34,35.04,31.56,26.03,24.80,24.34.

[0766] Example 70 Preparation of 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-N-((4-methoxyphenyl)sulfonyl)-2-methylpropionamide, compound II-68

[0767]

[0768] II-2 (207 mg, 0.43 mmol) and a derivative of compound 34 (77 mg, 0.39 mmol) were dissolved in dichloromethane (15 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (243 mg, 0.64 mmol) and 4-dimethylaminopyridine (111 mg, 0.86 mmol) were added separately. The mixture was stirred overnight at room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to give 72 mg of a white solid, yield 42%.

[0769] 1 H NMR (400MHz, CD3OD) δ7.88-7.96(m,2H),7.51-7.71(m,4H),7.28-7.48(m,3H),6.45-7.10(m,6H),4.62-4.85(m,1H),3.85 (s,3H),3.65-3.77(m,1H),3.04-3.16(m,1H),2.78-2.88(m,1H),2.61-2.68(m,1H),1.68-1.95(m,4H),1.31-1.43(m,6H). 13 C NMR (100MHz, CD3OD) δ176.05,171.90,165.07,156.34,152.92,152.68,150.21,145.94,145.26,14 0.74,138.76,137.94,132.36,131.61,130.46,129.39,127.19,126.99,126.34,124.53-124.63(m ),122.46,121.91,119.08,118.91,118.74,118.65,117.10,116.91,114.94,81.52,81.38,56.32,55.67,44.82,43.71,43.58,32.70,32.50,31.80,30.71,27.18,26.22,25.42,25.05,24.86,24.32.

[0770] Example 71 β-catenin / BCL protein-protein affinity experiment

[0771] Fluorescence polarization experiment in The experiment was performed in two black 96-well plates and detected using Biotek Synergy H1 (BioTek). In the experiment, β-catenin (1-781) at a final concentration of 1 μM was added to a buffer solution (25 mM HEPES pH 7.4, 100 mM NaCl, 0.01% Triton-X100, 0.1% BSA), followed by serially diluted inhibitors. The mixture was incubated on a shaker at room temperature for 1 h. Then, BCL9-FAM (Tracer) at a final concentration of 20 nM was added. The DMSO concentration in the system was 10% (v / v), with a final volume of 200 μL. The plate was wrapped in aluminum foil and incubated on a shaker at room temperature for 1 h.

[0772] Finally, detection was performed using 485 nm excitation light and 520 nm emission light respectively, and the suppression percentage was calculated using the following equation:

[0773] %inhibition = 100[1-(mP-mP)] free ) / (mP bound -mP free )]

[0774] Where mP free This is the signal from the free probe well (positive control), mP bound This is the signal from the probe well (negative control).

[0775] IC 50 This means it can replace the inhibitor concentration required for 50% of tracer treatments. The nonlinear fitting in the model is analyzed.

[0776] The results are shown in Table 1:

[0777] Table 1. Results of β-catenin / BCL protein-protein affinity assay

[0778]

[0779]

[0780]

[0781] Experimental results show that most of the compounds in this invention exhibit good targeting effects on β-catenin / BCL9 protein-protein. Compared with reference compound c (Anal Biochem, 2015, 469, 43-53), compounds II-9, II-13, II-16, II-17, II-25, II-27, II-28, II-29, II-37, II-39, II-40, II-42, II-43, II-44, II-45, II-46, II-47, II-48, II-49, II-50, II-51, II-52, II-55, II-56, II-57, II-58, II-59, II-60, II-61, II-63, II-64, II-65, II-66, II-67, and II-68, which are small molecule inhibitors of β-catenin / BCL9 protein-protein interaction, exhibit superior β-catenin / BCL9 protein-protein affinity activity.

[0782] Example 72 Anti-tumor cell proliferation activity test

[0783] 1) The antiproliferative activity of some compounds of this invention at a single concentration (10 μM) against human breast cancer cells MDA-MB-231, human breast cancer cells MDA-MB-468, human colon cancer cells HCT-116, human liver cancer cell line HepG2, and MRC-5 normal human embryonic lung fibroblasts was determined using the CCK-8 assay. Compound c was selected as a control. Specific results are shown in Table 2 (units: in h% in 10 μM):

[0784] Table 2 Anti-tumor cell proliferation activity

[0785]

[0786] A:>90%; B:80%~90%; C:70%~80%; D:50%~70%E:<50%

[0787] As shown in the table above, the positive control compound c had virtually no activity against the cell lines, suggesting that it may have difficulty penetrating the cell membrane. In contrast, the small molecule inhibitors described in this invention that interact with the β-catenin / BCL9 protein showed in vitro anti-tumor cell proliferation activity against various tumor cell lines, with the best inhibitory activity against human breast cancer cells MDA-MB-468 and human colon cancer cells HCT-116. This indicates that the compounds of this invention can penetrate the cell membrane to act on their relevant targets, and that the compounds exhibit a certain degree of selectivity in inhibiting tumor cells.

[0788] Meanwhile, the compounds of this invention exhibit weak inhibitory activity against MRC-5 human normal embryonic lung fibroblasts and have lower toxicity, revealing that the compounds of this invention have better selectivity in inhibiting the proliferation of tumor cells and normal cells, suggesting that they will have lower toxicity when used as anti-tumor drugs.

[0789] 2) The antiproliferative activity of compound II-39 (10 μM) against human colon cancer cells HCT-116, CT-26, SW480, A549, RKO, and HEK293 normal cells was determined using the CCK-8 assay, with compound ICG-001 as a control. The specific results are shown in the table below:

[0790]

[0791] As shown in the table above, compound II-39 exhibits good anti-colon cancer activity, especially against CT-26 cells, which is significantly better than the positive control drug ICG-001. Moreover, II-39 has no effect on normal cells, demonstrating excellent cell selectivity.

[0792] Example 73: Experiment on the Influence of hERG Potassium Channels

[0793] Stable HEK293 cells were seeded onto glass slides at a density of less than 50% and cultured overnight. The cells were then transferred to a cell bath embedded in an inverted microscope platform and perfused with extracellular fluid at a rate of 2.7 ml / min. After stabilizing the cell pellet for 5 minutes, experiments could begin. Membrane currents were recorded using a HEKA EPC-10 patch-clamp amplifier and a PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were performed at room temperature (22-24°C). Electrodes (BF150-110-10) were straightened using a P-97 microelectrode straightener (Sutter Instrument Company, One Digital Drive, Novato, CA 94949). The electrode inner diameter was 1-1.5 mm, and the water resistance after filling with internal fluid was 2-4 MΩ.

[0794] The electrophysiological stimulation protocol for hERG potassium channels involves first clamping the membrane voltage to -80mV, applying a voltage of +20mV to the cells for 2 seconds to activate the hERG potassium channels, then repolarizing to -50mV for 5 seconds to generate an outward tail current. The stimulation frequency is once every 15 seconds. The current value is the peak value of the tail current.

[0795] In this experiment, whole-cell recording mode was used to record channel currents. First, extracellular fluid was perfused (approximately 2 mL per minute) and continuously recorded until the current stabilized (run-down less than 5% within 5 minutes). The peak tail current at this point was the control current value. Next, extracellular fluid containing the test drugs (listed in Table 3) was perfused and continuously recorded until the inhibitory effect of the drugs on hERG currents reached a steady state. The peak tail current at this point was the current value after drug administration. The criterion for a stable state was whether the three most recent consecutive current recording lines overlapped. After reaching a stable state, if the hERG current recovered to or approached the level before drug administration after perfusion with extracellular fluid, perfusion could continue to test other concentrations or drugs. 30 μM Quinidine was used as a positive control to ensure normal cell response. This study evaluated the effect of the test compound on hERG potassium channels at the test concentration by measuring the maximum current values ​​of the control and drug-treated groups and calculating the ratio of the maximum current value of the treated group to the maximum current value of the control group (Mean ± SE). Experimental data were collected using a PATCHMASTER V2X60 (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany) and analyzed and statistically processed using Origin 8.5 (OriginLab Corporation, Northampton, MA) software and Microsoft Excel.

[0796] Some compounds from this invention were selected for testing, and the results are shown in Table 3:

[0797] Table 3. Effects of each compound on the activity of potassium ion channels.

[0798] compound <![CDATA[hERG IC 50 (μM)]]> II-2 >10 II-13 >10 II-14 >10 II-25 >10 II-27 >10 II-28 >10 II-39 >10

[0799] Experimental results showed that compounds II-2, II-13, II-14, II-25, II-27, and II-28 had an inhibitory activity (IC50) of 5% on hERG potassium ion channels. 50 All values ​​were greater than 10 μM, suggesting that the small molecule inhibitors that interact with β-catenin / BCL9 protein described in this invention have low potential cardiotoxicity.

[0800] Example 75 Liver microsomal metabolic stability

[0801] Prepare 10 mM stock solutions of the test samples and positive controls listed in Tables 4 and 5 using DMSO as the solvent. Dilute the stock solutions to 0.25 mM with 70% acetonitrile. Prepare an NADPH (reduced coenzyme II) solution consisting of 6.5 mM NADP, 16.5 mM glucose-6-phosphate, and 3 U / mL glucose-6-phosphate dehydrogenase. The quencher consists of acetonitrile, toluenebutyramide, and propanol (as an internal standard). The buffer is a 100 mM potassium phosphate buffer containing 3.3 mM MgCl2. Incubate and mix a mixture containing 0.5 mg / mL liver microsomal protein and 1 μM test sample / positive control in the buffer. Add 80 μL aliquots of each incubation mixture to 400 μL of the quencher to precipitate the protein to prepare the initial sample. After vortexing the sample, add 20 μL of the NADPH solution aliquot. 80 μL of NADPH solution was added to 320 μL of the culture mixture to initiate the reaction. The mixture was incubated with gentle shaking in a 37 °C water bath. At 0, 10, 30, and 90 min, 100 μL of the mixture was transferred to a 96-well plate containing 400 μL of quencher, centrifuged (4000 rpm, 15 min), and 80 μL of the supernatant was added to a 96-well plate pre-filled with 160 μL of ultrapure water. The mixture was then analyzed by LC-MS / MS.

[0802] Calculate T using the following formula. 1 / 2 and CL int The slope is measured by the percentage of residual compounds and the natural logarithm of time, where V / M equals 1 / protein concentration.

[0803]

[0804] According to the incubation method 2 mL / mg

[0805] Table 4. Stability of liver microsomal metabolism

[0806]

[0807] Experimental results showed that compounds II-13, II-27 and II-28 were metabolized stably in liver microsomes.

[0808] Table 5. Stability of liver microsomal metabolism

[0809]

[0810] Compound II-39 has stable liver microsomal metabolism.

[0811] Example 76 In vivo anti-tumor experiment in mice

[0812] 1) In vivo experiment 1: In vivo tumor inhibition test of compounds II-25 and II-27

[0813] The procedures for animal experiments are as follows:

[0814] 1. Culture CT26 colon cancer cells. Once they reach the logarithmic growth phase, digest them, centrifuge at 800 rpm for 5 min, resuspend in PBS, and maintain a cell concentration of 5 × 10⁶ cells / mL. 6 Cells / ml were collected and inoculated subcutaneously into the right groin of BALB / c mice as soon as possible, with each mouse receiving 100 μL of cell suspension. The cell suspension could be placed in an ice-water bath during the procedure.

[0815] 2. Wait until the tumor grows to 30-50mm 3 Subsequently, mice were randomly grouped according to tumor volume, and tumor growth curves were recorded. The positive control compound 37 (Journal of Medicinal Chemistry, 2021, 64, 16, 12109-12131) was administered at a dose of 30 mg / kg once daily; test compounds II-25 and II-27 were administered at a dose of 30 mg / kg once daily. Tumor volume was measured daily. The tumor volume formula is: V = L * W * W * 1 / 2. Tumor growth was recorded when the tumor volume reached approximately 1200 mm². 3 The experiment was then terminated.

[0816] Experimental results are as follows Figure 1 As shown, the in vivo efficacy of the compounds was tested using a mouse model of colon cancer. The results showed that compounds II-25 and II-27 of this invention significantly inhibited tumor growth in mice after 5 days of administration, and were superior to the positive control compound 37. During the experiment, the animals in the groups of compounds II-25 and II-27 were well tolerated and had good safety.

[0817] 2) In vivo experiment 2: In vivo tumor inhibition test of compound II-39

[0818] The procedures for animal experiments are as follows:

[0819] 1. Culture CT26 colon cancer cells. Once they reach the logarithmic growth phase, digest them, centrifuge at 800 rpm for 5 min, resuspend in PBS, and maintain a cell concentration of 5 × 10⁶ cells / mL. 6 Cells / ml were collected and inoculated subcutaneously into the right groin of BALB / c mice as soon as possible, with each mouse receiving 100 μL of cell suspension. The cell suspension could be placed in an ice-water bath during the procedure.

[0820] 2. Wait until the tumor grows to 30-50mm 3Afterwards, mice were randomly grouped according to tumor volume, and tumor growth curves were recorded. The PD-1 antibody (Bio X Cell, BE0146-25MG, InVivoMAb anti-mouse PD-1, cloneRMP1-14) was administered intraperitoneally at a dose of 10 mg / kg, twice a week; the test compound II-39 was administered intraperitoneally at a dose of 30 mg / kg, once daily. Tumor volume was measured daily. The tumor volume formula is: V = L * W * W * 1 / 2. Tumor growth was recorded when the tumor volume reached approximately 1200 mm². 3 The experiment was then terminated.

[0821] Experimental results are as follows Figure 2 and Figure 3 As shown, in vivo experimental results indicate that compound II-39, at a dose of 30 mg / kg, effectively inhibited the growth of colon cancer. Furthermore, when combined with a PD-1 antibody, tumor growth was further inhibited, with a TGI of 81.1% (TGI = 1 - (tumor volume in the treatment group / tumor volume in the control group) × 100%. During the administration period, the animals in the compound II-39 administration group showed good tolerance and safety, and no significant weight loss was observed in the mice.

[0822] Example 77 Pharmaceutical Composition 1

[0823] The compound II-25 prepared in Example 25 was mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 1 with compound II-25 as the active ingredient.

[0824] Example 78 Pharmaceutical Composition 2

[0825] The compound II-27 prepared in Example 27 was mixed with a solvent and a stabilizer, filtered, and packaged to obtain pharmaceutical composition 2 with compound II-27 as the active ingredient.

[0826] Example 79 Pharmaceutical Composition 3

[0827] The compound II-39 prepared in Example 41 was mixed with a filler, a disintegrant, and a lubricant, granulated, and tableted to obtain a pharmaceutical composition 3 with compound II-39 as the active ingredient.

[0828] Example 80 Pharmaceutical Composition 4

[0829] Compound II-2 prepared in Example 2 and compound II-13 prepared in Example 13 were mixed with filler, disintegrant, and lubricant, granulated, and tableted to obtain pharmaceutical composition 4 with compounds II-2 and II-13 as active ingredients.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound being a compound of formula (III-1) or (III-2); In equation (III-1), R 1 It is a 5-12-membered heteroaryl, 3-6-membered cycloalkyl, 6-14-membered aryl, or surrounded by one or more R groups. b Substituted 6- to 14-membered aryl groups; Each R b It is independently a halogen or a C1-C6 alkyl group; R 4 It is a hydroxyl group, a 4- to 10-membered heterocyclic alkyl group, or -NH-(SO2)-R. c Or -NH-(CH2) k -R d k can be 0, 1, 2, 3, or 4; R c It is a 6-14 aryl group, surrounded by one or more R groups. c-1 Substituted 6-14 aryl or 5-12 heteroaryl; R d It consists of 6-14 aryl groups; Each R c-1 Independently cyano, with one or more R c-1-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, nitro, halogen, or with one or more R c-1-2 Substituted C1-C6 alkoxy or -NHC(=O)-R c-1-3 ; Each R c-1-1 and R c-1-2 Halogens are independent of each other; R c-1-3 It is a C1-C6 alkyl group; In each of the 5- to 12-membered heteroaryl groups and the 4- to 10-membered heterocyclic alkyl groups, the heteroatom is selected from N, O, or S, and the number of heteroatoms is 1, 2, or 3; In equation (III-2), R 1 It is a 5-12-membered heteroaryl, 3-6-membered cycloalkyl, 6-14-membered aryl, or surrounded by one or more R groups. b Substituted 6- to 14-membered aryl groups; R 2 is H or -OR a ; R a It is a 4- to 6-membered heterocyclic alkyl group; Each R b It is independently a halogen or a C1-C6 alkyl group; R 4 It is a hydroxyl group, a 4- to 10-membered heterocyclic alkyl group, or -NH-(SO2)-R. c -NH-(CH2) k -R d Or by one or more R e Substituted 4- to 10-membered heterocyclic alkyl groups; k is 0, 1, 2, 3, or 4; R c It is a 6-14 aryl group, surrounded by one or more R groups. c-1 Substituted 6-14 aryl or 5-12 heteroaryl; R d It is a 4- to 6-membered heterocyclic alkyl group; Each R c-1 Independently for one or more R c-1-1 Substituted C1-C6 alkyl or C1-C6 alkoxy; Each R e It can be an oxo group, hydroxyl group, or amino group independently; Each R c-1-1 and R c-1-2 Halogens are independent of each other; In each of the 5-12 membered heteroaryl, 4-6 membered heterocyclic alkyl and 4-10 membered heterocyclic alkyl groups, the heteroatom is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts include acid addition salts formed by the compound with one or more of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, and mandelic acid.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 R 2 The combinations shown in the table below are:

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, k is 0 or 1.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound satisfies one or more of the following conditions: (1)R 1 and R 2 In this context, the 3- to 6-membered cycloalkyl group is cyclopropane, cyclobutane, cyclopentane, or cyclohexane; (2)R 1 and R 2 In the case of the 6-14 aryl group and one or more R groups b In the substituted 6- to 14-membered aryl groups, the 6- to 14-membered aryl groups are phenyl or naphthyl; (3)R 1 and R 2 In this context, the 5-12 membered heteroaryl group is a 5-10 membered heteroaryl group; (4)R a In this context, the 4-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group; (5)R b In this context, the halogen is fluorine, chlorine, bromine, or iodine; (6)R b In this context, the C1-C6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, or isobutyl; (7)R 4 In this context, the 4- to 10-membered heterocyclic alkyl group and the one or more R e The substituted 4- to 10-membered heterocyclic alkyl groups are 4- to 7-membered heterocyclic alkyl groups; (8)R c In the case of the 6-14 aryl group and one or more R groups c-1 In the substituted 6- to 14-membered aryl groups, the 6- to 14-membered aryl groups are phenyl or naphthyl; (9)R c In this context, the 5-12 membered heteroaryl group is a 5-10 membered heteroaryl group; (10)R d In this context, the 6-14 aryl group is phenyl or naphthyl; (11)R d In this context, the 4-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group; (12)R c-1 In, the one or more R c-1-1 The substituted C1-C6 alkyl groups are methyl, ethyl, isopropyl, etc. n-propyl, n-butyl, sec-butyl, tert-butyl, or isobutyl; (13)R c-1 In this context, the C1-C6 alkoxy group and the group with one or more R c-1-2 The C1-C6 alkoxy group in the substituted C1-C6 alkoxy group is methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, or isobutoxy; (14)R c-1 In this context, the halogen is fluorine, chlorine, bromine, or iodine; (15)R c-1-1 and R c-1-2 In this context, the halogen is fluorine, chlorine, bromine, or iodine; (16)R c-1-3 In this context, the C1-C6 alkyl group is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, or isobutyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound satisfies one or more of the following conditions: (1)R 1 and R 2 In this context, the 3- to 6-membered cycloalkyl group is a cyclohexyl group; (2)R 1 and R 2 In the case of the 6-14 aryl group and one or more R groups b In the substituted 6-14 aryl groups, the 6-14 aryl groups are phenyl; (3)R 1 and R 2 In this context, the 5-12 membered heteroaryl group is a 5-10 membered heteroaryl group, wherein the heteroatom in the 5-10 membered heteroaryl group is N, O or S, and the number of heteroatoms is 1 or 2; (4)R a In this context, the 4-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group, wherein the heteroatom in the 5-6 membered heterocyclic alkyl group is N, O or S, and the number of heteroatoms is 1; (5)R b In this context, the halogen is fluorine; (6)R b In this context, the C1-C6 alkyl group is methyl, isopropyl, or tert-butyl; (7)R 4 In this context, the 4- to 10-membered heterocyclic alkyl group and the one or more R e The substituted 4- to 10-membered heterocyclic alkyl group is a 4- to 7-membered heterocyclic alkyl group, wherein the heteroatom in the 4- to 7-membered heterocyclic alkyl group is O or N; (8)R c In this context, the 5-12 membered heteroaryl group is a 5-10 membered heteroaryl group, and the heteroatom in the 5-10 membered heteroaryl group is S or O; (9)R d In this context, the 6-14 aryl group is a phenyl group; (10)R d In this context, the 4-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group, and the heteroatom in the 5-6 membered heterocyclic alkyl group is N; (11)R c-1 In, the one or more R c-1-1 In the substituted C1-C6 alkyl group, the C1-C6 alkyl group is methyl; (12)R c-1 In this context, the C1-C6 alkoxy group and the group with one or more R c-1-2 In the substituted C1-C6 alkoxy group, the C1-C6 alkoxy group is a methoxy group; (13)R c-1 In this context, the halogen is either fluorine or chlorine; (14)R c-1-1 and R c-1-2 In this context, the halogen is fluorine; (15)R c-1-3 In this context, the C1-C6 alkyl group is methyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound satisfies one or more of the following conditions: (1)R 1 and R 2 In this context, the 5-12 heteroaryl group is thienyl, pyrazole, or benzothienyl; (2)R a In this context, the 4- to 6-membered heterocyclic alkyl group is azacyclopentane; (3)R 4 In this context, the 4- to 10-membered heterocyclic alkyl group and the one or more R e The substituted 4- to 10-membered heterocyclic alkyl group is a 4- to 7-membered heterocyclic alkyl group, wherein the heteroatom in the 4- to 7-membered heterocyclic alkyl group is O or N, and the number of heteroatoms in the 4- to 7-membered heterocyclic alkyl group is 1 or 2; (4)R c In this context, the 5-12 membered heteroaryl group is a 5-10 membered heteroaryl group, and the heteroatom in the 5-10 membered heteroaryl group is S or O. The number of heteroatoms in the 5- to 10-membered heteroaryl groups is 1; (5)R d In this context, the 4-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group, and the heteroatom in the 5-6 membered heterocyclic alkyl group is N. The number of heteroatoms in the 5- to 6-membered heterocyclic alkyl group is 1.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound satisfies one or more of the following conditions: (1)R 4 In this context, the 4- to 10-membered heterocyclic alkyl group and the one or more R e The substituted 4- to 10-membered heterocyclic alkyl groups are: (2)R c In this context, the 5-12 member heteroaryl group is thiophene; (3)R d In this context, the 4-6 membered heterocyclic alkyl group is azircyclohexane.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound satisfies one or more of the following conditions: (1)R a It is a 4- to 6-membered heterocyclic alkyl group, and hydrochloric acid combines with the N atom in the 4- to 6-membered heterocyclic alkyl group to obtain the hydrochloride salt of the compound; (2)R e The amino group is formed by the combination of hydrochloric acid and the amino group to yield the hydrochloride salt of the compound. (3) The pharmaceutically acceptable salt of the compound is a hydrochloride salt; (5)R 1 and R 2 Each independently of hydrogen, (7)R 4 for 10. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any one of the following compounds:

11. Any of the following compounds: 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester; 2-(3-(1-(3',4'-difluoro-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester; 2-(3-(1-(3-(benzo[b]thiophen-6-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-(3-(1-(3-cyclohexylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-Methyl-2-(3-(1-(3-(thiophen-3-yl)benzoyl)piperidin-3-yl)phenoxy)propionate; 2-Methyl-2-(3-(1-(3-(thiophen-2-yl)benzoyl)piperidin-3-yl)phenoxy)methyl propionate; 2-(3-(1-(3-(1H-pyrazol-4-yl)benzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-(3-(1-(4'-isopropyl-[1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-propionate; 2-(3-(1-([1,1'-biphenyl]-3-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-(3-(1-([1,1'-biphenyl]-4-carbonyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-(3-(1-((3',4'-dimethyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester; 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate methyl ester; 2-(3-(1-((4'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-methyl-2-(3-(1-((3-(thiophen-3-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)propionate; 2-(3-(1-([1,1'-biphenyl]-3-ylsulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-(3-(1-((3-cyclohexylphenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-Methyl-2-(3-(1-((3-(thien-2-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)methyl propionate; 2-(3-(1-((3-(benzo[b]thiophene-6-yl)phenyl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester; 2-(3-(1-((3'-isopropyl-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-(3-(1-((4'-(tert-butyl)-[1,1'-biphenyl]-3-yl)sulfonyl)piperidin-3-yl)phenoxy)-2-propionate; Methyl 2-(3-(1-(3',4'-dimethyl-[1,1'-biphenyl]-3-yl)piperidin-3-yl)phenoxy)-2-propionate; 2-(3-(1-((3',4'-difluoro-[1,1'-biphenyl]-3-yl)methyl)piperidin-3-yl)phenoxy)-2-propionic acid methyl ester; 2-(3-(1-((3,4-dimethylbenzyl)carbamoyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-(3-(1-(3-(3,4-dimethylphenyl)propyl)piperidin-3-yl)phenoxy)-2-methylpropionate; 2-(3-(1-2-(4-isopropylphenylacetyl)piperidin-3-ylphenoxy)-2-methylpropionate; 3-(3-(3-(4-isopropylphenylacryloyl)piperidin-3-ylphenoxy-2-methylpropionate methyl ester; 2-(3-(1-(4-isopropylbenzyl)carbamoylpiperidin-3-ylphenoxy)-2-methylpropionate; 2-(3-1-Biphenyl)-4-carbonylpiperidine-3-phenoxy-2-methylpropionate methyl ester; 2-(3-1-(3'-isopropylbiphenyl)-3-sulfonylpiperidin-3-ylphenoxy-2-methylpropionate; 2-(3-1-tert-butyl)-3-sulfonyl-3-sulfonylpiperidine-2-methylpropionate methyl ester; 2-(3-(1-(3-isopropylbenzoyl)piperidin-3-yl)phenoxy)-2-methylpropionate.

12. A pharmaceutical composition, characterized in that, It is any of the following schemes: Option A: Pharmaceutical composition a: comprising a therapeutically effective amount of substance A and a pharmaceutical excipient; said substance A is a compound as described in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof; Option B: Pharmaceutical composition b: comprising substance A and an immune checkpoint inhibitor, wherein substance A is a compound as described in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients; The active ingredient comprises the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

14. The use of substance A in the preparation of a drug, characterized in that, The drug is used to treat and / or prevent tumors, wherein substance A is a compound as described in any one of claims 1-10 or a pharmaceutically acceptable salt thereof; or substance A is... Or its pharmaceutically acceptable salt.

15. The application as described in claim 14, characterized in that, The tumors mentioned are breast cancer, colon cancer, liver cancer, multiple myeloma, sarcoma, lung cancer, prostate cancer, rectal cancer, kidney cancer, pancreatic cancer, leukemia, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, stomach cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor, or skin cancer.

16. The application as described in claim 14, characterized in that, The tumor is breast cancer, colon cancer, or liver cancer.

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