CN104592211B

CN104592211B - Biphenyl compound and application thereof

Info

Publication number: CN104592211B
Application number: CN201410593507.2A
Authority: CN
Inventors: 张英俊; 王晓军; 杨新业; 潘圣强; 吴晨亮; 马发城; 吴守涛; 吴俊文
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2013-10-31
Filing date: 2014-10-28
Publication date: 2018-10-16
Anticipated expiration: 2034-10-28
Also published as: WO2015062486A1; CN104592211A

Abstract

Application the present invention relates to biphenyl analog derivative and its in medicine.Specifically, the present invention relates to stereoisomer, geometric isomer, tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, nitrogen oxides, hydrate, solvate, metabolite, hydrolysate, pharmaceutically acceptable salt or the prodrugs of compound shown in formula (I) compound represented or formula (I).The compound of the present invention can be used as therapeutic agent, especially as GPR40 agonists and for treating the diseases such as diabetes and metabolic disorder.

Description

Biphenyl compound and application thereof

Technical Field

The present invention relates to compounds having the activity of modulating GPR40 and their use for the treatment of GPR40 associated diseases. Furthermore, the invention relates to compounds, pharmaceutical compositions comprising these compounds and the therapeutic use of these compounds in certain diseases in which GPR40 activity is implicated.

Background

the recent understanding of the function of the G-protein coupled receptor GPR40 in regulating insulin secretion has provided an understanding of the metabolism of carbohydrates and lipids in vertebrates, and has also provided targets for the development of therapeutics for conditions such as obesity, diabetes, cardiovascular disease, and dyslipidemia.

GPR40 is a member of the gene superfamily of G-protein coupled receptors ("GPRs"), which are membrane proteins characterized by 7 putative transmembrane regions, responding to a variety of molecules by activating intracellular signaling pathways critical to a variety of physiological functions GPR40 was first identified from fragments of human genomic DNA as a lone receptor (i.e., a receptor without a known ligand) Sawzdargo et al (1997) biochem. Biophys. Res. Commun.239: 543-547. GPR40 is highly expressed in islet β cells and insulin-secreting cell lines GPR40 activates G with intracellular signaling proteins_qModulation of the family is associated with concomitant induction of elevated calcium levels. Fatty acids act as ligands of GPR40, and it is well known that fatty acids modulate insulin secretion via GPR 40. Itoh et al (2003) Nature 422: 173-176; briscor et al (2003) J.biol.chem.278: 11303-11311; kotarsky et al (2003) biochem. Biophys. Res. Commun.301: 406-410.

Many documents have been reported to disclose compounds having activity on GPR 40. For example, WO 2004/041266 and EP1559422 disclose compounds which are said to act as modulators of GPR40 receptor function. WO 2005/086661, U.S. patent publication No. 2006/0004012, U.S. patent publication No. 2006/0270724, and U.S. patent publication No. 2007/0066647 disclose compounds useful for modulating insulin levels in a subject and for treating type II diabetes.

Although a number of compounds have been disclosed which modulate the activity of GPR40, the high incidence of type II diabetes, obesity, hypertension, cardiovascular disease and dyslipidemia, suggests an urgent need for new therapies effective in the treatment or prevention of these diseases.

The present invention contemplates novel substituted biphenyls having the ability to modulate GPR40, thus the compounds are potentially useful for treating or preventing diabetes and related disorders.

Summary of the invention

The present invention provides compounds, pharmaceutical compositions and methods useful for treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, ketoacidosis, glucose intolerance, hypercholesterolemia, dyslipidemia, metabolic syndrome, cardiovascular disease, renal disease, thrombotic disorders, nephropathy, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, cancer, edema, diabetic complications, atherosclerosis, or hypertension. The compound or the pharmaceutical composition has good regulating effect on GPR40 receptor.

In one aspect, the invention relates to a compound of formula (I), or a stereoisomer, a geometric isomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a hydrolysate, a pharmaceutically acceptable salt or prodrug of a compound of formula (I),

wherein:

x is O, NH, CH₂Or S;

X¹is O, S, NH or CH₂；

X²O, S or NH;

y is alkylene or alkenylene; wherein one or more methylene groups in the alkylene and alkenylene chain may be replaced by NR^a、S、S(＝O)₂Or S (═ O), said alkylene and alkenylene groups may optionally be substituted by one or more groups independently selected from hydroxy, F, Cl, Br, I, cyano, amino, mercapto, and mixtures thereof,Nitro, oxo (═ O), alkyl, or heteroalkyl;

each R¹、R²And R³Independently is H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, or haloalkyl;

R⁴is H or alkyl;

each R⁵Independently is H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, alkyl, alkoxy, alkylamino, or heteroalkyl;

each k, n, m, b and q is independently 0,1,2, 3 or 4;

w is adamantyl, bridged cyclic group, bridged heterocyclic group, spiro cyclic group, spiro heterocyclic group, condensed cyclic group or condensed heterocyclic group, wherein the adamantyl, bridged cyclic group, bridged heterocyclic group, spiro cyclic group, spiro heterocyclic group, condensed cyclic group and condensed heterocyclic group may be optionally substituted with one or more independent R⁶Substituted by groups; or W is the following sub-structure:

wherein each R is⁶Independently H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, oxo (═ O), alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkylamino, alkyl-S (═ O)₂-or alkyl-S (═ O) -;

each R⁷Independently is H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl,Aminoalkyl, alkoxy, alkylamino, alkyl-S (═ O)₂-or alkyl-S (═ O) -;

R⁸is H, C_2-10Alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkyl-S (═ O)₂-or alkyl-S (═ O) -;

each R⁹Independently F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkylamino, alkyl-S (═ O)₂-or alkyl-S (═ O) -;

X³is NR^a、O、S、S(＝O)₂Or S (═ O);

X⁴is CH or N;

X⁵is CH₂Or NR^a；

X⁶Is CH₂O or NH;

X⁷is CH₂S, O or NR^a；

X^7aIs CH₂Or NR^a；

X^7bIs CH₂O or S;

X^7cis CH₂O or NR^a；

X⁸Is CH₂O or NH;

X^8ais CH or N;

X⁹is O or NH;

each R^aIndependently is alkyl-S (═ O)₂-or H;

each e is independently 0,1,2, 3,4, 5,6,7, or 8;

each t is independently 1,2,3,4 or 5;

t1 is 3,4 or 5; and

each t2 is independently 1 or 2.

In some of these embodiments, W is adamantyl, C_5-12Bridge ring radical, C_5-12Bridged heterocyclic radical, C_5-12Spiro ring radical, C_5-12Spiro heterocyclic group, C_4-12Condensed ring radicals or C_4-12Fused heterocyclic group, wherein said adamantyl group, C_5-12Bridge ring radical, C_5-12Bridged heterocyclic radical, C_5-12Spiro ring radical, C_5-12Spiro heterocyclic group, C_4-12Condensed ring radicals and C_4-12The fused heterocyclic group may optionally be substituted by one or more independent R⁶Substituted by groups; or W is the following sub-structure:

wherein each R is⁶Independently is H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, oxo (═ O), C_1-6Alkyl radical, C_2-6Heteroalkyl group, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Aminoalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6alkyl-S (═ O)₂-or C_1-6alkyl-S (═ O) -;

each R⁷Independently H, F, Cl, Br, I, hydroxyl, cyano, amino, mercapto, nitro, C_1-6Alkyl radical, C_2-6Heteroalkyl group, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Aminoalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6alkyl-S (═ O)₂-or C_1-6alkyl-S (═ O) -;

R⁸is H, C_2-6Alkyl radical, C_2-6Heteroalkyl group, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Aminoalkyl radical, C_1-6alkyl-S (═ O)₂-or C_1-6alkyl-S (═ O) -;

each R⁹Independently F, Cl, Br, I, hydroxyl, cyano, amino, mercapto, nitro, C_1-6Alkyl radical, C_2-6Heteroalkyl group, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Aminoalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6alkyl-S (═ O)₂-or C_1-6alkyl-S (═ O) -; and each R^aIndependently is C_1-6alkyl-S (═ O)₂-or H.

In other embodiments, each R is⁶Independently is H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, oxo (═ O), methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, methylamino, ethylamino, CH₃-S(＝O)₂-or CH₃-S(＝O)-；

Each R⁷Independently H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, methylamino, ethylamino, CH₃-S(＝O)₂-or CH₃-S(＝O)-；R⁸Is H, ethyl, trifluoromethyl, hydroxymethyl, aminomethyl, CH₃-S(＝O)₂-or CH₃-S(＝O)-；

Each R⁹Independently F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, methylamino, ethylamino, CH₃-S(＝O)₂-or CH₃-S (═ O) -; and

each R^aIndependently is CH₃-S(＝O)₂-or H.

In some of these embodiments, W is the following subformula:

wherein each R is⁶Independently is H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, oxo (═ O), methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, methylamino, ethylamino, CH₃-S(＝O)₂-or CH₃-S(＝O)-；

Each R⁷Independently H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, methylamino, ethylamino, CH₃-S(＝O)₂-or CH₃-S (═ O) -; and

each R⁹Independently F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, methylamino, ethylamino, CH₃-S(＝O)₂-or CH₃-S(＝O)-。

In some of these embodiments, Y is C_2-6Alkylene or C_2-6An alkenylene group; wherein said C_2-6Alkylene and C_2-6One or more methylene groups in the alkenylene chain may be replaced by NR^a、S、S(＝O)₂Or S (═ O) substitution, said C_2-6Alkylene and C_2-6Alkenylene may optionally be substituted with one or more substituents independently selected from hydroxy, F, Cl, Br, I, cyano, amino, mercapto, nitro, oxo (═ O), C_1-6Alkyl or C_2-6Substituted with a substituent of heteroalkyl; and

R^ais CH₃-S(＝O)₂-or H.

In some of these embodiments, each R is¹、R²And R³Independently H, F, Cl, Br, I, hydroxyl, cyano, amino, mercapto, nitro, C_1-6Alkyl radical, C_2-6Heteroalkyl group, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Hydroxyalkyl radical, C_1-6Aminoalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_2-10Heterocycloalkyl radical, C_6-10Aryl radical, C_1-9Heteroaryl or C_1-6A haloalkyl group;

R⁴is H or C_1-6An alkyl group; and

each R⁵Independently H, F, Cl, Br, I, hydroxyl, cyano, amino, mercapto, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino or C_2-6A heteroalkyl group.

In some of these embodiments, each R is¹、R²And R³Independently is H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, hydroxymethyl, aminomethyl, methoxy, methylamino, cyclopropane, tetrahydrofuranyl, phenyl, pyrrolyl, or trifluoromethyl;

R⁴is H, methyl or ethyl; and

each R⁵Independently H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, methyl, ethyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino or propylamino.

In another aspect, the present invention provides a pharmaceutical composition comprising any one of the compounds described above.

In some embodiments, the pharmaceutical composition further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.

In other embodiments, the pharmaceutical composition further comprises at least one of an anti-diabetic agent, an anti-hyperglycemic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-platelet agent, an anti-atherosclerotic agent, a lipid-lowering agent, and an anti-inflammatory agent.

in other embodiments, the antidiabetic agent is at least one of an SGLT-2 inhibitor, a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR agonist, an α P2 inhibitor, a PPAR α/gamma dual activator, a dipeptidyl peptidase IV (DPP-IV) inhibitor, a glinide, insulin, a glucagon-like peptide-1 (GLP-1) inhibitor, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, and a glucose-6-phosphatase inhibitor.

In other embodiments, the pharmaceutical composition further comprises at least one GPR40 receptor agonist.

In one aspect, the invention provides the use of said compound or said pharmaceutical composition for the preparation of a medicament for the prevention, treatment, alleviation or delay of elevated levels of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, ketoacidosis, glucose intolerance, hypercholesterolemia, dyslipidemia, metabolic syndrome, cardiovascular disease, renal disease, thrombotic disorders, nephropathy, sexual dysfunction, skin disorders, dyspepsia, hypoglycemia, cancer, edema, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels.

In another aspect, the invention provides the use of said compound or said pharmaceutical composition in the manufacture of a medicament for use as a G-protein coupled receptor agonist in a patient.

In some embodiments, the G-protein coupled receptor is the GPR40 receptor.

Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Description

Definitions and general terms

The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of a term, the usage of a term, the technology described, or the scope as controlled by the present application.

The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are according to the periodic Table of the elements, CAS version and handbook of chemistry and Physics, 75^thEd., 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltio, 1999, and "March's Advanced Organic Chemistry", Michael B&Sons, New York,2007, all of which are incorporated herein by reference.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the general formula above, or as specified in the examples, subclasses, and groups encompassed by the present invention. The term "optionally substituted" is understood to meanThe term "substituted or unsubstituted" is used interchangeably. In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (═ O), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (═ O) -, alkyl-S (═ O)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

Unless otherwise indicated, the term "alkyl" denotes a saturated straight or branched chain monovalent hydrocarbon group of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein, including, but not limited to, deuterium, amino, hydroxyl, cyano, F, Cl, Br, I, mercapto, nitro, oxo (═ O), and the like. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) T-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂)2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains. The term "alkylene" is used herein to denote a saturated divalent hydrocarbon radical resulting from the elimination of two hydrogen atoms from a straight or branched chain saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylidene, and the like.

The term "heteroalkyl" means that one or more heteroatoms may be inserted in the alkyl chain, wherein the alkyl group and the heteroatoms have the meaning as described herein. Unless otherwise specified, the heteroalkyl group contains from 1 to 10 carbon atoms, in other embodiments the heteroalkyl group contains from 1 to 8 carbon atoms, and in addition oneIn some embodiments, the heteroalkyl group contains from 1 to 6 carbon atoms, in other embodiments, the heteroalkyl group contains from 1 to 4 carbon atoms, and in yet other embodiments, the heteroalkyl group contains from 1 to 3 carbon atoms. Examples include, but are not limited to, CH₃OCH₂-、CH₃CH₂OCH₂-、CH₃SCH₂-、(CH₃)₂NCH₂-、(CH₃)₂CH₂OCH₂-、CH₃OCH₂CH₂-、CH₃CH₂OCH₂CH₂-and the like.

The term "alkenyl" denotes a straight or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one position of which is unsaturated, i.e. one C-C is sp²Double bonds in which an alkenyl group may be independently and optionally substituted with one or more substituents described herein, including where the group is "trans", "cis" or "E", "Z", where specific examples of alkenyl include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one position of which is unsaturated, i.e., one C-C is a sp triple bond, wherein the alkynyl radical may be independently and optionally substituted with one or more substituents as described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C ≡ CH), and the like.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon radical. And the alkylene group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercaptoNitro or aryloxy. Examples include, but are not limited to, methylene (-CH)₂-) ethylene (-CH₂-CH₂-) isopropylidene (-CH₂-CH(CH₃) -), ethane-1, 1-diyl, 2-methoxypropane-1, 1-diyl, 2-hydroxypropane-1, 1-diyl, 2-methyl-2-hydroxypropane-1, 1-diyl, and the like.

The term "alkenylene" denotes an alkenyl group derived from a straight or branched chain alkene by the removal of two hydrogen atoms. And the alkenylene group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, or aryloxy. Examples include, but are not limited to, ethenylene (-CH-), isopropenylene (-C (CH-)₃) CH-), 3-methoxypropene-1, 1-diyl, 2-methylbutene-1, 1-diyl, and the like.

The terms "hydroxyalkyl" or "hydroxyalkyl" mean that an alkyl group is substituted with one or more hydroxyl groups, wherein the alkyl group has the meaning described herein. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, and the like. ,

the terms "aminoalkyl", "aminoalkyl" means an alkyl group substituted with one or more amino groups, wherein the alkyl group has the meaning described herein, examples of which include, but are not limited to, aminomethyl, 2-aminoethyl, 2-aminoisopropyl, and the like.

The term "alkoxy", as it relates to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom, examples of which include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. And the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, and the like.

The term "alkylamino" refers to an alkyl group, as defined herein, attached to the main carbon chain through a nitrogen atom, examples of which include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, and the like. And the alkylamino group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, and the like.

The terms "cycloalkyl", "cycloaliphatic", "carbocyclic", or "carbocyclyl" refer to a mono-or polyvalent, non-aromatic, saturated or partially unsaturated ring, and contain no heteroatoms, including monocyclic rings of 3 to 12 carbon atoms or bicyclic rings of 7 to 12 carbon atoms. The bicyclic carbocyclic ring having 7 to 12 atoms may be bicyclo [4,5 ]]、[5,5]、[5,6]Or [6,6 ]]The bicyclic carbocyclic ring having 9 or 10 atoms may be bicyclo [5,6 ]]Or [6,6 ]]And (4) preparing the system. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of cycloaliphatic radicals include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the "cycloaliphatic" or "carbocycle", "carbocyclyl", "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (═ O) -, alkyl-S (═ O)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and all refer to a monocyclic, bicyclic, or bicyclic ringA ring or tricyclic ring system, wherein one or more carbon atoms in the ring are independently and optionally substituted by heteroatoms having the meaning as described herein, the ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic, and has one or more points of attachment to the rest of the molecule. One or more of the ring hydrogen atoms are independently and optionally substituted with one or more substituents as described herein. Some of these embodiments are "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" groups are monocyclic (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S) having 3-7 members rings, where S or P is optionally substituted with one or more oxygen atoms to yield, for example, SO₂、PO、PO₂When the ring is a three-membered ring, in which there is only one heteroatom), or a 7-to 10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give, for example, SO₂、PO、PO₂The group of (1).

The heterocyclic group may be a carbon-based or heteroatom group. "Heterocyclyl" also includes heterocyclic groups fused to saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepayl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3, 6-tetrahydropyridin-1-yl, oxaza-1-yl, oxa-pyridyl, thiaRadical diazaRadical, sulfur nitrogen heteroA group, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithienoalkyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2, 6-thiadiazinane 1, 1-dioxo-2-yl, 4-hydroxy-1, 4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1- (piperazin-1-yl) ethanone-4-yl, 2-hydroxy-1- (5, 6-dihydro-1, 2, 4-triazin-1 (4H) -yl) ethanon-4-yl, 5, 6-dihydro-4H-1, 2, 4-oxadiazin-4-yl, 2-hydroxy-1- (5, 6-dihydropyridin-1 (2H) -yl) ethanon-4-yl, 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 2-methyl-5, 6,7, 8-tetrahydro- [1.2.4 ]]Triazole [1,5-c ]]Pyrimidin-6-yl, 4,5,6, 7-tetrahydroisoxazole [4,3-c]Pyridin-5-yl, 3H-indolyl 2-oxo-5-azabicyclo [2.2.1]Heptane-5-yl, 2-oxo-5-azabicyclo [2.2.2 ]]Octane-5-yl, quinolizinyl and N-pyridyl urea. Examples of heterocyclic groups also include 1, 1-dioxothiomorpholinyl and wherein two carbon atoms of the ring are replaced by oxygen atoms such as pyrimidinedione. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (═ O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O)2-, hydroxyl-substituted alkyl-S (═ O)2-, carboxyl-substituted alkoxy, and the like.

The term "heteroatom" means one or more of O, S, N, P and Si atoms, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, e.g., N (e.g., N in 3, 4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl), or NR (e.g., NR in N-substituted pyrrolidinyl).

The term "aryl" may be used alone or as "aralkylA majority of the groups "," aralkoxy "or" aryloxyalkyl "represent monocyclic, bicyclic, and tricyclic carbon ring systems having a total of 6-14 membered rings, wherein at least one ring system is aromatic, wherein each ring system comprises 3-7 membered rings and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. And the aryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O) —, alkyl-S (═ O)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and denotes monocyclic, bicyclic and tricyclic ring systems containing a total of 5-14 membered rings, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning described herein, and wherein each ring system contains 3-7 membered rings and one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic" or "heteroaromatic". And the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

In still other embodiments, the aromatic heterocyclic ring includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3, 5-triazinyl, benzo [ d ] thiazol-2-yl, imidazo [1,5-a ] pyridin-6-yl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl).

The term "haloalkyl" denotes an alkyl group substituted with one or more of the same or different halogen atoms, wherein the alkyl group has the meaning as described herein, i.e., fluorine, chlorine, bromine or iodine, examples of which include, but are not limited to, trifluoromethyl, trifluoroethyl, chloromethyl, fluoromethyl and the like.

The terms "bridged ring", "bridged ring group" or "bridged ring group" mean a saturated or unsaturated bridged ring system, relating to a non-aromatic bridged ring system, as shown, for example, by formula (a1), i.e., ring a1 shares an alkane chain or a heteroalkyl chain with ring a2, wherein j is 1,2,3, or 4. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Each ring in the bridged ring is either a carbocyclic or a heteroalicyclic, examples of which include, but are not limited to, bisRing [2.2.1]Heptylalkyl, 7-oxabicyclo [2.2.1]Heptylalkyl, 2-azabicyclo [2.2.1]Heptalkyl, and the like. And the bridged ring may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (═ O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O) -, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, hydroxyl-substituted alkyl-S (═ O)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

The term "bridged heterocyclyl" denotes a saturated or unsaturated bridged ring system, involving a non-aromatic bridged ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). And at least one ring system comprising one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give, for example, SO₂、PO、PO₂Examples of such include, but are not limited to, 2-azabicyclo [2.2.1 ]]Heptane and the like. And the heterobridged ring group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (═ O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O) —)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

The term "spiro ringThe group "spiro" means that one ring originates from a particular cyclic carbon on the other ring. For example, as shown in formula (a2), ring a and ring B share a carbon atom in two saturated ring systems, and are referred to as "spirocycles". Each ring within the spiro ring is either a carbocyclic or a heteroalicyclic. Examples include, but are not limited to, 2, 7-diazaspiro [4.4 ]]Nonan-2-yl, 7-oxo-2-azaspiro [4.5 ]]Decan-2-yl, 4-azaspiro [2.4 ]]Heptane-5-yl, 4-oxaspiro [2.4 ]]Heptane-5-yl, 5-azaspiro [2.4 ]]Heptane-5-yl, spiro [2.4 ]]Heptylalkyl, spiro [4.4 ]]Nonanyl, 7-hydroxy-5-azaspiro [2.4 ]]Heptane-5-yl, and the like. And the spirocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (═ O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O) —)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

The term "spiroheterocyclyl" means that one ring originates from a particular cyclic carbon on another ring. For example, as described above, ring a and ring B share a carbon atom in two saturated ring systems, and are referred to as "spirocycles. And at least one ring system comprising one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give, for example, SO₂、PO、PO₂Examples of such include, but are not limited to, 4-azaspiro [2.4 ]]Heptane-5-yl, 4-oxaspiro [2.4 ]]Heptane-5-yl, 5-azaspiro [2.4 ]]Heptane-5-yl, 7-hydroxy-5-azaspiro [2.4 ]]Heptane-5-yl, 5-azaspiro [2.4 ]]Heptane-6-yl, 1, 4-dioxo-7-azaspiro [4.4 ]]Nonan-8-yl and the like. And the spiroheterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (═ O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O) —)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

The terms "fused ring", "fused ring group" and "fused ring group" refer to a saturated or unsaturated fused ring system, and refer to a non-aromatic fused ring system, for example, as shown in formula (B1), i.e., ring B1 shares a bond with ring B2. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Each ring in the fused ring is either a carbocyclic or a heteroalicyclic, examples of which include, but are not limited to, hexahydro-furo [3,2-b ] furan]Furan, 2,3,3a,4,7,7 a-hexahydro-1H-indene, 7-azabicyclo [2.3.0 ]]Heptane, fused bicyclo [3.3.0]Octane, fused bicyclo [3.1.0]Hexane, 1,2,3,4,4a,5,8,8 a-octahydronaphthalene, all of which are contained within a fused ring system. And the condensed ring group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (═ O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O) —)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

The term "fused heterocyclyl" denotes saturated or unsaturated fused ring systems,to non-aromatic fused ring systems. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). And at least one ring system comprising one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give, for example, SO₂、PO、PO₂Examples of such include, but are not limited to hexahydro-furo [3.2-b ]]Furan, 6-azabicyclo [3.2.0]Heptane, 2-azabicyclo [3.1.0]Heptane, 3-azabicyclo [3.1.0]Heptane, 7-azabicyclo [2.3.0]Heptane. And the fused heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, deuterium, oxo (═ O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C (═ O) -, alkyl-S (═ O) -, hydroxyl-substituted alkoxy group, hydroxyl-substituted alkyl-C (═ O) -, hydroxyl-substituted alkyl-S (═ O)₂-, hydroxy-substituted alkyl-S (═ O)₂-, carboxy-substituted alkoxy, and the like.

The term "oxo" indicates that a substitutable position is substituted by ═ O.

The term "halogen" denotes F, Cl, Br and I.

As described herein, a ring system formed by a substituent drawing a ring bonded to the center (as shown in formula (a)) represents a substituent R⁵Substitutions may be made at any substitutable position on the ring. For example, formula (a) represents that any possible substituted position on the ring of W1 or W2 may be substituted.

As described herein, there are two attachment points in the ring system that are attached to the rest of the molecule, as shown in formula (b), which means that either the E or E' end is attached to the rest of the molecule, i.e., the attachment of the two ends can be interchanged.

As described herein, the dashed bond within the ring system represents a double or single bond. For example, the structure of formula (c) represents any one selected from the structures of formula (d).

Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.

In addition, unless otherwise expressly indicated, the recitations "… independently for each … and" … and … independently for each … and … "as used throughout this document are interchangeable and should be broadly understood to mean that particular items represented by the same reference numbers do not interact with each other in different groups, or that particular items represented by the same reference numbers do not interact with each other in the same groups, e.g., structuresAnd structureR in both⁶Detailed description of the preferred embodimentAre not affected by each other, and multiple Rs appear in the same structure⁶A plurality of R⁶Do not influence each other by specific options, i.e. R⁶The specific options of (a) may be the same or different.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: t.higuchi and v.stella, Pro-drugs as Novel delivery systems, vol.1 of the a.c.s.symposium Series, Edward b.roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association and permamonpress, 1987, j.rautio et al, produgs: design and Clinical Applications, Nature review Drug Discovery,2008,7,255-270, and S.J. Hecker et al, Prodrugs of Phosphates and Phosphates, Journal of medical Chemistry,2008,51, 2328-2345.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, a mixture of isomers commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, J.pharmaceutical Sciences,66,1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulphates, perchlorates, and salts of organic acids, such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, bisulfates, salts of sodium, potassium, sodium, potassium, sodium, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptableAcceptable salts further include suitable non-toxic ammonium/quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The terms "protecting group", "Pg" or "Pg" refer to a substituent that when reacted with another functional group, is typically used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons, New York, 1991; and p.j.kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

Description of the Compounds of the invention

The biphenyl compound, the pharmaceutical composition and the pharmaceutical preparation thereof can effectively regulate GPR40 receptor.

In one aspect, the invention relates to a compound of formula (I), or a stereoisomer, a geometric isomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a hydrolysate, a pharmaceutically acceptable salt or a prodrug of the compound of formula (I),

wherein:

x is O, NH, CH₂Or S;

X¹is O, S, NH or CH₂；

X²O, S or NH;

y is alkylene or alkenylene; wherein one or more methylene groups in the alkylene and alkenylene chain may be replaced by NR^a、S、S(＝O)₂Or S (═ O), said alkylene and alkenylene groups may be optionally substituted with one or more substituents independently selected from hydroxy, F, Cl, Br, I, cyano, amino, mercapto, nitro, oxo (═ O), alkyl or heteroalkyl;

R⁴is H or alkyl;

each k, n, m, b and q is independently 0,1,2, 3 or 4;

each R⁷Independently H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkylamino, alkyl-S (═ O)₂-or alkyl-S (═ O) -;

X³is NR^a、O、S、S(＝O)₂Or S (═ O);

X⁴is CH or N;

X⁵is CH₂Or NR^a；

X⁶Is CH₂O or NH;

X⁷is CH₂S, O or NR^a；

X^7aIs CH₂Or NR^a；

X^7bIs CH₂O or S;

X^7cis CH₂O or NR^a；

X⁸Is CH₂O or NH;

X^8ais CH or N;

X⁹is O or NH;

each R^aIndependently is alkyl-S (═ O)₂-or H;

each e is independently 0,1,2, 3,4, 5,6,7, or 8;

each t is independently 1,2,3,4 or 5;

t1 is 3,4 or 5; and

each t2 is independently 1 or 2.

each R⁹Independently F, Cl, Br, I, hydroxyl, cyano, amino, mercapto, nitro, C_1-6Alkyl radical, C_2-6Heteroalkyl group, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Aminoalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6alkyl-S (═ O)₂-or C_1-6alkyl-S (═ O) -; and

each R^aIndependently is C_1-6alkyl-S (═ O)₂-or H.

Each R⁷Independently H, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, nitro, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, methylamino, ethylamino, CH₃-S(＝O)₂-or CH₃-S(＝O)-；

R⁸Is H, ethyl, trifluoromethyl, hydroxymethyl, aminomethyl, CH₃-S(＝O)₂-or CH₃-S(＝O)-；

each R^aIndependently is CH₃-S(＝O)₂-or H.

In some of these embodiments, W is the following subformula:

R^ais CH₃-S(＝O)₂-or H.

R⁴is H or C_1-6An alkyl group; and

R⁴is H, methyl or ethyl; and

In some of these embodiments, the invention comprises the structure of one of the following:

or a stereoisomer, geometric isomer, tautomer, or mixture thereof,A meso form, a racemate, an enantiomer, a diastereomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a hydrolysate, a pharmaceutically acceptable salt or a prodrug.

The compounds of the invention (in the description "compounds of formula (I) and stereoisomers, geometric isomers, tautomers, mesomers, racemates, enantiomers, diastereomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts and prodrugs thereof" may be collectively referred to as "compounds of the invention") may be used for the production of a pharmaceutical product for the prevention, treatment, alleviation or delay of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, ketoacidosis, glucose intolerance, hypercholesterolemia, dyslipidemia, metabolic syndrome, cardiovascular disease, renal disease, kidney disease, Thrombotic disorders, kidney disease, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, cancer, edema, diabetic complications, atherosclerosis or hypertension or for increasing high density lipoprotein levels, including those described herein. Further, the compounds of the present invention may be used in the manufacture of preparations that modulate receptors for GPRs. Thus, the compounds of the invention may be used in the manufacture of a medicament for alleviating, preventing, controlling or treating disorders mediated by the receptors for the GPRs, in particular GPR 40. Thus, the compounds of the present invention may be used as active ingredients of pharmaceutical compositions which may include the compounds represented by formula (I), and which may further comprise at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" means that the substance or composition employed must be compatible chemically or toxicologically with the other ingredients comprising the formulation and the mammal being treated. The "pharmaceutically acceptable" substance or composition may be specifically selected by those skilled in the art depending on the other components employed and the subject, e.g., human, being treated.

if the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic or organic acids, wherein examples of inorganic acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, and phosphoric acids, and the like.

If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compositions, formulations and administration of the Compounds of the invention

The present invention provides pharmaceutical compositions suitable for pharmaceutical use comprising one or more compounds of the invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof. The pharmaceutical composition can be used for the treatment of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, ketoacidosis, glucose intolerance, hypercholesterolemia, dyslipidemia, metabolic syndrome, cardiovascular diseases, renal diseases, thrombotic disorders, nephropathy, sexual dysfunction, skin disorders, dyspepsia, hypoglycemia, cancer, edema, diabetic complications, atherosclerosis or hypertension or for increasing high density lipoprotein level diseases, in particular, it has a good modulating effect on the GPR40 receptor.

the pharmaceutical compositions further comprise other antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, lipid lowering agents, anti-inflammatory agents or combinations thereof, which may be any other known antidiabetic agent useful other than the compounds of the present invention, for example, SGLT-2 inhibitors, biguanide agents, sulfonylurea agents, glucosidase inhibitors, PPAR agonists, α P2 inhibitors, PPAR α/γ dual activators, dipeptidyl peptidase IV (DPP-IV) inhibitors, glinide agents, insulin, glucagon-like peptide-1 (GLP-1) inhibitors, PTP1B inhibitors, glycogen phosphorylase inhibitors or glucose-6-phosphatase inhibitors.

When useful in therapy, a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I) and pharmaceutically acceptable salts thereof, may be administered as the raw chemical or as the active ingredient of a pharmaceutical composition. Accordingly, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to exhibit meaningful patient benefit (e.g., blood glucose reduction). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds of the invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation which comprises mixing a compound of the present invention, especially a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

When the compositions of the present disclosure comprise a combination of a compound of the present disclosure and one or more other therapeutic or prophylactic agents, the dosage level of the compound and the additional agent(s) will generally be from about 10% to about 150% of the normally administered dose, more preferably from about 10% to about 80% of the normally administered dose, in a monotherapy regimen. The pharmaceutical formulations are adapted for administration by any suitable route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.

Pharmaceutical compositions for use of the compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Generally, the pharmaceutical compositions are prepared by the following method: the active ingredient is combined uniformly and intimately with liquid carriers or finely divided solid carriers or both, and the product is then, if necessary, brought into the desired formulation. In pharmaceutical compositions, the active object compound is included in a sufficient amount to produce the desired effect on the course or condition of the disease.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granules and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. nos. 4256108, 4160452 and 4265874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives (e.g., ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose or saccharin).

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders or granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil or a mineral oil such as liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, such as gum acacia or gum tragacanth; naturally occurring phosphatides, such as soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate; and condensation products of the said partial esters with ethylene oxide, such as polyethylene sorbitan monooleate. The emulsions may also include sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. The suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents as already mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Thus, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable pharmaceuticals.

The pharmaceutical compositions may also be in the form of suppositories or enemas for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical use, ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oil preparations or transdermal patches comprising the compounds of the invention are employed. Topical application as used herein is also intended to include the use of mouthwashes and mouthwashes.

The pharmaceutical compositions and methods of the invention may also include, as indicated herein, other therapeutically active compounds useful in the treatment of: type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, renal disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, cancer, and edema.

In the treatment or prevention of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, renal disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, hypoglycemia, cancer and edema, or other conditions or disorders associated with GPR40, suitable dosage levels are typically from about 0.001 to 100mg per kg of patient body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level is from about 0.01 to about 25mg/kg per day; more preferably, from about 0.05 to about 10mg/kg per day. Suitable dosage levels may be about 0.01 to 25mg/kg per day, about 0.05 to 10mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range, the dose may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0mg/kg per day. For oral administration, the composition is preferably provided in the form of a tablet comprising 1.0 to 1000 milligrams of the active ingredient, in particular 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered in a treatment regimen of 1 to 4 times per day, preferably once per day or twice per day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The compounds of the present invention may be used in combination or combination with other agents that are useful in the treatment, prevention, inhibition, or amelioration of diseases or conditions for which the compounds of the present invention are useful, including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, renal disease, ketoacidosis, thrombotic disorders, renal disease, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disorders, dyspepsia, hypoglycemia, cancer, and edema, diseases or conditions mediated by GPR 40. Such other agents or drugs may be administered by commonly used routes and in commonly used amounts so as to be administered simultaneously, sequentially or separately with the compounds of the present invention. When the compounds of the present invention are used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compounds of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more additional active ingredients or therapeutic agents in addition to the compounds of the present invention.

Examples of other therapeutic agents that may be combined with, administered separately from, or administered in the same pharmaceutical composition as the compounds of the present invention include, but are not limited to: (a) cholesterol lowering agents, such as HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), vitamin B₃(also known as nicotinic acid or niacin), vitamin B₆(Pidotoxin) and vitamin B₁₂(cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate and bezafibrate), probucol, nitroglycerin and cholesterol absorption inhibitors (e.g., β -sitosterol and acyl CoA-cholesterol acyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthase inhibitors, squalene epoxidase inhibitors and squalene synthase inhibitors), (b) antithrombotic agents such as thrombolytic agents (e.g., streptokinase, alteplase, anistreplase and reteplase), heparin, hirudin and warfarin derivatives, β -blockers (e.g., atenolol), β -adrenergic agonists (e.g., isoproterenol), ACE inhibitors and vasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride, nitroglycerin and enalapril), and (c) antidiabetic agents such as insulin and insulin-like drugs, sulfonylureas (e.g., Benzide, meglitinide), biguanides such as metforminα -glucosidase inhibitors (acarbose), insulin sensitizers such as thiazolidinone compounds, rosiglitazoneTroglitazoneCiglitazone and pioglitazoneAnd englitazone, DPP-IV inhibitors such as vildagliptinSitagliptin (Januvia (TM)) and GLP-1 analogs such as exenatide (exenatide)In certain embodiments, the instant inventionThe compounds of the invention may be administered with DPP-IV inhibitors or GLP-1 analogs. In certain embodiments, the compounds of the present invention are administered with any of the DPP-IV inhibitors set forth in U.S. patent publication No. 2006/0270701, which is hereby incorporated by reference in its entirety and for all purposes as if specifically set forth herein.

The weight ratio of the compound of the invention to the second active ingredient can vary and will depend upon the effective dosage of each ingredient. Generally, each effective dose will be used. Combinations of the compounds of the invention with other active ingredients will generally also be within the aforementioned ranges, but in each case an effective dose of each active ingredient should be used.

Use of the Compounds and pharmaceutical compositions of the invention

The present invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the modulation of a G-protein coupled receptor, preferably the GPR40 receptor.

A method of treatment comprising administering a compound or pharmaceutical composition of the invention further comprising administering to the patient an additional GPR40 modulator, SGLT-2 inhibitor, biguanide, sulfonylurea, glucosidase inhibitor, PPAR agonist, α P2 inhibitor, PPAR α/γ dual activator, dipeptidyl peptidase IV (DPP-IV) inhibitor, glinide, insulin, glucagon-like peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, glycogen phosphorylase inhibitor or glucose-6-phosphatase inhibitor, whereby the compound of the invention may be administered in combination with the additional GPR40 modulator, SGLT-2 inhibitor, biguanide, sulfonylurea, glucosidase inhibitor, PPAR agonist, α P2 inhibitor, PPAR α/γ dual activator, dipeptidyl peptidase IV (DPP-IV) inhibitor, glinide, insulin, glucagon-like peptide-1 (GLP-1) antidiabetic inhibitor, inhibitor of glucose-1B, glycogen phosphorylase inhibitor or glucose-6-phosphatase inhibitor, as a single dose, separate dose, as a single dose of the compound, as a dose of the combination of the compound, as a dose of the combination of the administration of the compound, as a dose of the compound of the combination of the compound, as the combination of.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.

General synthetic procedure

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were used by being dried beforehand over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao oceanic plants. Nuclear magnetic resonance spectroscopy with CDC1₃,DMSO-d₆,CD₃OD or acetone-d₆As solvent (reported in ppm) TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet ), t (triplet, triplet), q (quatet, quartet), m (multiplet ), br (broadpede, broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

TABLE 1

Time (min)	A(CH₃CN，0.1％HCOOH)	B(H₂O，0.1％HCOOH)
			0-3	5-100	95-0

3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.

The following acronyms are used throughout the invention:

an AD-Mix-. beta.asymmetric dihydroxylation reaction mixture containing hydroquinidine 1,4- (2, 3-naphthyridine) diether 0.0016 mol, potassium carbonate powder 0.4988 mol, potassium ferricyanide 0.4988 mol, potassium osmate dihydrate 0.0007 mol

g

mg of

mmol millimole

mL, mL mL

L liter

DEG C

¹H NMR Hydrogen 1 Nuclear magnetic resonance Spectroscopy

¹³C NMR carbon 13 nuclear magnetic resonance spectrum

MS Mass Spectrometry

MHz

Hz

DMSO-d₆Deuterated dimethyl sulfoxide

CDCl₃Deuterated chloroform

CD₃OD deuterated methanol

DMSO dimethyl sulfoxide

Ion positive ion of pos

neg.ion anion

ESI electrospray ionization

m/z mass-to-charge ratio

DCM dichloromethane

DMF N, N-dimethylformamide

Pd/C palladium on carbon

TLC thin layer chromatography

TBSO tert-butyl dimethylsilyloxy

Me methyl group

Bn benzyl group

TMS trimethyl silicon base

Cbz benzyloxycarbonyl

h hours

EtOAc ethyl acetate

PET petroleum ether

MeOH methanol

THF tetrahydrofuran

Na₂SO₄Sodium sulfate

NaHCO₃Sodium bicarbonate

DMF N, N-dimethylformamide

Synthesis method

The first scheme is as follows:

W、Y、R¹、R²、R³、R⁵、X、X¹、X²b, q, m, n are as defined in formula (I), R^4aIs C_1-6Alkyl, s is 0,1,2 or 3, R' is a hydrogen atom or optionally substituted C_1-6An alkoxy group.

Step A1:

when L is a leaving group, W-Y-L reacts with a compound II in a solvent under alkaline conditions to obtain a compound III. Examples of the leaving group represented by L include a halogen atom, a methanesulfonyloxy group, a p-methylbenzenesulfonyloxy group and the like. As the base, for example, potassium carbonate and the like can be mentioned. The reaction is carried out in a solvent which is inert to the reaction. Solvents used include, but are not limited to, N-dimethylformamide and the like.

When L is hydroxyl, W-Y-L and the compound II are subjected to Mitsunobu reaction to obtain a compound III. In the Mitsunobu reaction, the reaction raw materials are reacted in a solvent in the presence of an azodicarbonyl compound (e.g., diisopropyl azodicarboxylate, 1' - (azodicarbonyl) dipiperidine) and a phosphine (e.g., triphenylphosphine, tributylphosphine). The reaction is preferably carried out in a solvent inert to the reaction. Solvents used include, but are not limited to, toluene and the like.

Step A2:

when Q is hydroxy, the compound IV can be prepared by subjecting the compound III to a reduction reaction. The reduction reaction is generally carried out according to a conventional method using a reducing agent; as the reducing agent, for example, sodium borohydride, lithium aluminum hydride and the like can be mentioned. The reduction is preferably carried out using a solvent inert to the reaction. Solvents used include, but are not limited to, methanol, tetrahydrofuran, and the like; or a mixed solvent thereof.

When Q is a leaving group, compound III is reduced in the presence of a reducing agent (e.g., sodium borohydride, lithium aluminum hydride, etc.) in an inert solvent (e.g., methanol, tetrahydrofuran, etc.), and then reacted with a halogenating agent or a sulfonylating agent to produce compound IV. Wherein the reaction with the halogenating agent is carried out in the absence of a solvent or with a solvent which is inert to the reaction; as the halogenating agent, for example, phosphorus oxychloride and the like; solvents used include, but are not limited to, N-dimethylformamide, dichloromethane, and the like; alternatively, an excess of the halogenating agent is used instead of the solvent. The reaction with the sulfonylating agent is generally carried out in a solvent inert to the reaction in the presence of a base; examples of the sulfonylating agent include methanesulfonyl chloride, p-toluenesulfonyl chloride and the like; as the solvent inert to the reaction, those listed in the above-mentioned reaction with the halogenating agent; as the base, for example, triethylamine and the like can be mentioned.

Step A3:

compound I can be prepared by reacting compound IV with compound V according to the method shown in step A1 or a method analogous thereto.

Step A4:

the compounds I' can be prepared by hydrolysis of the compounds I under alkaline conditions. As the base, for example, lithium hydroxide, sodium hydroxide and the like can be mentioned. The hydrolysis reaction is carried out without a solvent or with a solvent inert to the reaction. Solvents used include, but are not limited to, methanol, tetrahydrofuran, water, and the like; or a mixed solvent thereof.

Scheme II:

W、Y、R¹、R²、R³、R⁵、X、X¹、X²b, q, m, n are as defined in formula (I). R^4aQ, L has the same meaning as in scheme I.

Step B1:

compound IV may be prepared by reacting compound W-Y-L with compound VI according to the method shown in scheme one step A1 or a similar method.

Step B2:

compound i can be prepared by reacting compound iv with compound v according to the method shown in scheme one, step a3, or a similar method.

Step B3:

compound i' may be prepared by reacting compound i according to the method shown in scheme one, step a4 or a similar method.

The third scheme is as follows:

W、Y、R¹、R²、R³、R⁵、X、X¹、X²b, q, m, n are as defined in formula (I), R^4aQ, L has the same meaning as in scheme I. When X is present¹And PG is a corresponding protecting group when it is an oxygen atom or a nitrogen atom.

Step C1:

compound VIII can be prepared by reacting compound VII with compound V according to the method shown in scheme two, step B2 or a similar method.

Step C2:

the compound IX can be prepared by subjecting the compound VIII to deprotection reaction by selecting an appropriate method for different protecting groups. For example, an alkylsiloxy substituted phenyl compound (t-butyldimethylsiloxy substituted phenyl compound) in a solvent under the conditions of a fluorinating agent (tetrabutylammonium fluoride) gives a deprotected compound. The reaction is carried out in a solvent which is inert to the reaction. Solvents used include, but are not limited to, tetrahydrofuran and the like.

Step C3:

compound i can be prepared by reacting compound IX with compound W-Y-L according to the method shown in scheme one step a1 or a method analogous thereto.

Step C4:

And the scheme is as follows:

W、Y、R¹、R²、R³、R⁵、X、X¹、X²b, q, m, n are as defined in formula (I), Hal is Cl, Br or I, R^4aAnd Q has the same meaning as in scheme I.

Step D1:

compound xi may be prepared by reacting compound x with compound v according to the procedure shown in scheme three step C1 or a similar procedure.

Step D2:

the compound I can be prepared by a compound XI and W-Y-X¹-H is prepared by a coupling reaction in a solvent in the presence of a catalyst and a ligand. The catalyst may be a copper catalyst including, but not limited to, cuprous iodide, cuprous chloride, and the like. The ligand can be matched with the catalyst for use, and includes but is not limited to L-proline, trans-N, N' -dimethyl-1, 2-cyclohexanediamine and the like. The reaction is carried out in a solvent inert to the reaction, including but not limited to dimethylsulfoxide, and the like.

Step D3:

Examples

Example 1

3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-ol

First, 4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde

4-bromo-3, 5-dimethylphenol (10.2g,51mmol) and 3-formylphenylboronic acid (7.67g,51.2mmol) were dissolved in a mixed solution of 1M aqueous sodium carbonate (150mL), ethanol (50mL) and toluene (150mL), tetrakis (triphenylphosphine) palladium (2.95g,2.55mmol) was added under nitrogen protection, and the reaction was warmed to 80 ℃ and stirred for 24 hours. The reaction mixture was cooled to room temperature, diluted with water (50mL), extracted with ethyl acetate (200mL), and the organic phase was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (8.7g, 75.4%) as a white solid.

MS(ESI,neg.ion)m/z:225.2[M-H]^-.

Second, 3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-ol

4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (7.3g,32mmol) was dissolved in a mixed solution of tetrahydrofuran (50mL) and methanol (25mL), sodium borohydride (1.45g,38mmol) was added in portions under ice bath, and the reaction solution was stirred overnight under ice bath. The reaction solution was quenched with water (10mL), extracted with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1), to give the title compound (6.0g, 69%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.43(t,J＝7.6Hz,1H),7.36(d,J＝7.7Hz,1H),7.15(s,1H),7.09(d,J＝7.5Hz,1H),6.62(s,2H),4.76(s,2H),2.00(s,6H).

Example 2

2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester

First step, 4'- ((tert-butyldimethylsilyl) oxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde

4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (10.2g,45.3mmol) and imidazole (3.7g,54.3mmol) were dissolved in dichloromethane (200mL) and tert-butyldimethylchlorosilane (8.2g,54.3mmol) was added under ice bath. The reaction was stirred at room temperature overnight, quenched with water (50mL), extracted with dichloromethane (100 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30/1) to give the title compound (15g, 97.4%) as a pale yellow oil.

In the second step, (4'- ((tert-butyldimethylsilyl) oxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol

4'- ((tert-butyldimethylsilyl) oxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (49g,143.9mmol) was dissolved in a mixed solution of tetrahydrofuran (200mL) and methanol (100mL), sodium borohydride (5.7g,150mmol) was added portionwise under ice bath, and the reaction was stirred in ice bath overnight. The reaction solution was quenched with water (50mL), extracted with ethyl acetate (200 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1), to give the title compound (42g, 85.2%) as a pale yellow oil.

The third step, methyl 2- (6- ((4'- ((tert-butyldimethylsilyl) oxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(4'- ((tert-butyldimethylsilyl) oxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol (6.9g,20mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (4.2g,20mmol, prepared as ACS med.chem.lett.,2010,1, 290-294) were dissolved in toluene (50mL), tributylphosphine (8.1mL,32mmol) and azobisformyldipiperidine (8.1g,32mmol) were added and the mixture was stirred at room temperature under nitrogen for 1 hour. Water (50mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (9g, 84%) as a white solid.

The fourth step, methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl 2- (6- ((4'- ((tert-butyldimethylsilyl) oxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (9g,16.9mmol) was dissolved in tetrahydrofuran (30mL), and a 1M tetrabutylammonium fluoride tetrahydrofuran solution (26mL,26mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with water (100mL), extracted with ethyl acetate (100 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (6.7g, 95%) as a white solid.

¹H NMR(600MHz,CDCl₃)δ7.44(t,J＝7.5Hz,1H),7.40(d,J＝7.7Hz,1H),7.19(s,1H),7.10(d,J＝7.4Hz,1H),7.04(d,J＝8.1Hz,1H),6.62(s,2H),6.53–6.45(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.29(dd,J＝9.1,6.1Hz,1H),3.87–3.79(m,1H),3.74(s,3H),2.77(dd,J＝16.4,5.4Hz,1H),2.58(dd,J＝16.4,9.3Hz,1H),1.99(s,6H).

Example 3

2- (6- ((2',6' -dimethyl-4 '- ((1- (methylsulfonyl) azetidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (1- (methylsulfonyl) azetidin-3-yl) methylmethanesulfonate

Under the protection of nitrogen, 3-hydroxymethyl azetidine hydrochloride (2g,16.18mmol) and triethylamine (7.7mL,55mmol) were dissolved in dichloromethane (50mL), and methanesulfonyl chloride (3mL,38.8mmol) was added dropwise under ice bath, and the reaction solution was allowed to react at room temperature for 2 hours after dropwise addition. The reaction was quenched with saturated sodium bicarbonate solution (20mL), extracted with dichloromethane (30 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound (430mg, 10.9%) as a yellow oil.

Second step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((1- (methylsulfonyl) azetidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl (1- (methylsulfonyl) azetidin-3-yl) methyl methanesulfonate (407mg,1.67mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.478mmol) and potassium carbonate (264.2mg,1.91mmol) were dissolved in N, N-dimethylformamide (5mL) and raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (288mg, 96.0%) as a pale yellow oil.

The third step, 2- (6- ((2',6' -dimethyl-4 '- ((1- (methylsulfonyl) azetidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((1- (methylsulfonyl) azetidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (288mg,0.51mmol) was dissolved in a mixed solution of tetrahydrofuran (4.8mL) and methanol (2.4mL), a 2M aqueous sodium hydroxide solution (0.51mL) was added, and the reaction solution was stirred at 50 ℃ for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (5mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (250mg, 89.0%) as a white solid.

MS(ESI,pos.ion)m/z:552.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.43(dt,J＝15.1,7.6Hz,2H),7.19(s,1H),7.12–7.04(m,2H),6.68(s,2H),6.56–6.45(m,2H),5.09(s,2H),4.77(d,J＝9.0Hz,1H),4.31(dd,J＝9.2,6.1Hz,1H),4.18–4.10(m,4H),3.95(dd,J＝7.9,6.2Hz,2H),3.89–3.77(m,1H),3.17–3.05(m,1H),2.96(s,3H),2.83(dd,J＝16.9,5.3Hz,1H),2.64(dd,J＝16.8,9.3Hz,1H),2.02(s,6H).

Example 4

2- (6- ((2',6' -dimethyl-4 '- (((S) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (S) - (1- (methylsulfonyl) pyrrolidin-2-yl) methylmethanesulfonate

Under the protection of nitrogen, L-prolinol (2g,19.77mmol) and triethylamine (6.67mL,47.45mmol) are dissolved in dichloromethane (50mL), methanesulfonyl chloride (3.67mL,47.45mmol) is added dropwise under ice bath, and after dropwise addition, the reaction solution is raised to room temperature for reaction for 2 hours. After the reaction solution was quenched with a saturated sodium bicarbonate solution (20mL), extracted with dichloromethane (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (2.1g, 41.0%) as a yellow solid.

¹H NMR(400MHz,CDCl₃)δ4.33–4.23(m,2H),4.04–3.95(m,1H),3.55–3.43(m,1H),3.40–3.32(m,1H),3.07(s,3H),2.91(s,3H),2.17–1.87(m,4H).

Second step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((((S) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl (S) - (1- (methylsulfonyl) pyrrolidin-2-yl) methyl methanesulfonate (258mg,1.1mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (140mg,0.33mmol) and potassium carbonate (138mg,1.1mmol) were dissolved in N, N-dimethylformamide (5mL) and raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (160mg, 47.0%) as a white solid.

The third step, 2- (6- ((2',6' -dimethyl-4 '- (((S) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- (((S) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (140mg,0.24mmol) was dissolved in a mixed solution of tetrahydrofuran (2.4mL) and methanol (1.2mL), and a 2M aqueous sodium hydroxide solution (0.24mL) was added and the mixture was stirred at 50 ℃ for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (2mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (110mg, 81.0%) as a white solid.

MS(ESI,pos.ion)m/z:566.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.45–7.35(m,2H),7.16(s,1H),7.09–7.02(m,2H),6.68(s,2H),6.53–6.44(m,2H),5.06(s,2H),4.76(t,J＝9.0Hz,1H),4.29(dd,J＝9.2,6.1Hz,1H),4.17(dd,J＝9.3,3.9Hz,1H),4.13–4.04(m,1H),3.93(dd,J＝9.3,7.5Hz,1H),3.86–3.73(m,1H),3.53–3.46(m,1H),3.45–3.31(m,1H),2.90(s,3H),2.81(dd,J＝16.9,5.3Hz,1H),2.61(dd,J＝16.8,9.3Hz,1H),2.17–2.03(m,3H),2.03–1.87(m,7H).

Example 5

2- (6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (R) - (1- (methylsulfonyl) pyrrolidin-2-yl) methylmethanesulfonate

D-prolinol (2g,19.77mmol) and triethylamine (6.67mL,47.45mmol) were dissolved in dichloromethane (50mL) under nitrogen, methanesulfonyl chloride (3.67mL,47.45mmol) was added dropwise under ice bath, and the reaction was allowed to warm to room temperature for 2 hours. After the reaction solution was quenched with a saturated sodium bicarbonate solution (20mL), extracted with dichloromethane (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (1.7g, 34.0%) as a yellow solid.

Second step, methyl 2- (6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl (R) - (1- (methylsulfonyl) pyrrolidin-2-yl) methyl methanesulfonate (492mg,1.91mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.48mmol) and potassium carbonate (264mg,1.91mmol) were dissolved in N, N-dimethylformamide (5mL) and raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (150mg, 55.6%) as a yellow solid.

The third step, 2- (6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (150mg,0.26mmol) was dissolved in a mixed solution of tetrahydrofuran (2.4mL) and methanol (1.2mL), and a 2M aqueous sodium hydroxide solution (0.26mL) was added and the mixture was stirred at 50 ℃ for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (2mL) and extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (130mg, 89.0%).

MS(ESI,pos.ion)m/z:566.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.45–7.35(m,2H),7.16(s,1H),7.11–7.03(m,2H),6.67(s,2H),6.53–6.43(m,2H),5.06(s,2H),4.76(t,J＝9.0Hz,1H),4.29(dd,J＝9.2,6.0Hz,1H),4.17(dd,J＝9.4,3.9Hz,1H),4.13–4.05(m,1H),3.92(dd,J＝9.3,7.5Hz,1H),3.78–3.83(m,1H),3.52–3.47(m,1H),3.39(dd,J＝12.0,4.8Hz,1H),2.89(s,3H),2.81(dd,J＝16.8,5.4Hz,1H),2.62(dd,J＝16.8,9.3Hz,1H),2.15–2.03(m,3H),1.98(s,6H),1.96–1.94(m,1H).

Example 6

2- ((S) -6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (R) -2',6' -dimethyl-4 '- ((1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-carbaldehyde

(R) - (1- (methylsulfonyl) pyrrolidin-2-yl) methylmethanesulfonate (4.55g,17.7mmol), 4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (1g,4.4mmol) and potassium carbonate (2.44g,17.7mmol) were dissolved in N, N-dimethylformamide (5mL) and allowed to react overnight at 100 ℃. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound (790mg, 46.0%) as a white solid.

MS(ESI,pos.ion)m/z:388.2[M+H]⁺.

Second step, (R) - (2',6' -dimethyl-4 '- ((1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methanol

(R) -2',6' -dimethyl-4 '- ((1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-carbaldehyde (790mg,2.04mmol) was dissolved in a mixed solution of tetrahydrofuran (8mL) and methanol (4mL), and sodium borohydride (81mg,2.14mmol) was added portionwise under ice bath and stirred at 0 ℃ overnight. The solvent was removed under reduced pressure, diluted with water (10mL), extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (463mg, 58.0%) as a white solid.

¹H NMR(400MHz,CDCl₃)δ7.43(t,J＝7.5Hz,1H),7.36(d,J＝7.7Hz,1H),7.14(s,1H),7.08(d,J＝7.4Hz,1H),6.70(s,2H),4.75(s,2H),4.19(dd,J＝9.4,3.9Hz,1H),4.11(dt,J＝7.4,4.4Hz,1H),3.95(dd,J＝9.3,7.5Hz,1H),3.51(dt,J＝7.0,5.5Hz,1H),3.40(dt,J＝9.8,7.7Hz,1H),2.91(s,3H),2.14-2.10(m,4H),2.02(s,6H).

Third step, methyl 2- ((S) -6- ((2',6' -dimethyl-4 '- ((((R) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(R) - (2',6' -dimethyl-4 '- ((1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methanol (187mg,0.48mmol) and methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (100mg,0.48mmol, available from Shanghai Kabushei spectral Lin pharmaceutical development Co., Ltd.) were dissolved in toluene (5mL), tributylphosphine (155mg,0.77mmol) and azobisformyldipiperidine (194mg,0.77mmol) were added at room temperature, and after completion, under nitrogen, stirring at room temperature for 1 hour. Water (20mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (40 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (220mg, 79.0%) as a white solid.

¹H NMR(400MHz,CDCl₃)δ7.42(dt,J＝15.1,7.7Hz,2H),7.18(s,1H),7.06(dd,J＝22.5,7.5Hz,2H),6.69(s,2H),6.51–6.47(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.28(dd,J＝9.2,6.1Hz,1H),4.19(dd,J＝9.8,4.4Hz,1H),4.12–4.08(m,1H),3.97(ddd,J＝16.7,8.4,6.5Hz,2H),3.82(td,J＝9.1,4.5Hz,1H),3.74(s,3H),3.51(dt,J＝6.9,5.4Hz,1H),3.440-3.36(m,1H),2.91(s,3H),2.77(dd,J＝16.4,5.5Hz,1H),2.57(dd,J＝16.4,9.3Hz,1H),2.16(d,J＝4.2Hz,1H),2.00(s,6H),1.90-1.82(m,2H).

The fourth step, 2- ((S) -6- ((2',6' -dimethyl-4 '- ((((R) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- ((S) -6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (220mg,0.38mmol) was dissolved in tetrahydrofuran (4mL), and 1M aqueous lithium hydroxide (3.8mL) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (5mL) and extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (191mg, 89.0%) as a white solid.

MS(ESI,pos.ion)m/z:566.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.46–7.39(m,2H),7.19(s,1H),7.09(dd,J＝14.7,7.8Hz,2H),6.70(s,2H),6.52(dd,J＝15.1,6.9Hz,2H),5.09(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.0,6.2Hz,1H),4.20(dd,J＝9.4,3.8Hz,1H),4.12(dd,J＝7.0,3.5Hz,1H),3.95–3.94(m,1H),3.83–3.81(m,1H),3.53–3.50(m,1H),3.41(dd,J＝16.6,7.0Hz,1H),2.92(s,3H),2.83(dd,J＝16.8,5.2Hz,1H),2.64(dd,J＝16.8,9.3Hz,1H),2.13–2.08(m,3H),2.01(s,6H),1.99–1.97(m,1H).

Example 7

2- (6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (R) - (1- (methylsulfonyl) pyrrolidin-3-yl) methylmethanesulfonate

Under the protection of nitrogen, (R) -pyrrolidine-3-methanol (5g,49.4mmol) and triethylamine (17mL,118.6mmol) were dissolved in dichloromethane (200mL), methanesulfonyl chloride (9.18mL,118.6mmol) was added dropwise under ice bath, and the reaction solution was reacted at room temperature for 2 hours after completion of dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (30mL), extracted with dichloromethane (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (11g, 86.6%) as a yellow solid.

Second step, methyl 2- (6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl (R) - (1- (methylsulfonyl) pyrrolidin-3-yl) methyl methanesulfonate (739mg,2.87mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (300mg,0.72mmol) and potassium carbonate (396mg,2.87mmol) were dissolved in N, N-dimethylformamide (5mL) and raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (379mg, 91.0%) as a yellow solid.

MS(ESI,pos.ion)m/z:580.3[M+H]⁺.

The third step, 2- (6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- (((R) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (379mg,0.65mmol) was dissolved in tetrahydrofuran (6.5mL), and 1M aqueous lithium hydroxide (6.5mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (349mg, 94.0%).

MS(ESI,pos.ion)m/z:566.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.42(dt,J＝15.0,7.6Hz,2H),7.18(s,1H),7.13–7.04(m,2H),6.66(s,2H),6.56–6.45(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.2,6.1Hz,1H),4.06–3.90(m,3H),3.88–3.78(m,1H),3.63(dd,J＝10.0,7.7Hz,1H),3.58–3.48(m,1H),3.46–3.37(m,1H),3.31(dd,J＝10.1,6.7Hz,1H),2.89(s,3H),2.87–2.74(m,2H),2.63(dd,J＝16.8,9.3Hz,1H),2.21(dd,J＝12.6,5.2Hz,1H),2.01(s,6H).

Example 8

2- (6- ((2',6' -dimethyl-4 '- (((S) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (S) - (1- (methylsulfonyl) pyrrolidin-3-yl) methylmethanesulfonate

Under nitrogen protection, (S) -pyrrolidine-3-methanol (5g,49.4mmol) and triethylamine (17mL,118.6mmol) were dissolved in dichloromethane (200mL), methanesulfonyl chloride (9.18mL,118.6mmol) was added dropwise under ice bath, and the reaction solution was allowed to react at room temperature for 2 hours after completion of dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (30mL), extracted with dichloromethane (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (11.3g, 89.0%) as a yellow solid.

Second step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((((S) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl (S) - (1- (methylsulfonyl) pyrrolidin-3-yl) methyl methanesulfonate (739mg,2.87mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (300mg,0.72mmol) and potassium carbonate (396mg,2.87mmol) were dissolved in N, N-dimethylformamide (5mL) and raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (350mg, 94.3%) as a white solid.

MS(ESI,pos.ion)m/z:580.3[M+H]⁺.

The third step, 2- (6- ((2',6' -dimethyl-4 '- (((S) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- (((S) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (350mg,0.6mmol) was dissolved in tetrahydrofuran (6mL), and after addition of 1M aqueous lithium hydroxide (6mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (323mg, 94.6%).

MS(ESI,pos.ion)m/z:566.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.51–7.36(m,2H),7.19(s,1H),7.08(t,J＝7.9Hz,2H),6.67(s,2H),6.58–6.44(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.30(dd,J＝9.0,6.2Hz,1H),4.05–3.95(m,3H),3.88–3.77(m,1H),3.62(dd,J＝9.7,7.9Hz,1H),3.56–3.47(m,1H),3.42(dd,J＝17.0,7.5Hz,1H),3.31(dd,J＝9.9,6.7Hz,1H),2.90(s,3H),2.86–2.77(m,2H),2.63(dd,J＝16.8,9.3Hz,1H),2.21(dd,J＝12.6,5.2Hz,1H),2.01(s,6H).

Example 9

2- ((S) -6- ((2',6' -dimethyl-4 '- (((S) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (S) -2',6' -dimethyl-4 '- ((1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-carbaldehyde

(S) - (1- (methylsulfonyl) pyrrolidin-3-yl) methylmethanesulfonate (6.8g,26.5mmol), 4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (1.5g,6.63mmol) and potassium carbonate (3.66g,26.5mmol) were dissolved in N, N-dimethylformamide (15mL) and then raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (15mL), extracted with ethyl acetate (15mL), and the organic phase was washed with saturated sodium chloride solution (15mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (2.0g, 78.0%) as a white solid.

¹H NMR(600MHz,CDCl₃)δ10.07(s,1H),7.88(d,J＝7.7Hz,1H),7.68(s,1H),7.61(t,J＝7.6Hz,1H),7.46–7.40(m,1H),6.68(s,2H),4.04(dd,J＝9.2,5.9Hz,1H),3.96(dd,J＝9.2,7.1Hz,1H),3.63(dd,J＝10.1,7.6Hz,1H),3.56–3.52(m,1H),3.40–3.38(m,1H),3.32(dd,J＝10.1,6.6Hz,1H),2.90(s,3H),2.82(dt,J＝13.8,6.9Hz,1H),2.25–2.19(m,1H),2.01(s,6H),1.96–1.90(m,1H).

Second step, (S) - (2',6' -dimethyl-4 '- ((1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methanol

(S) -2',6' -dimethyl-4 '- ((1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-carbaldehyde (2.0g,5.16mmol) was dissolved in a mixed solution of tetrahydrofuran (20mL) and methanol (10mL), and sodium borohydride (206mg,5.42mmol) was added portionwise on an ice bath and stirred at 0 ℃ overnight. The reaction solvent was removed under reduced pressure, diluted with water (20mL), extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (1.7g, 84.5%) as a white solid.

Third step, methyl 2- ((S) -6- ((2',6' -dimethyl-4 '- ((((S) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(S) - (2',6' -dimethyl-4 '- ((1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methanol (280mg,0.72mmol) and methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (150mg,0.72mmol) were dissolved in toluene (10mL), tributylphosphine (233mg,1.15mmol) and azobisformyldipiperidine (290mg,1.15mmol) were added at room temperature, and after addition, the mixture was stirred at room temperature under nitrogen for 1.5 hours. Water (20mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (40 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (300mg, 72.0%) as a white solid.

¹H NMR(600MHz,CDCl₃)δ7.47–7.37(m,2H),7.18(s,1H),7.09(d,J＝7.4Hz,1H),7.04(d,J＝8.2Hz,1H),6.66(s,2H),6.53–6.45(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.28(dd,J＝9.2,6.1Hz,1H),4.03(dd,J＝9.2,5.9Hz,1H),3.95(dd,J＝9.2,7.0Hz,1H),3.85–3.79(m,1H),3.74(s,3H),3.63(dd,J＝10.0,7.6Hz,1H),3.56–3.50(m,1H),3.42(dt,J＝9.8,7.5Hz,1H),3.31(dd,J＝10.1,6.7Hz,1H),2.89(s,3H),2.85–2.73(m,2H),2.58(dd,J＝16.4,9.3Hz,1H),2.24–2.17(m,1H),2.01(s,6H),1.96–1.90(m,1H).

The fourth step, 2- ((S) -6- ((2',6' -dimethyl-4 '- ((((S) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- ((S) -6- ((2',6' -dimethyl-4 '- (((S) -1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (300mg,0.52mmol) was dissolved in tetrahydrofuran (5.2mL), and 1M aqueous lithium hydroxide (5.2mL) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (280mg, 95.9%).

MS(ESI,pos.ion)m/z:566.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.48–7.36(m,2H),7.18(s,1H),7.08(dd,J＝14.1,7.8Hz,2H),6.66(s,2H),6.55–6.45(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.30(dd,J＝9.2,6.1Hz,1H),4.04–3.92(m,3H),3.87–3.79(m,1H),3.62(dd,J＝10.0,7.7Hz,1H),3.56–3.48(m,1H),3.46–3.38(m,1H),3.30(dd,J＝10.1,6.7Hz,1H),2.89(s,3H),2.85–2.78(m,2H),2.63(dd,J＝16.8,9.3Hz,1H),2.01(s,6H),1.96–1.90(m,1H).

Example 10

2- (6- ((2',6' -dimethyl-4 '- ((5- (methylsulfonyl) thiophen-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (5- (methylsulfonyl) thiophen-2-yl) methanol

(5-bromothien-2-yl) methanol (1g,5.18mmol), cuprous iodide (99mg,0.52mmol), sodium methanesulfinate (794mg,7.77mmol) and L-proline sodium salt (142mg,1.03mmol) were dissolved in dimethyl sulfoxide (10mL) under nitrogen and reacted for 24 h while raising the temperature to 95 ℃. The reaction solution was cooled to room temperature, diluted with water (20mL), extracted with ethyl acetate (40mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (419mg, 42.1%) as a yellow oil.

Second, 2- (chloromethyl) -5- (methylsulfonyl) thiophene

(5- (methylsulfonyl) thiophen-2-yl) methanol (419mg,2.18mmol) was dissolved in N, N-dimethylformamide (5mL), and phosphorus oxychloride (0.25mL,2.70mmol) was added dropwise at room temperature, followed by stirring at room temperature for 5 hours. The reaction mixture was diluted with water (20mL), extracted with ethyl acetate (20 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give the title compound (438mg, 95.4%) as a yellow solid.

¹H NMR(400MHz,CDCl₃)δ7.59(d,J＝3.7Hz,1H),7.13(d,J＝3.7Hz,1H),4.79(s,2H),3.20(s,3H).

The third step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((5- (methylsulfonyl) thiophen-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

2- (chloromethyl) -5- (methylsulfonyl) thiophene (76mg,0.36mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (100mg,0.24mmol) and potassium phosphate (82mg,0.39mmol) were dissolved in N, N-dimethylformamide (5mL) and stirred under nitrogen at 60 ℃ overnight. Water (5mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (139mg, 98.2%) as a yellow solid.

MS(ESI,pos.ion)m/z:593.1[M+H]⁺.

The fourth step, 2- (-6- ((2',6' -dimethyl-4 '- ((5- (methylsulfonyl) thiophen-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((5- (methylsulfonyl) thiophen-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (139mg,0.23mmol) was dissolved in tetrahydrofuran (2.4mL), and 1M aqueous lithium hydroxide solution (2.4mL) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (5mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (90mg, 66.3%).

MS(ESI,pos.ion)m/z:579.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.66(d,J＝3.8Hz,1H),7.45(t,J＝7.5Hz,1H),7.41(d,J＝7.7Hz,1H),7.19(s,1H),7.15(d,J＝3.7Hz,1H),7.09(dd,J＝16.5,7.8Hz,2H),6.75(s,2H),6.53–6.47(m,2H),5.29(s,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.2,6.1Hz,1H),3.83(ddd,J＝14.6,9.1,5.7Hz,1H),3.22(s,3H),2.83(dd,J＝16.8,5.3Hz,1H),2.64(dd,J＝16.8,9.3Hz,1H),2.02(s,6H).

Example 11

2- (6- ((2',6' -dimethyl-4 '- ((1- (methylsulfonyl) piperidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (1- (methylsulfonyl) piperidin-2-yl) methylmethanesulfonate

Under the protection of nitrogen, 2-piperidyl methanol (4g,34.7mmol) and triethylamine (12.0mL,85.0mmol) are dissolved in dichloromethane (100mL), and methanesulfonyl chloride (7.0mL,88.6mmol) is added dropwise under ice bath, and the reaction solution is reacted for 1 hour at room temperature after dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (50mL), extracted with dichloromethane (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 60/1) to give the title compound (7.0g, 74.3%) as a yellow solid.

¹H NMR(600MHz,CDCl₃)δ4.52(dd,J＝10.3,8.9Hz,1H),4.36(td,J＝8.7,4.2Hz,1H),4.21(dd,J＝10.4,5.8Hz,1H),3.77(d,J＝14.3Hz,1H),3.11–3.04(m,4H),2.95(s,3H),1.82–1.68(m,4H),1.61–1.46(m,2H).

Second step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((1- (methylsulfonyl) piperidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl (1- (methylsulfonyl) piperidin-2-yl) methyl methanesulfonate (389mg,1.43mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (400mg,0.96mmol) and potassium carbonate (400mg,2.89mmol) were dissolved in N, N-dimethylformamide (10mL) and then raised to 80 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/3), to give the title compound (220mg, 38.8%) as a yellow oil.

The third step, 2- (6- ((2',6' -dimethyl-4 '- ((1- (methylsulfonyl) piperidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((1- (methylsulfonyl) piperidin-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (220mg,0.37mmol) was dissolved in tetrahydrofuran (4mL), and after addition of 1M aqueous lithium hydroxide (4mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (160mg, 79.1%).

MS(ESI,pos.ion)m/z:580.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.47–7.38(m,2H),7.18(s,1H),7.08(dd,J＝14.2,7.8Hz,2H),6.68(s,2H),6.54–6.46(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.52–4.46(m,1H),4.36–4.27(m,2H),4.01(dd,J＝9.8,5.6Hz,1H),3.82(dd,J＝13.3,10.3Hz,2H),3.13–3.06(m,1H),3.03(s,3H),2.82(dd,J＝16.8,5.3Hz,1H),2.63(dd,J＝16.8,9.4Hz,1H),2.02(s,6H),1.92(d,J＝13.4Hz,1H),1.88–1.81(m,1H),1.75(t,J＝11.4Hz,2H),1.63(dd,J＝15.6,6.2Hz,2H).

Example 12

2- (6- ((2',6' -dimethyl-4 '- ((3-methyl-1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, 1-benzyl-3-methylpyrrolidine-3-carboxylic acid methyl ester

N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (10.8mL,44.9mmol) and methyl methacrylate (4.78mL,44.8mmol) were dissolved in dry dichloromethane (50mL) under nitrogen, and a solution of trifluoroacetic acid (0.33mL,4.4mmol) in dry DCM (4mL) was added dropwise over an ice bath, and the reaction solution was allowed to warm up for 4 hours after dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (20mL), extracted with dichloromethane (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1), to give the title compound (8.2g, 78.0%) as a colorless liquid.

¹H NMR(400MHz,CDCl₃)δ7.36–7.24(m,5H),3.71(s,3H),3.63(s,2H),2.97(d,J＝9.4Hz,1H),2.76–2.58(m,2H),2.49–2.36(m,2H),1.74–1.62(m,1H),1.37(s,3H).

Second step, (1-benzyl-3-methylpyrrolidin-3-yl) methanol

Lithium aluminum hydride (2.0g,52.6mmol) was suspended in anhydrous tetrahydrofuran (60mL), and a solution of methyl 1-benzyl-3-methylpyrrolidine-3-carboxylate (8.2g,35mmol) in anhydrous tetrahydrofuran (20mL) was added dropwise under ice-cooling, and the reaction solution was allowed to warm overnight after completion of the dropwise addition. Water (2mL) and a 10% aqueous solution of sodium hydroxide (20mL) were slowly added dropwise to the reaction mixture in an ice bath, followed by filtration, and the filter cake was washed with tetrahydrofuran (20mL), and then the filtrates were combined and concentrated under reduced pressure. The residue was diluted with water (10mL), extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (5.5g, 76.0%) as a yellow oil.

¹H NMR(400MHz,CDCl₃)δ7.36–7.22(m,5H),3.56(dd,J＝11.3,6.9Hz,3H),3.36(d,J＝9.6Hz,1H),3.03(td,J＝9.0,2.9Hz,1H),2.85(d,J＝9.0Hz,1H),2.31(dd,J＝17.7,9.0Hz,1H),2.15(d,J＝9.0Hz,1H),2.10–2.01(m,1H),1.69–1.57(m,1H),1.02(s,3H).

Step three, (3-methylpyrrolidin-3-yl) methanol

(1-benzyl-3-methylpyrrolidin-3-yl) methanol (5.5g,27.0mmol) was dissolved in methanol (150mL), and the mixture was reacted at room temperature under a hydrogen atmosphere overnight with the addition of a 10% Pd/C catalyst (0.6 g). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (3.0g, 97.0%) as a pale yellow oil.

¹H NMR(400MHz,CDCl₃)δ3.46(dd,J＝16.0,10.0Hz,2H),3.08–2.98(m,1H),2.98–2.89(m,2H),2.56(d,J＝10.5Hz,1H),1.82–1.69(m,1H),1.56–1.44(m,1H),1.06(s,3H).

The fourth step, (3-methyl-1- (methylsulfonyl) pyrrolidin-3-yl) methylmethanesulfonate

(3-Methylpyrrolidin-3-yl) methanol (1.0g,8.68mmol) and triethylamine (2.9mL,21.0mmol) were dissolved in dichloromethane (60mL) under nitrogen, methanesulfonyl chloride (1.65mL,20.9mmol) was added dropwise under ice bath, and the reaction solution was allowed to warm up for 1 hour after completion of dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (30mL), extracted with dichloromethane (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound (1.75g, 74.3%) as a yellow oil.

¹H NMR(400MHz,CDCl₃)δ4.10(s,2H),3.48(t,J＝7.2Hz,2H),3.39(d,J＝10.1Hz,1H),3.18–3.02(m,4H),2.89(s,3H),2.01(dt,J＝13.8,8.9Hz,1H),1.88–1.75(m,1H),1.25(s,3H).

The fifth step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((3-methyl-1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(3-methyl-1- (methylsulfonyl) pyrrolidin-3-yl) methyl methanesulfonate (518mg,1.91mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (400mg,0.96mmol) and potassium carbonate (400mg,2.89mmol) were dissolved in N, N-dimethylformamide (5mL) and raised to 80 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (170mg, 30.1%) as a yellow oil.

MS(ESI,pos.ion)m/z:594.2[M+H]⁺.

The sixth step, 2- (6- ((2',6' -dimethyl-4 '- ((3-methyl-1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((3-methyl-1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (171mg,0.29mmol) was dissolved in tetrahydrofuran (3mL), and after addition of 1M aqueous lithium hydroxide (3mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (10mL), and extracted with ethyl acetate (20mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (100mg, 59.9%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:580.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.45(t,J＝7.5Hz,1H),7.40(d,J＝7.6Hz,1H),7.19(s,1H),7.09(dd,J＝14.2,7.8Hz,2H),6.68(s,2H),6.56–6.46(m,2H),5.09(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.1,6.1Hz,1H),3.86(dd,J＝21.0,8.9Hz,3H),3.56–3.46(m,3H),3.20(d,J＝9.9Hz,1H),2.90(s,3H),2.83(dd,J＝16.8,5.2Hz,1H),2.64(dd,J＝16.8,9.4Hz,1H),2.19–2.11(m,1H),2.02(s,6H),1.87–1.79(m,1H),1.30(s,3H).

Example 13

2- (6- ((4'- ((3-fluoro-1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, 1-benzyl-3-fluoropyrrolidine-3-carboxylic acid methyl ester

Under the protection of nitrogen, N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (2.6mL,10.0mmol) and methyl 2-fluoroacrylate (0.9mL,10.0mmol) were dissolved in dry dichloromethane (30mL), and a solution of trifluoroacetic acid (0.1mL,1.0mmol) in dry DCM (2mL) was added dropwise under ice-bath, after completion of dropwise addition, the reaction solution was reacted at room temperature for 4 hours. After the reaction solution was quenched with a saturated sodium bicarbonate solution (20mL), extracted with dichloromethane (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1), to give the title compound (1.8g, 80.0%) as a colorless liquid.

MS(ESI,pos.ion)m/z:238.2[M+H]⁺.

The second step, (1-benzyl-3-fluoropyrrolidin-3-yl) methanol

Lithium aluminum hydride (2.14g,56.3mmol) was suspended in anhydrous tetrahydrofuran (60mL), and a solution of methyl 1-benzyl-3-methylpyrrolidine-3-carboxylate (8.91g,37.5mmol) in anhydrous tetrahydrofuran (20mL) was added dropwise under ice-bath conditions, after which the reaction solution was allowed to warm overnight. Water (2mL) and a 10% aqueous solution of sodium hydroxide (20mL) were slowly added dropwise to the reaction mixture in an ice bath, followed by filtration, and the filter cake was washed with tetrahydrofuran (20mL), and then the filtrates were combined and concentrated under reduced pressure. The residue was diluted with water (10mL), extracted with ethyl acetate (20 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound (7.0g, 89.1%) as a yellow oil.

The third step, (3-fluoropyrrolidin-3-yl) methanol

(1-benzyl-3-fluoropyrrolidin-3-yl) methanol (5.62g,26.9mmol) was dissolved in methanol (50mL), and the mixture was reacted at room temperature under a hydrogen atmosphere overnight with the addition of a 10% Pd/C catalyst (1.0 g). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (2.78g, 86.7%) as a pale yellow oil.

The fourth step, (3-fluoro-1- (methylsulfonyl) pyrrolidin-3-yl) methylmethanesulfonate

Under the protection of nitrogen, (3-fluoropyrrolidin-3-yl) methanol (500mg,4.2mmol) and triethylamine (1.4mL,10.0mmol) were dissolved in dichloromethane (60mL), and methanesulfonyl chloride (0.8mL,10.0mmol) was added dropwise under ice bath, and the reaction solution was allowed to react at room temperature for 1 hour after completion of dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (15mL), extracted with dichloromethane (25 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 30/1) to give the title compound (880mg, 76.2%) as a yellow oil.

¹H NMR(400MHz,DMSO-d₆)δ4.58(s,1H),4.53(s,1H),3.57(s,1H),3.51(t,J＝9.2Hz,2H),3.46–3.39(m,1H),3.26(s,3H),2.95(s,3H),2.17(ddd,J＝24.2,15.4,6.2Hz,2H).

The fifth step, methyl 2- (6- ((4'- ((3-fluoro-1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(3-fluoro-1- (methylsulfonyl) pyrrolidin-3-yl) methyl methanesulfonate (160mg,0.58mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.48mmol) and potassium carbonate (200mg,1.45mmol) were dissolved in N, N-dimethylformamide (10mL) and raised to 80 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (130mg, 45.5%) as a yellow oil.

MS(ESI,pos.ion)m/z:598.2[M+H]⁺.

The sixth step, 2- (6- ((4'- ((3-fluoro-1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((3-fluoro-1- (methylsulfonyl) pyrrolidin-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (260mg,0.44mmol) was dissolved in tetrahydrofuran (4mL), and after addition of 1M aqueous lithium hydroxide (4mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (90mg, 35.5%).

¹H NMR(600MHz,CDCl₃)δ7.49–7.37(m,2H),7.18(s,1H),7.08(dd,J＝11.0,8.0Hz,2H),6.69(s,2H),6.57–6.41(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.29(ddd,J＝23.9,11.4,8.2Hz,2H),4.22–4.12(m,1H),3.83(ddd,J＝14.6,9.0,5.8Hz,1H),3.79–3.68(m,3H),3.56(td,J＝10.1,6.8Hz,1H),2.93(s,3H),2.83(dd,J＝16.8,5.3Hz,1H),2.64(dd,J＝16.8,9.3Hz,1H),2.42–2.24(m,2H),2.02(s,6H).

Example 14

2- (6- ((2',6' -dimethyl-4 '- (2- ((R) -1- (methylsulfonyl) pyrrolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step (R) -1- ((benzyloxy) carbonyl) pyrrolidine-2-carboxylic acid

D-proline (4.0g,34.7mmol) was dissolved in toluene (50mL), a 2M aqueous solution of sodium hydroxide (50mL) and a solution of benzyl chloroformate (10.0mL,71.1mmol) in toluene (50mL) were added under ice-bath conditions, and the reaction was allowed to react at room temperature under nitrogen for 1 hour. The reaction was quenched with water (50mL), the aqueous phase was acidified with 4M hydrochloric acid (100mL), extracted with ethyl acetate (200 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (8.66g, 100%) as a yellow oil.

Second step, benzyl (R) -2- (diazoacetyl) pyrrolidine-1-carboxylate

(R) -1- ((benzyloxy) carbonyl) pyrrolidine-2-carboxylic acid (2.0g,8.02mmol) was dissolved in anhydrous N, N-dimethylformamide (0.3mL) and anhydrous dichloromethane (20mL), and oxalyl chloride (0.92mL,11.0mmol) was added dropwise under ice bath. The reaction was carried out at room temperature for 2 hours under the protection of liquid nitrogen. The reaction mixture was concentrated under reduced pressure to give a yellow oily residue, which was dissolved in a mixed solvent of tetrahydrofuran (30mL) and acetonitrile (30mL), and triethylamine (1.6g,16.04mmol) and a 2M solution of trimethylsilylated diazomethane in n-hexane (9mL,18mmol) were sequentially added under ice-cooling to react the reaction mixture at 0 ℃ for 5 hours. The reaction solution was quenched with glacial acetic acid and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound (1.54g, 70.2%) as a yellow oil.

MS(ESI,pos.ion)m/z:296.1[M+Na]⁺.

Step three, (R) -2- (methoxycarbonylmethyl) pyrrolidine-1-carboxylic acid benzyl ester

(R) -benzyl 2- (diazoacetyl) pyrrolidine-1-carboxylate (1.54g,5.63mmol) was dissolved in anhydrous methanol (25mL), a solution of silver benzoate (130mg,0.57mmol) in triethylamine (2.3mL) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with saturated sodium sulfite solution (50mL) and then filtered, the filtrate was extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound (825mg, 52.8%) as a colorless oil.

MS(ESI,pos.ion)m/z:278.2[M+H]⁺.

The fourth step, benzyl (R) -2- (2-hydroxyethyl) pyrrolidine-1-carboxylate

(R) -benzyl 2- (methoxycarbonylmethyl) pyrrolidine-1-carboxylate (1.9g,6.9mmol) was dissolved in ethanol (50mL), a solution of sodium borohydride (2.6g,68mmol) in water (20mL) was added dropwise, the reaction solution was allowed to warm overnight after the addition, and the reaction was continued for 1 hour at reflux. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with water (10mL), extracted with ethyl acetate (20 mL. times.2), and the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (510mg, 30.0%) as a yellow oil.

The fifth step, (R) -2- (pyrrolidin-2-yl) ethanol

(R) -benzyl 2- (2-hydroxyethyl) pyrrolidine-1-carboxylate (510mg,0.5mmol) was dissolved in methanol (10mL), and the mixture was reacted at room temperature under a hydrogen atmosphere overnight with the addition of a 10% Pd/C catalyst (50 mg). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (230mg, 97.6%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ3.84(dd,J＝10.1,5.1Hz,1H),3.80–3.73(m,1H),3.52–3.41(m,1H),3.13–2.99(m,2H),2.03–1.94(m,1H),1.94–1.86(m,1H),1.82–1.70(m,3H),1.54(dt,J＝20.5,8.0Hz,1H).

Sixth step, (R) -2- (1- (methylsulfonyl) pyrrolidin-2-yl) ethyl methanesulfonate

(R) -2- (pyrrolidin-2-yl) ethanol (230mg,2.0mmol) and triethylamine (0.67mL,4.8mmol) were dissolved in dichloromethane (20mL) under nitrogen, methanesulfonyl chloride (0.4mL,5.0mmol) was added dropwise under ice bath, and the reaction solution was allowed to react at room temperature for 1 hour after completion of dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (10mL), extracted with dichloromethane (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound (350mg, 64.6%) as a yellow oil.

Seventh step, methyl 2- (6- ((2',6' -dimethyl-4 '- (2- ((R) -1- (methylsulfonyl) pyrrolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(R) -2- (1- (methylsulfonyl) pyrrolidin-2-yl) ethyl methanesulfonate (340mg,1.25mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (400mg,0.96mmol) and potassium carbonate (400mg,2.89mmol) were dissolved in N, N-dimethylformamide (10mL) and raised to 80 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound (375mg, 66.1%) as a pale yellow oil.

MS(ESI,pos.ion)m/z:594.2[M+H]⁺.

Eighth step, 2- (6- ((2',6' -dimethyl-4 '- (2- ((R) -1- (methylsulfonyl) pyrrolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- (2- ((R) -1- (methylsulfonyl) pyrrolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (375mg,0.63mmol) was dissolved in tetrahydrofuran (6mL), and after addition of 1M aqueous lithium hydroxide (6mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (20mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (170mg, 46.4%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:580.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.48–7.37(m,2H),7.19(s,1H),7.09(dd,J＝18.2,7.8Hz,2H),6.67(s,2H),6.55–6.46(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.1,6.1Hz,1H),4.10(t,J＝6.1Hz,2H),3.96(dt,J＝8.0,6.4Hz,1H),3.83(ddd,J＝14.5,9.1,5.8Hz,1H),3.46(dt,J＝11.8,6.0Hz,1H),3.39(dt,J＝10.4,7.0Hz,1H),2.90–2.78(m,4H),2.63(dd,J＝16.8,9.4Hz,1H),2.30(dt,J＝19.8,5.8Hz,1H),2.10(dt,J＝12.9,7.9Hz,1H),2.05–1.92(m,10H).

Example 15

2- (6- ((4'- (3- (N-cyclopentylmethylsulfonylamino) propoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, N- (3- (benzyloxy) propyl) cyclopentylamine

Cyclopentylamine (0.4mL,4.1mmol) and potassium carbonate (553mg,4.1mmol) were dissolved in acetonitrile (15mL), ((3-bromopropoxy) methyl) benzene (0.36mL,2.0mmol) was added, and the reaction was allowed to warm to 60 ℃ overnight. The reaction was cooled to room temperature, and concentrated under reduced pressure to give the title compound (467mg, 98.0%) as a pale yellow oil.

Second, N- (3- (benzyloxy) propyl) -N-cyclopentylmethanesulfonamide

N- (3- (benzyloxy) propyl) cyclopentylamine (467mg,2.0mmol) and triethylamine (1.1mL,7.8mmol) were dissolved in dichloromethane (20mL) under nitrogen, methanesulfonyl chloride (0.62mL,8.0mmol) was added dropwise in an ice bath, and the reaction solution was allowed to react at room temperature for 1 hour after completion of dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (15mL), extracted with dichloromethane (45 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1), to give the title compound (477mg, 76.6%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.36–7.26(m,5H),4.48(s,2H),4.16–4.07(m,1H),3.51(t,J＝5.9Hz,2H),3.16(dd,J＝8.5,6.8Hz,2H),2.81(s,3H),2.01–1.94(m,2H),1.87(t,J＝10.0Hz,2H),1.66(dd,J＝8.2,5.9Hz,2H),1.59–1.48(m,4H).

The third step, N-cyclopentyl-N- (3-hydroxypropyl) methanesulfonamide

N- (3- (benzyloxy) propyl) -N-cyclopentylmethanesulfonamide (477mg,1.5mmol) was dissolved in methanol (10mL), and the mixture was reacted under a hydrogen atmosphere at room temperature overnight with the addition of a 10% Pd/C catalyst (85 mg). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (333mg, 98.3%) as a pale yellow oil.

Step four, 3- (N-cyclopentylmethylsulfonylamino) propyl methanesulfonate

Under the protection of nitrogen, N-cyclopentyl-N- (3-hydroxypropyl) methanesulfonamide (333mg,1.5mmol) and triethylamine (0.3mL,2.3mmol) were dissolved in dichloromethane (10mL), and methanesulfonyl chloride (0.18mL,2.3mmol) was added dropwise under ice bath, and the reaction solution was allowed to react at room temperature for 1 hour after completion of dropwise addition. After the reaction solution was quenched with saturated sodium bicarbonate solution (8mL), extracted with dichloromethane (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound (239mg, 53.1%) as a pale yellow oil.

The fifth step, methyl 2- (6- ((4'- (3- (N-cyclopentylmethylsulfonylamino) propoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

3- (N-Cyclopentylmethylsulfonylamino) propyl methanesulfonate (259mg,0.9mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (241mg,0.6mmol) and potassium carbonate (239mg,1.7mmol) were dissolved in N, N-dimethylformamide (5mL) and raised to 80 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 40/1) to give the title compound (260mg, 72.5%) as a pale yellow oil.

The sixth step, 2- (6- ((4'- (3- (N-cyclopentylmethylsulfonylamino) propoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- (3- (N-cyclopentylmethylsulfonylamino) propoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (260mg,0.42mmol) was dissolved in tetrahydrofuran (4.2mL), and after addition of 1M aqueous lithium hydroxide (4.2mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (140mg, 55.1%).

¹H NMR(600MHz,CDCl₃)δ7.46–7.38(m,2H),7.18(s,1H),7.09(dd,J＝16.5,7.8Hz,2H),6.66(s,2H),6.54–6.44(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.2,6.1Hz,1H),4.21–4.14(m,1H),4.04(t,J＝5.6Hz,2H),3.86–3.79(m,1H),3.33–3.23(m,2H),2.88(s,3H),2.82(dd,J＝16.8,5.3Hz,1H),2.63(dd,J＝16.8,9.3Hz,1H),2.19(dt,J＝11.9,5.8Hz,2H),2.01(s,6H),1.98–1.85(m,4H),1.79–1.68(m,4H).

Example 16

2- (6- ((2',6' -dimethyl-4 '- (3- (N-phenylmethylsulfonamido) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, 3- (phenylamino) -1-propanol

Iodobenzene (5.46mL,49.0mmol), 3-amino-1-propanol (5.6mL,74mmol), cuprous iodide (0.93g,4.9mmol), L-proline (1.2g,9.9mmol) and potassium carbonate (13.54g,97.9mmol) were dissolved in DMSO (30mL) under nitrogen and the reaction was heated to 80 ℃ for 12 h. The reaction solution was cooled to room temperature, diluted with water (50mL), extracted with ethyl acetate (100mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (6.5g, 88.0%) as a yellow oil.

Second step, 3- (N-phenylmethanesulfonamido) propyl methanesulfonate

Under nitrogen protection, 3- (phenylamino) -1-propanol (500mg,3.31mmol) and triethylamine (1.2mL,8.5mmol) were dissolved in dichloromethane (15mL), and methanesulfonyl chloride (0.6mL,8mmol) was added dropwise under ice bath, after completion of dropwise addition, the reaction solution was allowed to warm up overnight. After the reaction solution was quenched with a saturated sodium bicarbonate solution (10mL), extracted with dichloromethane (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (700mg, 68.9%) as a pale yellow solid.

¹H NMR(600MHz,CDCl₃)δ7.46–7.32(m,5H),4.29(t,J＝5.9Hz,2H),3.84(t,J＝6.4Hz,2H),2.99(s,3H),2.89(s,3H),1.95–1.89(m,2H).

The third step, methyl 2- (6- ((2',6' -dimethyl-4 '- (3- (N-phenylmethanesulfonamido) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

3- (N-phenylmethanesulfonamido) propyl methanesulfonate (280mg,0.92mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (250mg,0.60mmol) and potassium carbonate (250mg,1.81mmol) were dissolved in N, N-dimethylformamide (10mL) and raised to 80 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (30mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound (320mg, 85.1%) as a yellow oil.

The fourth step, 2- (6- ((2',6' -dimethyl-4 '- (3- (N-phenylmethanesulfonamido) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- (3- (N-phenylmethanesulfonamido) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (320mg,0.51mmol) was dissolved in tetrahydrofuran (5mL), and after addition of 1M aqueous lithium hydroxide (5mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (166mg, 53.1%) as a white solid.

MS(ESI,neg.ion)m/z:614.3[M-H]^-；

¹H NMR(600MHz,CDCl₃)δ7.50–7.33(m,7H),7.19(s,1H),7.09(dd,J＝13.1,7.8Hz,2H),6.62(s,2H),6.55–6.47(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.1,6.2Hz,1H),4.05(t,J＝6.0Hz,2H),3.97–3.90(m,2H),3.86–3.79(m,1H),2.93(s,3H),2.83(dd,J＝16.9,5.3Hz,1H),2.64(dd,J＝16.8,9.4Hz,1H),2.05–1.94(m,8H).

Example 17

(S) -2- (6- ((2',6' -dimethyl-4 '- (3- (N-phenylmethylsulfonylamino) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, N- (3- ((3 '-formyl-2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) propyl) -N-phenylmethanesulfonamide

3- (N-phenylmethanesulfonamido) propyl methanesulfonate (2g,6.51mmol), 4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (1.0g,4.42mmol) and potassium carbonate (2.0g,14.5mmol) were dissolved in N, N-dimethylformamide (15mL) and then raised to 80 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound (1.5g, 78.0%) as a yellow oil.

¹H NMR(600MHz,CDCl₃)δ10.07(s,1H),7.88(d,J＝7.7Hz,1H),7.67(s,1H),7.61(t,J＝7.6Hz,1H),7.47–7.36(m,6H),6.63(s,2H),4.06(t,J＝6.1Hz,2H),3.95(t,J＝6.9Hz,2H),2.93(s,3H),2.03(dd,J＝13.1,6.4Hz,2H),1.99(s,6H).

Second step, N- (3- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) propyl) -N-phenylmethanesulfonamide

N- (3- ((3 '-formyl-2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) propyl) -N-phenylmethanesulfonamide (1.5g,3.4mmol) was dissolved in a mixed solution of tetrahydrofuran (16mL) and methanol (8mL), and sodium borohydride (140mg,3.68mmol) was added in portions under ice bath and stirred at 0 ℃ overnight. The reaction mixture was removed under reduced pressure, diluted with water (10mL), extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1), to give the title compound (1.0g, 66.0%) as a pale yellow oil.

The third step, N- (3- ((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) propyl) -N-phenylmethanesulfonamide

N- (3- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) propyl) -N-phenylmethanesulfonamide (500mg,1.14mmol) was dissolved in N, N-dimethylformamide (10mL), and phosphorus oxychloride (0.13mL,1.37mmol) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10mL), extracted with ethyl acetate (10 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound (450mg, 86.4%) as a pale yellow oil.

MS(ESI,pos.ion)m/z:458.1[M+H]⁺.

The fourth step, methyl (S) -2- (6- ((2',6' -dimethyl-4 '- (3- (N-phenylmethylsulfonylamino) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

N- (3- ((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) propyl) -N-phenylmethanesulfonamide (120mg,0.26mmol), methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (50mg,0.24mmol) and potassium phosphate (76mg,0.36mmol) were dissolved in N, N-dimethylformamide (5mL) and then raised to 60 ℃ for reaction at 3 hours. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (140mg, 92.6%) as a yellow oil.

The fifth step, (S) -2- (6- ((2',6' -dimethyl-4 '- (3- (N-phenylmethylsulfonylamino) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl (S) -2- (6- ((2',6' -dimethyl-4 '- (3- (N-phenylmethylsulfonylamino) propoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (140mg,0.22mmol) was dissolved in tetrahydrofuran (2.5mL), and 1M aqueous lithium hydroxide solution (2.5mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (5mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (120mg, 87.7%).

¹H NMR(600MHz,CDCl₃)δ7.48–7.35(m,7H),7.19(s,1H),7.09(dd,J＝13.2,7.8Hz,2H),6.62(s,2H),6.56–6.46(m,2H),5.09(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.1,6.1Hz,1H),4.05(t,J＝6.0Hz,2H),3.95(t,J＝6.9Hz,2H),3.83(ddd,J＝14.5,9.1,5.8Hz,1H),2.93(s,3H),2.83(dd,J＝16.9,5.3Hz,1H),2.64(dd,J＝16.8,9.4Hz,1H),2.06–1.94(m,8H).

Example 18

2- (6- ((4'- ((4-hydroxycyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (4-hydroxycyclohexyl) methyl 4-methylbenzenesulfonate

4- (hydroxymethyl) cyclohexanol (130mg,0.98mmol), triethylamine (0.21mL,1.50mmol) and N, N, N ', N' -tetramethyl-1, 6-hexanediamine (0.02mL,0.09mmol) were dissolved in toluene (5mL) under nitrogen, p-toluenesulfonyl chloride (190mg,1.0mmol) was added under ice bath, and the reaction mixture was reacted at 0 ℃ for 3 hours after the addition. After the reaction solution was quenched with water (10mL), extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (80mg, 28.5%) as a white solid.

¹H NMR(600MHz,CDCl₃)δ7.80(d,J＝8.2Hz,2H),7.37(d,J＝8.0Hz,2H),3.85(d,J＝6.4Hz,2H),3.54(ddd,J＝15.1,10.8,4.2Hz,1H),2.47(s,3H),2.03–1.94(m,2H),1.82–1.75(m,2H),1.64–1.60(m,1H),1.26–1.19(m,2H),1.02(ddd,J＝25.6,13.3,3.3Hz,2H).

Second step, methyl 2- (6- ((4'- ((4-hydroxycyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(4-Hydroxycyclohexyl) methyl 4-methylbenzenesulfonate (80mg,0.28mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (141mg,0.34mmol) and potassium carbonate (115mg,0.84mmol) were dissolved in N, N-dimethylformamide (3mL) and raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound (50mg, 33.5%) as a yellow oil.

MS(ESI,pos.ion)m/z:531.3[M+H]⁺.

The third step, 2- (6- ((4'- ((4-hydroxycyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- ((4-hydroxycyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (50mg,0.1mmol) was dissolved in a mixed solution of tetrahydrofuran (1mL) and methanol (0.5mL), and after addition of a 2M aqueous sodium hydroxide solution (0.1mL), stirring was carried out at 50 ℃ for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (1mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (36mg, 73.7%) as a yellow solid.

MS(ESI,neg.ion)m/z:515.2[M-H]^-；

¹H NMR(400MHz,CDCl₃)δ7.42(dt,J＝15.3,7.7Hz,2H),7.19(s,1H),7.08(dd,J＝12.2,7.8Hz,2H),6.66(s,2H),6.54–6.45(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.2,6.1Hz,1H),3.88–3.82(m,1H),3.80(d,J＝6.3Hz,2H),3.69–3.58(m,1H),2.82(dd,J＝16.8,5.4Hz,1H),2.63(dd,J＝16.8,9.3Hz,1H),2.08(d,J＝7.6Hz,2H),1.99(d,J＝14.1Hz,8H),1.39–1.32(m,3H),1.17(d,J＝15.0Hz,2H).

Example 19

2- (6- ((2',6' -dimethyl-4 '- ((4- (trifluoromethyl) cyclohexyl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((4- (trifluoromethyl) cyclohexyl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(4- (trifluoromethyl) cyclohexyl) methanol (0.14mL,0.92mmol) and methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (250mg,0.6mmol) were dissolved in toluene (10mL), triphenylphosphine (240mg,0.9mmol) and diisopropyl azodicarboxylate (0.2mL,1.0mmol) were added under ice-bath, and after addition, stirring was carried out under nitrogen in ice-bath for 1 hour. Water (10mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15/1) to give the title compound (150mg, 43.1%) as a pale yellow oil.

Second, 2- (6- ((2',6' -dimethyl-4 '- ((4- (trifluoromethyl) cyclohexyl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((4- (trifluoromethyl) cyclohexyl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (143mg,0.25mmol) was dissolved in tetrahydrofuran (3mL), and 1M aqueous lithium hydroxide solution (3mL) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (125mg, 89.6%).

MS(ESI,pos.ion)m/z:569.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.43(dt,J＝15.3,7.6Hz,2H),7.20(s,1H),7.14–7.05(m,2H),6.68(d,J＝7.5Hz,2H),6.56–6.46(m,2H),5.09(s,2H),4.79(t,J＝9.0Hz,1H),4.31(dd,J＝9.2,6.1Hz,1H),3.95(d,J＝7.2Hz,1H),3.87–3.78(m,2H),2.84(dd,J＝16.8,5.3Hz,1H),2.64(dd,J＝16.8,9.3Hz,1H),2.17(dd,J＝11.3,7.1Hz,1H),2.02(s,6H),1.89–1.72(m,3H),1.67-1.64(m,3H),1.41(m,1H),1.23–1.07(m,1H),0.96–0.80(m,1H).

Example 20

2- (6- ((4'- ((4, 4-difluorocyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (4, 4-difluorocyclohexyl) methanol

4, 4-Difluorocyclohexanecarboxylic acid (500mg,3.1mmol) was dissolved in tetrahydrofuran (6mL), and a solution of sodium borohydride (120mg,3.2mmol) in tetrahydrofuran (6mL) was added dropwise under ice bath, and the reaction solution was allowed to warm for 1 hour after completion of the addition. Boron trifluoride diethyl etherate (0.38mL,3.1mmol) was added dropwise to the reaction mixture, followed by reaction at room temperature overnight. The reaction was quenched with ethanol (12mL), extracted with dichloromethane (10mL × 2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow liquid (450mg, 98.0%).

Second step, (4, 4-difluorocyclohexyl) methylmethanesulfonate

Under nitrogen protection, (4, 4-difluorocyclohexyl) methanol (450mg,3.0mmol) and triethylamine (0.7mL,5.0mmol) were dissolved in dichloromethane (20mL), methanesulfonyl chloride (0.4mL,5.0mmol) was added dropwise under ice bath, and the reaction solution was reacted at room temperature for 1 hour after completion of dropwise addition. After the reaction solution was quenched with a saturated sodium bicarbonate solution (10mL), extracted with dichloromethane (15 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (130mg, 20.0%) as a yellow oil.

¹H NMR(400MHz,CDCl₃)δ4.10(d,J＝6.2Hz,2H),3.04(s,3H),2.22–2.09(m,2H),1.93–1.67(m,5H),1.48–1.37(m,2H).

The third step, methyl 2- (6- ((4'- ((4, 4-difluorocyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(4, 4-Difluorocyclohexyl) methylmethanesulfonate (130mg,0.57mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (350mg,0.84mmol) and potassium carbonate (240mg,1.74mmol) were dissolved in N, N-dimethylformamide (10mL) and raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (170mg, 54.2%) as a yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.48–7.37(m,2H),7.19(s,1H),7.07(dd,J＝37.1,7.8Hz,2H),6.67(s,2H),6.53–6.43(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.28(dd,J＝9.1,6.1Hz,1H),3.91–3.78(m,3H),3.74(s,3H),2.77(dd,J＝16.4,5.4Hz,1H),2.58(dd,J＝16.4,9.3Hz,1H),2.22–2.13(m,2H),2.00(d,J＝13.9Hz,7H),1.91(d,J＝8.5Hz,1H),1.87–1.72(m,2H),1.52–1.41(m,2H),1.31(s,1H).

The fourth step, 2- (6- ((4'- ((4, 4-difluorocyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- ((4, 4-difluorocyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (170mg,0.3mmol) was dissolved in tetrahydrofuran (3mL), and after addition of 1M aqueous lithium hydroxide solution (3mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (130mg, 78.5%).

MS(ESI,pos.ion)m/z:537.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.43(dt,J＝15.1,7.6Hz,2H),7.20(s,1H),7.10(dd,J＝12.6,7.7Hz,2H),6.68(s,2H),6.57–6.44(m,2H),5.09(s,2H),4.79(t,J＝9.0Hz,1H),4.32(dd,J＝9.2,6.1Hz,1H),3.89–3.78(m,3H),2.84(dd,J＝16.8,5.3Hz,1H),2.65(dd,J＝16.8,9.3Hz,1H),2.19(ddd,J＝11.0,8.7,4.3Hz,2H),2.05–1.72(m,11H),1.55–1.42(m,2H).

Example 21

2- (6- ((2',6' -dimethyl-4 '- ((tetrahydro-2H-pyran-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydro-2H-pyran-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(tetrahydro-2H-pyran-2-yl) -methanol (146mg,1.3mmol) and methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (350mg,0.8mmol) were dissolved in toluene (20mL), tributylphosphine (0.33mL,1.3mmol) and azobisformyldipiperidine (338mg,1.3mmol) were added at room temperature, and stirring was completed at room temperature under nitrogen for 1 hour. Water (20mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (40 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (72mg, 16.7%) as a pale yellow oil.

MS(ESI,pos.ion)m/z:517.2[M+H]⁺.

Second step, 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydro-2H-pyran-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydro-2H-pyran-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (72mg,0.14mmol) was dissolved in tetrahydrofuran (2mL), and after addition of 1M aqueous lithium hydroxide (2mL), the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (5mL), and extracted with ethyl acetate (40mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (2mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (44mg, 62.8%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:503.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.42(d,J＝21.7Hz,2H),7.19(s,1H),7.09(dd,J＝20.4,7.1Hz,2H),6.71(s,2H),6.57–6.44(m,2H),5.08(s,2H),4.78(t,J＝8.5Hz,1H),4.30(d,J＝7.0Hz,1H),4.10(d,J＝9.0Hz,1H),4.02(d,J＝6.2Hz,1H),3.92(d,J＝5.8Hz,1H),3.79(d,J＝40.4Hz,2H),3.56(t,J＝11.1Hz,1H),2.86–2.77(m,1H),2.63(dd,J＝16.3,9.3Hz,1H),2.01(s,6H),1.94(d,J＝6.4Hz,1H),1.75(d,J＝12.0Hz,1H),1.70–1.61(m,1H),1.59(s,2H),1.49(dd,J＝23.0,11.7Hz,1H).

Example 22

2- (6- ((2',6' -dimethyl-4 '- ((tetrahydro-2H-pyran-4-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydro-2H-pyran-4-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(tetrahydro-2H-pyran-4-yl) -methanol (104mg,0.90mmol) and methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (250mg,0.60mmol) were dissolved in toluene (4mL), tributylphosphine (0.24mL,0.96mmol) and azobisformyldipiperidine (244mg,0.96mmol) were added at room temperature, and stirring was completed at room temperature under nitrogen for 1 hour. Water (20mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (40 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (143mg, 46.3%) as a pale yellow solid.

¹H NMR(600MHz,CDCl₃)δ7.48–7.34(m,2H),7.19(s,1H),7.07(dd,J＝37.9,7.8Hz,2H),6.67(s,2H),6.53–6.45(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.28(dd,J＝9.1,6.1Hz,1H),4.05(dd,J＝11.1,3.6Hz,2H),3.88–3.79(m,3H),3.74(s,3H),3.48(dd,J＝11.5,10.4Hz,2H),2.76(dd,J＝16.4,5.4Hz,1H),2.57(dd,J＝16.4,9.3Hz,1H),2.14–2.08(m,1H),2.01(s,6H),1.80(dd,J＝12.9,1.4Hz,2H),1.52–1.42(m,2H).

Second step, 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydro-2H-pyran-4-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydro-2H-pyran-4-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.39mmol) was dissolved in tetrahydrofuran (4mL), and after addition of 1M aqueous lithium hydroxide (4mL), the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (5mL), and extracted with ethyl acetate (40mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (2mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (180mg, 92.5%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:503.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.48–7.36(m,2H),7.19(s,1H),7.09(dd,J＝19.4,7.7Hz,2H),6.68(s,2H),6.57–6.45(m,2H),5.08(s,2H),4.79(t,J＝9.0Hz,1H),4.31(dd,J＝9.1,6.1Hz,1H),4.07(dd,J＝10.9,3.2Hz,2H),3.86–3.82(m,3H),3.50(t,J＝11.1Hz,2H),2.83(dd,J＝16.8,5.2Hz,1H),2.64(dd,J＝16.8,9.4Hz,1H),2.16–2.06(m,1H),2.02(s,6H),1.81(d,J＝12.0Hz,2H),1.55–1.44(m,2H).

Example 23

2- (6- ((2',6' -dimethyl-4 '- ((tetrahydrofuran-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydrofuran-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(tetrahydrofuran-2-yl) methanol (0.07mL,0.72mmol) and methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.48mmol) were dissolved in toluene (5mL), triphenylphosphine (188mg,0.72mmol) and diisopropyl azodicarboxylate (0.14mL,0.72mmol) were added under ice-bath, and stirring was completed under nitrogen protection in ice-bath for 1 hour. Water (10mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1) to give the title compound (195mg, 81.2%) as a pale yellow oil.

MS(ESI,pos.ion)m/z:503.2[M+H]⁺.

Second step, 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydrofuran-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydrofuran-2-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (195mg,0.39mmol) was dissolved in tetrahydrofuran (4mL), and after addition of 1M aqueous lithium hydroxide solution (4mL), the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (10mL), and extracted with ethyl acetate (20mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (100mg, 52.7%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:489.2[M+H]⁺；

¹H NMR(600MHz,CDCl3)δ7.45–7.37(m,2H),7.18(s,1H),7.08(dd,J＝18.1,7.8Hz,2H),6.70(s,2H),6.52–6.47(m,2H),5.07(s,2H),5.00(dt,J＝12.5,6.2Hz,3H),4.77(t,J＝9.0Hz,1H),4.35–4.27(m,2H),4.03–3.95(m,3H),3.89–3.79(m,2H),2.81(dd,J＝16.8,5.3Hz,1H),2.61(dd,J＝16.8,9.4Hz,1H),2.10(dt,J＝7.2,4.1Hz,1H),2.00(s,6H).

Example 24

2- (6- ((4'- ((4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, 4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Ethyl glyoxylate (6.3mL,30mmol) and bismuth trichloride (500mg,1.6mmol) were dissolved in chloroform (150mL) under nitrogen, a solution of 2, 3-dimethyl-1, 3-butadiene (10mL,88.4mmol) in chloroform (50mL) was added dropwise, and the temperature was raised to 60 ℃ for reaction for 2 hours. After the reaction solution was quenched with a saturated sodium carbonate solution (20mL), extracted with dichloromethane (80 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50/1 petroleum ether/ethyl acetate (v/v)) to give the title compound (2.3g, 41.0%) as a colorless liquid.

Second step, (4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) -methanol

Lithium aluminum hydride (93mg,2.5mmol) was suspended in anhydrous tetrahydrofuran (5mL), and a solution of ethyl 4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-carboxylate (300mg,1.6mmol) in anhydrous tetrahydrofuran (5mL) was added dropwise under ice-cooling, and the reaction solution was allowed to warm overnight. Water (5mL) and 10% aqueous sodium hydroxide (25mL) were slowly added dropwise to the reaction solution in an ice bath, followed by filtration, and the cake was washed with tetrahydrofuran (20mL), and then the filtrates were combined and concentrated under reduced pressure. The residue was diluted with water (10mL), extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound (220mg, 95.0%) as a yellow oil.

¹H NMR(600MHz,CDCl₃)δ4.07(d,J＝15.4Hz,1H),3.99(d,J＝15.4Hz,1H),3.70–3.62(m,2H),3.57(dd,J＝11.4,7.3Hz,1H),2.36(s,1H),2.08–2.00(m,1H),1.73(d,J＝16.6Hz,1H),1.66(s,3H),1.55(s,3H).

Third step, (4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate

(4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) -methanol (1.33g,9.4mmol), triethylamine (2.0mL,14.2mmol) and N, N, N ', N' -tetramethyl-1, 6-hexanediamine (0.2mL,0.96mmol) were dissolved in toluene (25mL) under nitrogen protection, p-toluenesulfonyl chloride (2.7g,14.0mmol) was added under ice bath, and the reaction mixture was reacted at 0 ℃ for 3 hours after the addition was completed. After the reaction solution was quenched with water (10mL), extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), to give the title compound (2.4g, 86.0%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.83(d,J＝8.3Hz,2H),7.36(d,J＝8.0Hz,2H),4.06–4.02(m,2H),3.98(d,J＝15.6Hz,1H),3.91(d,J＝15.5Hz,1H),3.79(ddd,J＝10.5,9.2,5.1Hz,1H),2.47(s,3H),2.02–1.94(m,1H),1.79(d,J＝16.4Hz,1H),1.64(s,3H),1.53(s,3H).

The fourth step, methyl 2- (6- ((4'- ((4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (425mg,1.43mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (400mg,0.96mmol) and potassium carbonate (400mg,2.89mmol) were dissolved in N, N-dimethylformamide (10mL) and raised to 90 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 12/1) to give the title compound (282mg, 54.4%) as a yellow oil.

MS(ESI,pos.ion)m/z:543.3[M+H]⁺；

The fifth step, 2- (6- ((4'- ((4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- ((4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (77mg,0.14mmol) was dissolved in tetrahydrofuran (2mL), and 1M aqueous lithium hydroxide (2mL) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (5mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (41mg, 54.5%) as a yellow solid.

MS(ESI,pos.ion)m/z:529.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.46–7.37(m,2H),7.19(s,1H),7.09(dd,J＝20.7,7.7Hz,2H),6.72(s,2H),6.54–6.46(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝8.9,6.2Hz,1H),4.16(d,J＝15.2Hz,1H),4.12–4.03(m,2H),4.03–3.95(m,2H),3.83(d,J＝5.0Hz,1H),2.83(dd,J＝16.8,5.0Hz,1H),2.63(dd,J＝16.8,9.4Hz,1H),2.27–2.15(m,1H),2.01(s,6H),1.95(d,J＝16.5Hz,1H),1.71(s,3H),1.59(s,3H).

Example 25

2- (6- ((4'- ((5-hydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (3, 4-dihydro-2H-pyran-2-yl) -methyl-4-methylbenzenesulfonate

(3, 4-dihydro-2H-pyran-2-yl) -methanol (3g,26.3mmol), triethylamine (5.5mL,39mmol) and N, N, N ', N' -tetramethyl-1, 6-hexanediamine (0.56mL,2.6mmol) were dissolved in toluene (50mL) under nitrogen protection, p-toluenesulfonyl chloride (7.6g,40mmol) was added under ice bath, and the reaction was reacted at 0 ℃ for 3 hours after completion of the addition. After the reaction solution was quenched with water (30mL), extracted with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50/1 petroleum ether/ethyl acetate (v/v)) to give the title compound (7g, 99.3%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.83(d,J＝8.2Hz,2H),7.37(d,J＝8.1Hz,2H),6.28(d,J＝6.1Hz,1H),4.69(dd,J＝6.8,5.7Hz,1H),4.16–3.99(m,3H),2.47(s,3H),2.11–2.04(m,1H),2.01–1.92(m,1H),1.88–1.81(m,1H),1.71–1.62(m,1H).

Second step, (5-hydroxytetrahydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate

(3, 4-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (3g,11.2mmol) was dissolved in dry tetrahydrofuran (20mL), a 1M borane tetrahydrofuran solution (33.6mL) was added dropwise under ice bath, the reaction solution was stirred overnight at room temperature, then a 2.5M aqueous sodium hydroxide solution (26mL) and a 30% aqueous hydrogen peroxide solution (4.6mL) were added dropwise in this order, and the reaction was heated to 60 ℃ for 1 hour after completion of the dropwise addition. Cooled to 0 ℃, potassium carbonate (14g) was added, the reaction solution was extracted with ethyl acetate (40mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1), to give the title compound (2g, 62.5%) as a colorless oil.

¹H NMR(600MHz,CDCl₃)δ7.80(d,J＝8.2Hz,2H),7.36(d,J＝8.3Hz,2H),4.01–3.93(m,3H),3.68(t,J＝6.4Hz,1H),3.54–3.47(m,1H),3.07(t,J＝10.5Hz,1H),2.46(s,3H),2.19–2.10(m,1H),1.65–1.55(m,2H),1.43–1.33(m,2H).

The third step, methyl 2- (6- ((4'- ((5-hydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(5-Hydroxytetrahydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (200mg,0.70mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.48mmol) and potassium carbonate (200mg,1.45mmol) were dissolved in N, N-dimethylformamide (10mL) and raised to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), to give the title compound (200mg, 78.6%) as a pale yellow oil.

MS(ESI,pos.ion)m/z:533.2[M+H]⁺.

The fourth step, 2- (6- ((4'- ((5-hydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- ((5-hydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.39mmol) was dissolved in tetrahydrofuran (4mL), and 1M aqueous lithium hydroxide (4mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (4mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (40 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (77mg, 39.5%).

MS(ESI,pos.ion)m/z:519.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.49–7.35(m,2H),7.18(s,1H),7.08(dd,J＝11.8,7.7Hz,2H),6.70(s,2H),6.59–6.37(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.2,6.1Hz,1H),4.15–4.08(m,1H),4.04(dd,J＝9.9,6.1Hz,1H),3.94(dd,J＝9.9,4.3Hz,1H),3.87–3.75(m,2H),3.75–3.66(m,1H),3.24(t,J＝10.4Hz,1H),2.82(dd,J＝16.8,5.3Hz,1H),2.62(dd,J＝16.8,9.3Hz,1H),2.22(dd,J＝10.6,5.5Hz,1H),2.00(s,6H),1.91(dd,J＝8.8,6.0Hz,1H),1.64–1.45(m,2H).

Example 26

2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step (S) -1- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) but-3-en-1-ol

Suspending zinc powder (20g,307mmol) in anhydrous tetrahydrofuran (100mL), slowly adding (R) - (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde (20g,153mmol) and 3-bromopropylene (26mL,307mmol) dropwise in sequence under ice bath, and reacting the reaction solution under nitrogen protection in ice bath for 4 hours. The reaction solution was quenched with a saturated aqueous solution of ammonium chloride (30mL), filtered, the filtrate was extracted with ethyl acetate (80 mL. times.2), the organic phases were combined, washed with a saturated solution of sodium chloride (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 60/1) to give the title compound (22.2g, 83.9%) as a yellow liquid.

¹H NMR(600MHz,CDCl₃)δ5.92–5.81(m,1H),5.16(ddd,J＝21.3,14.5,5.6Hz,2H),4.04(ddd,J＝14.6,10.7,6.3Hz,2H),3.95(td,J＝9.3,5.2Hz,1H),3.84–3.75(m,1H),2.42–2.31(m,1H),2.28–2.21(m,1H),1.45(s,3H),1.38(s,3H).

Second step, (R) -4- ((S) -1- (allyloxy) but-3-en-1-yl) -2, 2-dimethyl-1, 3-dioxolane

Sodium hydride (10.3g,258mmol) was suspended in anhydrous N, N-dimethylformamide (100mL), a solution of (S) -1- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) but-3-en-1-ol (20g,129mmol) in tetrahydrofuran (200mL) was added dropwise under ice bath, and after stirring for 19 hours under ice bath, 3-bromopropene (112mL,1.29mol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was quenched with a saturated aqueous solution of ammonium chloride (30mL), filtered, the filtrate was extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with a saturated solution of sodium chloride (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), to give the title compound (14g, 51.2%) as a pale yellow liquid.

The third step is (2R,3S) -3- (allyloxy) hex-5-ene-1, 2-diol

(R) -4- ((S) -1- (allyloxy) but-3-en-1-yl) -2, 2-dimethyl-1, 3-dioxolane (14g,66mmol) was dissolved in tetrahydrofuran (150mL), 2M hydrochloric acid solution (150mL) was added under ice bath, and the reaction was stirred at room temperature until the starting material was reacted (TLC plate follow-up reaction). The reaction solution was extracted with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with a saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (9.0g, 79.2%) as a yellow oil.

The fourth step, (S) -2- (allyloxy) pent-4-enal

(2R,3S) -3- (allyloxy) hex-5-ene-1, 2-diol (9g,52mmol) was dissolved in dichloromethane (200mL), and sodium periodate (28g,131mmol) and a saturated aqueous solution of sodium bicarbonate (15mL) were added in this order at room temperature, followed by stirring at room temperature for 5 minutes and then sodium bicarbonate (2.2g) was added. The reaction solution was stirred at room temperature for 2 hours, then anhydrous sodium sulfate (30g) was added to remove water, the reaction solution was filtered, and concentrated under reduced pressure to give the title compound (7.3g, 100%) as a yellow oil.

The fifth step, (S) -2- (allyloxy) pent-4-en-1-ol

(S) -2- (allyloxy) pent-4-enal (7.3g,52mmol) was dissolved in a mixed solution of tetrahydrofuran (60mL) and methanol (30mL), sodium borohydride (2.1g,55mmol) was added in portions under ice bath, and the reaction solution was stirred overnight in ice bath. The reaction solution was quenched with water (5mL), extracted with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1), to give the title compound (5.1g, 69%) as a pale yellow oil.

Sixth step (S) -2- (allyloxy) pent-4-en-1-yl 4-methylbenzenesulfonate

(S) -2- (allyloxy) pent-4-en-1-ol (4.64g,32.6mmol), triethylamine (6.9mL,49mmol) and N, N, N ', N' -tetramethyl-1, 6-hexanediamine (0.7mL,3mmol) were dissolved in toluene (50mL) under nitrogen, p-toluenesulfonyl chloride (9.3g,49mmol) was added under ice bath, and the reaction was reacted at 0 ℃ for 3 hours after completion of the addition. After the reaction solution was quenched with water (30mL), extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50/1 petroleum ether/ethyl acetate (v/v)) to give the title compound (6.7g, 69%) as a pale yellow oil.

Seventh step, (S) - (3, 6-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate

(S) -2- (allyloxy) pent-4-en-1-yl 4-methylbenzenesulfonate (6.7g,23mmol) was dissolved in dichloromethane (200mL), Grubb' S I th-e catalyst (380mg,2 mol%) was added, the reaction solution was stirred at room temperature for 1.5 hours and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1) to give the title compound as a black oil (5.76g, 95%).

Eighth step, (S) - (4'- ((3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol

(S) - (3, 6-dihydro-2H-pyran-2-yl) -methyl-4-methylbenzenesulfonate (5.76g,21.5mmol), 3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-ol (5.88g,25.8mmol) and potassium carbonate (8.9g,64mmol) were dissolved in N, N-dimethylformamide (50mL) and allowed to warm to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (30mL), extracted with ethyl acetate (30mL), and the organic phase was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (4.7g, 67.0%) as a pale yellow oil.

MS(ESI,pos.ion)m/z:325.2[M+H]⁺.

Ninth step, (S) -2- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran

(S) - (4'- ((3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol (4.7g,14mmol) was dissolved in N, N-dimethylformamide (20mL), and phosphorus oxychloride (1.6mL,17mmol) was added dropwise at room temperature and stirred at room temperature for 1.5 hours. The reaction solution was quenched with water (20mL), extracted with ethyl acetate (20 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), to give the title compound (4.57g, 92%) as a pale yellow oil.

The tenth step, methyl 2- (6- ((4'- (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(S) -2- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran (500mg,1.46mmol), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (303mg,1.46mmol) and potassium carbonate (500mg,2.36mmol) were dissolved in N, N-dimethylformamide (40mL) and raised to 60 ℃ for reaction overnight. The reaction solution was cooled to room temperature, diluted with water (10mL), extracted with ethyl acetate (10mL), and the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (690mg, 92.0%) as a pale yellow oil.

The tenth step, methyl 2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

methyl 2- (6- ((4'- (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (690mg,1.34mmol) was dissolved in tert-butanol (10mL) and water (10mL), added AD-Mix- β (2g) at room temperature and reacted overnight, the reaction was quenched with sodium sulfite, extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/3) to give the title compound as a colorless oil (200mg, 27.2%).

MS(ESI,pos.ion)m/z:549.2[M+H]⁺.

The twelfth step, 2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.36mmol) was dissolved in tetrahydrofuran (4mL), and after addition of 1M aqueous lithium hydroxide (4mL), the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (10mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (160mg, 82.1%) as a white solid.

MS(ESI,pos.ion)m/z:535.2[M+H]⁺；

¹HNMR(600MHz,CDCl₃)δ7.36–7.26(m,2H),7.08(s,1H),6.98(dd,J＝16.5,7.8Hz,2H),6.59(s,2H),6.45–6.34(m,2H),5.01–4.94(m,2H),4.67(t,J＝9.0Hz,1H),4.20(dd,J＝9.1,6.1Hz,1H),4.15(d,J＝2.1Hz,1H),4.05–4.01(m,1H),3.92–3.88(m,2H),3.79–3.68(m,3H),3.61–3.56(m,1H),2.71(dd,J＝16.8,5.3Hz,1H),2.52(dd,J＝16.8,9.3Hz,1H),1.95–1.84(m,7H),1.74(t,J＝12.0Hz,1H).

Example 27

2- (6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((4'- ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

The title compound (151mg, 41%) was obtained as a colorless oil by the synthesis of the tenth step of example 26.

MS(ESI,pos.ion)m/z:549.2[M+H]⁺.

The second step, 2- (6- ((4'- ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (151mg,0.28mmol) as a starting material, the title compound (90mg, 61.1%) was prepared as a white solid according to the synthesis method of the twelfth step of example 26.

MS(ESI,pos.ion)m/z:535.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.37–7.26(m,2H),7.07(s,1H),6.97(dd,J＝15.6,7.8Hz,2H),6.59(s,2H),6.45–6.35(m,2H),4.97(s,2H),4.67(t,J＝9.0Hz,1H),4.20(dd,J＝9.2,6.1Hz,1H),4.08–4.05(m,1H),3.99(dd,J＝10.1,6.1Hz,1H),3.90(dd,J＝10.1,3.9Hz,1H),3.78–3.65(m,4H),3.54(d,J＝12.6Hz,1H),2.71(dd,J＝16.8,5.4Hz,1H),2.52(dd,J＝16.8,9.3Hz,1H),1.95–1.80(m,7H),1.70–1.67(m,1H).

Example 28

2- ((S) -6- ((4'- ((((2S, 4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- ((S) -6- ((4'- (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

The title compound (2.87g, 89%) was prepared as a pale yellow oil using (S) -methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (1.3g,6.2mmol) and (S) -2- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxo) methyl) -3, 6-dihydro-2H-pyran (2.1g,6.1mmol) as starting materials according to the synthesis method of the tenth step of example 26.

MS(ESI,pos.ion)m/z:515.2[M+H]⁺.

Second step, methyl 2- ((S) -6- ((4'- ((((2S, 4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Using methyl 2- ((S) -6- ((4'- (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (3.1g,6mmol) as a starting material, the title compound (1.19g, 36%) was produced as a colorless oil by the synthesis of the tenth step of example 26.

MS(ESI,pos.ion)m/z:549.2[M+H]⁺.

The third step, 2- ((S) -6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- ((S) -6- ((4'- ((((2S, 4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (1.19g,2.17mmol) as a starting material, the title compound (1.16g, 100%) was prepared as a white solid according to the synthesis method of the tenth step of example 26.

MS(ESI,pos.ion)m/z:535.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.45–7.36(m,2H),7.18(s,1H),7.08(dd,J＝16.4,7.8Hz,2H),6.69(s,2H),6.56–6.45(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.30(dd,J＝9.2,6.1Hz,1H),4.25(d,J＝2.2Hz,1H),4.16–4.10(m,1H),4.03–3.96(m,2H),3.86–3.83(m,3H),3.71–3.65(m,1H),2.82(dd,J＝16.8,5.4Hz,1H),2.63(dd,J＝16.8,9.3Hz,1H),2.06–1.95(m,7H),1.87–1.82(m,1H).

Example 29

2- ((S) -6- ((4'- ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- ((S) -6- ((4'- ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

The title compound (1.38g, 42%) was obtained as a colorless oil by the second synthesis step of example 28.

MS(ESI,pos.ion)m/z:549.2[M+H]⁺.

Second, 2- ((S) -6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- ((S) -6- ((4'- ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (1.38g,2.52mmol) as a starting material, the title compound (1.29g, 95.9%) was prepared as a white solid according to the synthesis method of the tenth step of example 26.

MS(ESI,pos.ion)m/z:535.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.46–7.35(m,2H),7.17(s,1H),7.08(dd,J＝15.5,7.8Hz,2H),6.69(s,2H),6.54–6.45(m,2H),5.07(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.1,6.1Hz,1H),4.18–4.15(m,1H),4.09(dd,J＝10.0,6.1Hz,1H),3.99(dd,J＝10.1,3.9Hz,1H),3.89–3.74(m,4H),3.64(d,J＝12.7Hz,1H),2.81(dd,J＝16.8,5.4Hz,1H),2.62(dd,J＝16.8,9.3Hz,1H),1.98–1.95(m 7H),1.78–1.72(m,1H).

Example 30

2- (6- ((4'- (((2R,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step (R) -1- ((S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) but-3-en-1-ol

Starting from (S) - (-) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde (20g,153mmol) and 3-bromopropene (26mL,307mmol), the title compound (22.2g, 83.9%) was prepared as a pale yellow solid by the synthetic method according to the first step of example 26.

Second step, (S) -4- ((R) -1- (allyloxy) -but-3-en-1-yl) -2, 2-dimethyl-1, 3-dioxolane

Starting from (R) -1- ((S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) but-3-en-1-ol (20g,129mmol) and 3-bromopropene (112mL,1.29mol), the title compound was prepared as a pale yellow solid (14g, 51.2%) by the synthetic method of the second step of example 26.

The third step is (2S,3R) -3- (allyloxy) hex-5-ene-1, 2-diol

Starting from (S) -4- ((R) -1- (allyloxy) -but-3-en-1-yl) -2, 2-dimethyl-1, 3-dioxolane (14g,66mmol), the title compound (9.0g, 79.2%) was prepared as a yellow liquid by the synthetic method according to the third step of example 26.

The fourth step, (R) -2- (allyloxy) pent-4-enal

Starting from (2S,3R) -3- (allyloxy) hex-5-ene-1, 2-diol (9.0g,52mmol) and sodium periodate (28g,131mmol), the title compound (7.3g, 100%) was prepared as a yellow liquid by the fourth synthesis step of example 26.

The fifth step, (R) -2- (allyloxy) pent-4-en-1-ol

Using (R) -2- (allyloxy) pent-4-enal (7.3g,52mmol) as a starting material, the title compound (5.1g, 69%) was obtained as a pale yellow oil by the synthesis method according to the fifth step of example 26.

Sixth step (R) -2- (allyloxy) pent-4-en-1-yl 4-methylbenzenesulfonate

Starting from (R) -2- (allyloxy) pent-4-en-1-ol (4.64g,32.6mmol) and p-toluenesulfonyl chloride (9.3g,49mmol), the title compound (6.7g, 69%) was prepared as a yellow oil by the synthetic method in the sixth step of example 26.

Seventh step, (R) - (3, 6-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate

Using (R) -2- (allyloxy) pent-4-en-1-yl 4-methylbenzenesulfonate (6.7g,23mmol) as a starting material, the title compound (5.76g, 95%) was prepared as a brown oil by the synthetic method according to the seventh step of example 26.

Eighth step, (R) - (4'- ((3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol

Starting from (R) - (3, 6-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (5.76g,21.5mmol) and 3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-ol (5.88g,25.8mmol), the title compound was prepared as a yellow liquid (4.7g, 67.0%) by the synthesis in the eighth step of example 26.

Ninth step, (R) -2- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxo) methyl) -3, 6-dihydro-2H-pyran

Starting from (R) - (4'- ((3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol (4.7g,14mmol) and phosphorus oxychloride (1.6mL,17mmol), the title compound (4.57g, 92%) was prepared as a yellow oil by the synthesis in the ninth step of example 26.

The tenth step, methyl 2- (6- ((4'- (((R) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Starting from (R) -2- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxo) methyl) -3, 6-dihydro-2H-pyran (500mg,1.46mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (303mg,1.46mmol), the title compound (690mg, 92.0%) was prepared as a pale yellow oil by the synthesis method of the tenth step of example 26.

The tenth step, methyl 2- (6- ((4'- (((2R,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Using methyl 2- (6- ((4'- (((R) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (690mg,1.34mmol) as a starting material, the title compound (200mg, 27%) was prepared as a colorless oil by the synthesis of the tenth step of example 26.

MS(ESI,pos.ion)m/z:549.2[M+H]⁺.

The twelfth step, 2- (6- ((4'- (((2R,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- (((2R,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.36mmol) as a starting material, the objective compound (160mg, 82.1%) was obtained as a white solid according to the synthesis method of the tenth step of example 26.

MS(ESI,pos.ion)m/z:535.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.48–7.35(m,2H),7.18(s,1H),7.08(dd,J＝16.1,7.8Hz,2H),6.69(s,2H),6.55–6.42(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.2,6.1Hz,1H),4.25(d,J＝2.2Hz,1H),4.14–4.10(m,1H),4.04–3.96(m,2H),3.90–3.78(m,3H),3.71–3.65(m,1H),2.82(dd,J＝16.9,5.2Hz,1H),2.63(dd,J＝16.8,9.3Hz,1H),2.05–1.92(m,7H),1.84(t,J＝12.2Hz,1H).

Example 31

2- (6- ((4'- (((2R,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((4'- ((((2R, 4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

The title compound (200mg, 27%) was obtained as a colorless oil by the synthesis of the tenth step of example 30.

MS(ESI,pos.ion)m/z:549.2[M+H]⁺.

Second step, 2- (6- ((4'- (((2R,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- (((2R,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.36mmol) as a starting material, the title compound (133mg, 68.2%) was prepared as a white solid according to the twelfth synthesis step of example 26.

MS(ESI,pos.ion)m/z:535.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.48–7.36(m,2H),7.17(s,1H),7.08(dd,J＝15.8,7.8Hz,2H),6.69(s,2H),6.57–6.41(m,2H),5.07(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.1,6.1Hz,1H),4.19–4.14(m,1H),4.09(dd,J＝10.0,6.1Hz,1H),3.99(dd,J＝10.1,3.9Hz,1H),3.89–3.74(m,4H),3.64(d,J＝12.6Hz,1H),2.81(dd,J＝16.8,5.3Hz,1H),2.62(dd,J＝16.8,9.3Hz,1H),1.99(d,J＝16.3Hz,7H),1.76(dd,J＝23.8,11.9Hz,1H).

Example 32

2- (6- ((4'- (((2S,4R,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (1S,4S,6R) -4- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 7-dioxabicyclo [4.1.0] heptane

(S) -2- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran (1.5g,4.4mmol) was dissolved in dichloromethane (80mL), m-chloroperoxybenzoic acid (2.6g,11mmol) was added under ice-bath, the reaction was stirred for 1 hour in ice-bath and quenched with dimethyl sulfide (2mL), ethyl acetate was extracted (10mL), the organic phase was washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound (390mg, 24.6%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.42(t,J＝7.7Hz,1H),7.37(d,J＝7.7Hz,1H),7.17(s,1H),7.10(d,J＝7.4Hz,1H),6.69(s,2H),4.64(s,2H),4.34(dd,J＝13.6,4.1Hz,1H),4.05(d,J＝13.6Hz,1H),3.97(d,J＝4.5Hz,2H),3.82(ddd,J＝11.9,7.6,4.6Hz,1H),3.49(d,J＝3.5Hz,1H),3.34(t,J＝4.2Hz,1H),2.16(d,J＝14.5Hz,1H),2.02–2.00(m,7H).

The second step, (3R,4R,6S) -6- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) tetrahydro-2H-pyran-3, 4-diol

(1S,4S,6R) -4- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 7-dioxabicyclo [4.1.0] heptane (340mg,0.95mmol) was dissolved in a mixed solution of water (20mL) and acetonitrile (20mL), bismuth trichloride (60mg,0.19mmol) was added at room temperature, the reaction solution was stirred for 2 days at room temperature and then filtered, the filtrate was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (170mg, 47.6%) as a pale yellow oil.

¹H NMR(400MHz,CDCl₃)δ7.45–7.34(m,2H),7.18(s,1H),7.13–7.08(m,1H),6.71(s,2H),4.64(s,2H),4.20–4.02(m,4H),3.99(dd,J＝10.0,4.2Hz,1H),3.88(d,J＝12.3Hz,1H),3.59(s,1H),2.12(ddd,J＝14.4,11.5,3.1Hz,1H),2.02(s,6H),1.74(d,J＝14.3Hz,1H).

The third step, methyl 2- (6- ((4'- ((((2S, 4R,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(3R,4R,6S) -6- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) tetrahydro-2H-pyran-3, 4-diol (170mg,0.45mmol), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (100mg,0.48mmol) and potassium phosphate (150mg,0.71mmol) were dissolved in N, N-dimethylformamide (10mL) and raised to 60 ℃ for reaction at 60 ℃ for 3 hours. The reaction solution was cooled to room temperature, diluted with water (5mL), extracted with ethyl acetate (20 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/2) to give the title compound (180mg, 72.7%) as a pale yellow oil.

MS(ESI,pos.ion)m/z:549.2[M+H]⁺.

The fourth step, 2- (6- ((4'- (((2S,4R,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- (((2S,4R,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (180mg,0.33mmol) was dissolved in tetrahydrofuran (4mL), and 1M aqueous lithium hydroxide (4mL) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (3mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (53mg, 30.2%).

MS(ESI,pos.ion)m/z:535.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.42(dt,J＝15.0,7.6Hz,2H),7.18(s,1H),7.08(dd,J＝10.9,7.8Hz,2H),6.70(s,2H),6.55–6.44(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.2,6.0Hz,1H),4.13(ddd,J＝18.1,12.1,4.2Hz,3H),4.04(dd,J＝10.1,5.7Hz,1H),3.99(dd,J＝10.1,4.1Hz,1H),3.88(d,J＝12.7Hz,1H),3.85–3.78(m,1H),3.59(s,1H),2.81(dd,J＝16.8,5.4Hz,1H),2.62(dd,J＝16.8,9.2Hz,1H),2.05–1.97(m,7H),1.74(d,J＝14.6Hz,1H).

Example 33

2- (6- ((4'- (((2S,4S,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (1R,4S,6S) -4- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 7-dioxabicyclo [4.1.0] heptane

The title compound (290mg, 18.3%) was prepared as a pale yellow oil according to the synthesis of the first step of example 32.

The second step, (3S,4S,6S) -6- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) tetrahydro-2H-pyran-3, 4-diol

Starting from (1R,4S,6S) -4- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 7-dioxabicyclo [4.1.0] heptane (290mg,0.81mmol), the title compound was prepared as a pale yellow oil (110mg, 36.1%) by the synthesis method of the second step of example 32.

The third step, methyl 2- (6- ((4'- ((((2S, 4S,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Starting from (3S,4S,6S) -6- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) tetrahydro-2H-pyran-3, 4-diol (110mg,0.29mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (60mg,0.28mmol), the title compound was prepared as a pale yellow oil (120mg, 75.0%) by the synthesis in the third step of example 32.

The fourth step, 2- (6- ((4'- (((2S,4S,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- (((2S,4S,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (120mg,0.22mmol) as a starting material, the title compound (73mg, 62.4%) was prepared as a white solid according to the synthesis method of the fourth step of example 32.

MS(ESI,pos.ion)m/z:535.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ12.32(s,1H),7.49–7.33(m,2H),7.20–7.02(m,3H),6.69(s,2H),6.47(dd,J＝10.9,2.7Hz,2H),5.09(s,2H),4.93(d,J＝2.9Hz,1H),4.80(d,J＝4.1Hz,1H),4.68(t,J＝9.0Hz,1H),4.19(dd,J＝8.9,6.8Hz,1H),3.90(ddd,J＝12.4,9.9,5.4Hz,3H),3.81–3.55(m,4H),3.29(s,1H),2.69(dd,J＝16.6,5.6Hz,1H),2.46(d,J＝9.0Hz,1H),1.96–1.81(m,7H),1.49(d,J＝12.7Hz,1H).

Example 34

2- (6- ((4'- (((2R,4S,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

(1S,4R,6R) -4- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxo) methyl) -3, 7-dioxabicyclo [4.1.0] heptane

Starting from (R) -2- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran (1.5g,4.4mmol) and m-chloroperoxybenzoic acid (2.6g,11mmol), the title compound was prepared as a pale yellow oil (310mg, 20%) by the synthesis of the first step of example 32.

The second step, (3S,4S,6R) -6- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) tetrahydro-2H-pyran-3, 4-diol

Starting from (1S,4R,6R) -4- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxo) methyl) -3, 7-dioxabicyclo [4.1.0] heptane (310mg,0.86mmol), the title compound was prepared as a pale yellow oil (130mg, 39.9%) by the method for the second step of synthesis in referential example 32.

The third step, methyl 2- (6- ((4'- ((((2R, 4S,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Starting from (3S,4S,6R) -6- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) tetrahydro-2H-pyran-3, 4-diol (130mg,0.34mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (72mg,0.34mmol), the title compound was prepared as a pale yellow oil (123mg, 65.0%) by the method of synthesis in the third step of example 32.

The fourth step, 2- (6- ((4'- (((2R,4S,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

With 2- (6- ((4'- ((((2R, 4S,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl)]Methyl (123mg,0.22mmol) of (e) -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate was used as a starting material according to the synthesis method of the fourth step of example 32 to prepare a target compound (73mg, 60.9%) as a white solid. MS (ESI, pos.ion) M/z 535.3[ M + H ]]⁺；

¹H NMR(400MHz,CD₃OD)δ7.48–7.36(m,2H),7.14(s,1H),7.07(dd,J＝15.0,7.7Hz,2H),6.69(s,2H),6.49(dd,J＝8.2,2.2Hz,1H),6.42(d,J＝2.1Hz,1H),5.08(s,2H),4.70(t,J＝9.0Hz,1H),4.23(dd,J＝9.1,6.3Hz,1H),4.14–4.06(m,1H),4.04–3.85(m,4H),3.76(dd,J＝16.0,9.3Hz,2H),3.49(s,1H),2.72(dd,J＝16.4,5.8Hz,1H),2.52(dd,J＝16.4,8.9Hz,1H),2.09–1.99(m,1H),1.95(s,6H),1.67(d,J＝13.8Hz,1H).

Example 35

2- (6- ((4'- (((2R,4R,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, (1R,4R,6S) -4- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 7-dioxabicyclo [4.1.0] heptane

The title compound (240mg, 15.2%) was prepared as a pale yellow oil according to the synthesis of the first step of example 32.

The second step, (3R,4R,6R) -6- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) tetrahydro-2H-pyran-3, 4-diol

Starting from (1R,4R,6S) -4- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 7-dioxabicyclo [4.1.0] heptane (240mg,0.67mmol), the title compound was prepared as a pale yellow oil (53mg, 21.0%) by the synthesis method of the second step of example 34.

The third step, methyl 2- (6- ((4'- ((((2R, 4R,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Starting from (3R,4R,6R) -6- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) tetrahydro-2H-pyran-3, 4-diol (53mg,0.14mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (35mg,0.16mmol), the title compound was prepared as a pale yellow oil (40mg, 51.8%) by the synthesis in the third step of example 32.

The fourth step, 2- (6- ((4'- (((2R,4R,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

With 2- (6- ((4'- ((((2R, 4R,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl)]-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester (40mg,0.073mmol) as starting material,referring to the synthesis method of the fourth step of example 32, the title compound (28mg, 71.8%) was prepared as a white solid. MS (ESI, pos.ion) M/z 535.3[ M + H ]]⁺；

¹H NMR(400MHz,CDCl₃)δ7.42(dt,J＝15.1,7.6Hz,2H),7.18(s,1H),7.08(dd,J＝11.2,7.8Hz,2H),6.70(s,2H),6.54–6.44(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.1,6.1Hz,1H),4.19–3.98(m,5H),3.88(d,J＝12.4Hz,1H),3.83(d,J＝5.8Hz,1H),3.59(s,1H),2.81(dd,J＝16.8,5.4Hz,1H),2.62(dd,J＝16.7,9.2Hz,1H),2.04–2.00(m,7H),1.74(d,J＝14.3Hz,1H).

Example 36

2- (6- ((4'- ((4, 5-dihydroxy-4, 5-dimethyltetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, 4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-carboxylic acid ethyl ester

Ethyl glyoxylate (6.3mL,30mmol) and bismuth trichloride (0.5g,1.58mmol) were dissolved in chloroform (150mL), and the mixture was stirred at room temperature for 20 minutes, a solution of 2, 3-dimethyl-1, 3-butadiene (20g,153mmol) in chloroform (50mL) was slowly added dropwise, and the reaction mixture was reacted at 60 ℃ for 2 hours after completion of the addition. The reaction solution was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (20mL), extracted with dichloromethane (80 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50/1 petroleum ether/ethyl acetate (v/v)) to give the title compound (2.3g, 41%) as a colorless liquid.

Second step, (4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) -methanol

Lithium aluminum hydride (93mg,2.45mmol) was suspended in anhydrous tetrahydrofuran (5mL), a solution of ethyl 4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-carboxylate (300mg,1.6mmol) in tetrahydrofuran (5mL) was added dropwise under ice-cooling, after stirring overnight at room temperature, water (5mL) and 10% aqueous sodium hydroxide solution (25mL) were added dropwise in this order, extraction was performed with ethyl acetate (100mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound (220mg, 95%) as a yellow oil.

(4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) -methanol (1.33g,9.36mmol), triethylamine (2.0mL,14.2mmol) and N, N, N ', N' -tetramethyl-1, 6-hexanediamine (0.21mL,0.96mmol) were dissolved in toluene (30mL) under nitrogen protection, p-toluenesulfonyl chloride (2.7g,14mmol) was added under ice bath, and the reaction mixture was reacted at 0 ℃ for 3 hours after completion of the addition. After the reaction solution was quenched with water (10mL), extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1), to give the title compound (2.4g, 86%) as a pale yellow oil.

(4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (425mg,1.43mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy-2, 3-dihydrobenzofuran-3-yl) acetate (400mg,0.96mmol) and potassium carbonate (401mg,2.88mmol) were dissolved in N, N-dimethylformamide (10mL) and then raised to 90 ℃ for reaction overnight, the reaction solution was cooled to room temperature and then diluted with water (30mL), ethyl acetate was extracted (30mL), the organic phase was washed with a saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 12/1) to give the title compound as a pale yellow oil (282mg, 54.4%).

MS(ESI,pos.ion)m/z:543.3[M+H]⁺.

The fifth step, methyl 2- (6- ((4'- ((4, 5-dihydroxy-4, 5-dimethyltetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl 2- (6- ((4'- ((4, 5-dimethyl-3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (204mg,0.38mmol) and oxi-4-methylmorpholine monohydrate (158mg,1.13mmol) were dissolved in acetone (3mL) and water (0.5mL), and osmium tetroxide (7mg) was added and reacted at room temperature for 48 hours. The reaction was quenched with sodium sulfite, extracted with ethyl acetate (20 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound (131mg, 60.4%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:599.3[M+Na]⁺.

The sixth step, 2- (6- ((4'- ((4, 5-dihydroxy-4, 5-dimethyltetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- ((4, 5-dihydroxy-4, 5-dimethyltetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (83mg,0.14mmol) was dissolved in tetrahydrofuran (2mL), and 1M aqueous lithium hydroxide (2mL) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (3mL) and extracted with ethyl acetate (10 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the title compound as a white solid (40mg, 49.4%).

MS(ESI,neg.ion)m/z:561.3[M-H]^-；

¹H NMR(400MHz,CDCl₃)δ7.41(dt,J＝14.9,7.6Hz,2H),7.18(s,1H),7.08(dd,J＝10.0,7.9Hz,2H),6.69(s,2H),6.54–6.44(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.2,6.1Hz,1H),4.22–4.11(m,1H),4.03(dd,J＝9.9,5.8Hz,1H),3.96(dd,J＝9.9,4.3Hz,1H),3.87–3.75(m,2H),3.49(d,J＝10.7Hz,1H),2.82(dd,J＝16.8,5.2Hz,1H),2.62(dd,J＝16.8,9.3Hz,1H),2.00(s,6H),1.79(dd,J＝6.8,5.3Hz,2H),1.39(s,3H),1.31(s,3H).

Example 37

2- ((S) -6- ((4'- (((S) -1, 4-dioxan-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First, 4'- (allyloxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde

4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (10g,44.19mmol) and potassium phosphate (15.4g,71.1mmol) were dissolved in N, N-dimethylformamide (200mL), 3-bromopropylene (6mL,67.95mmol) was added thereto at room temperature, and the reaction mixture was reacted at 60 ℃ overnight. The reaction mixture was washed with water (200mL), extracted with ethyl acetate (200 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 25/1), to give the title compound (11.46g, 97.4%) as a colorless liquid.

¹H NMR(600MHz,CDCl₃)δ10.07(s,1H),7.88(d,J＝7.7Hz,1H),7.69(s,1H),7.61(t,J＝7.6Hz,1H),7.45(d,J＝7.5Hz,1H),6.72(s,2H),6.11(ddd,J＝22.4,10.5,5.3Hz,1H),5.47(dd,J＝17.3,1.3Hz,1H),5.32(s,1H),4.59(d,J＝5.2Hz,2H),2.02(s,6H).

Second step, (S) -4'- (2, 3-dihydroxypropoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde

4'- (allyloxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (600mg,2.25mmol) was dissolved in a mixed solution of t-butanol (15mL) and water (15mL), AD-Mix- α (3.2g) was added thereto, and the mixture was stirred at room temperature overnight, the reaction solution was quenched by addition of sodium sulfite (500mg), extracted with ethyl acetate (100mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a colorless oil (675mg, 99.7%).

The third step is (S) -4'- ((1, 4-dioxane-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde

(S) -4'- (2, 3-dihydroxypropoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (677mg,2.25mmol) and tetrabutylammonium bromide (148mg,0.45mmol) were dissolved in 1, 2-dichloroethane (15mL), an aqueous solution of sodium hydroxide (10mL) was added at room temperature, and after the addition, the reaction mixture was reacted at 50 ℃ for 18 hours. The reaction mixture was supplemented with 1, 2-dichloroethane (15mL) and aqueous sodium hydroxide (10mL) and then allowed to react at 50 ℃ for 8 hours. The reaction mixture was diluted with water (50mL) and extracted with dichloromethane (100 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 8/1), to give the title compound (424mg, 57.6%) as a pale yellow oil.

¹H NMR(400MHz,CDCl₃)δ10.07(s,1H),7.88(d,J＝7.7Hz,1H),7.68(s,1H),7.61(t,J＝7.6Hz,1H),7.43(d,J＝7.5Hz,1H),6.71(s,2H),4.03(ddd,J＝12.0,6.6,3.3Hz,2H),3.99–3.91(m,2H),3.86(dd,J＝10.6,2.9Hz,2H),3.78–3.67(m,2H),3.58(dd,J＝11.3,9.7Hz,1H),2.01(s,6H).

The fourth step, (S) - (4'- ((1, 4-dioxane-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol

(S) -4'- ((1, 4-dioxan-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (424mg,1.3mmol) was dissolved in a mixed solution of tetrahydrofuran (10mL) and methanol (5mL), and sodium borohydride (76mg,1.97mmol) was added in portions and reacted at 0 ℃ overnight. The reaction mixture was diluted with water (30mL), extracted with ethyl acetate (30mL), and the organic phase was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1), to give the title compound (395mg, 92.3%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.43(t,J＝7.6Hz,1H),7.36(d,J＝7.7Hz,1H),7.14(s,1H),7.08(d,J＝7.5Hz,1H),6.69(s,2H),4.75(s,2H),4.08–4.01(m,2H),3.99–3.92(m,2H),3.86(dtd,J＝14.4,11.7,2.6Hz,2H),3.73(ddd,J＝24.2,14.7,7.5Hz,2H),3.58(dd,J＝11.4,9.8Hz,1H),2.02(s,6H).

The fifth step, methyl 2- ((S) -6- ((4'- (((S) -1, 4-dioxan-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(S) - (4'- ((1, 4-dioxane-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol (174mg,0.53mmol) and methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (100mg,0.48mmol) were dissolved in toluene (10mL), and tributylphosphine (0.2mL,0.8mmol) and azobisformyldipiperidine (200mg,0.78mmol) were added in this order and reacted at room temperature for 3 hours. The reaction was quenched with water, extracted with ethyl acetate (20 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1), to give the title compound (211mg, 84.7%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.44(t,J＝7.5Hz,1H),7.39(d,J＝7.7Hz,1H),7.18(s,1H),7.09(d,J＝7.4Hz,1H),7.04(d,J＝8.2Hz,1H),6.69(s,2H),6.50(dd,J＝8.2,2.2Hz,1H),6.48(d,J＝2.1Hz,1H),5.07(s,2H),4.77(t,J＝9.0Hz,1H),4.28(dd,J＝9.1,6.1Hz,1H),4.07–4.00(m,2H),3.97–3.93(m,2H),3.89(dd,J＝11.6,2.2Hz,1H),3.84(ddd,J＝14.7,9.3,3.0Hz,2H),3.80–3.76(m,1H),3.74(s,3H),3.73–3.68(m,1H),3.57(dd,J＝11.4,9.8Hz,1H),2.77(dd,J＝16.4,5.4Hz,1H),2.58(dd,J＝16.4,9.3Hz,1H),2.01(s,6H).

The sixth step, 2- ((S) -6- ((4'- (((S) -1, 4-dioxane-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- ((S) -6- ((4'- (((S) -1, 4-dioxan-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (210mg,0.40mmol) was dissolved in tetrahydrofuran (4mL), and after addition of 1M aqueous lithium hydroxide solution (4mL), stirring was carried out at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (6mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (116mg, 56.7%) as a white solid.

MS(ESI,pos.ion)m/z:505.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.46–7.38(m,2H),7.18(s,1H),7.08(dd,J＝15.3,7.8Hz,2H),6.69(s,2H),6.54–6.47(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.1,6.1Hz,1H),4.08–4.00(m,2H),3.99-3.94(m,2H),3.92–3.76(m,4H),3.75-3.69(m,1H),3.61–3.55(m,1H),2.83(dd,J＝16.8,5.2Hz,1H),2.64(dd,J＝16.8,9.4Hz,1H),2.01(s,6H).

Example 38

2- ((S) -6- ((4' - ((((2S, 4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, 4-bromo-2-fluoro-3, 5-dimethylphenol

4-bromo-3, 5-dimethylphenol (3g,14.9mmol) and N-pyridinium trifluoromethanesulfonate (9g,36.4mmol) were dissolved in 1, 2-dichloroethane (40mL) and the reaction was heated to reflux for 8 hours. The reaction solution was cooled to room temperature, quenched with saturated aqueous sodium thiosulfate (50mL), extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100/1) to give the title compound (800mg, 24.5%) as a white solid.

MS(ESI,neg.ion)m/z:217.1[M-H]^-.

Second, 3' -fluoro-4 ' -hydroxy-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-carbaldehyde

4-bromo-2-fluoro-3, 5-xylenol (1.5g,6.8mmol), 3-formylphenylboronic acid (1.1g,7.3mmol), sodium carbonate (2.23g,21mmol) and tetrakis (triphenylphosphine) palladium (0.4g,0.3mmol) were dissolved in a mixed solution of ethanol (10mL), water (21mL) and toluene (30mL), and the reaction solution was stirred at 80 ℃ overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (20 mL. times.2). The combined organic phases were washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (910mg, 54%) as a yellow oil.

MS(ESI,neg.ion)m/z:243.1[M-H]^-.

The third step, 3-fluoro-3 '- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-phenol

3' -fluoro-4 ' -hydroxy-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (0.91g,3.7mmol) was dissolved in tetrahydrofuran (20mL) and methanol (10mL), sodium borohydride (0.15g,3.9mmol) was added under ice bath, and the reaction mixture was reacted at 0 ℃ overnight after the addition. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound (710mg, 77%) as a white solid.

MS(ESI,neg.ion)m/z:245.2[M-H]^-.

The fourth step, (S) - (4' - ((3, 6-dihydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methanol

(S) - (3, 6-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (600mg,2.24mmol), 3-fluoro-3 '- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-ol (600mg,2.44mmol) and potassium carbonate (1g,7.24mmol) were dissolved in DMF (30mL) and the reaction was reacted overnight at 100 ℃. The reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (100 mL. times.2). The combined organic phases were washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound (760mg, 99%) as a pale yellow oil.

The fifth step, (S) -2- (((3'- (chloromethyl) -3-fluoro-2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran

(S) - (4' - ((3, 6-dihydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methanol (760mg,2.22mmol) was dissolved in DMF (20mL), and phosphorus oxychloride (0.25mL,2.7mmol) was added and reacted at room temperature for 3 hours. The reaction solution was quenched with water (20mL), extracted with ethyl acetate (40 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound (628mg, 78.4%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.44(t,J＝7.6Hz,1H),7.39(d,J＝7.7Hz,1H),7.16(d,J＝1.2Hz,1H),7.09(d,J＝6.6Hz,1H),6.78(d,J＝8.3Hz,1H),5.90(ddd,J＝9.9,5.2,2.2Hz,1H),5.81(d,J＝10.2Hz,1H),4.64(s,2H),4.35–4.27(m,2H),4.21–4.14(m,1H),4.09–4.01(m,2H),2.29–2.22(m,1H),2.15(dd,J＝17.2,1.8Hz,1H),2.00(s,3H),1.95(d,J＝2.7Hz,3H).

Sixth step, methyl 2- ((S) -6- ((4' - (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(S) -2- (((3'- (chloromethyl) -3-fluoro-2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran (628mg,1.74mmol), (S) -methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (350mg,1.68mmol) and potassium phosphate (530mg,2.5mmol) were dissolved in DMF (20mL) and the reaction mixture was reacted at 60 ℃ for 3 hours. The reaction solution was quenched with water (20mL), extracted with ethyl acetate (40 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound (750mg, 83.8%) as a pale yellow oil.

MS(ES-API,pos.ion)m/z:533.3[M+H]⁺.

Seventh step, methyl 2- ((S) -6- ((4' - (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl 2- ((S) -6- ((4' - (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (750mg,1.41mmol), osmium tetroxide (170mg,0.676mmol), N-methyl-N-morpholine oxide (500mg,4.27mmol) were dissolved in a mixed solution of acetone (40mL) and water (8mL), and the reaction solution was stirred overnight at room temperature. The reaction solution was quenched with saturated aqueous sodium thiosulfate (20mL), extracted with ethyl acetate (40 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (340mg, 42%) as a pale yellow oil.

Eighth step, 2- ((S) -6- ((4' - (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- ((S) -6- ((4' - ((((2S, 4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (340mg,0.60mmol) was dissolved in tetrahydrofuran (6mL), and after addition of 1M aqueous lithium hydroxide (6mL), it was stirred at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (258mg, 77.8%).

MS(ESI,pos.ion)m/z:553.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.48–7.39(m,2H),7.15(s,1H),7.07(d,J＝7.9Hz,2H),6.74(d,J＝8.2Hz,1H),6.49(dd,J＝18.2,5.1Hz,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.2,6.1Hz,1H),4.25(d,J＝2.4Hz,1H),4.14(s,1H),4.11–4.02(m,2H),3.91–3.80(m,3H),3.72–3.64(m,1H),2.82(dd,J＝16.8,5.4Hz,1H),2.63(dd,J＝16.8,9.3Hz,1H),2.07–2.02(m,1H),1.97(s,3H),1.93(d,J＝2.3Hz,3H),1.88–1.84(m,1H).

Example 39

2- ((S) -6- ((4' - ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- ((S) -6- ((4' - ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

The title compound (240mg, 30%) was prepared as a pale yellow oil by the synthetic method of the seventh step of example 38.

Second, 2- ((S) -6- ((4' - (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- ((S) -6- ((4' - ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -3' -fluoro-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (240mg,0.43mmol) as a starting material, the title compound was prepared as a white solid (178mg, 76.1%) according to the synthesis method of the eighth step of example 38.

MS(ESI,neg.ion)m/z:551.3[M-H]^-；

¹H NMR(600MHz,CDCl₃)δ7.46–7.39(m,2H),7.15(s,1H),7.06(d,J＝8.1Hz,2H),6.73(d,J＝8.2Hz,1H),6.54–6.45(m,2H),5.07(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝8.9,6.2Hz,1H),4.15(s,2H),4.06(dd,J＝10.1,3.9Hz,1H),3.86(d,J＝7.3Hz,2H),3.83–3.79(m,2H),3.65(d,J＝12.7Hz,1H),2.81(dd,J＝16.8,5.3Hz,1H),2.62(dd,J＝16.8,9.3Hz,1H),1.99(d,J＝13.0Hz,1H),1.97(s,3H),1.93(s,3H),1.79(d,J＝12.1Hz,1H).

Example 40

2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First, 6-fluoro-4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde

Starting from 4-bromo-3, 5-dimethylphenol (3.50g,17.4mmol) and (2-fluoro-5-formylphenyl) phenylboronic acid (3.22g,19.2mmol), the title compound (1.3g, 31%) was prepared as a yellow oil by the second-step synthesis of example 38.

Second, 2' -fluoro-5 ' - (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-ol

Starting from 6-fluoro-4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carbaldehyde (1.3g,5.3mmol), the title compound (1.1g, 84%) was obtained as a yellow oil by the method of synthesis in the third step of example 38.

The third step, (S) - (4'- ((3, 6-dihydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol

Starting from 2' -fluoro-5 ' - (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-ol (1.1g,4.47mmol) and (S) - (3, 6-dihydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (1.2g,4.47mmol), the title compound (1.5g, 98%) was obtained as a yellow oil by the synthesis in the fourth step of example 38.

The fourth step, (S) -2- (((5' - (chloromethyl) -2' -fluoro-2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran

Starting from (S) - (4'- ((3, 6-dihydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol (1.5g,4.38mmol) and phosphorus oxychloride (0.50mL,5.33mmol), the title compound (1.4g, 88.6%) was prepared as a yellow oil by the synthesis in the fifth step of example 38.

The fifth step, methyl 2- ((S) -6- ((4'- (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Starting from (S) -2- (((5' - (chloromethyl) -2' -fluoro-2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran (1.4g,3.88mmol) and methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (808mg,3.88mmol), the title compound was prepared as a yellow oil (1.8g, 87%) by the synthesis in the sixth step of example 38.

Sixth step, methyl 2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Using methyl 2- ((S) -6- ((4'- (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (400mg,0.75mmol) as a starting material, the title compound was prepared as a yellow oil (145mg, 41.1%) by referring to the synthesis method of the seventh step of example 38.

The seventh step, 2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- ((((2S, 4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (132mg,0.23mmol) as a starting material, the title compound (90mg, 70%) was prepared as a white solid according to the synthesis method of the eighth step of example 38.

MS(ESI,pos.ion)m/z:553.25[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.39(s,1H),7.16(dd,J＝10.7,7.1Hz,2H),7.07(d,J＝8.1Hz,1H),6.71(s,2H),6.49(d,J＝8.2Hz,1H),6.46(s,1H),5.03(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.0,6.2Hz,1H),4.24(s,1H),4.17–4.07(m,1H),4.00(d,J＝4.5Hz,2H),3.86(dd,J＝9.8,5.2Hz,2H),3.80(dd,J＝11.0,7.9Hz,1H),3.68(t,J＝12.8Hz,1H),2.81(dd,J＝16.8,5.1Hz,1H),2.62(dd,J＝16.8,9.2Hz,1H),2.02(s,6H),1.83(t,J＝12.2Hz,1H),1.28–1.18(m,1H).

EXAMPLE 41

2- (6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((4'- ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -6-fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

The title compound (175mg, 41.1%) was prepared as a yellow oil according to the synthesis of the sixth step of example 40.

Second step, 2- (6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -6 fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- ((((2S, 4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -6 fluoro-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (162mg,0.29mmol) as a starting material, the title compound (100mg, 63.3%) was prepared as a white solid according to the synthesis method of the eighth step of example 38.

MS(ESI,pos.ion)m/z:553.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.43–7.37(m,1H),7.15(t,J＝8.7Hz,2H),7.06(d,J＝8.2Hz,1H),6.70(s,2H),6.48(dd,J＝8.2,1.9Hz,1H),6.46(d,J＝1.8Hz,1H),5.01(s,2H),4.76(t,J＝9.0Hz,1H),4.29(dd,J＝9.1,6.2Hz,1H),4.16(d,J＝12.3Hz,1H),4.08(dd,J＝10.0,6.1Hz,1H),3.99(dd,J＝9.9,3.8Hz,1H),3.89–3.83(m,2H),3.82–3.77(m,2H),3.63(d,J＝12.6Hz,1H),2.79(dd,J＝16.8,5.3Hz,1H),2.61(dd,J＝16.8,9.3Hz,1H),2.02(s,6H),1.98–1.93(m,1H),1.78(dd,J＝23.8,12.0Hz,1H).

Example 42

2- (6- ((4 '-iodo-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester

First step, methyl 4 '-amino-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carboxylate

4-bromo-3, 5-dimethylaniline (1g,10mmol), (3- (methoxycarbonyl) phenyl) boronic acid (2.7g,15mmol), potassium carbonate (4.14g,30mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (0.37g,0.5mmol) was dissolved in a mixed solution of N, N-dimethylformamide (30mL) and water (10mL), and the reaction was stirred at 90 ℃ for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (30mL), extracted with ethyl acetate (200mL), and the organic phase was washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound (2.1g, 82%) as a pale yellow solid.

Second, methyl 4 '-iodo-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carboxylate

Methyl 4 '-amino-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carboxylate (1.5g,5.9mmol) was dissolved in concentrated hydrochloric acid (6mL) and a solution of sodium nitrite (0.811g,11.8mmol) in water (5mL) was added dropwise under ice-bath. After the dropwise addition, the reaction solution was stirred for 15 minutes in ice bath for further use. In another reaction flask, potassium iodide (9.75g,59mmol) was dissolved in water (20mL), and the solution was added dropwise in ice bath, after dropping, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated aqueous sodium thiosulfate (20mL), extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (1.6g, 74%) as a pale yellow solid.

The third step, (4 '-iodo-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol

Methyl 4 '-iodo-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-carboxylate (3g,8.2mmol) was dissolved in toluene (100mL), and 1M diisobutylaluminum hydride solution in toluene (33mL,33mmol) was added thereto at-10 ℃ and allowed to spontaneously warm to room temperature for overnight reaction. The reaction solution was quenched with 1M aqueous hydrochloric acid (50mL), extracted with ethyl acetate (50mL), and the organic phase was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1), to give the title compound (2.5g, 90%) as a pale yellow oil.

¹H NMR(600MHz,CDCl₃)δ7.49(s,2H),7.45(t,J＝7.6Hz,1H),7.38(d,J＝7.7Hz,1H),7.13(s,1H),7.06(d,J＝7.5Hz,1H),4.76(s,2H),1.99(s,6H).

The fourth step, methyl 2- (6- ((4 '-iodo-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(4 '-iodo-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methanol (2.5g,7.4mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (1.5g,7.2mmol) were dissolved in toluene (120mL) under nitrogen, and tri-n-butylphosphine (3mL,12mmol) and azobisformyldipiperidine (3g,12mmol) were sequentially added and reacted at room temperature for 3 hours. The reaction mixture was diluted with water (50mL), extracted with ethyl acetate (30mL), and the organic phase was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (3.2g, 82%) as a white solid.

¹H NMR(600MHz,CDCl₃)δ7.49(s,2H),7.45(d,J＝7.5Hz,1H),7.42(s,1H),7.16(s,1H),7.06(dd,J＝20.2,7.8Hz,2H),6.49(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.28(dd,J＝9.2,6.1Hz,1H),3.85-3.80(m,1H),3.74(s,3H),2.77(dd,J＝16.4,5.5Hz,1H),2.58(dd,J＝16.4,9.3Hz,1H),1.98(s,6H).

Example 43

2- (6- ((2',6' -dimethyl-4 '- (((tetrahydro-2H-pyran-4-yl) methyl) amino) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((2',6' -dimethyl-4 '- (((tetrahydro-2H-pyran-4-yl) methyl) amino) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(tetrahydro-2H-pyran-4-yl) -methylamine (90mg,0.76mmol), potassium carbonate (106mg,0.76mmol), cuprous iodide (8mg,0.04mmol), L-proline (9mg,0.08mmol) and methyl 2- (6- ((4 '-iodo-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.38mmol) were dissolved in dimethyl sulfoxide (4mL) and the reaction was allowed to react overnight at 100 ℃. The reaction solution was quenched with water (20mL), extracted with ethyl acetate (80 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound (44mg, 23%) as a yellow oil.

MS(ESI,pos.ion)m/z:516.3[M+H]⁺.

Second, 2- (6- ((2',6' -dimethyl-4 '- (((tetrahydro-2H-pyran-4-yl) methyl) amino) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- (((tetrahydro-2H-pyran-4-yl) methyl) amino) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (44mg,0.08mmol) was dissolved in tetrahydrofuran (2mL), and 1M aqueous lithium hydroxide solution (2mL) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (4mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (16mg, 37.4%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:502.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.45–7.35(m,2H),7.20(s,1H),7.09(dd,J＝30.1,7.5Hz,2H),6.55–6.46(m,2H),6.40(s,2H),5.07(s,2H),4.78(t,J＝8.9Hz,1H),4.34–4.27(m,1H),4.04(d,J＝9.2Hz,2H),3.83(s,1H),3.45(t,J＝11.6Hz,2H),3.07(d,J＝6.5Hz,2H),2.82(dd,J＝16.8,4.5Hz,1H),2.63(dd,J＝16.6,9.4Hz,1H),1.98(s,6H),1.90(s,1H),1.76(d,J＝12.7Hz,2H),1.46–1.36(m,2H).

Example 44

2- (6- ((2',6' -dimethyl-4 '- (tetrahydro-2H-pyran-4-carboxamido) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, tetrahydro-2H-pyran-4-carboxylic acid methyl ester

tetrahydro-2H-pyran-4-carboxylic acid (2g,15mmol) was dissolved in methanol (10mL), sulfoxide chloride (1.7mL,23mmol) was added under ice bath, and after the addition, the reaction mixture was reacted at 90 ℃ overnight. Cooled to room temperature, the solvent was removed under reduced pressure and quenched with water (20mL), extracted with ethyl acetate (80 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a yellow oil (1.65g, 75.8%).

Second step, tetrahydro-2H-pyran-4-carboxamide

tetrahydro-2H-pyran-4-carboxylic acid methyl ester (450mg,3.12mmol) was dissolved in 25% aqueous ammonia (10mL), and the reaction mixture was reacted overnight at room temperature in a sealed tube. The solvent was removed under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound (353mg, 87.5%) as a white solid.

¹H NMR(600MHz,DMSO-d₆)δ7.24(s,1H),6.76(s,1H),3.87–3.80(m,2H),3.35–3.25(m,2H),2.33–2.28(m,1H),1.57–1.53(m,4H).

The third step, methyl 2- (6- ((2',6' -dimethyl-4 '- (tetrahydro-2H-pyran-4-carboxamido) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(tetrahydro-2H-pyran-4-yl) -carboxamide (59mg,0.46mmol), cesium carbonate (252mg,0.76mmol), cuprous iodide (4mg,0.02mmol), trans-N, N ' -dimethyl-1, 2-cyclohexanediamine (6mg,0.04mmol) and methyl 2- (6- ((4' -iodo-2 ',6' -dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.38mmol) were dissolved in 1, 4-dioxane (2mL) and the reaction was allowed to react overnight at 110 ℃. The reaction solution was quenched with water (20mL), extracted with ethyl acetate (80 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound (84mg, 42%) as a white solid.

MS(ESI,pos.ion)m/z:530.3[M+H]⁺.

The fourth step, 2- (6- ((2',6' -dimethyl-4 '- (tetrahydro-2H-pyran-4-carboxamido) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- (tetrahydro-2H-pyran-4-carboxamido) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (84mg,0.16mmol) was dissolved in tetrahydrofuran (3mL), and after addition of 1M aqueous lithium hydroxide (3mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (5mL) and extracted with ethyl acetate (10 mL. times.2), the organic phases combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound as a white solid (72mg, 87.4%).

MS(ESI,pos.ion)m/z:516.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.49–7.38(m,2H),7.30(s,3H),7.16(s,1H),7.07(s,2H),6.61–6.38(m,2H),5.08(s,2H),4.78(t,J＝8.7Hz,1H),4.35–4.25(m,1H),4.10(d,J＝8.6Hz,2H),3.82(s,1H),3.49(t,J＝10.6Hz,2H),2.81(dd,J＝16.6,4.8Hz,1H),2.63(dd,J＝16.5,9.2Hz,1H),2.53(s,1H),2.01(s,6H),1.92(dd,J＝50.8,11.7Hz,4H).

Example 45

2- (6- ((4'- (bicyclo [2.2.1] heptan-2-ylmethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, bicyclo [2.2.1] heptan-2-ylmethyl methanesulfonate

Bicyclo [2.2.1] heptan-2-ylmethanol (2g,15.8mmol) and triethylamine (2.7mL,19mmol) were dissolved in dichloromethane (50mL) and methanesulfonyl chloride (1.5mL,19mmol) was slowly added dropwise under ice bath. After completion of the dropwise addition, the reaction mixture was reacted at room temperature for 1 hour. The reaction solution was quenched with water (20mL), extracted with dichloromethane (80 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50/1 petroleum ether/ethyl acetate (v/v)) to give the title compound (2.3g, 71%) as a yellow oil.

¹H NMR(600MHz,CDCl₃)δ4.27(dd,J＝9.6,7.0Hz,1H),4.13(t,J＝9.5Hz,1H),3.02(s,3H),1.80–1.73(m,1H),1.60–1.53(m,2H),1.51–1.41(m,3H),1.32–1.05(m,4H),0.72(ddd,J＝12.5,5.1,2.1Hz,1H).

Second step, methyl 2- (6- ((4'- (bicyclo [2.2.1] heptan-2-ylmethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Bicyclo [2.2.1] heptan-2-ylmethyl methanesulfonate (370mg,1.81mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy-2, 3-dihydrobenzofuran-3-yl) acetate (500mg,1.2mmol) and potassium carbonate (500mg,3.62mmol) were dissolved in N, N-dimethylformamide (10mL) and reacted overnight, the reaction solution was cooled to room temperature and then diluted with water (30mL), ethyl acetate was extracted (30mL), the organic phase was washed with a saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 50/1), the title compound was obtained as a pale yellow oil (200mg, 31.8%).

The third step, 2- (6- ((4'- (bicyclo [2.2.1] heptan-2-ylmethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- (bicyclo [2.2.1] heptan-2-ylmethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (200mg,0.38mmol) was dissolved in tetrahydrofuran (3.8mL), and a 1M aqueous lithium hydroxide solution (3.8mL) was added thereto and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (7mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (130mg, 66.8%) as a white solid.

MS(ESI,pos.ion)m/z:513.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.41(dd,J＝14.8,7.3Hz,2H),7.20(s,1H),7.09(dd,J＝14.9,7.5Hz,2H),6.69(d,J＝5.7Hz,2H),6.56–6.45(m,2H),5.08(s,2H),4.78(t,J＝8.9Hz,1H),4.32–4.24(m,2H),4.15(t,J＝9.4Hz,1H),3.84(d,J＝8.9Hz,1H),2.83(dd,J＝16.8,5.0Hz,1H),2.64(dd,J＝16.8,9.3Hz,1H),2.02(s,8H),1.50-1.36(m,11H).

Example 46

2- (6- ((4'- ((3, 4-dihydroxycyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, 3-cyclohexen-1-ylmethyl 4-methylbenzenesulfonate

Under the protection of nitrogen, 3-cyclohexene-1-methanol (2.32g,20.7mmol), triethylamine (4.36mL,31.1mmol) and N, N, N ', N' -tetramethyl-1, 6-hexanediamine (0.45mL,2.0mmol) were dissolved in toluene (50mL), p-toluenesulfonyl chloride (5.97g,31mmol) was added under ice bath, and after addition, the reaction mixture was reacted at 0 ℃ overnight. After the reaction solution was quenched with water (10mL), extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50/1 petroleum ether/ethyl acetate (v/v)) to give the title compound (4.64g, 84.2%) as a pale yellow oil.

Second step, methyl 2- (6- ((4'- (3-cyclohexen-1-ylmethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

3-cyclohexen-1-ylmethyl-4-methylbenzenesulfonate (287mg,1.08mmol), methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy-2, 3-dihydrobenzofuran-3-yl) acetate (300mg,0.72mmol) and potassium carbonate (301mg,2.16mmol) were dissolved in N, N-dimethylformamide (8mL) and reacted overnight, the reaction solution was cooled to room temperature and then diluted with water (30mL), ethyl acetate was extracted (30mL), the organic phase was washed with a saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1), the title compound was obtained as a pale yellow oil (234mg, 63.7%).

MS(ESI,pos.ion)m/z:513.3[M+H]⁺.

The third step, methyl 2- (6- ((4'- ((3, 4-dihydroxycyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

methyl 2- (6- ((4'- (3-cyclohexen-1-ylmethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (234mg,0.46mmol) was dissolved in tert-butanol (7mL) and water (75mL), AD-Mix- α (917mg) was added and stirred at room temperature overnight, the reaction was quenched by addition of sodium sulfite (500mg), extracted with ethyl acetate (100mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v) ═ 60/1) to give the title compound as a white solid (214mg, 85.8%).

The fourth step, 2- (6- ((4'- ((3, 4-dihydroxycyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((4'- ((3, 4-dihydroxycyclohexyl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (214mg,0.39mmol) was dissolved in tetrahydrofuran (4mL), and after addition of 1M aqueous lithium hydroxide solution (4mL), the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (8mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (150mg, 71.9%) as a white solid.

MS(ESI,pos.ion)m/z:533.3[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ7.48–7.34(m,2H),7.14(s,1H),7.10(d,J＝8.1Hz,1H),7.05(d,J＝7.4Hz,1H),6.68(d,J＝6.2Hz,2H),6.47(dd,J＝12.8,4.6Hz,2H),5.10(s,2H),4.68(t,J＝9.0Hz,1H),4.38(d,J＝26.3Hz,1H),4.23–4.06(m,2H),3.83–3.73(m,3H),3.71–3.63(m,1H),3.43(d,J＝8.7Hz,1H),2.69(dd,J＝16.6,5.5Hz,1H),1.91(d,J＝1.6Hz,6H),1.87–1.71(m,2H),1.68–1.28(m,5H).

Example 47

2- (6- ((2',6' -dimethyl-4 '- ((tetrahydrofuran-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydrofuran-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

(tetrahydrofuran-3-yl) methanol (56mg,0.54mmol) and methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (150mg,0.36mmol) were dissolved in toluene (10mL), tributylphosphine (0.15mL,0.57mmol) and azobisformyldipiperidine (146mg,0.57mmol) were added and after addition, stirring was carried out at room temperature for 1 hour under nitrogen. Water (20mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (40 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound (144mg, 80%) as a white solid.

MS(ESI,pos.ion)m/z:503.2[M+H]⁺.

Second step, 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydrofuran-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Methyl 2- (6- ((2',6' -dimethyl-4 '- ((tetrahydrofuran-3-yl) methoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (144mg,0.28mmol) was dissolved in tetrahydrofuran (3mL), and 1M aqueous lithium hydroxide solution (3mL) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with water (5mL), acidified with 1M hydrochloric acid (6mL), and extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (76mg, 54.3%) as a white solid.

MS(ESI,pos.ion)m/z:489.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ7.48–7.36(m,2H),7.19(s,1H),7.13–7.03(m,2H),6.68(s,2H),6.54–6.46(m,2H),5.08(s,2H),4.78(t,J＝9.0Hz,1H),4.34–4.26(m,1H),4.01–3.88(m,4H),3.87–3.78(m,2H),3.78–3.70(m,1H),2.87–2.70(m,2H),2.63(dd,J＝16.8,9.4Hz,1H),2.21–2.09(m,1H),2.01(s,6H),1.85–1.72(m,1H).

Example 48

2- (6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((4'- (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetate

Starting from (S) -2- (((3'- (chloromethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) methyl) -3, 6-dihydro-2H-pyran (712mg,2.1mmol) and methyl 2- (5-fluoro-6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (470mg,2.1mmol), the title compound was prepared as a pale yellow oil (845mg, 76.4%) by the synthesis method of the tenth step of example 26.

MS(ESI,pos.ion)m/z:533.3[M+H]⁺.

Second step, methyl 2- (6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetate

Using methyl 2- (6- ((4'- (((S) -3, 6-dihydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetate (854mg,1.6mmol) as a starting material, the title compound was prepared as a pale yellow oil (326mg, 36%) by the synthesis of the tenth step of example 26.

The third step, 2- (6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- (((2S,4S,5R) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetate (326mg,0.57mmol) as a starting material, the title compound (250mg, 78.6%) was prepared as a white solid according to the synthesis method of the tenth step of example 26.

MS(ESI,pos.ion)m/z:553.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.48–7.38(m,2H),7.17(s,1H),7.10(d,J＝7.3Hz,1H),6.94(d,J＝10.2Hz,1H),6.69(s,2H),6.50(d,J＝6.6Hz,1H),5.14(s,2H),4.74(t,J＝9.0Hz,1H),4.27(dd,J＝9.1,6.1Hz,1H),4.17(d,J＝14.2Hz,1H),4.10(dd,J＝10.0,6.1Hz,1H),3.99(dd,J＝10.1,4.0Hz,1H),3.84–3.81(m,2H),3.80-3.76(m,1H),3.65(d,J＝12.6Hz,1H),2.78(dd,J＝16.9,5.8Hz,1H),2.63(dd,J＝16.9,8.9Hz,1H),2.31–2.19(m,1H),2.03(d,J＝6.2Hz,1H),1.99(d,J＝3.6Hz,6H),1.74(d,J＝12.3Hz,1H).

Example 49

2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((4'- ((((2S, 4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetate

The title compound was prepared as a pale yellow oil (356mg, 39.3%) according to the second synthesis of example 48.

The second step, 2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- (((2S,4R,5S) -4, 5-dihydroxytetrahydro-2H-pyran-2-yl) methoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -5-fluoro-2, 3-dihydrobenzofuran-3-yl) acetate (356mg,0.63mmol) as a starting material, the title compound (290mg, 83.5%) was prepared as a white solid according to the synthesis method of the tenth step of example 26.

MS(ESI,pos.ion)m/z:553.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.46–7.38(m,2H),7.16(d,J＝4.5Hz,1H),7.10(d,J＝7.1Hz,1H),6.94(d,J＝9.3Hz,1H),6.69(d,J＝5.8Hz,2H),6.51–6.47(m,1H),5.15(d,J＝4.0Hz,2H),4.76–4.72(m,1H),4.30–4.22(m,2H),4.12–4.11(m,1H),4.00–3.98(m,1H),3.91–3.85(m,2H),3.83–3.79(m,1H),3.70–3.66(m,1H),2.79–2.75(m,1H),2.62(dd,J＝16.9,8.9Hz,1H),2.25(t,J＝7.6Hz,1H),2.04–1.98(m,7H),1.87–1.84(m,1H).

Example 50

2- (6- ((4'- (2- (1, 4-dioxan-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

First step, methyl 2- (6- ((4'- (3-en-1-butoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Starting from methyl 2- (6- ((4 '-hydroxy-2', 6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (500mg,1.20mmol) and 4-bromo-1-butene (0.25mL,2.4mmol), the title compound was prepared as a pale yellow oil (419mg, 74.2%) by referring to the synthesis in the first step of example 37.

Second step, methyl 2- (6- ((4'- (3, 4-dihydroxybutoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Methyl 2- (6- ((4'- (3-en-1-butoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (507mg,1.07mmol) was dissolved in a mixed solution of acetone (9mL) and water (1.5mL), osmium tetroxide (5mg,0.02mmol) and N-methyl-N-morpholine oxide (398mg,3.4mmol) were added at room temperature, and the reaction solution was reacted at room temperature overnight after the addition. The reaction mixture was filtered to remove osmium tetroxide, the filtrate was diluted with water (5mL), extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound (476mg, 87.6%) as a pale yellow oil.

The third step, methyl 2- (6- ((4'- (2- (1, 4-dioxan-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Using methyl 2- (6- ((4'- (3, 4-dihydroxybutoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (476mg,0.94mmol) as a starting material, the title compound (80mg, 16.0%) was prepared as a pale yellow oil by referring to the synthesis method in the third step of example 37.

MS(ESI,pos.ion)m/z:533.3[M+H]⁺.

The fourth step, 2- (6- ((4'- (2- (1, 4-dioxan-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid

Using methyl 2- (6- ((4'- (2- (1, 4-dioxan-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (77mg,0.15mmol) as a starting material, the title compound (35mg, 46.7%) was prepared as a light yellow solid according to the synthesis method in the sixth step of example 37.

MS(ESI,pos.ion)m/z:519.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ7.48–7.37(m,2H),7.19(s,1H),7.09(dd,J＝19.8,7.6Hz,2H),6.69(s,2H),6.55–6.47(m,2H),5.08(s,2H),4.78(t,J＝8.9Hz,1H),4.35–4.27(m,1H),4.15-4.06(m,2H),3.89–3.72(m,6H),3.69-3.62(m,1H),3.41(t,J＝10.9Hz,1H),2.83(dd,J＝16.8,4.8Hz,1H),2.64(dd,J＝16.7,9.4Hz,1H),2.02(s,6H),1.92-1.74(m,2H).

Examples 51 to 82

The compounds of examples 51-82 were prepared according to the synthesis procedure of example 4.

Examples 83 to 89

By referring to the synthesis of example 38, the compounds of examples 83-84 were prepared.

The compound of example 85 was prepared by a method similar to that of example 36.

The compound of example 86 was prepared according to the synthesis procedure of example 16.

The compound of example 87 was prepared by a method similar to that of example 37.

By referring to the synthesis of example 26, the compounds of examples 88-89 were prepared.

EXAMPLE 90 GPR40 cell activating Activity of the Compounds of the invention

High-expressing hGPR40 cells (HEK 293 cell line stably expressing hGPR40, constructed by Kunno technology (Beijing) Co., Ltd.) were seeded in 384-well plates at a density of 8000 cells/well. Cells were incubated at 37 ℃ with 5% CO₂Incubated under conditions for 24 hours. During the experiment, the 384-well plate with the cells spread thereon was taken out from the incubator, and the culture was discardedCalcium dye (preparation of Calcium dye: 20mL HBSS (20mM HEPES) +2tube dye + 200. mu.L 10% BSA, Calcium 4assay kit, molecular DNA) was added to the medium at 40. mu.L/well. The 384 well plates were returned to the incubator and incubated for 1 hour. The FLIPR real-time fluorescence imaging experiment program is set, 3 times of the compound of the invention is added into each hole, 10 mu L/hole is added, and the FLIPR real-time fluorescence imaging instrument is used for increasing the intracellular Ca²⁺And (4) detecting the concentration. The raw data were fitted with XLFit to give the EC for each compound₅₀The value is obtained. The results of the experiments are shown in table 2 below.

TABLE 2 activating Activity of the Compounds of the invention on GPR40 cells

Compound numbering	EC₅₀(nM)	Compound numbering	EC₅₀(nM)	Compound numbering	EC₅₀(nM)
						Example 3	121	Example 18	53	Example 32	52
Example 4	108	Example 19	201	Example 33	44
						Example 5	93	Example 20	100	Example 34	65
Example 6	25	Example 21	119	Example 35	62
						Example 7	93	Example 22	59	Example 36	20
Example 8	95	Example 23	100	Example 37	15
						Example 9	43	Example 24	105	Example 40	15
Example 10	62	Example 25	38	EXAMPLE 41	20
						Example 11	117	Example 26	55	Example 43	94
Example 12	72	Example 27	53	Example 44	38
						Example 13	158	Example 28	25	Example 45	104
Example 14	76	Example 29	24	Example 46	48
						Example 15	147	Example 30	28	Example 47	66
Example 16	129	Example 31	29

And (4) conclusion: as can be seen from the data in table 2, the compounds of the present invention have significant agonistic activity on GPR 40.

Example 91 pharmacokinetic testing

Experimental animals: healthy adult SD rats 6 per group were subjected to intravenous and oral gavage, male, purchased from slagoff laboratory animals limited, han, hu nan.

The preparation of the medicine comprises the following steps: an amount of the compound of the invention was weighed out and prepared as a clear solution by adding 5% DMSO, 10% Kolliphor HS15 and 85% saline.

Administration and sample collection: animals were fasted for 12h before administration and water was freely available. Food was consumed 3h after dosing. The administration was performed by intravenous injection (IV, 2mg/kg) and oral gavage (PO,5mg/kg) to the hind limb and the foot of SD rats, respectively. The blood collecting mode is rat tail vein blood collection, the blood collecting amount is about 200-400 mu L/time point, and the blood collecting time point is 0, 0.083, 0.25, 0.5, 1,2, 4, 6, 8 and 24 h. After collecting whole blood at each time point, placing the whole blood into a K2EDTA anticoagulation test tube, and placing the anticoagulation test tube into a heat preservation box with an ice bag for preservation. All samples were centrifuged at 4600r/min at 4 ℃ for 5min within 15min and plasma was isolated. The samples were stored at-80 ℃ and assayed. A backup sample, stored for 1 week after the end of the analysis.

The analysis method comprises the following steps: the LC/MS method was used to determine the amount of test compound in rat plasma after administration of the different compounds.

The results of the experiment are shown in Table 3 below:

TABLE 3 pharmacokinetic Activity of the Compounds of the invention

Note: N/A means "none".

And (4) conclusion: as can be seen from Table 3, the compound of the present invention has high blood concentration and exposure in rats after oral administration, low clearance rate, long half-life and good pharmacokinetic characteristics.

Example 92 in vivo pharmacodynamic test

1. Purpose of testing

And observing and detecting the influence of the tested compound on the intraperitoneal glucose tolerance of the SD rat.

2. Laboratory animal

Healthy adult SD rats 24, 6 per group, male, were purchased from the experimental animals of slagochada, han, hannam.

3. Drug configuration

An amount of drug was weighed out and made into a clear solution by adding 5% DMSO, 10% Kolliphor HS15 and 85% saline.

4. Experimental methods

4.1 grouping

Rats were fasted overnight for 16h and were randomly assigned to a blank group, each test drug group, based on fasting blood glucose and body weight.

4.2 dose design

The dose was 20mg/kg or 30mg/kg and blank groups were given blank vehicle (5% DMSO, 10% KolliphorHS15 and 85% saline).

4.3 methods of administration

Gavage was performed by injecting 2g/kg of 20% glucose solution (10mL/kg) into the abdominal cavity 30min after administration.

4.4 blood glucose determination

The blood sugar of rats was measured before-30 min, 2g/kg of 20% glucose was intraperitoneally injected 30min after administration, and the blood sugar of each rat was measured using a Roche glucometer at 0, 15, 30, 45, 60, 120 min.

4.5 data statistics

Using Excel statistical software: the average is calculated as avg; the SD value is calculated as STDEV; p-values for differences between groups were calculated as TTEST.

AUC calculation formula:

AUC＝1/2×(BG0+BG1)×T1+1/2×(BG1+BG2)×T2+1/2×(BG2+BG3)×T3+.....+1/2×(BGn-1+BGn)×Tn

where Tn is the time difference between the time for measuring the blood glucose at the nth measurement and the last measurement, and BGn is the blood glucose value at the nth measurement.

5. The results of the experiments are shown in table 4 below:

TABLE 4 in vivo pharmacodynamic Activity of Compounds of the invention

And (4) conclusion: as shown in Table 4, the compound of the present invention has a significant hypoglycemic effect on the intraperitoneal glucose tolerance of SD rats when the oral administration dosage is 20mg/kg or 30 mg/kg.

In the description herein, references to the terms "one embodiment," "some embodiments," "an example," "a specific example," or "some examples" or the like, mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (I), or a pharmaceutically acceptable salt of the compound represented by formula (I),

wherein:

x is O;

X¹is O;

X²is O;

y is C_1-6Alkylene radical(ii) a Each R¹Independently H, F, Cl, Br, I or methyl;

each R²Independently H, F, Cl, Br, I or cyano;

R³is H;

R⁴is H; and

each R⁵Independently H, F, Cl, Br or I;

each n and m is independently 0,1,2, 3 or 4;

k is 0 or 1;

b is 1;

q is 0;

w is the following subformula:

wherein,

each R⁶Independently is a hydroxyl group;

e is 2.

2. A compound having the structure of one of:

3. a pharmaceutical composition comprising a compound of any one of claims 1-2.

4. The pharmaceutical composition of claim 3, further comprising a pharmaceutically acceptable adjuvant comprising at least one of an excipient and a diluent.

5. The pharmaceutical composition of claim 3, further comprising at least one of an anti-diabetic drug, an anti-hyperglycemic drug, an anti-obesity drug, an anti-hypertensive drug, an anti-platelet drug, an anti-atherosclerotic drug, a lipid-lowering drug, and an anti-inflammatory drug.

6. the composition of claim 5, wherein said antidiabetic agent is at least one of an SGLT-2 inhibitor, a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR agonist, an α P2 inhibitor, a dipeptidyl peptidase IV inhibitor, a glinide, insulin, a glucagon-like peptide-1 inhibitor, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, and a glucose-6-phosphatase inhibitor.

7. the pharmaceutical composition of claim 6, wherein the PPAR agonist is a PPAR α/γ dual activator.

8. The pharmaceutical composition of any one of claims 3-7, further comprising at least one GPR40 receptor agonist.

9. Use of a compound according to any one of claims 1-2 or a pharmaceutical composition according to any one of claims 3-8 for the preparation of a GPR40 receptor agonist medicament for the prevention, treatment, alleviation or delay of diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, obesity, syndrome X, ketoacidosis, glucose intolerance, dyslipidemia, metabolic syndrome, cardiovascular disease, renal disease, thrombotic disorders, sexual dysfunction, skin disorders, dyspepsia, hypoglycemia, cancer, edema, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels.

10. The use of claim 9, wherein the dyslipidemia comprises hyperlipidemia, hypertriglyceridemia or hypercholesterolemia.

11. The use of claim 9, wherein the diabetic complication comprises diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy.

12. Use of a compound according to any one of claims 1 to 2 or a pharmaceutical composition according to any one of claims 3 to 8 in the manufacture of a medicament for use as a G-protein coupled receptor agonist in a patient.

13. The use according to claim 12, wherein the G-protein coupled receptor is the GPR40 receptor.