CN104507921A

CN104507921A - Benzocyclobutene derivative and preparation method and pharmaceutical application thereof

Info

Publication number: CN104507921A
Application number: CN201480000823.2A
Authority: CN
Inventors: 张晨; 王健民; 黄安邦; 雷鸣; 何平; 徐立宁; 魏用刚
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2013-07-02
Filing date: 2014-07-02
Publication date: 2015-04-08
Anticipated expiration: 2034-07-02
Also published as: CN104507921B; WO2015000412A1

Abstract

The present invention relates to a benzocyclobutene derivative and a preparation method and pharmaceutical application thereof. Specifically, the present invention relates to a compound expressed by formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic, or prodrug thereof, preparation methods thereof, a pharmaceutical composition thereof, and a pharmaceutical purpose of the compound or pharmaceutical composition of the present invention, especially a purpose of functioning as a GPR40 receptor (G-protein coupled receptor) agonist. Definitions of substituent groups in formula (I) are the same as those in the specification.

Description

Benzocyclobutene derivative and preparation method and pharmaceutical application thereof

Benzocyclobutene derivatives, preparation method thereof and application technical field of benzocyclobutene derivatives in medicine

The invention relates to a benzocyclobutene derivative, a preparation method thereof and application thereof in medicine, in particular to a novel benzofuran derivative with a function regulation effect on a G protein coupled receptor 40 (GPR40) receptor, or a stereoisomer, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic crystal or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the benzofuran derivative and application thereof in medicine. Background

Diabetes and its complications seriously affect the quality of life of people and are one of the leading causes of death, excessive blood glucose levels in diabetes cause patients to develop typical symptoms of polyuria, polydipsia, and polyphagia, and complications of diabetes such as kidney damage, diabetes ketoacidosis, heart disease, etc. can endanger life. Type II diabetes is the most common type of diabetes, mainly occurring in the adult stage, and mainly manifested as insulin resistance due to insufficient secretion of insulin or insulin resistance (i.e. body tissues are unable to respond effectively to endogenous insulin), heredity and environment, etc.

If the diabetic can not effectively control the blood sugar through diet and exercise, hormone medicines or oral hypoglycemic medicines need to be injected. Oral hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazole alkadione (TZDs), a-glucosidase inhibitors, dextrin analogues, dipeptidyl peptidase inhibitors (DPP-IV), sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and the like. However, these hypoglycemic agents all have side effects such as hypoglycemia, weight gain, cardiovascular risk, urogenital infection, etc. (visible s. Deshmukh, etc. (2013) International Journal of Basic & Clinical Pharmacology, 2, 4-11), which further burden diabetic patients, and therefore, there is a need to develop a new generation of hypoglycemic agents having a novel mechanism of action.

GPR40 (also called fatty acid receptor 1 (FFAR 1)) is a membrane receptor belonging to the superfamily of homologous G protein-coupled receptors, which is highly conserved in various species, the G protein-coupled receptor has 7 transmembrane structures, can sense extracellular signals, activate intracellular signal transduction pathways and finally cause cell responses, GPR40 can be activated by medium-long chain free fatty acid CFFAs (Itoh Y et al (2003), Nature, 422, 173-176), FFAs is also an important signal molecule besides being an energy source and can promote insulin secretion, the function is mainly realized through GPR 2, after the FFAs interacts with GPR 3875, PLC or L-type Ca in islet β cells can be realized²⁺Increase of Ca in channel signal pathway²⁺The flux, in turn, provokes a cellular response (Fujiwara et al (2005). Am J Physiol Endocrinol Metab, 289, E670-E677). Studies have shown that GPR40 agonism is effective in lowering blood glucose in animal models; in clinical trials, patients treated with GPR40 agonists both on short and long term basis promoted glucose-induced insulin secretion and improved glucose tolerance (K Nagasumi et al (2009) Diabetes, 58, 1067-. Faiglifam hemihydrates (TAK-875) is a GPR40 agonist that has currently entered the third phase of the clinic and has been shown to be effective. The research shows that: in diabetic animal models, the fastigifam hemihydrate CTAK-875) can promote insulin secretion and effectively control blood sugar, but does not promote insulin secretion in normal rats (Tsujihata Y et al (2010). Diabetes 59, A165). in clinical trials, the fastigifam hemihydrates (TAK-875) also shows obvious blood sugar reduction effect and has lower risk of hypoglycemia (T, Araki et al (2012). Diabetes, Obesity and metabolism 4, 271-278). Several other agonists of GPR40 have also been developed in tandem, such as JTT-851, LY-2881835, and the like.

In conclusion, GPR40 is a safe and feasible novel target of oral hypoglycemic drugs, and the development of GPR40 agonist has very important research value and application prospect. Several studies on GPR40 agonist-related studies are currently in sequential publication.

US2006258722 describes GPR40 receptor modulators useful as insulin secretion promoters and preventive and/or therapeutic agents for diabetes, having the structural formula:

wherein Ar is a cyclic group optionally substituted, A is a cyclic group optionally substituted and not substituted with thiazole, oxazole, imidazole and pyrazole, Xa and Xb are each independently selected from a bond or a chain comprising 1 to 5 atoms, Xc is selected from 0, S, SO or S0₂Xd is selected from the group consisting of a bond, CH or CH₂D is selected from benzene ring, thiophene or thiazole, B is selected from 5-to 7-membered ring, R¹Selected from hydroxyl groups. And are not considered to be part of the present invention as specifically described in this patent.

CN101616913 describes condensed ring compounds with GPR40 receptor function modulating action as insulin secretion promoter and preventive and/or therapeutic agent for diabetes, the structural formula of which is as follows:

wherein R is¹Is selected from-S0₂-R⁶， R⁶Is selected from d-₆An alkyl group or an optionally substituted 1, 1-dioxotetrahydrothiopyranyl group, X being selected from a bond or a divalent hydrocarbon group; r²And R³Selected from H, halogen atoms, substituted hydrocarbon groups or substituted hydroxyl groups; r⁴And R⁵Selected from the group consisting of d-substituted by hydroxy₆A alkyl group; a is selected from benzene ring, B is selected from 5-to 7-membered ring, Y is selected from bond or CH₂And R is selected from hydroxyl. And are not considered to be part of the present invention as specifically described in this patent.

US7786165 describes GPR40 as having the following structural formula:

wherein Ar is optionally substituted cyclic and is not substituted with 4-piperidinyl, B is optionally substituted cyclic and is not substituted with thiazole or oxazole, V is selected from a bond or a chain containing 1 to 3 atoms and which chain is not a-N = N-group, and W is selected from a bond or d-)₆Alkanyl, X, Xa being selected from CH or N, Y being selected from O or CR⁶R⁷， R¹And R^laSelected from H, halogen, d-₆Alkyl or d-₆Alkyl oxygen radical, R²Is selected from H, d-₆Alkyl or optionally substituted acyl, R³And R⁴Selected from H or halogen, R⁵Selected from substituted hydroxyl groups or substituted amine groups, the compounds specifically described in US7786165 are not considered to be part of the present invention.

WO2010143733 describes GPR40 receptor modulators useful as insulin secretion promoters and preventive and/or therapeutic agents for diabetes, which have the following structural formula:

wherein R is¹Selected from halogen, hydroxy, optionally substituted d-₆Alkyl or optionally substituted d-₆A alkyl group; r²Selected from substituted hydroxy, R³Selected from H, halogen or optionally substituted d-₆Alkyl radical, X is CH₂Y is selected from CH₂NH or 0, Z is selected from CH or N, A is selected from halogen, optionally substituted amino or a 4-13 membered ring. The compounds specifically described in WO2010143733 are not considered to be part of the present invention. Disclosure of Invention

The invention relates to a compound shown in a general formula or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,

wherein:

r is selected from H or d-₈A alkyl group;

ring A is selected from 5-to 8-membered carbocyclyl or 5-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 4 substituents selected from N, 0 or 3(=0)₁₁The carbocyclyl or heterocyclyl group may optionally be further substituted with 0 to 4 atoms or groups selected from F, Cl, Br, I, =0, hydroxy, nitro, cyano, d \u₈Alkyl radical, d _₈Alkyl radical, C₂_₈Alkenyl radical, C₂_₈Alkynyl, -0-C (=0) -OR⁷、 -(CH₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷Or- (CH)₂)_m-NR⁷R^7aSubstituted with the substituent(s); wherein when a plurality of substituents are present, each substituent may be the same or different, and the following descriptions similar thereto have the same meaning and are not repeated;

ring B, including the atoms attached to the benzene ring together form a four-membered ring, and ring B may optionally be further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, nitro, cyano, d —)₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷Or- (CH)₂)_m-NR⁷R^7aSubstituted with the substituent(s); r¹And R⁴Each independently selected from F, Cl, Br, I, hydroxyl, amino, nitro, cyano, carboxyl and d-₈Alkyl or d-₈Alkyl, said amino, alkyl or alkyl is further selected from 0 to 4 selected from F, Cl, Br, I, hydroxyl, cyano, Ci _₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7aOr- (CH)₂)_m-C(=0)-NR⁷R^7aSubstituted with the substituent(s); r²And R³Each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, d-₈Alkyl or d-₈Alkanyl, said amino, alkanyl or alkanyl group optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, cyano, Ci —)₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)n-R⁷、 -(CH₂)_m-NR⁷R^7aOr- (CH)₂)_m-C(=0)-NR⁷R^7aSubstituted with the substituent(s);

R⁵and R⁶Each independently selected from H, F, Cl, Br, I, hydroxyl, nitro, cyano and d-₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7a、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-R⁷3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy, or 4-to 10-membered heterocyclyloxy, the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy, or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from the group consisting ofF. Cl, Br, I, =0, hydroxyl, cyano, d —₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R\ -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7a、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-R⁷3-to 10-membered carbocyclic group, 4-to 10-membered heterocyclic group, 3-to 10-membered carbocyclic oxy group or 4-to 10-membered heterocyclic oxy group, and said heterocyclic group contains 1 to 4 substituents selected from N, 0 or 3(= (microspheres)₁An atom or group of (a); wherein when a plurality of heteroatoms are present, each heteroatom may be the same or different, and the following similar descriptions have the same meaning and are not repeated;

alternatively, R⁵And R⁶A 4 to 8 membered carbocyclic or 5 to 8 membered heterocyclic ring may be formed, which carbocyclic or heterocyclic ring may optionally be further substituted by 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, nitro, cyano, d —₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷Or- (CH)₂)_m-NR⁷R^7aAnd said heterocycle contains 1 to 4 substituents selected from N, 0 or S (=0)_nAn atom or group of (a);

y is selected from the group consisting of a single bond, -0-, -NR⁷-、 -S(=0)_n-、 -C(=0)-、 -d_₈An alkyl-sub-base or-O-Cu alkyl-sub-base, said alkyl-sub-base being optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-₈Alkyl radical, Ci \₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、-(CH₂)_m-C(=0)-0-R⁷、-(CH₂)_m-C(=0)-NR⁷R^7a、 -(CH₂)_m-S(=0)_n-R⁷、 -0-C(=0)-0-R⁷or-NR⁷R^7aSubstituted with the substituent(s);

x is selected from H, F, Cl, Br, I, hydroxyl, nitro, cyano and d-₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl, \\ u₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7a、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-R⁷、 -(CH₂)_n-3 to 10 membered carbocyclyl, - (CH)₂)_n-4 to 10 membered heterocyclyl, - (CH)₂)_n-0-3 to 10 membered carbocyclyl or 4 to 10 membered heterocyclyloxy, said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, nitro, cyano, d — ]₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)n-R⁷、 -(CH₂)_m-NR⁷R^7a、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-R⁷3-to 10-membered carbocyclic group, 4-to 10-membered carbocyclic groupA heterocyclic group, a 3-to 10-membered carbocyclyloxy group or a 4-to 10-membered heterocyclyloxy group, and said heterocyclic group contains 1 to 4 substituents selected from N, 0 or 3(=0)₁₁An atom or group of (a);

R⁷1 and R^7bEach independently selected from H, hydroxy, amino, carboxyl, d \u₈Alkyl radical, d _₈Alkyl radical, C₂_₈An alkenyl group,

C₂.₈Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy, or 4-to 10-membered heterocyclyloxy, said amino, alkanyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy, or heterocyclyloxy being optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, amino, nitro, cyano, carboxy, d —, n₈Alkyl radical, d _₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or S (=0)_nAn atom or group of (a);

p is selected from 0, 1,2 or 3;

q is selected from 0, 1,2,3 or 4;

t is selected from 0, 1 or 2 (when t is 0, it means that-COOR is directly linked to the ring A; when t is 2, two identical or different Rs in the compound²And two identical or different R³) ；

m is selected from 0, 1,2,3,4 or 5;

n is selected from 0, 1 or 2.

In the present invention, the term "as selected" means that the scheme after "as selected" and the scheme before "as selected" are in a parallel selection relationship, and not further selected in the aforementioned schemes.

In a preferred embodiment of the present invention, the compound is a stereoisomer, a hydrate, an ester, a metabolite, a solvate, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, wherein the compound is selected from compounds represented by the general formula (II):

wherein:

r is selected from H or d-₄Alkyl, preferably H or d-₂Alkyl, more preferably H;

V) Χ°>") N rS ^ Y 、^Sring A is selected from among ^ E, \\\ \ E, \\ \ E, \ or' U, preferably Y. And Y. \ A

Or, more preferably ^ a, and ring A may be further substituted by 0 to 3 groups selected from F, Cl, Br, I, =0, amino, hydroxy, d-₄Alkyl or ^ - -₄Alkyl substituted by substituent of alkyl;

ring B, including the atoms attached to the benzene ring together form a four-membered ring, and ring B may optionally be further substituted with 0 to 4 substituents selected from F,

Cl, Br, I, =0, hydroxyl, nitro, cyano, d-₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷Or- (CH)₂)_m-NR⁷R^7aSubstituted with the substituent(s);

R¹and R⁴Each independently selected from F, Cl, Br, I, hydroxyl, amino, nitro, cyano, carboxyl and d-₄Root of Chinese Yak₄Alkyl oxy, preferably F, C1 or d-₄Alkyl, said amino, alkyl or alkyl is further selected from 0 to 3

F. Cl, Br, I or a substituent of hydroxyl;

R⁵and R⁶Each independently selected from H, F, Cl, Br, I, hydroxylRadical, amino, nitro, cyano, carboxyl, d-₄Alkyl or d-₄Alkyl oxy, preferably H, F, Cl, Br, I, hydroxy or —)₄Alkyl group, more preferably H, F, Cl, hydroxyl group or d u₄Alkyl group, further preferably H, C1 or d-₄An alkyl group, said alkyl or alkyl group being optionally further substituted by 0 to 3 substituents selected from F,

Cl, Br, I, hydroxyl, d-4 alkyl or-4 alkyl substituent;

y is selected from the group consisting of a single bond, -0-, -NR⁷-、 -S(=0)_n-、 -C(=0)-、 -d_₄An alkanyl group or-O-CM alkanyl group, preferably a single bond,

-0—、 -_NR⁷-、 -d_₄An alkanyl group or-O-CM alkanyl group, more preferably a single bond, -0-or-NR⁷-, more preferably-0-, said sub-alkyl group being optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, or a salt thereof,

Alkyl 4, d-4 alkyl-C₂-4 alkenyl, C₂-4 alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-0-R⁷、

-(CH₂)_m-C(=0)-NR⁷R^7a、 -(CH₂)_m-S(=0)_n-R⁷、 -0-C(=0)-0-R⁷or-NR⁷R^7aSubstituted with the substituent(s);

x is selected from H, F, d \ u₄Alkyl radical, d _₄Alkyl radical, C₂_₈Alkenyl radical, C₂_₈Alkynyl, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl, - (CH)₂)_n-0-3 to 8 membered carbocyclyl or 4 to 8 membered heterocyclyloxy, preferably H, d \\ u₄Alkyl radical, d _₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl, - (CH)₂)_n-0-3 to 8 membered carbocyclyl or 4 to 8 membered heterocyclyloxy, more preferably H, d —₄Radix Et rhizoma Rhei₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, further preferably H, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, said alkanyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d _ \ u₄Alkyl radical, d _₄Alkyl radical, C₂_₈Alkenyl radical, C₂_₈Alkynyl, - (CH)₂)_m-S(=0)_n-R⁷3-to 8-membered carbocyclyl, 4-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 4-to 8-membered heterocyclyloxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or 3(=0)₁₁An atom or group of (a);

R⁷and R^7aEach independently selected from H, hydroxy, amino, carboxy, d-₄Radix Et rhizoma Rhei₄Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, 3-to 8-membered carbocyclyl, 4-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 4-to 8-membered heterocyclyloxy, preferably H, hydroxy, amino, d —₄Root of Chinese Yak₄Alkyl oxy, further preferably hydroxy or d —₄Alkanyl, said amino, alkanyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 4 substituents g F, Cl, Br, I, hydroxy, aminoNitro, cyano, carboxyl, d-₄Radix Et rhizoma Rhei₄Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, 3-to 8-membered carbocyclyl, 4-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 4-to 8-membered heterocyclyloxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or 3(=0)₁₁An atom or group of (a);

p is selected from 0, 1 or 2;

q is selected from 0, 1 or 2;

m is selected from 0, 1,2,3,4 or 5;

n is selected from 0, 1 or 2.

wherein-

R is selectedPreferably (in)And ring A may be further substituted by 0 to 3 groups selected from F, Cl, Br, I, =0, amino, hydroxy, d —)₄Alkyl or ^ - -₄Alkyl substituted by substituent of alkyl;

ring B, including the atoms attached to the benzene ring together form a four-membered ring, and ring B may optionally be further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, amino, nitro, cyano, carboxy, d — ]₄Root of Chinese Yak₄Alkyl substituted by substituent of alkyl;

R¹and R⁴Each independently selected from F, Cl, Br, I, hydroxyRadical, amino, nitro, cyano, carboxyl, d-₄Alkyl or ^ - -₄An alkanyl group, preferably F, C1 or methyl, said amino, alkanyl or alkanyl group optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I or hydroxy;

R⁵and R⁶Each independently selected from H, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, carboxyl and d-₄Alkyl or CM alkyl, preferably H, F, Cl, Br, I or d-₄Alkyl, more preferably H, F, CI or d-₄Alkyl, more preferably H or d-4 alkyl, said amino, alkyl or alkyl is further optionally substituted by 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, d —₄Alkyl or ^ - -₄Alkyl substituted by substituent of alkyl;

y is selected from the group consisting of a single bond, -0-, -NR⁷-、 -S(=0)_n-、 -C(=0)-、 -d_₄An alkanyl group or-O-CM alkanyl group, preferably a single bond, -0-or-NR⁷-, more preferably-0-, said sub-alkyl group being optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxyl, d-4 alkyl, C₂-4 alkenyl, C₂-4 alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-0-R⁷、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -(CH₂)_m-S(=0)_n-R⁷、 -0-C(=0)-0-R⁷or-NR⁷R^7aSubstituted with the substituent(s);

x is selected from H, F, d-4 alkyl, d-4 alkyl, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl, - (CH)₂)_n-0-3 to 8 membered carbocyclyl or 4 to 8 membered heterocyclyloxy, preferably H, d \\ u₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, more preferably H, - (CH)₂)₃-S(=0)2-R⁷、 -(CH₂)_n-4 to 6 membered carbocyclyl, - (CH)₂)_n-5 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 5 membered carbocyclyl, said alkanyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d _ \ u₄Alkyl radical, d _₄Alkyl radical, C₂_₈Alkenyl radical, C₂_₈Alkynyl, - (CH)₂)_m-S(=0)_n-R⁷3-to 8-membered carbocyclyl, 4-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 4-to 8-membered heterocyclyloxy, preferably with 0 to 4 substituents selected from F, Cl, hydroxy or d —₄Alkyl-oxy, more preferably 0 to 2 substituents selected from hydroxy or methoxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or 3(=0)₁₁An atom or group of (a);

R⁷and R^7aEach independently selected from H, hydroxy, amino, carboxy, d-₄Radix Et rhizoma Rhei₄Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, 3-to 8-membered carbocyclyl, 4-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 4-to 8-membered heterocyclyloxy, preferably H, hydroxy, amino, d —₄Root of Chinese Yak₄Alkyl oxy, further preferably hydroxy or d —₄Alkanyl, said amino, alkanyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from g F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d —₄Radix Et rhizoma Rhei₄Alkyl radical, C₂—₈Alkenyl, \\ u₈Alkynyl, 3-to 8-membered carbocyclyl, 4-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 4-to 8-membered heterocyclyloxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or 3(=0)₁₁An atom or group of (a);

p is selected from 0, 1 or 2;

q is selected from 0, 1 or 2;

m is selected from 0, 1,2,3,4 or 5;

n is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the compound of formula (II) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof,

wherein:

r is selected from H_;Ring (C)

Ring B, including the atoms to which the phenyl ring is attached, together forming a four-membered ring, and which may optionally be further substituted with 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, d-4 alkyl, or ^ -4 alkyl;

R¹and R⁴Each independently selected from F, Cl, Br, I, hydroxy or ^ -F ^ -I₄Alkyl, preferably F, CI or methyl;

R⁵and R⁶Each independently selected from H, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, carboxyl and d-₄Alkyl or CM alkyl, preferably H, F, Cl, Br, I or d-₄Alkyl radical, more preferably H, F, CI or C_MAlkyl, further preferably H or d-₄A alkyl group;

y is selected from the group consisting of a single bond, -0-, -NR⁷-、 -d_₄An alkanyl group or-O-CM alkanyl group, preferably a single bond, -0-or-NR⁷-, more preferably-0-, said sub-alkyl group being optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Hydroxy, CM alkyl or-₄Alkyl substituted by substituent of alkyl;

x is selected from H, d \ u₄Alkyl radical, d _₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl, - (CH)₂)_n-0-3 to 8 membered carbocyclyl or 4 to 8 membered heterocyclyloxy, preferably H, d —₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R\ -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl or, more preferably, H, - (CH)₂)₃-S(=0)₂-R⁷, -(CH₂)_n-4 to 6 membered carbocyclyl, - (CH)₂)_n-5 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 5 membered carbocyclyl, said alkanyl, carbocyclyl, heterocyclyl or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d — -, alkyl, alkoxy₄Radix Et rhizoma Rhei₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R \ 3-to 8-membered carbocyclyl, 4-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy or 4-to 8-membered heterocyclyloxy, preferably substituted with 0 to 4 substituents selected from F, Cl, hydroxy or ^ -4₄Alkyl-oxy, more preferably 0 to 2 substituents selected from hydroxy or methoxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or 3(= 0;)₁₁An atom or group of (a);

R⁷selected from H, hydroxyl, amino, carboxyl and d-₄Radix Et rhizoma Rhei₄Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, 3-to 8-membered carbocyclyl or 4-to 8-membered heterocyclyl, preferably H, amino, d —₄Root of Chinese Yak₄Alkyl oxy, more preferably d-₄Is ground andthe heterocyclic group contains 1 to 4 hetero atoms selected from N, 0 or S;

p is selected from 0 or 1;

q is selected from 0 or 1;

m is selected from 0, 1,2,3,4 or 5, preferably 3 or 4, more preferably 3;

n is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the compound or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, or cocrystal III) thereof is:

wherein-ring B, including the atoms to which the phenyl rings are attached, together form a four-membered ring, and ring B may optionally be further substituted with 0 to 4 substituents selected from F or C1;

R⁵and R⁶Each independently selected from H, F, Cl, Br, I, hydroxy or d-₄Alkyl, preferably H, F, CI or d-₄Alkyl, more preferably H, C1 or d-₄Alkyl, further preferably H or d-₂A alkyl group;

y is selected from the group consisting of a single bond, -0 or-NR⁷-, preferably-0-; x is selected from H, d \ u₄Alkyl radical, d _₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, preferably H, d \ u₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, more preferably H, - (CH)₂)_m-S(=0)_n-R⁷(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclic group, said alkyl, carbocyclyl or heterocyclyl group optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, CM alkyl, d —₄Alkyl, 3 to 8 membered carbocyclyl or 4 to 8 membered heterocyclyl, preferably 0 to 4 substituents selected from hydroxy or methoxy, and said heterocyclyl containing 1 to 4 substituents selected from N, 0 or S (=0)_nAn atom or group of (a);

R⁷selected from H, hydroxy, amino, d-₄Alkyl or d-₄Alkyl oxy, preferably d-₄Alkyl group, further preferably d-₂A alkyl group; m is selected from 0, 1,2,3 or 4, preferably 3 or 4, more preferably 3;

n is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the compound or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, or cocrystal IV) thereof is:

wherein-

R⁵And R⁶Each independently selected from H, F, Cl, hydroxy or d \u₄Alkyl radical, preferably H, C1 or d _₄Alkyl, more preferably H or d-₂A alkyl group;

x is selected from H, d \ u₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, preferably H, - (CH)₂)₃-S(=0)₂-R⁷、-(CH₂)_n-4 to 6 membered carbocyclyl, - (CH)₂)_n-5 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 5-membered carbocyclyl, said alkyl,The carbocyclyl or heterocyclyl is optionally further substituted with 0 to 4 substituents selected from F, Cl, hydroxy, d-₄Alkyl or a 4-to 8-membered heterocyclic group, preferably 0 to 4 substituents selected from F, C1, hydroxy or methoxy, and said heterocyclic group contains 1 to 2 substituents selected from N, 0 or S (=0)_nAn atom or group of (a);

R⁷selected from hydroxy or CM alkyl, preferably d —)₄Alkyl, more preferably d-₂A alkyl group;

m is selected from 2,3 or 4, preferably 3 or 4, more preferably 3;

n is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the compound of formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R⁵and R⁶Each is independently selected from H or d-₄Alkyl, preferably H or d-₂A alkyl group;

x is selected from H, d \ u₂Alkyl radical, - (CH)₂)₃-S(=0)2-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, preferably H, - (CH)₂)₃-S(=0)₂-R⁷、-(CH₂)_n-4 to 6 membered carbocyclyl, - (CH)₂)_n-5 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 5 membered carbocyclyl, said alkyl or heterocyclyl being optionally further substituted with 0 to 2 substituents selected from hydroxy, d —, or₄Alkyl-oxy or a 4-to 6-membered heterocyclic group, preferably 0 to 2 substituents selected from hydroxyl or methoxy, and the heterocyclic group contains 1 to 2 substituents selected from N, 0 or 3(= (microspheres)₁An atom or group of (a);

R⁷is selected from d-₄Alkyl radical, preferably d-₂A alkyl group;

n is selected from 0, 1 or 2.

R⁵and R⁶Each independently selected from H, methyl, ethyl, n-propyl or isopropyl, preferably H, methyl or ethyl;

cb or fl is preferably H, - (CH)₂)₃-S(=0)2-R⁷、

R⁷Selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl.

R⁵and R⁶Each independently selected from H, methyl or ethyl, preferably methyl;

x is selected from H, - (CH)₂)₃-S(=0)₂-R⁷、

R⁷Selected from methyl or ethyl, preferably methyl.

In a preferred embodiment of the present invention, the compound of formula (I) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the compound is selected from compounds represented by formula (II):

wherein-R is selected from H or d-₄Alkyl, preferably H;

and (4) Y.

Ring A is

Ring B, including the atoms to which the phenyl rings are attached together to form a four-membered ring;

R¹and R⁴Each independently selected from F, Cl, Br or d-4 alkyl, preferably F, CI or methyl;

R⁵and R⁶Each independently selected from H, F, Cl, Br or d-4 alkyl, preferably H or methyl;

y is selected from a single bond, -0-or-O-CM alkanyl, preferably-0-, said alkanyl being optionally further substituted by 0 to 4 substituents selected from- (CH)₂)_m-S(=0)_n-R⁷Substituted with the substituent(s);

x is selected from H, d \ u₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, preferably H, - (CH)₂)_m-S(=0)_n-R⁷、-(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, more preferably H, - (CH)₂)_m-S(=0)_n-R⁷, -(CH₂)_n-4 to 6 membered carbocyclyl, - (CH)₂)_n-5 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 5 membered carbocyclyl, said alkanyl, carbocyclyl or heterocyclyl optionally further substituted with 0 to 4 substituents selected from hydroxy or d —)₄Alkyl substituted by substituent(s) of alkyl, and said heterocyclic radical contains 1 to 4 substituents selected from N, 0 or 3(=0)₁₁An atom or group of (a);

R⁷is selected from H or d-₄Alkyl, preferably H or d-₂Alkyl, more preferably methyl;

p is selected from 0, 1 or 2;

q is selected from 0, 1 or 2;

m is selected from 0, 1,2,3,4 or 5;

n is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the compound represented by the general formula (II) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the compound is selected from compounds represented by the general formula (III):

wherein:

R⁵and R⁶Each independently selected from H, F, Cl, Br or d-₄Alkyl base, preferred! | A Or ^ a ^ b ^ a₂Alkyl, more preferably H or methyl;

y is selected from-0-or-O-CM alkyl, preferably-0-;

x is selected from H, d \ u₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, preferably H, - (CH)₂)_m-S(=0)_n-R⁷、-(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_N-0-3 to 8 membered carbocyclyl, more preferably H, - (CH)₂)_M-S(=0)_N-R⁷, -(CH₂)_N-4 to 6 membered carbocyclyl, - (CH)₂)_N-5 to 8 membered heterocyclyl or- (CH)₂)_N-a 0-3 to 5 membered carbocyclyl, said alkanyl, carbocyclyl or heterocyclyl optionally further substituted with 0 to 4 substituents selected from hydroxyl or CM alkanyl;

R⁷is selected from H or d-₄A alkyl group;

m is selected from 0, 1,2,3 or 4;

n is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the compound of formula (III) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable, co-crystal or prodrug thereof, wherein the compound is selected from compounds of formula 0V):

wherein:

R⁵is selected from H or d-₄Alkyl, preferably H or d-₂Alkyl, more preferably H or methyl;

R⁶is H;

x is selected from H, - (CH)₂)_M-S(=0)_N-R⁷、 -(CH₂)_N-4 to 6 membered carbocyclyl, - (CH)₂)_N-5 to 8 membered heterocyclyl or

-(CH₂)_N-0-3 to 5 membered carbocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 2 substituents selected from hydroxy or d —)₄Alkyl substituted by substituent of alkyl;

R⁷selected from CM alkyl, preferably d-₂Alkyl, more preferably methyl;

m is selected from 2,3 or 4, preferably 3;

n is selected from 0, 1 or 2.

R⁵selected from H, methyl, ethyl, n-propyl or isopropyl, preferably H or methyl;

R⁶is H;

X H、 -(CH₂)₃-S(=0)₂-R⁷、preferably H, - (CH)₂)₃-S(=0)2-R⁷、 i、 C^^QOr

R⁷Selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl-according to a preferred embodiment of the invention, formula v) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R⁵selected from H, methyl or ethyl, preferably methyl;

R⁶is H;

x is selected from H, - (CH)₂)₃-S(=0)₂-R⁷、i、 X - ^⁷Or- ί

R⁷Is methyl.

In a preferred embodiment of the present invention, the compound of formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the compound is selected from the group consisting of compounds represented by formula (V):

wherein:

R⁴selected from H, F, CI or methyl;

x is selected from H, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-4 to 6 membered carbocyclyl, - (CH)₂)_n-5 to 8 membered heteroCyclic radical or- (CH)₂)_n-0-3 to 5 membered carbocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 2 substituents selected from hydroxy or d —)₄Alkyl substituted by substituent of alkyl;

m is selected from 0, 1,2,3 or 4, preferably 3;

n is selected from 0, 1 or 2.

In a preferred embodiment of the present invention, the compound of formula (V) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R⁴selected from H, F, CI or methyl;

R⁵is H or methyl, preferably H_;

、ο

X is selected from H, - (CH)₂)₃-S(=0)2-CH₃、 U 、

In a preferred embodiment of the invention, the invention relates to a compound selected from, but not limited to:

the compound of the present invention or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, cocrystal or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the salt in the pharmaceutically acceptable salt thereof is selected from, but not limited to, sodium salt, potassium salt, aluminum salt, lithium salt, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridine salt, picoline salt, 2, 6-dimethylpyridine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, purine salt, piperazine salt, or a pharmaceutically acceptable salt thereof, A piperidine salt, an N-ethylpiperidinium salt, a polyamine resin salt, a phentermine salt, or a combination thereof. Preferably sodium salt, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, or a combination thereof. The invention also relates to a synthetic method of the compound. One skilled in the art will appreciate that the compounds of the present invention can be synthesized by a variety of preparative methods. Preferred methods include, but are not limited to, the methods described below. One skilled in the art will appreciate that the functionality exhibited on the molecule should be consistent with the proposed transformation. In order to obtain the desired compounds of the present invention, a judgment is sometimes required to change the order of synthetic steps or to select a specific process scheme. Reasonable protecting groups are chosen for protecting reactive functional groups present in the compounds described herein.

The invention relates to a method for preparing a compound represented by the general formula omega, which can be selected from the first method or the second method comprising the following steps:

the compound of the general formula (I-aO is subjected to Clemenson reduction, improved Clemenson reduction, Wallford-Kacherner reduction, Huang Minlon reduction or carbonyl reduction by a reducing agent-Lewis acid combined method to obtain a compound of the general formula (I-a) (when the ring B carries a substituent, the carbonyl can be reduced firstly and then the substituent is introduced to obtain the compound of the general formula (I-a), or the substituent is introduced firstly and then the compound is reduced to obtain the compound of the general formula (I-a));

carrying out suzuki coupling reaction on the compound with the general formula (I-a) and the compound with the general formula (I-b), and further carrying out hydrogenation reduction on the obtained product under the action of a reducing agent to obtain a compound with the general formula (I-c);

the compound of the general formula (I-c) undergoes S_N2 reacting to obtain a compound of a general formula (I-d);

(l-d)

the compound of the general formula (I-d) and the compound of the general formula (I-e) are subjected to Mistunobu reaction to obtain a product, and the product is further hydrolyzed to obtain the compound of the general formula (I).

The second method comprises the following steps:

(l-ai) (l-a₂)

the general formula (I-aO is reduced into hydroxyl under the action of a reducing agent to obtain the general formula (I-a)₂) A compound; or the general formula (I-aO is reduced into hydroxyl under the action of a reducing agent and then undergoes nucleophilic substitution reaction to obtain a compound with the general formula (1-);

general formula (I-a)₂) Reducing hydroxyl by the compound to obtain a compound of a general formula (I-a); or the compound of the general formula (1-) reduces halogen to obtain a compound of the general formula (I-a);

(l-c) (l-d) Compounds of formula I-c) to S_N2 reacting to obtain a compound of a general formula (I-d);

V³Wherein R is⁹Or R¹²Each independently selected from H, F, Cl, Br, I, hydroxy,cT^eF3Or ά

R^1USelected from H, F, Cl, Br, I, hydroxy, d-₆Alkyl or d-₆Alkanyloxy, X, Y, ring B, R, R¹, R²、 R³、 R⁴、 R⁵、 R⁶P, q and t are as defined for formula (I).

More specifically, the invention relates to a method for preparing a compound of general formula (I), which comprises the following steps:

acetic acid, trifluoroacetic acid and hydrochloric acid/tetrahydrofuran are used as solvents, carbonyl is reduced by the general formula (I-a) under the action of zinc powder or zinc amalgam to obtain the compound of the general formula (I-a), or the compound of the general formula (I-a) is reduced by the general formula (I-a) under the action of hydrazine hydrate and anhydrous hydrazine under the action of ethylene glycol, ethylene glycol dimethyl ether and polyethylene glycol as solvents and the presence of potassium hydroxide, sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide_ai) Reducing the carbonyl group to obtain a compound of the general formula (I-a); or N, N-dimethyl formamide, tetrahydrofuran or dimethyl sulfoxide as solvent, and aluminum lithium hydride in the presence of aluminum trichloride or zinc dichloride to obtain carbonyl compound of the general formula (I-a)Alcohol/water, acetonitrile/water, 1, 4-dioxane/water or tetrahydrofuran/water are used as solvents, under the condition of potassium carbonate, sodium carbonate or potassium phosphate and under the action of a palladium catalyst, a compound in a general formula (I-a) and a compound in a general formula (I-b) undergo a suzuki coupling reaction, the obtained product is further subjected to hydrogenation reduction under the action of a reducing agent to obtain a compound in a general formula (I-c), wherein the palladium catalyst is selected from palladium tetratriphenylphosphine, palladium dichloride, palladium acetate or bis (triphenylphosphine) palladium dichloride, the reducing agent is selected from sodium borohydride, potassium borohydride, zinc borohydride, sodium cyanoborohydride, potassium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, sodium thioborohydride or lithium tri-sec-butylborohydride; heating and refluxing N, N-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide as solvent in the presence of potassium carbonate or cesium carbonate to generate S in the compound of formula (I-c)_N2 reacting to obtain a compound of a general formula (I-d); taking dichloromethyl alkyl or tetrahydrofuran as a solvent, in the presence of diisopropyl azodicarboxylate or 1,1- (azodicarbonyl) dipiperidine under the condition of tributyl phosphine, carrying out Mistunobu reaction on the compound of the general formula (I-d) and the compound of the general formula (I-e) to obtain a product, and further hydrolyzing to obtain the compound of the general formula (I).

The second method comprises the following steps:

(l-_ai) (l-a₂) (l-ai

the fourth step

d-d) (i) under the action of a reducing agent, a compound of the formula (i-_ai) Reducing the carbonyl group to a hydroxyl group to obtain a compound of formula (1-); or under the action of a reducing agent, the general formula (I-_ai) Reducing carbonyl to hydroxyl, and then using dichloro-methyl-alkyl, N-dimethyl formamide, tetrahydrofuran or dimethyl sulfoxide as solvent inIn the presence of triethylamine, pyridine, N-diisopropylethylamine, further reacting with trifluoromethanesulfonic anhydride, and nucleophilic substituting with iodo reagent to obtain general formula (I-a)₂) A compound; or under the action of a reducing agent, the general formula (I-aO is reduced to be hydroxyl, then benzene, toluene, tetrahydrofuran, dichloro-methyl-alkyl, chloroform or 1, 2-dichloro-ethyl-alkyl is used as a solvent, and nucleophilic substitution reaction is carried out on the general formula (I-a) and an iodine simple substance under the existence of triphenylphosphine/imidazole to obtain the general formula (I-a)₂) A compound; benzene, toluene, tetrahydrofuran, dichloroalkyl, N-dimethylformamide, dimethyl sulfoxide, chloroform or 1, 2-dichloroethylene is used as a solvent, and the general formula (I-a) is shown in the specification under the action of aluminum lithium hydride, triethyl silicon and sodium borohydride in the presence of aluminum trichloride, zinc dichloride, trifluoroacetic acid, acetic acid and hydrochloric acid₂) The compound reduces hydroxyl to obtain a compound of a general formula (I-a); or benzene, toluene, tetrahydrofuran, dichloro-methyl-alkyl, N-dimethyl formamide, dimethyl sulfoxide, chloroform or 1, 2-dichloro-ethyl-alkyl is used as a solvent, and lithium aluminum hydride, triethyl silicon, sodium borohydride, triethyl lithium borohydride and tri-sec-butyl lithium borohydride are reduced to form the general formula (I-a)₂) The compound reduces halogen to obtain the compound of the general formula (I-a). Toluene/ethanol/water, acetonitrile/water, 1, 4-dioxane/water or tetrahydrofuran/water are taken as a solvent, a suzuki coupling reaction is carried out on a compound with a general formula (I-a) and a compound with a general formula (I-b) under the action of a palladium catalyst in the presence of potassium carbonate, sodium carbonate or potassium phosphate, the obtained product is further subjected to hydrogenation reduction under the action of a reducing agent to obtain a compound with a general formula (I-c), wherein the palladium catalyst is selected from palladium tetratriphenylphosphine, palladium dichloride, palladium acetate or bis (triphenylphosphine) palladium dichloride, the reducing agent is selected from sodium borohydride, potassium borohydride, zinc borohydride, sodium cyanoborohydride, potassium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, sodium thioborohydride or lithium tri-sec-butylborohydride; n, N-dimethyl formamide, tetrahydrofuran or dimethyl sulfoxide as solvent and potassium carbonate or cesium carbonate as solvent are heated and refluxed to produce S in the general expression of the compound_N2 reaction to give compounds of the formula (I-d)A compound; using dichloromethyl alkan or tetrahydrofuran as solvent, in the presence of tributyl phosphine, diisopropyl azodicarboxylate or 1,1- (azodicarbonyl) dipiperidine, carrying out Mistimobu reaction on the compound of general formula (I-d) and the compound of general formula (I-e) to obtain a product, and further hydrolyzing to obtain the compound of general formula (I), wherein R is⁹Or R¹²Each independently selected from H, F, Cl, Br, I or hydroxy, R^1QSelected from H, F, Cl, Br, I, hydroxyl and d-₆Alkyl or d-₆Alkanyloxy, X, Y, ring B, R, R¹, R²、 R³、 R⁴、 R⁵、 R⁶P, q and t are as defined for formula (I). The invention also relates to a pharmaceutical composition comprising: an effective amount of a compound of formula (I) or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals, pharmaceutically acceptable salts or prodrugs thereof together with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient; the composition may further comprise one or more other therapeutic agents. Wherein said other therapeutic agents include:

(a) a GPR40 agonist or a pharmaceutically acceptable salt, and/or

(b) A DPP-IV inhibitor or a pharmaceutically acceptable salt, and/or

(c) SGLT-2 inhibitor or pharmaceutically acceptable salt, and/or

(d) PPAR_TAgonists or Pp Α I_γPartial agonists or pharmaceutically acceptable salts, and/or

(e) PPAR dual agonists or pharmaceutically acceptable salts, and/or

(； f) PPAR_sAn agonist or a pharmaceutically acceptable salt, and/or

(g) Insulin or insulin mimetic or pharmaceutically acceptable salt, and/or

(h) A protein tyrosine phosphatase-IB (PTP-1B) inhibitor or a pharmaceutically acceptable salt, and/or

(i) Sulfonylurea inhibitors or pharmaceutically acceptable salts, and/or

(D a-glucosidase inhibitor or pharmaceutically acceptable salt, and/or

(k) GLP-K GLP-1 analog, GIP-1, HSD-1 or a pharmaceutically acceptable salt, and/or

(1) A glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or

(m) an anti-inflammatory agent, and/or

(n) an ileal bile acid transporter inhibitor or a pharmaceutically acceptable salt, and/or

(0) An anti-obesity agent, and/or

(p) an agent that improves lipid profile in a patient, the agent selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, nicotinic acid or salts thereof? Is there a I! ^ agonists, cholesterol absorption inhibitors, acyl-CoA (cholesterol acyltransferase (ACAT)) inhibitors, CETP inhibitors or phenolic antioxidants or pharmaceutically acceptable salts, and/or

(q) biguanides, thiazole alkadiones, glinides, or pharmaceutically acceptable salts or prodrugs thereof.

In a preferred embodiment of the invention, the GPR40 agonist is selected from the group consisting of familifam hemihydrates (TAK-875) or a pharmaceutically acceptable salt or prodrug thereof. The DDP-IV inhibitor is selected from linagliptin (linagliptin) and omarigliptin

(MK-3102), sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (alogliptin), saxagliptin (saxagliptin), denagliptin (digagliptin), Carmegliptin (Carmegliptin), Melogliptin (Merliptin), Dutogliptin (dulagliptin), Teneliiptin (Trilinat), Gemigliptin (Geogliptin) or Trelagliptin (Trelagliptin). The SGLT-2 inhibitor is selected from Dapagliflozin (Dapagliflozin), Canagliflozin (Canagliflozin), Atigliflozin (argagliflozin), Empagliflozin (Empagliflozin), Ipagliflozin (Empagliflozin), Tofogliflozin (tofacizin), Lusegliflozin (Lupulzin), Remogliflozin (regagliflozin), Sergliflozin (seragliflozin), orErtugliflozin (etogliflozin); PPAR (PPAR) device_YAgonists include Ciglitazone (Ciglitazone), Troglitazone (Troglitazone), Pioglitazone (Pioglitazone), Rosglitazone (Rosiglitazone), Englitazone (Englitazone), Darglitazone (daglipzone), PPAR dual agonists including muraglitazor (mogentazole) or aleglitazor (Aleglitazar), PPAR_SAgonists include pioglitazone (pioglitazone;) or rosiglitazone (rosiglitazone). The biguanide therapeutic agent is selected from metformin or diethylene biguanide. The thiazole alkadione therapeutic agent is selected from the group consisting of ciglitazone, pioglitazone, rosiglitazone, troglitazone, faglitazone and darglitazone. The sulfonylurea therapeutic agent is selected from glimepiride, glibornuride, glibenclamide, gliquidone, glipizide or gliclazide. The glinide therapeutic agent is selected from nateglinide, repaglinide or miglitide. The GLP-1 analogue is selected from Exenatide (Exenatide) or Liraglutide (Liraglutide).

The invention also relates to the application of the compound or the stereoisomer, the hydrate, the solvate, the ester, the metabolite, the co-crystal, the pharmaceutically acceptable salt or the prodrug thereof or the pharmaceutical composition in medicine, in particular to the application in preparing a G protein-coupled receptor 40 agonist, in particular to the application in preparing a pharmaceutical preparation, preferably the pharmaceutical preparation for treating and/or preventing metabolic diseases as the G protein-coupled receptor 40 agonist. Wherein the metabolic disease comprises one or more of diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, renal disease, ketoacidosis, elevated levels of fatty acids or glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, syndrome X, insulin resistance, insulin allergy, glucose intolerance, skin diseases, atherosclerosis and its sequelae angina pectoris, claudication, heart attack, or stroke, further preferred includes type II diabetes.

The present invention also relates to a method for the treatment and/or prevention of the above metabolic diseases, which comprises administering to a subject an effective amount of a compound of the present invention or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of the present invention.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

Where carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium; I, isotopes of oxygen including¹⁶0、¹⁷0 and¹⁸0, isotopes of sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F include¹⁷F and¹⁹isotopes of F, chlorine including³⁵C1 and³⁷c1, isotopes of bromine including⁷Microspheres of formula I and⁸¹Br。

the alkyl group means a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, and further preferably an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-heptyl, n-octyl and various branched isomers thereof; the alkyl group can be further selected from 0 to 5F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Hydroxy, -SR^UNitro, cyano, isocyano, alkenyl, alkynyl, alkanyl, hydroxyalkyl, alkanyl, carbocyclyl, heterocyclyl, C₂—₈Alkenyl radical, C₂—₈Alkynyl, alkynyl,

-(CH₂)_m-C(=0)-0-R^u、 -(CH₂)_m-C(=0)-N R¹¹R^lla、 -(CH₂)_m-S(=0)_n-R^u、 -0-C(=0)-0-Rⁿor-NR¹¹R^{l la}Wherein R is substituted by a substituent of (1)¹¹And R^{l la}Each independently selected from H, hydroxy, amino, carboxy, d-₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, m is selected from 0, 1,2,3,4 or 5 and n is selected from 0, 1 or 2. Alkyl, R appearing herein¹¹And R^llaAs defined above.

"alkyl-oxy" means-0-alkyl, non-limiting examples of which include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy.

"alkenyl" means a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms containing 1 to 3 carbon-carbon double bonds, preferably an alkenyl group of 2 to 12 carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-3-yl. The alkenyl group may optionally be further substituted with 0 to 4 substituents selected from F, Cl, Br, I, alkanyl, linear alkenyl, linear alkynyl, amino, nitro, cyano, mercapto, amido, carbocyclyl, or heterocyclyl.

"alkynyl" means a straight or branched chain unsaturated aliphatic hydrocarbon group containing from 1 to 3 carbon-carbon triple bonds and consisting of 2 to 20 carbon atoms, preferably alkynyl of 2 to 12 carbon atoms, more preferably alkynyl of 2 to 8 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, butyn-3-yl, pentyn-1-yl, hexyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undec-3-yl, dodecyn-4-yl. The alkynyl group may optionally be further substituted with 0 to 4 substituents selected from F, Cl, Br, I, alkanyl, straight chain alkenyl, straight chain alkynyl, amino, nitro, cyano, mercapto, amido, carbocyclyl, or heterocyclyl.

"carbocyclyl" refers to a saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 10-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system to which the carbocyclyl may be attached a bridged or spiro ring, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, phenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, decyl, cycloundecyl, cyclododecanyl, phenyl, naphthyl, anthracenyl, phenanthryl, and the like,. The carbocyclyl may optionally be further substituted with 0 to 8 substituents selected from F, Cl, Br, I, =0,

-CH₂F、 -CHF₂、 -CF₃Hydroxy, -SR^UNitro, cyano, isocyano, alkenyl, alkynyl, alkanyl, hydroxyalkyl, alkanyl, carbocyclyl, heterocyclyl, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R^u、 -(CH₂)_m-C(=0)-0-R^u、 -(CH₂)_m-C(=0)-NR^uR^{l la}、 -(CH₂)_m-S(=0)_n-R^u、 -0-C(=0)-0-Rⁿor-NR^uR^{l la}M is selected from 0, 1,2,3,4 or 5, and n is selected from 0, 1 or 2. Carbocyclyl as appearing herein, is defined as above.

"Heterocyclyl" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 10-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and which contains 1 to 4 heteroatoms or groups selected from N, 0, or S (= 0;. N), preferably a 4-to 8-membered heterocyclic group, optionally substituted N, S in the heterocyclic ring being oxidizable to various oxidation states the heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include epoxyethyl, epoxypropyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, oxaziridinyl, azetidinyl, thioheterocycloalkyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, or a 10-to 15-membered tricyclic ring system, 1, 3-dioxane group, azepin group, oxepanyl group, thiepin group, oxazepin group, azepin group, diazepine group, thiazepin group, pyridyl group, piperidyl group, homopiperidinyl group, furyl group, thienyl group, pyranyl group, N-alkanylpyrrolyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, piperazinyl group, homopiperazinyl group, imidazolyl group, piperidyl group, peridinyl group, morpholinyl group, thiomorpholinyl group, thiazyl group, 1, 3-dithanyl group, dihydrofuryl group, dihydropyranyl group, dithianyl group, tetrahydrofuranyl group, tetrahydrothienyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, thiazyl group, thiopyranyl group, pyrrolopyridyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, a pyrazolylimidazolinyl group, an imidazolidyl group, a1, 2,3, 4-tetrahydroisoquinolinyl group, a 3-azabicyclo [ 3-fold 0] hexyl group, a 3-azabicyclo [4.1.0] heptyl group, an azabicyclo [2.2.2] hexyl group, a 3H-indolylquinolizinyl group, an N-pyridylurea group, a1, 1-dioxothiomorpholinyl group, an azabicyclo [3.2.1], an azabicyclo [5.2.0] nonalkalinyl group, and an oxatricyclo [5.3.1.1 ].

Alkyl, aza-adamantyl, oxaspiro [3.3 ]]A alkyl group,The heterocyclic group may be optionally further substituted by 0 to 8 groups selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Hydroxy, -SR^UNitro, cyano, isocyano, alkenyl, alkynyl, alkanyl, hydroxyalkyl, alkanyl, carbocyclyl, heterocyclyl, C₂—₈Alkenyl radical, C₂.₈Alkynyl, - (CH)₂)_m-C(=0)-R^u、 -(CH₂)_m-C(=0)-0-Rⁿ、 -(CH₂)_m-C(=0)-NRⁿR^{l la}、 -(CH₂)_m-S(=0)_n-R^u、 -0-C(=0)-0-R^uor-NR^uR^llaM is selected from 0, 1,2,3,4 or 5, and n is selected from 0, 1 or 2. Heterocyclyl, as used herein, is defined as above. "amino" means-NH₂。

By "cyano" is meant^N。

"isocyano" refers to a cyano group^≡G_。

'Miao' for treating nitriteThe radical "means-N0₂。

"hydroxy" means-OH.

"mercapto" means-SH.

"acid group" means-C (=0) H.

"carboxyl" means-COOH.

"=0" is a common usage in the art and refers to doubly bonded oxygen atoms, such as doubly bonded oxygen atoms bonded to carbon atoms in a carbonyl group.

The "hydroxyl-alkyl" refers to an alkyl substituted with 1,2 or 3 hydroxyl groups, and the alkyl is preferably a C1-4 alkyl. Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxypropyl, 1, 3-dihydroxypropyl and 2, 3-dihydroxypropyl.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid, and which is obtained by reaction with a non-toxic inorganic or organic base. Non-limiting examples of the inorganic base include sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, barium; non-limiting examples of the organic base include ammonia, trimethylamine, tetramethylammonium, diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2, 6-lutidine, caffeine, procaine, choline, betaine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, penicillin benzathine salts.

"carrier" means a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

An "adjuvant" is a non-specific immunopotentiator that, when injected with or pre-injected into a body with an antigen, enhances the body's immune response to the antigen or alters the type of immune response.

The "diluent" is also called "filler". When the raw medicine is processed into powder, or inert substances which are added for dilution are conveniently sprayed. Such as: clay, kaolin, china clay, talc, etc.

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying functional groups in compounds of the invention, which modifications may be removed by routine manipulation or in vivo, to yield the parent compound. Prodrugs include compounds of the present invention wherein one of the carboxyl groups is attached to any group that, when administered to a mammalian subject, cleaves to form a free carboxyl group. Examples of prodrugs include, but are not limited to, compounds of the present invention wherein the carboxyl functional group is bonded to methanol, ethanol, or benzyl alcohol.

"cocrystal" refers to a crystal in which the active pharmaceutical ingredient and a cocrystal former are bound by hydrogen bonding or other non-covalent bonds, wherein the API (active pharmaceutical ingredient) and CCF (cocrystal former) are both solid in pure form at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate. Non-limiting examples of the "co-crystal former" include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid, pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, and lactic acid, Maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethane-sulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phentermine, ethylenediamine, glucosamine, methylglucamine, dihydrogenate, pantothenic acid, stearic acid, succinic, Theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine and N-ethylpiperidine.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.

"optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group that is selectively substituted by an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclic group is substituted by an alkyl group, and cases where the heterocyclic group is not substituted by an alkyl group.

By "pharmaceutical composition" is meant a combination of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof or/and one or more other therapeutic agents, as well as pharmaceutically acceptable excipients, adjuvants, diluents and carriers.

"EC₅₀"half effective concentration" means the concentration at which half of the maximum effect is achieved. Detailed Description

The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) in

10"⁶The units in (ppm) are given.

NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDC 1)₃) Deuterated methanol (CD)₃OD), internal standard is tetramethylsilane alkyl (TMS). MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C181004.6 mm). The thin-layer chromatography silica gel plate uses a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by thin-layer chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 column chromatography, and generally, the tobacco yellow sea silica gel 200-300 meshes is used as a carrier.

Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatanchitechnology, Anniji chemistry, Shanghai Demer, Chengdong chemical, Shaoshi chemical technology, Bailingwei technology, and the like.

The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is room temperature, unless otherwise specified.

The room temperature is the most suitable reaction temperature and is 20 ℃ to 30 ℃.

Other symbols used herein have the following meanings:

s is a single peak;

d is a doublet peak;

t is a triplet;

q is quartet;

m is a multiplet;

br is broad peak;

hz is Hz;

bn is benzyl;

me is methyl;

et is ethyl;

ts is p-toluenesulfonyl;

TBS is tert-butyl dimethyl silicon base. Intermediate 1: 5- [3- (hydroxymethyl) phenyl ] -4-methyl-bicyclo [4.2.0] octan-1, 3, 5-trizin-2-ol (lm)

5-[3-(hydroxymethyl)phenyl]-4-methyl-bicyclo[4.2.0]octa-l,3,5-trien-2-ol

The first step is as follows: 2-benzyloxy-4-methyl-1-nitrobenzene (lb)

2-benzyloxy-4-methyl- 1 -nitro-benzen

5-methyl-2-hydroxy-1-nitrobenzene la (51.04 g, 333 mmol) was dissolved in acetonitrile (300 mL), benzyl bromide (57.00 g, 333 mmol) and potassium carbonate (92.13 g, 666 mmol) were added in this order, and the mixture was heated under reflux for 1.5 hours, filtered, and the filtrate was concentrated under reduced pressure to give 2-benzyloxy-4-methyl-1-nitrobenzene lb (80.77 g, 99.7% yield) as a pale yellow solid.

¾ NMR (300 MHz, CDC1₃) δ 7.81 (d, 1Η), 7.56― 7.30 (m, 5H), 6.93 (s, 1H), 6.83 (d, 1H), 5.22 (s, 2H), 2.39 (s, 3H).

The second step is that: 2-benzyloxy-4-methylaniline (lc)

2-benzyloxy-4-methyl-aniline

Iron powder (10.39 g, 186 mmol) and ammonium chloride (2.16 g, 40 mmol) were dissolved in a mixed solution of ethanol (150 mL) and water (150 mL), heated under reflux for 15 minutes, 2-benzyloxy-4-methyl-1-nitrobenzene lb (15.08 g, 62 mmol) was added to the reaction flask, heated under reflux for 1.5 hours, filtered, the filtrate was extracted with ethyl acetate (100 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-benzyloxy-4-methylaniline lc as a tan solid (11.87 g, yield 89.8%).

The third step: 2-oxy-1-bromo-4-methyl-benzene (Id)

2-benzyloxy- 1 -bromo-4-methyl -benze

Dissolving 2-benzyloxy-4-methylaniline lc in acetone (80 mL), adding a hydrobromic acid solution (45 mL, hydrobromic acid content w/w = 48%) under an ice salt bath, stirring uniformly, then slowly adding a solution of sodium nitrite (4.22 g, 61.21 mmol) in water (20 mL), stirring for 10 minutes, slowly adding a solution of cuprous bromide (5.18 g, 64.00 mmol) in hydrobromic acid (10mL, hydrobromic acid content w/w = 48%), heating to 75 ℃, stirring for 2.5 hours, naturally cooling to room temperature, adding saturated saline (lOO mL), extracting with ethyl acetate (100 mL x2), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ) = 100: 1) to give 2-benzyloxy-1-bromo-4-methyl-benzene Id as pale yellow oil (2.94 g, yield 89.8%)

The fourth step: 1, 1-diethoxyethylene (If)

1 , 1 -diethoxyethene

CH₂

. A human.

Bromoacetaldehyde diethyl acetal (58.80 g, 29.84 mmol, Astatech), and octadecanoyl hexaether were added to the reaction flask in this order

(1.59 g, 6.00 mmol) and anhydrous tetrahydrofuran (200 mL), potassium tert-butoxide (34.20 g, 30.48 mmol) was added at 0 ℃ and the reaction was stirred in an ice bath for 2 hours, filtered, distilled at atmospheric pressure, the tetrahydrofuran and tert-butanol fractions were collected at 130 ℃ and distilled under reduced pressure with a water pump to give 1, 1-diethoxyethylene If as a colorless oil (15.00 g, 43.3% yield).

¾ NMR (400 MHz, CDC1₃): δ 3.83― 3.73 (m, 4H), 3.04 (d, 2H), 1.33― 1.24 (m, 6H)。

The fifth step: 5-benzyloxy-3-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-7-one (lg) 5-benzylioxy-3-methyl-bicyclo [4.2.0] o 7-one

Dissolving 2-benzyloxy-1-bromo-4-methylbenzene Id in tetrahydrofuran (150 mL), sequentially adding sodium amide (4.5 g, 115.5 mmol) and 1, 1-diethoxyethylene If (13.4 g, 115.5 mmol), heating and refluxing for 20 hours, slowly pouring the reaction solution into ice water (100 mL), adding 12 mol/L concentrated hydrochloric acid (5 mL), stirring at room temperature for 1 hour, extracting with ethyl acetate (100 mL x2), combining organic phases, concentrating under reduced pressure, and separating and purifying the residue by silica gel column chromatography (n-hexyl/ethyl acetate (v & ltu & gt)_V1) to give 5-benzyloxy-3-methyl-bicyclo [4.2.0] as a yellow oil]Oct-1, 3, 5-trien-7-one lg (2.01 g, yield 16.0%).

¾ NMR (400 MHz, CDC1₃) δ 7.44 (d, 2Η), 7.40― 7.31 (m, 3H), 6.87 (s, 1H), 6.71 (s, 1H), 5.44 (s, 2H), 3.87 (s, 2H), 2.38 (s, 3H).

And a sixth step: 5-benzyloxy-2-bromo-3-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-7-one (lh)

5-benzyloxy-2-bromo-3-methyl-bicycl -l,3,5-trien-7-one

Reacting 5-benzyloxy-3-methyl-bicyclo [4.2.0]Octyl-1, 3, 5-trien-7-one lg (2.00 g, 8.40 mmol) was dissolved in glacial acetic acid (150 mL), and benzyltrimethylammonium tribromide (PhCH) was added in sequence₂N⁺(CH₃)₃Br₃3.59 g, 9.24 mmol) and zinc chloride (1.34 g, 10.08 mmol) were stirred at room temperature for 6 hours, and an aqueous sodium sulfite solution (100 mL, Na) was added to the reaction mixture₂S0₃Content (wt.)_WExtracting with ethyl acetate (50 mL x2), combining organic phases, concentrating under reduced pressure, separating and purifying residues by silica gel column chromatography (n-hexyl-alkyl/ethyl acetate (v/v) = 80: 1) to obtain 5-benzyloxy-2-bromine-3-methyl-bicyclo [4.2.0] yellow oily]Oct-1, 3, 5-trien-7-one lh (2.02 g, 76.0% yield).

¾ NMR (300 MHz, DMSO-₆) δ 7.69 (d, 1H), 7.47― 7.37 (m, 4H), 6.93 (d, 1H), 5.38 (s, 2H), 3.99 (s, 2H), 2.51 (s, 3H).

The seventh step: 2-benzyloxy-5-bromo-4-methyl-bicyclo [4.2.0] octa-1, 3, 5-triene (li)

2-benzyloxy-5-bromo-4-methyl-bicyclo[4.2.0]octa-l,3,5-triene

Dissolving 5-benzyloxy-2-bromo-3-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-7-one lh in glacial acetic acid (100 mL), adding zinc powder (2.05 g, 31.5 mmol), heating to 60 ℃, stirring and reacting for 6 hours, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (n-hexyl/ethyl acetate (v/v) = 100: 1) to obtain 2-benzyloxy-5-bromo-4-methyl-bicyclo [4.2.0] octa-1, 3,5-trien li (2.02 g, yield 76.0%) as yellow oil.

Eighth step: 3- (2-benzyloxy-4-methyl-5-bicyclo [4.2.0] octa-1, 3, 5-triene) -benzaldehyde (lj)

3-(2-benzyloxy-4-methyl-5-bicy -l,3,5-trienyl)benzaldehyde

Reacting 2-benzyloxy-5-bromo-4-methyl-bicyclo [4.2.0]]Octyl-1, 3,5-trienyl li (600 mg, 1.98 mmol) was dissolved in a mixed solution of toluene (15 mL), water (15 mL) and ethanol (3 mL), and 3-formylphenylboronic acid (330 mg, 2.17 mmol), potassium carbonate (550 mg, 3.96 mmol) and tetrakis (triphenylphosphine) palladium (8 mg, 0.05 mmol) were added in this order and heated to 90 deg.C. C stirring reaction for 8 hours, extracting with ethyl acetate (50 mL x2), combining organic phases, concentrating under reduced pressure, separating and purifying residues by silica gel column chromatography (n-hexyl alkyl/ethyl acetate (v:)_V;» = 20_:l) to give 3- (2-benzyloxy-4-methyl-5-bicyclo [4.2.0] as a yellow oil]Octa-1, 3, 5-triene) -benzaldehyde lj (201 mg, yield 31.0%).

¾ NMR (400 MHz, CDC1₃) δ 10.05 (s, 1Η), 7.81 (t, 2H), 7.59― 7.53 (m, 2H), 7.51― 7.36 (m, 5H), 6.76 (s, 1H), 5.20 (s, 2H), 3.28 - 3.18 (m, 2H), 3.12 - 3.04 (m, 2H), 2.25 (s, 3H).

The ninth step: [3- (2-benzyloxy-4-methyl-5-bicyclo [4.2.0] octa-1, 3, 5-triene) -phenyl ] methanol (lk)

[3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenyl]methanol

3- (2-benzyloxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3-ene) -benzaldehyde lj (0.20 g, 0.61 mmol) was dissolved in methanol

(40 mL), sodium borohydride (46 mg, 1.22 mmol) was added, the mixture was stirred at room temperature for 30 minutes, a saturated ammonium chloride solution (5 mL) was added to the reaction solution, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexylalkyl/ethyl acetate (v/v) =10: 1) to obtain [3- (2-oxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene) -phenyl ] methanol lk (0.19 g, 95.0% yield) as a white solid

The tenth step: 5- [3- (hydroxymethyl) phenyl ] -4-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (lm)

5-[3-(hydroxymethyl)phenyl]-4-methyl-bicyclo[4.2.0]octa-l,3,5-trien-2-ol

[3- (2-benzyloxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene) -phenyl ] methanol lk (0.19 g, 0.58 mmol) was dissolved in methanol (50 mL), palladium/carbon (0.10 g, palladium content w/w =10%) was added and the mixture was reacted at room temperature for 2 hours under a hydrogen atmosphere, followed by filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5: 1) to obtain 5- [3- (hydroxymethyl) phenyl ] -4-methyl-bicyclo [4.2.0] oct-1, 3, 5-triene-2-ol lm (0.13 g, yield 93.0%).

^ NMR (400 MHz, CDC1₃) δ 7.40 (t, lH), 7.31 (d, 2H), 7.23 (d, IH), 6.61 (S, IH), 4.74 (S, 2H), 3.07 (m, 4H), 2.24 (S, 3H), intermediate 2 methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (2 d)

-methyl-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate

2- (6-hydroxybenzofuran-3-yl) acetic acid (200g, 1.04 mol) was dissolved in methanol (1.2L), triethylamine (13 mlL, 0.1 mol), palladium on carbon (20 g, palladium content w/w =10%) were added, and after replacement of hydrogen gas, the reaction was carried out at room temperature for 24 hours. Filtering, concentrating the filtrate, dissolving the residue with ethyl acetate (1L), adding water for dilution, adjusting the pH to be less than or equal to 2 by concentrated hydrochloric acid, then sequentially washing the organic layer with water and saturated saline solution, drying the organic layer with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and recrystallizing the residue with a dichloromethyl to obtain the offwhite powdery 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid (180 g, yield 90%).

¾ NMR (400 MHz, DMSO-d₆) δ 12.28 (s, IH), 9.24 (s, IH), 6.97 (d, IH), 6.23 (dd, IH), 6.15 (d, IH), 4.64 (t, IH), 4.14 (dd, IH), 3.62 (m, IH), 2.65 (dd, IH), 2.45 (dd, IH).

The second step is that: (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid (R) -l-phenethylamine salt (2 b)

(R)- 1 -phenylethanaminium (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate

2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid 2a (9.32 g, 48 mmol) was dissolved in acetone (80 mL), and an acetone solution of R-phenethylamine (2.91 g, 24 mmol, 13 mL) was slowly dropped into the reaction solution under reflux. After the dropwise addition, the heating was stopped, the temperature was naturally decreased to room temperature, and the mixture was stirred overnight. Filtering, suspending the solid in a mixed solution of ethyl acetate and water, dropwise adding 1M diluted hydrochloric acid until the pH of the filtrate is less than 2, adding ethyl acetate for extraction, concentrating under reduced pressure, dissolving the concentrate in acetone (35 mL), heating to reflux, and slowly dropwise adding an acetone solution (1.53 g, 12.7 mmol) of R-phenylethylamine into the reaction solution. After the dropwise addition, the heating was turned off, the temperature was naturally decreased to room temperature, and the mixture was stirred overnight. Filtration, washing of the precipitate with a small amount of acetone, and recrystallization of the precipitate in acetone (25 mL) gave (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl;) acetic acid (R-l-phenethylamine salt 2b (600 mg, 60%)

The third step: (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid (2 c)

(S)-2-(6-hydroxy-2,3-dihydrobenz

(S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid (R-l-phenethylamine salt 2b) was dissolved in 1M hydrochloric acid solution, extracted with ethyl acetate (50 mL 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (S) 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid 2c (370 mg, 99%).

The fourth step: (S) -methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (2 d)

(S)-methyl-2-(6-hydroxy-2,3-dihy e

At room temperature, (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid 2C was dissolved in methanol, concentrated sulfuric acid (0.2 mL) was added dropwise, after heating to 50 ℃ and reacting for 2 hours, a saturated sodium carbonate solution was added to terminate the reaction, ethyl acetate (50 mL × 3) was used for extraction, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) =30: 1) to obtain (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) methyl acetate 2d as a white solid (317 mg, 80%, ee% = 99%).

Intermediate 3 5-bromo-4-methyl-bicyclo [4.2.0] oct-1, 3, 5-trien-2-ol (3 e)

A third step of 5-bromo-4-methyl-bicyclo [4.2.0] octa-l,3, 5-trien-2-ol

The first step is as follows: 5-benzyloxy-3-methyl-bicyclo [4.2.0]Octane-1, 3, 5-trien-7-ol

5-benzyloxy-3-methyl-bicyclo[4.2.0]octa-l,3,5-trien-7-ol

5-benzyloxy-3-methyl-bicyclo [4.2.0] oct-1, 3, 5-trien-7-one lg (10.0 g, 41.97 mmol) was dissolved in a mixed solution of methanol (30 mL) and tetrahydrofuran (50 mL), and sodium borohydride (3.18 g, 83.94 mmol) was added in portions at 0 ℃, and after completion of the addition, the mixture was warmed to room temperature to react for 30 minutes. After the reaction was completed, water (30 mL) was added to quench the reaction, saturated aqueous ammonium chloride (60 mL) was added, extraction was performed with ethyl acetate (50 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and purified by slurrying with petroleum ether to give 5-benzyloxy-3-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-7-ol 3a (9.35 g, 93% yield) as a white solid

The second step is that: 5-benzyloxy-7-iodo-3-methyl-bicyclo [4.2.0] octa-1, 3, 5-triene (3 b)

5-benzyloxy-7-iodo-3-methyl-bicyclo[4.2.0]octa-l,3,5-triene

Anhydrous oxygen-free treatment, nitrogen protection, iodine (26.3 g, 103.62 mmol) was added to toluene (120 mL), triphenylphosphine (23.6 g,89.80 mmol) was added, stirring was carried out for 5 minutes, imidazole (14.1 g,207.23 mmol) was added, stirring was carried out for 10 minutes, and 5-benzyloxy-3-methyl-bicyclo [4.2.0]]Octane-1, 3, 5-trien-7-ol 3a (8.3 g, 34.54 mmol) was dissolved in toluene (40 mL), and the mixture was added to the reaction, followed by stirring at room temperature for 1 hour. After completion of the reaction, a saturated aqueous solution of sodium thiosulfate (100 mL) was added thereto and stirred for 5 minutes. Extracting the aqueous layer with petroleum ether (100 mL x 3) after layering, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (petroleum ether/dichloromethyl alkyl (v/v) =20/l) to obtain 5-benzyloxy-7-iodine-3-methyl-bicyclo [4.2.0] as a light yellow solid]Octa-1, 3, 5-triene 3b (9.9 g, 82% yield).

The third step: 5-benzyloxy-3-methyl-bicyclo [4.2.0] octa-1, 3, 5-triene (3 c)

5-benzyloxy-3-methyl-bicyclo[4.2.0]octa-l,3,5-triene

Anhydrous and oxygen-free treatment, nitrogen protection, and adding lithium aluminum hydride (2.68)g,70.67 mmol) was added to tetrahydrofuran (120 mL) and 5-benzyloxy-7-iodo-3-methyl-bicyclo [4.2.0]Octane-1, 3, 5-triene 3b (9.9 g, 28.26 mmol) was dissolved in tetrahydrofuran (180 mL), and the solution was added dropwise to the reaction, followed by stirring at room temperature for 30 minutes after completion of the addition. After the reaction is finished, water (100 mL) is slowly added to quench the reaction, concentrated hydrochloric acid is added to adjust the pH value to 5, then ethyl acetate is used for extraction (100 mL x 3), organic phases are combined, anhydrous sodium sulfate is dried, filtration is carried out, the filtrate is decompressed and concentrated, and the residue is separated and purified by silica gel column chromatography (petroleum ether/dichloro-methyl alkyl (v & lter & gt)_V; (20/l) 5-benzyloxy-3-methyl-bicyclo [ 4.2.0) was obtained as a light yellow solid]Octa-1, 3, 5-triene 3c (6.27 g, yield: 98.9%).

¾ NMR (400 MHz, DMSO-d₆) δ 7.42― 7.30 (m, 5H), 6.56 (s, 1H), 6.50 (s, 1H), 5.13 (s, 2H), 3.21― 3.13 (m, 2H), 3.06 - 2.96 (m, 2H), 2.22 (s, 3H).

The fourth step: 3-methylbicyclo [4.2.0] octa-1, 3, 5-trien-5-ol (3 d)

3-methylbicyclo[4.2.0]octa-l,3,5-trien-5-ol

5-benzyloxy-3-methyl-bicyclo [4.2.0] octa-1, 3, 5-triene 3C (49.0 g, 218,42 mmol) was dissolved in methanol (500 mL), and palladium on carbon (5.0 g, palladium content w/w =10%) was added to react at 35 ℃ under a hydrogen atmosphere for 20 hours. After the reaction, the mixture was filtered, and the filtrate was concentrated and then slurried to obtain 3-methylbicyclo [4.2.0] octa-1, 3, 5-trien-5-ol 3d as a yellow solid (52.5 g, 93.9% yield).

The fifth step: 5-bromo-4-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol (3 e)

5-bromo-4-methyl-bicyclo[4.2.0]octa-l,3,5-trien-2-ol

3-Methylbicyclo [4.2.0] octa-1, 3, 5-trien-5-ol 3d (22.0 g, 0.16 mol) and benzyltrimethylammonium tribromide (63.9 g, 0.16 mol) were dissolved in acetonitrile (600 mL) and stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous solution (300 mL) of sodium thiosulfate was added and the mixture was stirred for 30 minutes. Extraction with ethyl acetate (300 mL x 3), combining the organic phases, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and slurrying of the residue with petroleum ether afforded 5-bromo-4-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol 3e (29.0 g, 84% yield) as a white solid.

¾ NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 6.55 (s, 1H), 2.93 (s, 4H), 2.21 (s, 3H) example 1: 2- [6- [ [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-pentacyclic [4.2.0] octan-alkyl-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (compound 1)

2-[6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l ,3,5-trienyl]phenyl]meth oxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

The first step is as follows: 3-methylthiopropyl-4-methylbenzenesulfonic acid (1B)

3 -methylsulfanylpropyl 4-methylbenzenesulfonate

Dissolving 3-methylthiopropyl-1-ol lA (20.0 g, 188 mmol, demer) in toluene (100 mL), adding Ν, Ν, Ν ', Ν' -tetramethyl-1, 6-hexanediamine (3.25 g, 19 mmol) and triethylamine (40 mL, 277 mmol) in this order under nitrogen protection, slowly adding p-toluenesulfonyl chloride (54.0 g, 283 mmol) in toluene (100 mL) under ice bath, stirring in ice bath for reaction for 3 hours, extracting with ethyl acetate (100 mL × 2), combining organic phases and drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate l, =30: 1) to obtain 3-methylthiopropyl-4-methylbenzenesulfonic acid 1B (32.34 g), yield 67.0%).

The second step is that: 3-Methylsulfanoylpropyl-4-methylbenzenesulfonic acid (1C)

3 -methylsulfonylpropyl 4-methylbenzenesulfonate

Dissolving 3-methylthiopropyl-4-methylbenzenesulfonic acid 1B (12.2 g, 46.9 mmol) in methanol (250 mL), stirring in an ice bath for 5 minutes, slowly adding a water (250 mL) solution of potassium peroxodisulfate complex salt (57.7 g, 93.8 mmol) dropwise, removing the ice bath, stirring at room temperature for 20 hours, slowly pouring the reaction solution into water (1L), stirring for 10 minutes, filtering, dissolving the filter cake in a bischloromethane (100 mL), drying anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 3-methylthiopropyl-4-methylbenzenesulfonic acid lC (11.89 g, yield 86.7%) as a white powder.

The third step: [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-bicyclo [4.2.0] octan-1, 3, 5-triene ] phenyl ] methanol (1D)

[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methanol

Dissolving 5- (3- (hydroxymethyl) phenyl) -4-methyl-bicyclo [4.2.0] octan-1, 3, 5-trien-2-ol lm (0.16 g, 0.67 mmol, intermediate 1) in Ν, Ν -dimethylformamide (25 mL), adding 3-methyl thioacyl-4-methylbenzenesulfonic acid 1C (0.11 g, 0.80 mmol) and cesium carbonate (0.26 g, 0.80 mmol), heating to 80 ℃, stirring for 2 hours, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate l, = 1: 2) to obtain [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-bicyclo [4.2.0] octan-1 as a white solid, 3, 5-Triene ] phenyl ] methanol 1D (0.18 g, 75.0% yield).

The fourth step: 2- (6-hydroxybenzofuran-3-yl) acetic acid (1F)

2-(6-hydroxybenzofuran-3-yl)acetic acid

Ethyl chloroformylacetate (28.00 g, 170 mmol) was dissolved in concentrated sulfuric acid at 0 ℃ and resorcinol 1E (17.62 g, 160 mmol) was added and reacted at room temperature for 2 hours, the reaction solution was poured into ice water, the mixture was filtered, the filter cake was washed with water (lOO mL x 3) and dried, the filter cake was dissolved in 1M sodium hydroxide solution (1L), heated under reflux for 2 hours, cooled to room temperature, the reaction solution was acidified with concentrated sulfuric acid, extracted with ethyl acetate (280 mL x 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1F (16.00 g, 52% yield) of 2- (6-hydroxybenzofuran-3-yl) acetic acid as a brown solid.

The fifth step: 2- (6-hydroxybenzofuran-3-yl;) methyl acetate (1G)

methyl 2-(6-hydroxybenzofuran-3-yl)acetate

2- (6-hydroxybenzofuran-3-yl) acetic acid lF (16.00 g, 83.3 mmol) was dissolved in methanol (75 mL), concentrated sulfuric acid (8 mL) was added dropwise, and the mixture was refluxed for 4 hours, cooling to room temperature, concentrating under reduced pressure, adding a dichlorosilane (300 mL), washing with water (100 mL x 3), washing with saturated brine (100 mL x 3), combining the organic phases, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate i N, =4: 1) to give methyl 2- (6-hydroxybenzofuran-3-yl) acetate 1G (8.37G, 49% yield) as a light yellow solid.

And a sixth step: (2, 3-dihydrobenzofuran-3-yl;) acetic acid methyl ester (1H)

methyl 2-(2,3-dihydrobenzofuran- -yl)acetate

Methyl 2- (6-hydroxybenzofuran-3-yl) acetate lG (7.38 g, 35.8 mmol) was dissolved in methanol (65 mL), palladium on carbon (1.38 g, palladium content w/w =10%) was added, reaction was carried out at room temperature for 18 hours under a hydrogen atmosphere, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate l, =5: 1) to obtain methyl (2, 3-dihydrobenzofuran-3-yl) acetate 1H (4.50 g, yield 60.0%) as a white solid.

The seventh step: methyl 2- [6- [ [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-nocyclic [4.2.0] octan-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (II)

2-[6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]meth oxy]-2,3-dihydrobenzo

Reacting [3- [ 4-methyl-2- (3-methylsulfonylpropoxy) -5-cyclo [4.2.0]]Alkan-1, 3, 5-triene]Phenyl radical]Methanol 1D (0.18 g,0.5 mmol) is dissolved in a methyl chloride alkyl (30 mL), methyl acetate 1H (0.13 g, 0.6 mmol), tributylphosphine (0.22 g, 1.1 mmol) and I, gamma- (azodicarbonyl) dipiperidine (0.28 g, 1.1 mmol) are sequentially added, stirring is carried out for 30 minutes at room temperature, decompression and concentration are carried out, and residues are separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v & ltu & gt & lt & gt)_V;» =l_:l) obtaining 2- [6- [ [3- [ 4-methyl-2-P-methanesulfonylpropoxy; ] 5-bicyclo [4.2.0] as a white solid]Alkan-1, 3, 5-triene]Phenyl radical]Methoxy radical]-2, 3-dihydrobenzofuran-3-yl]Methyl acetate II (0.22 g, 78.0% yield).

Eighth step: 2- [6- [ [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-nocyclic [4.2.0] octan-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 1)

Dissolving methyl 2- [6- [ [3- [ 4-methyl-2- (3-methylsulfonylpropoxy) -5-bicyclo [4.2.0] octan-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate II (0.21 g, 0.38 mmol) in a mixed solution of methanol (20 mL) and water (20 mL), adding sodium hydroxide (0.15 g, 3.82 mol), stirring at room temperature for 1 hour, dropwise adding 2M hydrochloric acid until the pH of the reaction solution is 3, extracting with ethyl acetate (20 mL x 3), combining organic phases, concentrating under reduced pressure, and separating and purifying by silica gel column chromatography (ethyl acetate) to obtain 2- [6- [ [3- [ 4-methyl-2- (3-methylsulfonylpropoxy) as a white solid Acylpropoxy) -5-benzocyclo [4.2.0] octa-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid compound 1 (0.13 g, 62.0% yield).

^ NMR (400 MHz, CDC1₃) δ 7.41 (t,lH), 7.34 (d, 2H), 7.23 (s, IH), 7.06 (d, IH), 6.62 (s, IH), 6.55 ― 6.45 (m, 2H), 5.06 (s, 2H), 4.77 (t, IH), 4.33― 4.28 (m, IH), 4.26 (dd, J = 15.4, 5.7 Hz, 2H), 3.86 ― 3.75 (m, IH), 3.30― 3.17 (m, 4H), 3.10― 3.03 (m, 2H), 2.97 (s, 3H), 2.81 (dd,lH), 2.62 (dd,lH), 2.32 (dt,2H), 2.22 (s, 3H).

Example 2- [ (3S) -6- [ [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-bicyclo [4.2.0] l,3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 2)

2-[(3S)-6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

The first step is as follows: 2- [ (3S) -6- [ [3- [ 4-methyl-2- (3-methanesulfonyl propane ]Oxy) -5-bicyclo [4.2.0]-1,3, 5-triene]Phenyl radical]Methoxy radical]-2, 3-dihydrobenzofuran-3-yl]Acetic acid methyl ester (2B)

2-[(3S)-6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrob

Dissolving [3- (4-methyl-2- (3-methylsulfonylpropoxy) -5-bicyclo [4.2.0] octa-1, 3, 5-triene ] phenyl) methanol 1D (0.21 g, 0.58 mmol) in a dichloro-methyl-alkyl (30 mL), sequentially adding (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 2D (0.15 g, 0.70 mmol, intermediate 2), tributylphosphine (0.26 g, 1.27 mmol) and gamma, azodicarbonyl dipiperidine (0.32 g, 1.27 mmol), stirring at room temperature for 1 hour, concentrating under reduced pressure, separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2: 1) to obtain 2- [ (3S) solid 2- [ (3S-ethyl acetate) =2: 1) ) Methyl-6- [ [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-nocyclo [4.2.0] -1,3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 2B (0.13 g, 41.0% yield).

The second step is that: 2- [ (3S) -6- [ [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-bicyclo [4.2.0] -1,3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 2)

2-[(3S)-6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzo

Dissolving methyl 2- [ (3S) -6- [ [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-bicyclo [4.2.0] -1,3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 2B (130 mg, 0.24 mmol) in a mixture of tetrahydrofuran (10mL), methanol (10mL) and water (20 mL), adding sodium hydroxide (20 mg,0.48 mmol), stirring at room temperature for 1 hour, concentrating under reduced pressure, adding 2M hydrochloric acid dropwise to a reaction solution pH of 3, extracting with ethyl acetate (50 mL x2), combining the organic phases, concentrating under reduced pressure, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1: 1) Compound 2- [ (3S) -6- [ [3- [ 4-methyl-2- (3-methanesulfonylpropoxy) -5-benzocyclo [4.2.0] -1,3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid compound 2 was obtained as a white solid (80 mg, yield 61.0%).

¾ NMR (400 MHz, CDC1₃) δ 7.40 (t,lH), 7.32(d, 2H), 7.21(s, 1H), 7.04 (d, 1H), 6.60 (s, 1H), 6.55 - 6.45 (m, 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.33 - 4.28 (m, 1H), 4.24(dd, 2H), 3.86 - 3.75 (m, 1H), 3.30― 3.17 (m, 4H), 3.10― 3.03 (m, 2H), 2.96 (s, 3H), 2.80 (dd, 1H), 2.61(dd, 1H), 2.30 (dt, 2H), 2.22 (s, 3H).

EXAMPLE 3- [6- [ [3- [5- (3-Methylsulfonylpropyloxy) -2-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 3)

2-[6-[[3-[5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3- di

The first step is as follows: 1-oxy-2-bromo-benzene (3B)

1 -benzyloxy-2-bromo-benzene

O-bromophenol 3A (60 g, 347 mmol) was dissolved in acetonitrile (300 mL), benzyl bromide (59 g, 347 mmol) and potassium carbonate (72 g, 520 mmol) were sequentially added, the mixture was refluxed for 1.5 hours, cooled to room temperature, saturated brine (200 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-benzyloxy-2-bromo-benzene 3B as a colorless liquid (91.12 g, 99% yield). The second step is that: 5-oxy-bicyclo [4.2.0] octa-1, 3, 5-trien-7-one (3C)

5-benzyloxybicyclo[4.2.0]octa-l,3,5-

Dissolving 1-benzyloxy-2-bromo-benzene 3B (30.00 g, 114.07 mmol) in tetrahydrofuran (250 mL), adding 1, 1-diethoxyethylene If (26.46 g, 230 mmol) and sodium amide (8.97 g, 230 mmol), stirring under nitrogen, heating and refluxing for 34 hours, adding ice water (100 g) and concentrated hydrochloric acid (30 mL) to the reaction solution, stirring at room temperature for 2 hours, extracting with ethyl acetate (200 mL. times.2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate: (petroleum ether/ethyl acetate) ((250 mL)_V/_V) =80_:l) to give 5-benzyloxy-bicyclo [4.2.0] as a white solid]Oct-1, 3, 5-trien-7-one 3C (3.2 g, 13% yield).

The third step: 5-oxy-2-bromo-bicyclo [4.2.0] octa-1, 3, 5-trien-7-one (3D)

5-benzyloxy-2-bromo-bicyclo[4.2.0]-one

Reacting the 5-benzyloxy-bicyclo [4.2.0]]Alkyl-1, 3,5-00g, 4.46 mmol) was dissolved in glacial acetic acid (60 mL), benzyltrimethylammonium tribromide (2.98 g, 19.89 mmol) and zinc chloride (1.48 g, 11.15 mmol) were added in that order, the mixture was stirred at room temperature for 5 hours, and water (40 mL) and a sodium sulfite solution (20 mL, Na) were added to the reaction mixture₂SO₃Content w/w = 5%), extraction with ethyl acetate (50 mL × 2), combination of the organic phases, concentration under reduced pressure, and column chromatography of the residue on silica gel (n-hexyl-alkyl/ethyl acetate (v/v) = 80: 1) to give 5-benzyloxy-2-bromocyclo [4.2.0] as a white solid]Oct-1, 3, 5-trien-7-one 3D (0.79 g, 59.0% yield).

The fourth step: 2-benzyloxy-5-bromo-bicyclo [4.2.0] octa-1, 3, 5-triene (3E)

2-benzyloxy-5-bromo-bicyclo[4.2.0]octa-l,3,5-triene

Reacting 5-benzyloxy-2-bromo-cyclo [4.2.0]]Octane-1, 3, 5-trien-7-one 3D (0.50 g, 1.65 mmol) was dissolved in glacial acetic acid (20 mL), zinc powder (1.07 g, 16.5 mmol) was added, the mixture was heated to 80 ℃ and stirred for 6 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate l, =50: 1) to give 2-benzyloxy-5-bromo-bicyclo [4.2.0] as a white solid]Octa-1, 3, 5-triene 3E (0.22 g, 47% yield).

¾ NMR (400 MHz, CDC1₃) δ 7.39 (m, 5H), 7.18 (d, 1H), 6.67 (d, 1H), 5.13 (s, 2H), 3.21 (m, 2H), 3.07 (m, 2H).

The fifth step: 3- (5-benzyloxy-2-cyclo [4.2.0] octa-1, 3, 5-triene) benzaldehyde (3F)

3-(5-benzyloxy-2-bicyclo[4.2.0]

2-benzyloxy-5-bromo-cyclo [4.2.0] octa-1, 3, 5-triene 3E (0.70 g, 2.42 mmol) was dissolved in toluene (15 mL), water

To a mixed solution of (15 mL) and ethanol (3 mL), 3-formylphenylboronic acid (0.54 g, 3.63 mmol), potassium carbonate (1.00 g, 7.26 mmol) and tetrakis (triphenylphosphine) palladium (0.14 g, 0.12 mmol) were added in this order, and the mixture was heated to 90 ℃. C was stirred for 6 hours, extracted with ethyl acetate (50 mL × 2), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate (v/v) = 8: 1), yielding 3- (5-benzyloxy-2-bicyclo [4.2.0] octa-1, 3, 5-triene) -benzaldehyde 3F (0.50 g, 66.0% yield) as a yellow oil.

And a sixth step: [3- (5-benzyloxy-2-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl ] methanol (3G)

[3-(5-benzyloxy-2-bicyclo[ -l,3,5-trienyl)phenyl]methanol

3- (5-benzyloxy-2-bicyclo [4.2.0] oct-1, 3, 5-triene) -benzaldehyde 3F (0.20G, 0.64 mmol) was dissolved in methanol (30 mL), and sodium borohydride (47 mg, 1.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give crude [3- (5-oxo-2-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl ] methanol 3G, which was used directly in the next reaction.

The seventh step: 2- [3- (hydroxymethyl) phenyl) cyclo [4.2.0] oct-1, 3, 5-triene ] -5-ol (3H)

2-[3-(hydroxymethyl)phenyl]bi 5-olReacting [3- (5-benzyloxy-2-cyclo [4.2.0]]Octane-1, 3, 5-triene) phenyl]Crude methanol 3G (200 mg, 0.63 mmol) was dissolved in methanol (10mL), palladium on charcoal (33 mg, palladium content w/w =10%) was added and reacted at room temperature for 2 hours under a hydrogen atmosphere, the filtrate was filtered, 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 obtain 2- [3- (hydroxymethyl) phenyl) bicyclo [4.2.0] cyclo [ 4.0 ] as a white solid]Octane-1, 3, 5-trienes]5-alcohol 3H (0.14 g, yield 98.0%).

Eighth step: [3- [5- (3-Methylsulfonylpropyloxy) -2-benzocyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methanol (31)

[3-[5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methanol

Dissolving 2- [3- (hydroxymethyl) phenyl) bicyclo [4.2.0] octa-1, 3,5-trien ] -5-ol 3H (0.15 g, 0.66 mmol) in N, N-dimethylformamide (10mL), adding 3-methylsulfamoylpropyl-4-methylbenzenesulfonic acid 1C (0.11 g, 0.79 mmol) and cesium carbonate (0.25 g, 0.77 mmol), heating to 80 ℃ and stirring for 1 hour, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate i N, = 1: 2) to obtain [3- [5- (3-methanesulfonylpropoxy) -2-bicyclo [4.2.0] octa-1 as a white solid, 3, 5-Triene ] phenyl ] methanol 31 (0.12 g, 52.0% yield).

The ninth step: methyl 2- [6- [ [3- [5- (3-methanesulfonylpropoxy) -2-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (3J)

methyl 2-[6-[[3-[5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydro

[3- [5- (3-methanesulfonylpropoxy) -2-benzocyclo [4.2.0] octa-1, 3, 5-triene ] phenyl ] methanol 31 (0.13 g,0.37 mmol) was dissolved in methyl dichloroalkyl (20 mL), methyl (2, 3-dihydrobenzofuran-3-yl) acetate 1H (0.094 g, 0.45 mmol), tributylphosphine (0.17 g, 0.83 mmol) and Γ - (azobiscarbonyl) dipiperidine (0.21 g, 0.83 mmol) were added in this order, and the mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate i N, = 1: 1) to give 2- [6- [ [3- [5- (3-methanesulfonylpropoxy) -2-benzocyclo ] methanol as a white solid 4.2.0] Oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid methyl ester 3J (0.13 g, 65.0% yield)

The tenth step: 2- [6- [ [3- [5- (3-methanesulfonylpropoxy) -2-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (compound 3)

2- [6- [ [3- [5- (3-methylsulfonylpropoxy) -2-bicyclo [4.2.0] octa-l,3,5-trienyl ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid methyl 2- [6- [ [3- [5- (3-methanesulfonylpropoxy) -2-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 3J (130 mg, 0.24 mmol) was dissolved in a mixture of methanol (5 mL) and water (5 mL), sodium hydroxide (48 mg, 1.21 mmol) was added, stirring was carried out at room temperature for 2 hours, the reaction was stopped, 2M hydrochloric acid was added dropwise to a reaction solution pH of 3, extraction was performed with ethyl acetate (50 mL × 2), the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethy =25: 1) to obtain compound 3 of 2- [6- [ [3- [5- (3-methanesulfonylpropoxy) -2-bicyclo [4.2.0] octa-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (80 mg, 64.0% yield).

¾ NMR (400 MHz, CDC1₃) δ 7.60 (s, IH), 7.52 (d, IH), 7.41 (m, 2H), 7.31 (d, IH), 7.07 (d, IH), 6.76 (d, IH), 6.51 (m, 2H), 5.06 (s, 2H), 4.77 (t, IH), 4.28 (dt, 3H), 3.82 (m, IH), 3.35 (dd, 4H), 3.26 (m, 2H), 2.97 (s, 3H), 2.81 (dd, IH), 2.62 (dd, IH), 2.33 (dt, 2H).

Example 4- [ (3S) -6- [ [3- [ 4-methyl-2- ((3R) -tetrahydrofuran-3-yl) -0-5-bicyclo [4.2.0] oct-1, 3, 5-TRI-Microphyll ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 4)

2-[(3S)-6-[[3-[4-methyl-2-[(3R)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phe nyljmethoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

The first step is as follows: [ (3S) -tetrahydrofuran-3-yl ] -4-methylbenzenesulfonic acid (4B)

[(3S)-tetrahydrofuran-3-yl]4-methylbenzenesulfonate

Dissolving (3S) -3-hydroxy-tetrahydrofuran 4A (881.1 mg, 20mmol) in toluene (20 mL), adding Ν, Ν, Ν ', Ν' -tetramethyl-1, 6-hexanediamine (1.72 g, 10 mmol), triethylamine (1.5 g, 15 mmol), 0 in sequence under nitrogen protection. C.A solution of p-toluenesulfonyl chloride (2.86 g, 15 mmol) in toluene (10mL) was slowly added dropwise, the reaction was stirred in an ice bath for 2 hours, quenched by addition of water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x2), the organic phases were combined and 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) =5: 1-4: 1) to give [ (3S) -tetrahydrofuran-3-yl ] -4-methylbenzenesulfonic acid 4B as a pale yellow liquid (1.68 g, yield 69.0%)

The second step is that: [3- [ 4-methyl-2- [ (3R) -tetrahydrofuran-3-yl ] -oxy-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methanol (4C)

[3-[4-methyl-2-[(3R)-tetrahydrofur -3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methanol

[ (3S) -tetrahydrofuran-3-yl ] -4-methylbenzenesulfonic acid 4B (145 mg, 0.6 mmol) was dissolved in N, N-dimethylformamide (5 mL), 5- (3- (hydroxymethyl) phenyl) -4-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol lm (120 mg,0.5 mmol, intermediate 1) and potassium carbonate (139 mg,1.0 mmol) were sequentially added, heated to 90 ℃ for reaction for 2 hours, quenched with water (20 mL), extracted with ethyl acetate (25 mL x 3), washed with water (20 mL x 3), the organic phases were combined and 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 i N, =2: 1) to give [3- [ 4-methyl-2- [ (3R) -tetrahydrofuran-3-yl ] -oxy-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methanol 4C as a pale yellow oil (155 mg, yield 99.0%).

¾ NMR (400 MHz, DMSO-₆): δ 7.36 (t, 1H), 7.27 - 7.21 (m, 2H), 7.17 (d, 1H), 6.60 (s, 1H), 5.20 (t, 1H), 5.05 (dt, 1H), 4.53 (d, 2H), 3.89― 3.70 (m, 4H), 3.22― 3.09 (m, 2H), 3.06― 2.98 (m, 2H), 2.24 - 2.00 (m, 5H).

The third step: methyl 2- [ (3S) -6- [ [3- [ 4-methyl-2- ((3R) -tetrahydrofuran-3-yl) -oxo-5-bicyclo [4.2.0] octa-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (4D)

Methyl2 (3S)-6 [3-[4-methyl-2 (3R)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trie nyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate

Dissolving [3- [ 4-methyl-2- [ (3R) -tetrahydrofuran-3-yl ] -oxygen-5-bicyclo [4.2.0] octa-1, 3, 5-triene ] phenyl ] methanol 4C (150 mg,0.48 mmol) in a double-calk (10mL), adding (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester 2d (110 mg,0.53 mmol and an intermediate 2), sequentially adding tributylphosphine (445 mg, 1.06 mmol) and gamma, azodicarbonyl dipiperidine (273 mg, 1.06 mmol) under the protection of nitrogen, stirring at room temperature for 2 hours, filtering, and concentrating the filtrate under reduced pressure to obtain 2- [ (3S) -6- [ [3- [ 4-methyl- Methyl 2- ((3R) -tetrahydrofuran-3-yl) -oxy-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 4D crude (240 mg). The fourth step: 2- [ (3S) -6- [ [3- (4-methyl-2- [ (3R) -tetrahydrofuran-3-yl ] -oxo-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 4)

2-[(3S)-6-[[3-[4-methyl-2-[(3R)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phe nyljmethoxy]-2,3-dihydrobe

Dissolving crude methyl 2- [ (3S) -6- [ [3- [ 4-methyl-2- ((3R) -tetrahydrofuran-3-yl) -oxy-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 4D (240 mg,0.48 mmol) in a mixed solution of methanol (3 mL) and tetrahydrofuran (6 mL), adding a 2M sodium hydroxide solution (1.2 mL), stirring at room temperature for 2 hours, concentrating under reduced pressure, adding water (25 mL) to the reaction solution, dropwise adding 1M dilute hydrochloric acid to a pH of the reaction solution of 1, extracting with ethyl acetate (25 mL. times.3), the organic phases were combined and 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) =4: 1-dichloroalkan/methanol (v/v) =70: 1) to obtain 2- [ (3S) -6- [ [3- (4-methyl-2- [ (3R) -tetrahydrofuran-3-yl ] -oxy-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid compound 4 in the form of a white bubble (150 mg, 64% yield).

¾ NMR (400 MHz, CDC1₃): δ 7.44― 7.38 (m, 1H), 7.33 (dd, 2H), 7.24 (s, 1H), 7.06 (d, 1H), 6.63 (s, 1H), 6.51 (dd, 1H), 6.47 (d, 1H), 5.06 (s, 2H), 5.02 (dd, 1H), 4.76 (t, 1H), 4.29 (dd, 1H), 4.06― 3.88 (m, 4H), 3.81 (ddd, 1H), 3.26― 3.11 (m, 2H), 3.07 (t, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.26― 2.10 (m, 5H).

Example 5- [ (3S) -6- [ [3- [2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydro-furan [2.3-b ] furan-4-yl ] -oxy ] -4-methyl

-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (compound 5)

2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]oxy]-4-methyl-5-bic yclo[4 -l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

The first step is as follows: [ (3aS,4R,6aR) -2,3,3a,4,5,6 a-hexahydrofuran [2,3-b ]]Furan-4-yl]-4-methylbenzenesulfonic acid (5B)

[(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]-4-methylbenzenesulfonate

Dissolving (3aS,4R,6aR) -2,3,3a,4,5,6 a-hexahydrofuro [2,3-b ] furan-4-hydroxy 5A in a dichloromethane-alkyl (30 mL), adding 4-dimethylaminopiperidine (0.61 g, 5mmol) and triethylamine (3.03 g), stirring for 10 minutes, adding p-toluenesulfonyl chloride (2.85 g, 15 mmol), reacting overnight at room temperature, adding water (30 mL) to the reaction solution, extracting with ethyl acetate (30 mL x 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating the residue with silica gel column chromatography to obtain pure (petroleum ether/ethyl acetate (v/v) =3: 1) to obtain [ (3 aS) aS colorless oil, 4R,6aR) -2,3,3a,4,5,6 a-hexahydrofuro [2,3-B ] furan-4-yl ] -4-methylbenzenesulfonic acid 5B (2.40 g, 85% yield).

The second step is that: [3- [2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydro-furan [2,3-b ] furan-4-yl ] oxy ] -4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methanol (5C)

[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]oxy]-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methanol

[ (3aS,4R,6aR) -2,3,3a,4,5,6 a-hexahydrofuro [2,3-B ] furan-4-yl ] -4-methylbenzenesulfonic acid 5B (117.22 mg, 0.41 mmol) was dissolved in N, N-dimethylformamide (5 mL), 5- (3- (hydroxymethyl) phenyl; 1-4-methyl-bicyclo [4.2.0] oct-1, 3, 5-trien-2-ol lm (90 mg,0.37 mmol, intermediate 1) and potassium carbonate (102.86 mg, 0.74 mmol) were sequentially added, heating was carried out to 90 ℃ for 17 hours, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined and 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) =5: 1) to give [3- [2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydro-furo [2,3-b ] furan-4-yl ] oxy ] -4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methanol 5C aS a colorless oil (120 mg, 92% yield).

¾ NMR (400 MHz, DMSO-₆) δ 7.36 (t, 1H), 7.25 (m, 2H), 7.17 (d, 1H), 6.60 (s, 1H), 5.77 (d, 1H), 5.20 (t, 1H), 4.89 (d, 1H), 4.53 (d, 2H), 3.99 (dt, 2H), 3.78 (m, 2H), 3.19 (m, 2H), 3.03 (m, 2H), 2.95 (m, 1H), 2.16 (m, 4H), 1.92 (m, 1H)。

The third step: methyl 2- [ (3S) -6- [ [3- [2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydro-furan [2,3-b ] furan-4-yl ] oxy ] -4-methyl-5-bicyclo [4.2.0] octa-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (5D)

methyl 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]oxy]-4- methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate

Reacting [3- [2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydrofuran [2,3-b ]]Furan-4-yl]Oxygen gas]-4-methyl-5-bicyclo [4.2.0]Octane-1, 3, 5-trienes]Phenyl radical]Methanol 5C (120 mg, 0.34 mmol) was dissolved in Dibromoalkyl (lOO mL) and methyl (S) 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl;) acetate 2d (78 mg,0.37 mm) was added_Ol, intermediate 2), under nitrogen protection, sequentially adding tributylphosphine (152 mg, 0.75 mmol) and I, Γ - (azodicarbonyl) dipiperidine (189 mg, 0.75 mmol), stirring at room temperature overnight, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate i N, =2: 1) to obtain colorless oily 2- [ (3S) -6- [ [3- [2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydrofuran [2,3-b ]]Furan-4-yl]Oxygen gas]-4-methyl-5-bicyclo [4.2.0]Octane-1, 3, 5-trienes]Phenyl radical]Methoxy radical]-2, 3-dihydrobenzofuran-3-yl]Methyl acetate 5D (110 mg, yield 60%)

The fourth step: 2- [ (3S) -6- [ [3- [2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydro-furan [2,3-b ] furan-4-yl ] oxy ] -4-methyl-5-bicyclo [4.2.0] octa-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 5)

2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]oxy]-4-methyl-5-bic yclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

2- [ (3S) -6- [ [3- [2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydro-furan [2,3-b ] furan-4-yl ] oxy ] -4-methyl-5-bicyclo

[4.2.0] Ocine-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid methyl ester 5D (110 mg,) is dissolved in a mixed solution of methanol (3 mL) and tetrahydrofuran (5 mL), 2M sodium hydroxide solution (5 mL) is added, the reaction is stopped by stirring overnight at room temperature, concentration under reduced pressure is performed, water (25 mL) is added to the residue, 1M dilute hydrochloric acid is added dropwise until the pH of the reaction solution is not more than 2, extraction is performed with ethyl acetate (30 mL. times.3), the organic phases are combined and dried over anhydrous sodium sulfate, filtration is performed, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether/ethyl acetate i N, =3:2) to obtain 2- [ (3S) -6- [ [3- [ 2] 2[ (+) -6 [ (+) -2- [ [ (3aS,6aR) -2,3,3a,4,5,6 a-hexahydrofuro [2,3-b ] furan-4-yl ] oxy ] -4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid compound 5 (67 mg, yield 63%).

MS m/z (ESI): 529.5 [M+l]⁺.

^ NMR (400 MHz, DMSO-₆) δ 12.31 (s, IH), 7.42 (t, IH), 7.35 (d, 2H), 7.26 (d, IH), 7.11 (d, IH) 6.60 (s, IH), 6.48 (dt, 2H), 5.76 (d, IH), 5.09 (s, 2H), 4.88 (d, IH), 4.68 (t, IH), 4.19 (dd, IH), 4.00 (m, 2H), 3.75 (m, 3H), 3.16 (m, 2H), 3.01 (m, 2H), 2.94 (m, IH), 2.69 (dd„ IH), 2.46 (d, IH), 2.16 (m, 4H), 1.90 (m, IH).

Example 6- [ (3S) -6- [ [3- [ 4-methyl-2- ((3S) -tetrahydrofuran-3-yl) oxy-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid methyl ester (Compound 6)

2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phe nyljmethoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

The first step is as follows: [ PR) -tetrahydrofuran-³-radical]Mesylate (A)⁶B)

[(3R)-tetrahydrofuran-3-yl]methanesulfonate

(3R) -tetrahydrofuran-3-ol 6A (441 mg,5.0 mmol) was dissolved in methylene chloride (15 mL), and triethylamine (708 mg, 7.0 mmol), 0, was added thereto, replacing with nitrogen. Methanesulfonyl chloride (687mg, 6.0 mmol) was slowly added dropwise, 0 after addition. C for 1 hour, quench the reaction with water (15 mL), extract with a dichloromethane alkyl (15 mL X2), combine the organic phases, wash the organic phases with 0.5M dilute hydrochloric acid (30 mL χ 1), dry over anhydrous sodium sulfate, and concentrate to give [ (3R tetrahydrofuran-3-yl ] methanesulfonate 6B as a pale yellow oil (825 mg, 99% yield).

¾ NMR (400 MHz, CDC1₃) δ 5.32 (ddd, 1H), 4.09-3.81 (m, 4H), 3.05 (s, 3H), 2.32-2.17 (m, 2H). second step: [3- [ 4-methyl-2- ((3S) -tetrahydrofuran-3-yl)]Oxy-5-bicyclo [4.2.0]Octane-1, 3,5-trienyl]Phenyl radical]Methanol (6C)

[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]metha nol

5- (3- (hydroxymethyl) phenyl) -4-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol lm (240 mg,1.0 mmol, intermediate 1) and [ (3R) -tetrahydrofuran-3-yl ] methanesulfonate 6B (199mg „ 1.2.2 mmol) were dissolved in N, N-dimethylformamide (10mL), replaced with nitrogen, and cesium carbonate (651 mg, 2.0 mmol) was added, and the temperature was raised to 80 ℃ and reacted for 30 minutes. The reaction solution was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give [3- [ 4-methyl-2- ((3S) -tetrahydrofuran-3-yl ] oxy-5-bicyclo [4.2.0] oct-1, 3,5-trienyl ] phenyl ] methanol 6C as a yellow oil (305 mg, yield 99%).

¾ NMR (400 MHz, CDC1₃) δ 7.39 (t, 1H), 7.32 - 7.27 (m, 2H), 7.23 (d, 1H), 6.63 (s, 1H), 5.06 - 4.97 (m, 1H), 4.72 (s, 2H), 4.06 - 3.85 (m, 4H), 3.19 (dd, 2H), 3.09 (t, 2H), 2.23 (s, 3H), 2.21 - 2.12 (m, 2H), 1.85 (s, 1H).

The third step: methyl 2- [ (3S) -6- [ [3- [ 4-methyl-2- [ (3S) -tetrahydrofuran-3-yl ] oxy-5-bicyclo [4.2.0] oct-1, 3,5-trienyl ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (6D)

methyl 2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3, 5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate

Adding [3- [ 4-methyl-2- ((3S) -tetrahydrofuran-3-yl ] oxy-5-bicyclo [4.2.0] oct-1, 3,5-trienyl ] phenyl ] methanol 6C (4.05 g,13.05 mmol) into a dichloromethyl alkan (100 mL), adding methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 2d (2.99 g, 14.35 mmol, intermediate 2) under the protection of nitrogen, cooling to 0. C, sequentially adding tributylphosphine (7.32 mL, 28.71 mmol) and gamma, azodicarbonyl dipiperidine (7.39 g, 28.71 mmol), stirring at room temperature for 3 hours, filtering the reaction solution, the filtrate was concentrated under reduced pressure to give a crude product of methyl 2- [ (3S) -6- [ [3- [ 4-methyl-2- [ (3S) -tetrahydrofuran-3-yl ] oxy-5-bicyclo [4.2.0] oct-1, 3,5-trienyl ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 6D, which was used directly in the next reaction.

The fourth step: methyl 2- [ (3S) -6- [ [3- [ 4-methyl-2- [ (3S) -tetrahydrofuran-3-yl) oxy-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl) methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (Compound 6)

2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2 ,3 -dihydrobenzofuran-3 -yl]acetic acid

Methyl 2- [ (3S) -6- [ [3- [ 4-methyl-2- [ (3S) -tetrahydrofuran-3-yl ] oxy-5-bicyclo [4.2.0] oct-1, 3,5-trienyl ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 6D crude product was dissolved in a mixed solution of methanol (60 mL) and tetrahydrofuran (102 mL), and 2M sodium hydroxide solution (32.6 mL) was added thereto, followed by stirring at room temperature for 2 hours, concentration under reduced pressure, addition of water (30 mL) to the reaction solution, and dropwise addition of 1M dilute hydrochloric acid until the pH of the reaction solution became 1. The reaction solution was extracted with ethyl acetate (50 mL × 3), the organic phase was combined and 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) =4: 1-dichloroalkyl/methanol (v/v) =70: 1) to obtain white vesicular methyl 2- [ (3S) -6- [ [3- [ 4-methyl-2- [ (3S) -tetrahydrofuran-3-yl) oxy-5-pentacyclic [4.2.0] oct-1, 3, 5-triene ] phenyl) methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate compound 6 (4.7 g, third and fourth step overall yield 74%).

¾ NMR (400 MHz, CDC1₃) δ 7.44 - 7.36 (m, IH), 7.36 - 7.30 (m, 2H), 7.25 (d, IH), 7.06 (d, IH), 6.63 (s, IH), 6.53 - 6.44 (m, 2H), 5.05 (d, 2H), 5.02 (ddd, IH), 4.76 (t, IH), 4.29 (dd, IH), 4.05 - 3.88 (m, 4H), 3.81 (ddd, IH), 3.24 - 3.12 (m, 2H), 3.07 (t, 2H), 2.80 (dd, IH), 2.61 (dd, IH), 2.26 - 2.11 (m, 5H).

MS: 485.0[M-1]—

Example 7 (S) -2- (6- ((3- (5- ((2-methoxypyridin-4-yl) methoxy) -3-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 7)

(S)-2-(6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]octa-l,3,5-trien-2-yl) benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

The first step is as follows: 2-Methoxyisonicotinic acid methyl ester (7B)

methyl 2-methoxyisonicotinate

Dissolving 2-chloroisonicotinic acid methyl ester 7A (523 mg, 3 mmol) in dioxane (5 mL), adding sodium methoxide (247 mg, 4.5 mmol), stirring at 103 ℃ for reaction for 2 hours under the protection of nitrogen, cooling the system, slowly adding water (50 mL) into the reaction solution for quenching, extracting with a dichlorosilane (30 mL x 3), combining organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 2-methoxyisonicotinic acid methyl ester 7B (0.39 g, yield 69%) in a light yellow liquid state.

¾ NMR (400 MHz, CDC1₃) δ 8.28 (d, IH), 7.40 (dd, IH), 7.31 (d, IH), 3.98 (s, 3H), 3.94 (s, 3H). 2-methoxypyridin-4-yl) methanol (7C)

Methyl 2-methoxyisonicotinate 7B (1.07 g, 6.4 mmol) was dissolved in tetrahydrofuran (10mL) and under nitrogen, lithium borohydride (224 mg, 10.33 mmol) was added with stirring at 0 ℃ and the reaction was maintained at 30 ℃ for 5 hours after the addition. Suction filtration, cake washing with a dichloroalkyl (10mL x2), organic phase combination, filtrate concentration under reduced pressure, residue purification by silica gel column chromatography (dichloroalkyl/methanol (v/v) =20: 1) yielded (2-methoxypyridin-4-yl) methanol 7C as a pale yellow liquid (0.8 g, 90% yield). Microspheres NMR (400 MHz, CDC 1)₃) 58.11 (t, 1H), 6.88-6.65 (m, 2H), 4.99-4.65 (m, 2H), 3.94 (s, 3H). (2-methoxy group)Pyridinyl-4-yl) methyl methanesulfonate (7D)

(2-methoxypyridin-4-yl)methyl methanesulfonate

(2-methoxypyridin-4-yl) methanol 7C (0.8 g, 5.75 mmol) was dissolved in ethyl acetate (30 mL) under nitrogen 0. Triethylamine (1.12 mL, 8.05 mmol) was added with stirring at C and the system was kept 0 after addition. C was stirred for 5 minutes, then methanesulfonyl chloride (0.79 g, 6.9 mmol) was slowly added dropwise, the reaction was maintained at 0 ℃ for 1.5 hours with the addition of the system, quenched by slowly adding water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined and 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) = 1: 1) to give (2-methoxypyridin-4-yl) methyl methanesulfonate 7D as a colorless oil (0.9 g, yield 72%).

¾ NMR (400 MHz, CDC1₃) δ 8.19 (d, 1H), 6.88 (d, 1H), 6.76 (s, 1H), 5.18 (s, 2H), 3.95 (d, 3H), 3.04 (s, 3H).

The fourth step: (3- (5- ((2-methoxypyridin-4-yl) methoxy) -3-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) phenyl) methanol

(7E)

(3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]octa-l,3,5-trien-2-yl)phenyl)me thanol

Dissolving (2-methoxypyridin-4-yl) methyl methanesulfonate 7D (284 mg, 1.31 mmol) and 5- (3- (hydroxymethyl) phenyl) -4-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol lm (262 mg, 1.09 mmol, intermediate 1) in N, N-dimethylformamide (10mL), adding cesium carbonate (355 mg, 2.18 mmol) under nitrogen protection, reacting at 85 ℃ for 2.5 hours after completion of the reaction, suction-filtering the system, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1: 1) to obtain (3- (5- ((2-methoxypyridin-4-yl) methoxy) as a yellow oil -3-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) phenyl) methanol 7E crude product (474 mg), which was used directly in the next reaction.

The fifth step: (S) -methyl 2-6- ((3- (5- ((2-methoxypyridin-4-yl) methoxy) -3-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (7F)

(S)-methyl2-(6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]octa- l ,3, 5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate

Dissolving (3- (5- ((2-methoxypyridin-4-yl) methoxy) -3-methylbicyclo [4.2.0] octan-1, 3, 5-trien-2-yl) phenyl) methanol 7E (450 mg, 1.25 mmol) and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 2d (285 mg, 1.37 mmol), dissolving the intermediate product in a dichloromethyl alkyl (10mL), sequentially adding tributylphosphine (0.68 mL, 2.74 mmol) and gamma, azodicarbonyl dipiperidine (0.69 g, 2.74 mmol) under nitrogen protection, stirring at room temperature for 3 hours, filtering, concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5: 1) to give methyl (S) -2-6- ((3- (5- ((2-methoxypyridin-4-yl) methoxy) -3-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 7F as a yellow oil (500 mg, yield 73%).

¾ NMR (400 MHz, CDC1₃) δ 8.16 (d, 1H), 7.39 (dd, 1H), 7.36 - 7.28 (m, 2H), 7.23 (d, 1H), 7.02 (d, 1H), 6.92 (d, 1H), 6.82 (s, 1H), 6.71 (s, 1H), 6.52― 6.44 (m, 2H), 5.14 (s, 2H), 5.05 (s, 2H), 4.74 (m, 1H), 4.26 (m, 1H), 3.95 (s, 3H), 3.79 (m, 1H), 3.71 (s, 3H), 3.19― 3.09 (m, 2H), 3.08― 2.98 (m, 2H), 2.74 (dd, 1H), 2.55 (dd, 1H), 2.22 (d, 3H).

And a sixth step: (S) -2- (6- ((3- (5- ((2-methoxypyridin-4-yl) methoxy) -3-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 7)

(S)-2-(6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4 .0]octa- l ,3,5-trien-2-yl) benzyl)oxy)-2,3-dihydr

Dissolving methyl (S) -2-6- ((3- (5- ((2-methoxypyridin-4-yl) methoxy) -3-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 7F (451 mg, 0.82 mmol) in a mixed solution of methanol (5 mL) and tetrahydrofuran (5 mL), adding a 2M sodium hydroxide solution (10mL), stirring at room temperature for 2 hours, concentrating under reduced pressure, adding water (25 mL) to the reaction solution, dropwise adding 1M dilute hydrochloric acid to the reaction solution to pH 1, extracting with ethyl acetate (25 mL x 3), the organic phases were combined and 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) =3: 1) to give (S) -2- (6- ((3- (5-; 2-methoxypyridin-4-yl) methoxy) -3-methyldicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid compound 7 (169 mg, 38% yield) as a pale yellow solid.

MS: 538.3[M+1].

¾ NMR (400 MHz, CDC1₃) δ 8.18 (d, IH), 7.40 (t, IH), 7.33 (d, 2H), 7.24 (d, IH), 7.05 (d, IH), 6.94 (d, IH), 6.85 (s, IH), 6.71 (s, IH), 6.53― 6.44 (m, 2H), 5.15 (s, 2H), 5.05 (s, 2H), 4.76 (t, IH), 4.33― 4.17 (m, IH), 3.97 (s, 3H), 3.81 (ddd, IH), 3.12 (d, 2H), 3.08― 2.98 (m, 2H), 2.80 (dd, IH), 2.61 (dd, IH), 2.23 (s, 3H).

Example 8 2- (3S) -6- (S)²-fluoro-5-, (⁴-methyl-²- (3- (methylsulfonyl) propoxy) -5-bicyclo [ 2], [⁴.²0] oct-1, 3, 5-triene) benzyloxy group) -2, 3-dihydrobenzofuran-3-yl) acetic acid (compound 8)

2-((3S)-6-((2-fhioro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trieny l)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

The first step is as follows: 2- (5- (benzyloxy) -3-methylbicyclo [ 4.2.0)]Oct-1, 3, 5-en-2-yl) -4,4,5, 5-tetramethyl-1, 3, 2-boronic acid pinacol ester (8B)

2-(5-(benzyloxy)-3-methylbicyclo[4.2.0]octa-l,3,5-trien-2-yl)-4,4,5,5-tetramethyl-l,3,2-dioxab orolane

Reacting 2-benzyloxy-5-bromo-4-methyl-bicyclo [4.2.0]]Dissolving octyl-1, 3, 5-triene li (6.06g, 20mmol) in ethanol (100 mL), sequentially adding pinacol diboron diboride (5.6 g, 19 mmol) and [ I, gamma-bis (; diphenylphosphino) ferrocene under the protection of nitrogen]Palladium dichloride (1.4g, 2 mmol, PdCl)₂(dppf)) and potassium acetate (5.9 g, 60 mmol), warmed to 90 ℃ and stirred at reflux for 6 hours. The reaction was concentrated to dryness, water (100 mL) was added, extraction was performed with ethyl acetate (100 mL), the organic phase was washed with water (50 mL × 2), 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) to give 2- (5- (benzyloxy) -3-methylbicyclo [4.2.0] as a colorless oil]Oct-1, 3, 5-en-2-yl) -4,4,5, 5-tetramethyl-1, 3, 2-boronic acid pinacol ester 8B (4.1 g, 58.6% yield)

The second step is that: 2-fluoro-4- (5-benzyloxy-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzaldehyde (8C)

2-floro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl)benzaldehyde

Reacting 2- (5- (benzyloxy) -3-methyl bicyclo [4.2.0]]Dissolving octa-1, 3, 5-en-2-yl) -4,4,5, 5-tetramethyl-1, 3, 2-boronic acid pinacol ester 8B (350 mg,1 mmol) in N, N-dimethylformamide (5 mL), and sequentially adding 2-fluoro-5-bromobenzaldehyde (203 mg,1 mmol), [ I, Γ -bis (diphenylphosphino) ferrocene]Palladium dichloride (37 mg, 0.05 mmol, PdCl)₂(dppf)), potassium carbonate (276 mg, 2 mmol), and the reaction was stirred at 90 ℃ for 1 hour to complete the reaction. Water (50 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (50 mL × l), the organic phase was washed with water (30 mL × 2), 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) =10: 1) to give 2-fluoro-4- (5-benzyloxy-3-methyl-2-bicyclo [4.2.0] as a colorless oil]Oct-1, 3, 5-triene) benzaldehyde 8C (290 mg, 83.8% yield).

The third step: 2-fluoro-4- (5-benzyloxy-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyl alcohol (8D)

2-floro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl) phenylmethanol

Dissolving 2-fluoro-4- (5-benzyloxy-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzaldehyde 8C (290 mg, 0.84 mmol) in methanol (10mL), cooling to 0 ℃, slowly adding sodium borohydride (37.83 mg,1 mmol), stirring at 0 ℃ for 0.5 hours, concentrating the reaction solution under reduced pressure, and separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3: 1) to obtain 2-fluoro-4- (5-benzyloxy-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyl alcohol 8D (210 mg, yield 72%).

The fourth step: 2-fluoro-4- (5-hydroxy-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyl alcohol (8E)

2-floro-4-(5-hydroxy-3-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl) phenylmethanol

2-fluoro-4- (5-benzyloxy-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyl alcohol 8D (210 mg, 0.6 mmol) was dissolved in methanol (5 mL), and palladium on carbon (21 mg, palladium content w/w =10%) and potassium carbonate (21 mg) were added in this order to displace hydrogen gas 3 times and reacted at 30 ℃ for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1: 1) to give 2-fluoro-4- (5-hydroxy-3-methyl-2-bicyclo [4.2.0] oct-1, 3, 5-triene) benzyl alcohol 8E (140 mg, yield 90%) as a colorless oil.

The fifth step: 2-fluoro-4- (5- (3-methanesulfonylpropoxy) -5-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyl alcohol (8F)

2-floro-4-(5-(3-methylsulfonylpropoxy)-3-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl) phenylmethanol

2-fluoro-4- (5-hydroxy-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyl alcohol 8E (140 mg, 0.54 mmol) was dissolved in Ν, Ν -dimethylformamide (2 mL), and 3-methylsulfamoylpropyl-4-methylbenzenesulfonic acid 1C (158 mg, 0.54 mmol) and cesium carbonate (352 mg, 1.08 mmol) were sequentially added, heated to 90 ℃ and reacted for 2 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, extraction was performed with ethyl acetate (20 mL), the organic layer was washed with water (10mL × 2), dried over anhydrous magnesium 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) = 1: 1) to obtain 2-fluoro-4- (5- (3-methanesulfonylpropoxy) -5-3-methyl-2-bicyclo [4.2.0] oct-1, 3, 5-triene) benzyl alcohol 8F (190 mg, yield 93%) as a colorless oil.

And a sixth step: methyl 2- (3S) -6- ((2-fluoro-5- (4-methyl-2- (3- (methylsulfonylpropoxy) -5-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (8G)

Methyl2-((3S)-6-((2-fluoro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-tr ienyl)phenyl)methoxy)-2 3-dihydrobenzofuran-3-yl)acetate

2-fluoro-4- (5- (3-methanesulfonylpropoxy) -5-3-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyl alcohol 8F (190 mg,0.5 mmol) was dissolved in a dichlorosilane (5 mL), and methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 2d (104 mg,0.5 mmol) and azobiscarbonyldipiperidine (251 mg,1 mmol) were added in this order and cooled to 0. C, 202 mg of tributylphosphine C, 1 mmol was slowly dropped thereto, the reaction was maintained at 0 ℃ for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1: 1) to obtain methyl 2- (3S) -6- ((2-fluoro-5- (4-methyl-2- (3- (methanesulfonylpropoxy) -5-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate 8G (210 mg, yield 76%) as a white solid.

The seventh step: 2- (3S) -6- ((2-fluoro-5- (4-methyl-2- (3- (methylsulfonylpropoxy) -5-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 8)

2-((3S)-6-((2-fluoro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trieny l)phenyl)methoxy)-2,3-dih drobenzofuran-3-yl)acetic acid

Methyl 2- (3S) -6- ((2-fluoro-5- (4-methyl-2- (3- (methanesulfonylpropoxy) -5-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate 8G (210 mg,0.37 mmol) was suspended in methanol (10mL), and a solution of sodium hydroxide (300 mg, 7.58 mmol) in water (1 mL) was added dropwise, followed by maintaining the reaction at room temperature for 4 hours. The reaction system was concentrated under reduced pressure, water (10mL) was added, the pH of the reaction solution was adjusted to 3 with 2M dilute hydrochloric acid, extracted with a dichloromethane alkyl (20 mL x2), the organic phases were combined, the organic phase was washed with water (10mL x2), dried over anhydrous sodium sulfate (2 g), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1: 2) to give 2- (3S) -6- ((2-fluoro-5- (4-methyl-2- (3- (methanesulfonylpropoxy) -5-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid compound 8 (140 mg, yield 68%).

MS: 554.7[M+1]⁺.

¾ NMR (400 MHz, CDC1₃) 57.36(m,lH) , 7.18(m,lH), 7.05(m,2H), 6.60(s,lH), 6.47(m,2H), 5.13(s,2H), 4.75(t,lH), 4.22(m,3H), 3.78(m,lH), 3.19(m,4H), 3.01(m,2H), 2.96(s,3H), 2.77(dd,lH), 2.58(dd,lH), 2.29(m,2H), 2.17(s,3H)。

Example 9- [ (3S) -6- [ [3- (2-benzyloxy-4-methyl-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (compound 9)

2-[(3S)-6-[[3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenyl]methoxy]-2,3-di hydrobenzofuran-3-yl]acetic acid

The first step is as follows: methyl 2- [ (3S) -6- [ [3- (2-benzyloxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (9B)

methyl2-[(3S)-6-[[3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenyl]methoxy]- 2 ,3 -dihydrobenzofuran-3 -yl]acetate

Dissolving 3- (5-benzyloxy) -2-bicyclo [4.2.0] octa-1, 3, 5-triene) phenyl) methanol 3G (0.62G, 1.88 mmol) in a dichlorosilane (10mL), adding (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester 2d (411 mg, 1.97 mmol, intermediate 2), sequentially adding tributylphosphine (838 mg, 4.14 mmol) and solid, gamma- (azodicarbonyl) dipiperidine (1.04G, 4.14 mmol) under nitrogen protection, stirring at room temperature for 1 hour, concentrating under reduced pressure, and separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =5: 1) to obtain white 2- [ (3S) -6: (1) Methyl- [ [3- (2-benzyloxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 9B (1.0 g, 100% yield).

The second step is that: 2- [ (3S) -6- [ [3- (2-benzyloxy-4-methyl-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 9)

2-[(3S)-6-[[3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenyl]methoxy]-2,3-dihydr obenzofuran-3 -yl]acetic acid

2- [ (3S) -6- [ [3- (2-benzyloxy-4-methyl-5-cyclo [4.2.0] cyclo]Octane-1, 3, 5-triene) phenyl]Methoxy radical]-2, 3-dihydrobenzofuran-3-yl]Methyl acetate 9B (1.0 g, 1.88 mmol) was dissolved in a mixed solution of methanol (5 mL) and tetrahydrofuran (5 mL), adding 2M sodium hydroxide solution (5 mL), stirring overnight at room temperature, stopping the reaction, concentrating under reduced pressure, adding water (25 mL) to the residue, dropwise adding 1M dilute hydrochloric acid until the pH of the reaction solution is less than or equal to 2, extracting with ethyl acetate (30 mL x 3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3:2) to obtain 2- [ (3S) -6- [ [3- (2-benzyloxy-4-methyl-bicyclo [4.2.0] as a white solid.]Octa-1, 3, 5-triene)Phenyl radical]Methoxy radical]-2, 3-dihydrobenzofuran-3-yl]Acetic acid compound 9 (400 mg, 45% yield).

¾ NMR (400 MHz, DMSO-₆) δ 12.31 (s, 1H), 7.44-7.33 (m, 8H), 7.25 (d, 1H), 7.11 (d, 1H), 6.71 (s, 1H), 6.49-6.46 (m, 2H), 5.19 (s, 2H), 5.09 (s, 2H) 4.68 (t, 1H), 4.19-4.17 (m, 1H), 3.69-3.66 (m, 1H), 3.17 (m, 2H), 2.98 (m, 2H), 2.69 (dd, 1H), 2.46 (dd, 1H), 2.17 (s, 3H)。

EXAMPLE 10- [ (3S) -6- [ [3- (2- (4-hydroxytetrahydrofuran-3-yl) oxy) -4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene) phenyl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (compound 10)

2-[(3S)-6-[[3-[2-(4-hydroxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trieny l]phenyl]methoxy]-2,3 -dihydrobenzofuran-3 -yl]acetic acid

In the first step, 3- (2-hydroxy-4-methyl-5-bicyclo [4.2.0]]Ocine-1, 3, 5-triene) -benzaldehyde (10A)

3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)benzaldehyde

5-bromo-4-methyl-bicyclo [4.2.0] oct-1, 3, 5-trien-2-ol 3e (32.6 g, 0.15 mol, intermediate 3) and 3-formylphenylboronic acid (27.53 g, 0.18 mol) were dissolved in toluene (500 mL), 2M potassium carbonate solution (460 mL) was added, ethanol was added

(200 mL), tetrakistriphenylphosphine palladium (14.14 g, 12.2 mmol), 90, was added under nitrogen. And C, reacting for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (500 mL) was added, the reaction mixture was washed with water (100 mL × 2), dried over anhydrous sodium sulfate for organic phase, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate i N, =6/1) to obtain 3- (2-hydroxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene) -benzaldehyde 10A as a yellow solid (30.0 g, yield 82.4%).

The second step is that: 3- (2- (4-Hydroxytetrahydrofuran-3-yl) oxy-4-methyl-5-bicyclo [4.2.0] octa-1, 3, 5-triene) benzaldehyde (10B)

3-[2-(4-hydroxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl]benzaldehyde

Mixing 3- (2-hydroxy-4-methyl 5-bicyclo [4.2.0]]Oct-1, 3, 5-triene) -benzaldehyde 10A (714.8 mg, 3.0 mmol), 3, 4-epoxy tetrahydrofuran (1.9 g, 22.5 mmol) and potassium carbonate (622 mg, 4.5 mmol) were sequentially added to ethanol (10mL) and reacted with a microwave at 100 ℃ for 75 minutes. Ethyl acetate (50 mL) was added to the reaction system, and the mixture was washed with saturated brine (10 mL. times.2), 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) =1/1) to give 3- (2- (4-hydroxytetrahydrofuran-3-yl) oxy-4-methyl-5-bicyclo [4.2.0] as a pale yellow oil]Oct-1, 3, 5-triene) benzaldehyde 10B (897 mg, 100% yield).

¾ NMR (400 MHz, DMSO-₆) δ 10.06 (s, 1H), 7.84 (dd, 2H), 7.73 - 7.60 (m, 2H), 6.68 (s, 1H)_:5.42 (d, 1H), 4.73 (d, 1H), 4.24 (t, 1H), 3.97 (ddd, 2H), 3.66 - 3.50 (m, 2H), 3.28 - 3.11 (m, 2H), 3.06 (t, 2H), 2.21 (s, 3H).

The third step: [4- [ [5- (3-formylphenyl) -4-methyl-2-bicyclo [4.2.0] oct-1, 3, 5-triene ] oxy ] -tetrahydrofuran-3-yl ] acetic acid ester (10C)

[4-[[5-(3-formylphenyl)-4-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl]oxy]tetrahydrofuran-3-yl]acetate

3- (2- (4-hydroxytetrahydrofuran-3-yl) oxy-4-methyl-5-bicyclo [4.2.0] octa-1, 3, 5-triene) benzaldehyde 10B (1.02 g, 3.15 mmol), acetyl chloride (600 mg) and triethylamine (1.4 g) were added to a dichlorome (20 ml) and reacted under nitrogen for 1 hour. The reaction solution was quenched by adding water (50 mL), separated, the aqueous layer was extracted with ethyl acetate (50 mL × 2), the organic phases were combined, 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) =7/l) to give [4- [ [5- (3-formylphenyl) -4-methyl 2-bicyclo [4.2.0] oct-1, 3, 5-triene ] oxy ] -tetrahydrofuran-3-yl ] acetate 10C as a pale yellow oil (600 mg, 54% yield). The fourth step: [4- [ [5- [3- (hydroxymethyl) phenyl ] -4-methyl-2-fused [4.2.0] oct-1, 3, 5-triene ] oxy ] tetrahydrofuran-3-yl ] acetic acid ester (10D)

[4-[[5-[3-(hydroxymethyl)phenyl]-4-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl]oxy]tetrahydrofu ran-3-yl]acetate

[4- [ [5- (3-formylphenyl) -4-methyl 2-bicyclo [4.2.0] oct-1, 3, 5-triene ] oxy ] -tetrahydrofuran-3-yl ] acetate 10C (600 mg, 1.64 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (10mL), cooled to 0 ℃ and sodium borohydride (124 mg, 3.27 mmol) was added, and the reaction was continued for 30 minutes after the addition was completed. To the reaction solution was added a saturated ammonium chloride solution (50 mL) to quench the reaction, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (50 mL × 2), the organic phases were combined, 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) =3/2) to give [4- [ [5- [3- (hydroxymethyl) phenyl ] -4-methyl-2-bicyclo [4.2.0] oct-1, 3, 5-triene ] oxy ] tetrahydrofuran-3-yl ] acetic acid ester 10D as a pale yellow oil (350 mg, yield 60%).

^ NMR (400 MHz, DMSO-₆) δ 7.36 (t, IH), 7.25 (d, 2H), 7.17 (d, IH), 6.68 (s, IH), 5.17 (dd, 2H), 4.95 (d, IH), 4.53 (d, 2H), 4.06 (ddd, 2H), 3.91 - 3.71 (m, 2H), 3.18 - 3.05 (m, 2H), 3.02 (t, 2H), 2.18 (s, 3H), 2.09 (s, 3H).

The fifth step: methyl 2- [ (3S) -6- [ [3- [2- (4-acetoxytetrahydrofuran-3-yl) oxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (10E)

methyl2-[(3S)-6-[[3-[2-(4-acetoxytetmhydrofiimn-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]octa- 1,3,5 rienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate

[4- [ [5- [3- (hydroxymethyl) phenyl ] -4-methyl-2-bicyclo [4.2.0] octa-1, 3, 5-triene ] oxy ] tetrahydrofuran-3-yl ] acetate 10D (340 mg, 0.932 mmol) was added to a bischlorokyrine (15 mL), and methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 2D (202 mg, 0.969 mmol, intermediate 2) was added, under nitrogen, and cooled to 0. And C, sequentially adding tributylphosphine (0.51 mL, 2.03 mmol) and I, gamma- (azodicarbonyl) dipiperidine (512 mg, 2.03 mmol), and stirring at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a crude product of methyl 2- [ (3S) -6- [ [3- [2- (4-acetoxytetrahydrofuran-3-yl) ] -oxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 10E, which was used directly in the next reaction.

And a sixth step: 2- ((S) -6- ((3- (5- (((3,4-S, S/R, R) -hydroxytetrahydrofuran-3-yl) oxy) -3-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) phenyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 10)

2-((S)-6-((3-(5-(((3,4-S,S/R,R)-4-hydroxytetrahydrofuran-3-yl)oxy)-3-methylbicyclo[4.2.0]octa ■l,3,5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

Methyl 2- [ (3S) -6- [ [3- [2- (4-acetoxytetrahydrofuran-3-yl) oxy-4-methyl-5-bicyclo [4.2.0] oct-1, 3, 5-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 10E crude product was dissolved in a mixed solution of methanol (5 mL) and tetrahydrofuran (10mL), and 2M sodium hydroxide solution (2.3 mL) was added and stirred at room temperature for 2 hours. Concentrating the reaction solution under reduced pressure, adding water (10mL) into the residue, dropwise adding 1M dilute hydrochloric acid until the pH value of the reaction solution is 1, extracting with ethyl acetate (15 mL x 3), merging the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4: 1 → dichloromethyl-alka/methanol (y, =70: 1) to obtain white bubble-shaped 2- ((S) -6- ((3- (5- (((3,4-S, S/R, R) -hydroxytetrahydrofuran-3-yl) oxy) -3-methylbicyclo [4.2.0] octan-1), 3, 5-trien-2-yl) phenyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid compound 10 (330 mg, 71% total yield from the fourth and fifth steps).

¾ NMR (400 MHz, DMSO-₆) δ 12.31 (s, IH), 7.42 (t, IH), 7.37 - 7.31 (m, 2H), 7.26 (d, IH),

7.11 (d, IH), 6.63 (s, IH), 6.48 (dt, 2H), 5.40 (d, IH), 5.09 (s, 2H), 4.75 - 4.64 (m, 2H), 4.29 - 4.14 (m, 2H), 4.05 (d, IH), 3.90 (dd, IH), 3.78 (d, IH), 3.73 - 3.64 (m, IH), 3.61 (dd, IH), 3.26 - 3.07 (m, 2H), 3.01 (t, 2H), 2.69 (dd, IH), 2.46 (d, IH), 2.17 (s, 3H).

MS 501.1 [ M-1] -example 11 2- [ (3S) -6- [ [3- [2- [2- (cyclopropoxy) ethoxy ] -4-methyl-bicyclo [4.2.0] oct-1 (6),2, 4-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] -acetic acid (compound 11)

2-[(3S)-6-[[3-[2-[2-(cyclopropoxy)ethoxy]-4-methyl-bicyclo[4.2.0]octa-l(6),2,4-trienyl]phenyl]methoxyl]-2,3-dihydrobenzofuran-3- l]acetic acid

First step 2-Cyclopropoxyethanol (11B)

2-cyclopropoxyethanol

Magnesium powder (8.9 g, 0.36 mol) is mixed with a catalytic amount of elemental iodine, and a dibromoethane-alkyl (46 g, 0.24 mol) solution in tetrahydrofuran (200 mL) is added into the mixture under a nitrogen atmosphere at 40-55 ℃. A solution of 2- (2-bromoethyl) -1, 3-dioxolane 11A (10 g, 0.056 mol) in tetrahydrofuran (75 mL) was added to the reaction, and reacted at 45 ℃ for 16 hours. The reaction was quenched with aqueous ammonium chloride (200 mL), extracted with dichloromethane (100 mLx2), the organic phase was washed with saturated sodium chloride solution (100 mLx2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue is separated and purified by column chromatography (petroleum ether/ethyl acetate (v;)_V; =10: 1) 2-cyclopropyloxyethanol 11B was obtained as a pale yellow oil (1.08 g, yield 19%).

The second step is that: 2-Cyclopropyloxyethyl 4-methylbenzenesulfonate (11C)

2-cyclopropoxyethyl 4-methylbenzenesulfonate

Adding 2-cyclopropyloxyethanol 11B (500 mg, 4.9 mmol) to a mixture of aqueous sodium hydroxide (588 mg, 14.7 mmol) and tetrahydrofuran (7 mL), cooling to 0 ℃, adding a tetrahydrofuran (4 mL) solution of p-toluenesulfonyl chloride (1 g, 5.4 mmol) dropwise to the mixture, reacting at 0 ℃ for 6 hours, extracting the reaction mixture with ethyl acetate (10 mLx2), washing the organic phase with a saturated sodium chloride solution (10mL x2), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by column chromatography (petroleum ether/ethyl acetate (v/v) =30: 1) to obtain 2-cyclopropyloxyethyl as a colorless oil

4-Methylbenzenesulfonate llC (540 mg, 43% yield).

The third step: 3- [2[2- (cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octa-1 (6),2, 4-triene) benzaldehyde (11D) 3- [2[2- (cyclopropoxy) ethyllox-4-methyl-5-bicyclo [4.2.0] octa-l (6),2,4-trienyl ] benzaldehyde

Dissolving 2-cyclopropyloxyethyl-4-methylbenzenesulfonate 11C (600 mg, 2.52 mmol) in N, N-dimethylformamide (15 mL), adding 3- (2-hydroxy-4-methyl 5-bicyclo [4.2.0] octa-1, 3, 5-triene) -benzaldehyde 10A (680 mg, 2.52 mmol) and cesium carbonate (12.50 g, 7.56 mmol) in this order, heating to 90 ℃ for 17 hours, adding water (50 mL) to dilute the reaction mixture, extracting with ethyl acetate (50 mL x 3), combining the organic phases and drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =20: 1) to give 3- "as a colorless oil 2[2- (Cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octa-1 (6),2, 4-triene) benzaldehyde 11D (620 mg, 76% yield).

The fourth step: 3- [2- [2- (cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octan-1 (6),2, 4-triene ] benzyl alcohol (11E) 3- [2[2- (cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octa-l (6),2,4-trienyl ]

phenyl]methanol

Dissolving 3- [2[2- (cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octan-1 (6),2, 4-triene) benzaldehyde 11D (520 mg, 1.61 mmol) in methanol (5 mL) and tetrahydrofuran (2.5 mL), adding sodium borohydride (122 mg, 3.22 mmol), stirring at room temperature for 1 hour, concentrating under reduced pressure, extracting with ethyl acetate (30 mL x 3), combining the organic phases and drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10: 1) to obtain 3- [2- [2- (cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octan-1 (6)) as colorless oil, 2, 4-Triene ] benzyl alcohol 11E (520 mg, 98% yield).

The fifth step: methyl 2- [ (3S) -6- [ [3- [2- [2- (cyclopropyloxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octan-1 (6),2, 4-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (11F)

Methyl-2-[(3S)-6-[[3-[2-[2-(cyclopropoxy)ethyloxy]-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trie nyl]phenyl]methoxyl]-2,3-dihydrobenzofuran-3-yl]acetate

Dissolving 3- [2[2- (cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octan-1 (6),2, 4-triene ] benzyl alcohol 11E (470 mg, 1.45 mmol) in a double-button-opening (7 mL), adding (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) methyl acetate 2d (304 mg, 1.52 mmol, intermediate 2), adding tributylphosphine (645 mg, 3.19 mmol) and gamma- (; azodicarbonyl) dipiperidine (805 mg, 3.19 mmol) in sequence under the protection of nitrogen, stirring overnight at room temperature, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate i hf =10: 1) to obtain 2d as colorless oil Methyl (- [ (3S) -6- [ [3- [2- [2- (cyclopropyloxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octa-1 (6),2, 4-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 11F (630 mg, 82% yield).

And a sixth step: 2- [ (3S) -6- [ [3- [2- [2- (cyclopropoxy) ethoxy ] ethoxy]-4-methyl-5-bicyclo [4.2.0]Octa-1- (6),2, 4-triene]Phenyl radical]Methoxy radical]-²3-dihydrobenzofuran-3-yl]Acetic acid (Compound 11)

2-[(3S)-6-[[3-[2-[2-(cyclopropoxy)ethyloxy]-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]phe nyljmethoxyl]-2,3 -di

Dissolving 11F (300 mg, 0.70 mmol) of methyl 2- [ (3S) -6- [ [3- [2- [2- (cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] octan-1 (6),2, 4-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate in a mixed solution of methanol (5 mL) and tetrahydrofuran (5 mL), adding 2M sodium hydroxide solution (5 mL), stirring overnight at room temperature, stopping the reaction, concentrating under reduced pressure, adding water (25 mL) to the residue, dropwise adding 1M dilute hydrochloric acid to a reaction solution pH of not more than 2, extracting with ethyl acetate (30 mL x 3), combining the organic phases and drying over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2: 1) to obtain 2- [ (3S) -6- [ [3- [2- [2- (cyclopropoxy) ethoxy ] -4-methyl-5-bicyclo [4.2.0] oct-1 (6),2, 4-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid compound 11 (400 mg, yield 77%) as a white solid.

¾ NMR (400 MHz, DMSO-₆) δ 12.32 (s, IH), 7.41 (t, 1 H), 7.35-7.33 (m, 2H), 7.25 (d, IH), 7.11 (d, IH), 6.61 (s, IH), 6.48-6.46 (m, 2H), 5.09 (s, 2H), 4.68 (t, IH), 4.21-4.17 (m, 3H), 3.74-3.64 (m, 3H), 3.38-3.33 (m, IH), 3.17 (td, 2H), 2.99 (td, 2H), 2.69 (dd, IH), 2.47 (dd, IH), 2.16 (s, 3H), 0.52-0.48 (m, 2 H), 0.46-0.43 (m, 2H).

Example 12- [ (3S) -6- [ [3- (2-hydroxy-4-methyl-bicyclo [4.2.0] oct-1 (6),2, 4-trivinyl) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 12)2- [ (3S) -6- [ [3- (2-hydroxy-4-methyl-5-bicyclo [4.2.0] octa-l (6),2,4-trienyl ] phenyl ] methyl ] -2, 3-dihydrobenzofuranyl-3-yl ] acetic acid

The first step is as follows: 3- [2- [ tert-butyl (dimethyl) silicon]Oxy-4-methyl-5-bicyclo [4.2.0]Ocine-1 (6),2, 4-triene) benzaldehyde (12B) 3- [2[ ter ^ butyl (dimethyl) lysine]ox -4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]benzadehyde

Dissolving 3- (2-hydroxy-4-methyl 5-bicyclo [4.2.0] octa-1, 3, 5-triene) -benzaldehyde 10A (0.50 g, 2.1 mmol) and tert-butyl dimethyl silicon chloride alkyl (0.63 mg, 4.2 mmol) in tetrahydrofuran (5 mL), adding imidazole (0.43 mg, 6.3 mmol) at room temperature for reaction for 30 minutes, adding water (10mL) for quenching reaction, extracting with ethyl acetate (30 mL x 3), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying residues with silica gel column chromatography (petroleum ether/ethyl acetate i l, =10: 1) to obtain 3- [2[ tert-butyl (dimethyl) silicon ] oxy-4-methyl-5-bicyclo [4.2.0] octa-1 (6),2, 4-Triene) benzaldehyde 12B (0.60 g, 81% yield).

The second step is that: 3- [2- [ tert-butyl (dimethyl) silyl ] oxy-4-methyl-5-bicyclo [4.2.0] octa-1 (6),2, 4-triene ] benzyl alcohol (12C)

[3-[2[tert-bu1yl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4 rienyl]phenyl]metha nol

Dissolving 3- [2- [ tert-butyl (dimethyl) silicon ] oxy-4-methyl-5-bicyclo [4.2.0] octa-1 (6),2, 4-triene) benzaldehyde 12B (0.6 g, 1.70 mmol) in methanol (5 mL) and tetrahydrofuran (2.5 mL), adding sodium borohydride (128 mg, 3.4 mmol), stirring at room temperature for 1 hour, concentrating under reduced pressure, extracting with ethyl acetate (30 mL x 3), combining the organic phases and drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =20: 1) to obtain 3- [2[ tert-butyl (dimethyl) silicon ] oxy-4-methyl-5-bicyclo [4.2.0] octa-1 (6, 2, 4-triene) as a colorless oil (6) 2, 4-triene) benzyl alcohol 12C (0.6 g, 98% yield).

The third step: methyl 2- [ (3S) -6- [ [3- [ 2-tert-butyl (dimethyl) silicon ] oxy-4-methyl-5-bicyclo [4.2.0] octa-1 (6),2, 4-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (12D)

Methyl-2-[(3S)-6-[[3-[2-teW-butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-tri enyl]phenyl]methoxyl]-2,3-dihydrobenzofuran-3-yl]acetate

Dissolving 3- [2[ tert-butyl (dimethyl) silicon ] oxy-4-methyl-5-bicyclo [4.2.0] octan-1 (6),2, 4-triene) benzyl alcohol 12C (600 mg, 1.70 mmol) in a dichloromethyl-alkan (7 mL), adding methyl (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 2d (374 mg, 1.80 mmol, intermediate 2), adding tributylphosphine (756 mg, 3.74 mmol) and gamma- (azodicarbonyl) dipiperidine (943 mg, 3.74 mmol) in sequence under the protection of nitrogen, stirring at room temperature overnight, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10: 1) to obtain colorless oily substance Methyl 2- [ (3S) -6- [ [3- [ 2-tert-butyl (dimethyl) silicon ] oxy-4-methyl-5-bicyclo [4.2.0] oct-1 (6),2, 4-triene ] phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 12D (573 mg, 57% yield).

The fourth step: methyl 2- [ (3S) -6- [ [3- (2-hydroxy-4-methyl-5-bicyclo [4.2.0] octa-1 (6),2, 4-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate (12E)

Methyl-2 (3S)-6 [3-(hydroxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl)phenyl]methoxyl]-2,3-dihydrobenzofuran-3 -yl]acetate

2- [ (3S) -6- [ [3- [ 2-tert-butyl (dimethyl) silicon]Oxy-4-methyl-5-bicyclo [4.2.0]Octa-1- (6),2, 4-triene]Phenyl radical]Methoxy radical]-2, 3-dihydrobenzofuran-3-yl]Methyl acetate 12D (470 mg, 0.86 mmol), tetrabutylammonium fluoride (818 mg, 2.6 mmol), dissolved in tetrahydrofuran (8 mL), stirred at room temperature for 30 min, quenched with water (50 mL), extracted with ethyl acetate (30 mL. times.3), the organic phases combined and dried over anhydrous sodium sulfateDrying, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate: (a))_V/v) = 10_:l) obtaining colorless viscous liquid 2- [ (3S) -6- [ [3- (2-hydroxy-4-methyl-5-bi-cyclo [4.2.0]]Octane-1 (6),2, 4-triene) phenyl]Methoxy radical]-2, 3-dihydrobenzofuran-3-yl]Methyl acetate 12E (300 mg, 81% yield).

The fifth step: 2- [ (3S) -6- [ [3- (2-hydroxy-4-methyl-bicyclo [4.2.0] octa-1 (6),2, 4-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (compound 12)

2-[(3S)-6-[[3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]phenyl]methoxyl]-2,3-

Dissolving methyl 2- [ (3S) -6- [ [3- (2-hydroxy-4-methyl-5-bicyclo [4.2.0] octan-1 (6),2, 4-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetate 12E (300 mg, 0.70 mmol) in a mixed solution of methanol (3 mL) and tetrahydrofuran (3 mL), adding a 2M sodium hydroxide solution (5 mL), stirring overnight at room temperature, stopping the reaction, concentrating under reduced pressure, adding water (25 mL) to the residue, dropwise adding 1M dilute hydrochloric acid to a reaction solution pH of not more than 2, extracting with ethyl acetate (30 mL. times.3), combining the organic phases and drying over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2: l) to give 2- [ (3S) -6- [ [3- (2-hydroxy-4-methyl-bicyclo [4.2.0] oct-1 (6),2, 4-triene) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid compound 12 as a white solid (280 mg, yield 90%).

¾NMR (400 MHz, DMSO-₆) δ 12.30 (s, IH), 9.33 (s, IH), 7.39 (t, IH), 7.32-7.30 (m, 2H),

7.23 (d, IH), 7.10 (d, IH), 6.50-6.45 (m, 3H), 5.08 (s, 2H), 4.68 (t, IH), 4.19 (dd, IH), 3.71-3.68 (m, IH), 2.93 (s, 4H), 2.69 (dd, IH), 2.47 (dd, IH), 2.14 (s, 3 H)。

Example 13: (S) -2- (6- ((2-chloro-5- (3-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] oct-l (6),2, 4-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 13)

(S)-2-(6-((2-chloro-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l(6),2,4-trien -2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

The first step is as follows: 5-bromo-4-methyl-2- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octa-1, 3, 5-triene (13A)

5-bromo-4-methyl-2-(3-methylsulfonylpropoxy)bicyclo[4.2.0]octa-1 ,5-triene

Dissolving 5-bromo-4-methyl-bicyclo [4.2.0] octa-1, 3, 5-trien-2-ol 3e (2.13 g, lO mmol, intermediate 3) in Ν, Ν -dimethylformamide (2 mL), adding 3-methylsulfamoylpropyl-4-methylbenzenesulfonic acid 1C (2.91 g, lO mmol) and cesium carbonate (6.5 g, 90 ℃ in that order, reacting for 4 hours, and reacting

20mmol), heated to room temperature, water (lioo mL) was added, extraction was performed with ethyl acetate (lioo mL x 1), the organic layer was washed with water (50 mL x2), dried over anhydrous magnesium sulfate (5 g), filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate i N, =3: 1) to give 5-bromo-4-methyl-2- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octa-1, 3, 5-triene 13A (1.67g, 50% yield) as a white solid. The second step is that: 4,4,5, 5-tetramethyl-2- (3-methyl-5- (3- (methylsulfonyl) propoxy) -2-bicyclo [4.2.0] octa-1, 3, 5-triene) -1,3, 2-boronic acid pinacol ester (13B)

4,4,5,5-tetramethyl-2-(3-methyl-5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl)-l ,3 ,2-dioxaborolane

Dissolving 5-bromo-4-methyl-2- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octa-1, 3, 5-triene 13A (1.67g, 5mmol) in ethanol (200 mL), sequentially adding pinacol diboron diboride (1.27 g, 5mmol), [ I, Γ -bis (; diphenylphosphino) ferrocene ] palladium dichloride (146 mg, 0.04 mmol, PdC12(dppf)) and potassium acetate (1.5 g, 15 mmol) under the protection of nitrogen, heating to 90 ℃, stirring and refluxing for 2 hours, concentrating the reaction system to dryness, and adding water (50 mL). Extraction was performed with ethyl acetate (50 mL × 1), the organic phase was washed with water (30 mL × 2), dried over anhydrous sodium sulfate (5 g), filtered, the filtrate 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 4,4,5, 5-tetramethyl-2-P-methyl-5- (3- (methylsulfonyl) propoxy) -2-bicyclo [4.2.0] octa-1, 3, 5-triene) -1,3, 2-boronic acid pinacol ester 13B as a colorless oil (1.78 g, 94% yield). The third step: 2-chloro-5- (4-methyl-2- (3- (methylsulfonyl) propoxy) -5-bicyclo [4.2.0] octa-1, 3, 5-triene) benzaldehyde (13C) 2-chloro-5- (4-methyl-2- (3-methylsulfoxypropoxy) -5-bicyclo [4.2.0] octa-l,3,5-trienyl) benzaldeh yde

Mixing 4,4,5, 5-tetramethyl-2- (3-methyl-5- (3- (methylsulfonyl) propoxy) -2-bicyclo [4.2.0]]Octa-1, 3, 5-triene) -1,3, 2-boronic acid pinacol ester 13B (1.78 mg, 4.68 mmol) is dissolved in Ν, Ν -dimethylformamide (20 mL), and 2-chloro-5-bromobenzaldehyde (1.03 g, 4.68 mmol), [ l, Γ -bis (diphenylphosphino) ferrocene is sequentially added]Palladium dichloride (171 mg, 0.234 mmol, PdCl)₂(dppf)) and potassium carbonate (1.29 g, 9.36 mmol), warmed to 90 ℃ and stirred for 2 hours, and reactedIt should be complete. Water (lOO mL) was added to the reaction mixture, extraction was performed with ethyl acetate (100 mL x 1), the organic phase was washed with water (50 mL x2), dried over anhydrous sodium sulfate (5 g), filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (R) ((R) ())_V/_V) =3: l) 2-chloro-5- (4-methyl-2- (3- (methylsulfonyl) propoxy) -5-bicyclo [ 4.2.0) was obtained as a colorless oil]Octanyl-1, 3, 5-triene) benzaldehyde 13C (570 mg, 31% yield).

The fourth step: 2-chloro-5- (4-methyl-2- (3- (methylsulfonyl) propoxy) -5-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyl alcohol (13D) 2-chloro-5- (4-methyl-2- (3-methylsulfonylpropyl) -5-bicyclo [4.2.0] octa-l,3,5-trienyl) phenyl me thane

Dissolving 2-chloro-5- (4-methyl-2- (3- (methylsulfonyl) propoxy) -5-bicyclo [4.2.0] octa-1, 3, 5-triene) benzaldehyde 13C (393 mg, lmmol) in methanol (10mL), cooling to 0 ℃, slowly adding sodium borohydride (37.83 mg,1 mmol), stirring at 0 ℃ for 0.5 hours, concentrating the reaction solution under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate i N) = 1: 1) to obtain 2-chloro-5- (4-methyl-2- (3- (methylsulfonyl) propoxy) -5-bicyclo [4.2.0] octa-1 as a colorless oil, 3, 5-triene) benzyl alcohol 13D (310 mg, 78.4% yield).

The fifth step: methyl 2- (3S) -6- ((2-chloro-5- (4-methyl-2- (3- (methylsulfonyl) propoxy) -5-bicyclo [4.2.0] octa-1, 3, 5-triene) benzyloxy) -2, 3-dihydrobenzofuran-3-yl) acetate (13E)

methyl 2-((3S)-6-((2-chloro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo [4.2.0]octa-l,3,5-trienyl)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate

2-chloro-5- (4-methyl-2- (3- (methylsulfonyl) propoxy)) -5-bicyclo [4.2.0]Dissolving octyl-1, 3, 5-triene) benzyl alcohol 13D (300 mg, 0.76 mmol) in a dichloro-methyl-alkan (5 mL), and sequentially adding (S) -2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl); ) Methyl acetate 2d (158 mg, 0.76 mmol) and azobiscarbonyldipiperidine (382 mg, 1.52 mmol), cooled to 0 ℃, and tributylphosphine (307 mg, 1.52 mmol) was slowly added dropwise, maintaining 0. C for 0.5 h, concentrating the reaction solution under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate i N, =3: 1) to obtain 2- (3S) -6- ((2-chloro-5- (4-methyl-₂- (3- (methylsulfonyl) propoxy) -5-bicyclo [4.2.0]Octyl-1, 3, 5-triene) benzyloxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester 13E (340 mg, yield 79%).

And a sixth step: (S) -2- (6- ((2-chloro-5- (3-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octa-1 (6),2, 4-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 13)

Methyl 2- (3S) -6- ((2-chloro-5- (4-methyl-2- (3- (methylsulfonyl) propoxy) -5-bicyclo [4.2.0] oct-1, 3, 5-triene) benzyloxy) -2, 3-dihydrobenzofuran-3-yl) acetate 13E (340 mg, 0.58 mmol) was suspended in methanol (5 mL), and a solution of sodium hydroxide (480 mg, 12 mmol) in water (1 mL) was added dropwise, followed by maintaining the room temperature for 4 hours after completion of dropping. The reaction was concentrated to l mL, water (10mL) was added, the reaction solution pH was adjusted to 3 with 2M dilute hydrochloric acid, extracted with a dichloromethane alkyl (20 mL x2), the organic phases were combined, the organic layer was washed with water (10mL x2), dried over anhydrous sodium sulfate (2 g), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1: 2) to give (S) -2- (6- ((2-chloro-5- (3-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] oct-1 (6),2, 4-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid compound 13 (198 mg, 60%)

MS: 570.8 [M+l]⁺.

¾ NMR (400 MHz, CDC1₃) 57.39(m,2H), 7.15(dd,lH) 7.05(d,lH), 6.59(s,lH), 6.46(m,2H), 5.16(s,2H), 4.75(t,lH), 4.22(m,3H), 3.78(m,lH), 3.18(m,4H), 2.97(m,5H), 2.77(dd,lH), 2.57(dd,lH), 2.28(m,2H), 2.16(s,3H)。

Example 14 (S) -2- (6- ((2-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octan-1, 3, 5-tris -)²-yl) benzyl) oxy) — or a salt thereof²3-dihydrobenzofuran-3-yl-acetic acid (Compound I)⁴)

(S)-2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l,3,5-trien-2- yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

The first step is as follows: 5- (5-hydroxy-3-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) -2-methylbenzaldehyde (14B)

5-(5-hydroxy-3-methylbicyclo[4.2. methylbenzaldehyde

Reacting 5-bromo-4-methyl-bicyclo [4.2.0]]Dissolving octa-1, 3, 5-trien-2-ol 3e (600 mg, 2.82 mmol, intermediate 3) in a mixed solution of N, N-dimethylformamide (6 mL) and potassium carbonate (2M, 6 mL), and sequentially adding (3-formyl-4-methylphenyl;) boronic acid 14A (555 mg, 3.38 mmol) and [ I, Γ -bis (diphenylphosphino) ferrocene]Palladium dichloride (103 mg, 0.141 mmol, Pd (dppf) Cl₂) Heating to 90 deg.C, stirring for 3 hr, vacuum filtering, extracting filtrate with ethyl acetate (50 mL x2), washing organic phase with water (80 mL x 3), drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying residue with silica gel column chromatography(n-hexyl alkyl/ethyl acetate (v/v) =10: 1) to obtain 5- (5-hydroxy-3-methyl bicyclo [4.2.0] in yellow solid state]Octa-1, 3, 5-trien-2-yl) -2-methylbenzaldehyde 14B (374 mg, 58.0% yield).

The second step is that: 5- (3- (hydroxymethyl) -4-methylphenyl) -4-methylcyclo [4.2.0] octa-1, 3, 5-trien-2-ol (14C)

5-(3-(hydroxymethyl)-4-methylphenyl)-4-methylbicyclo[4.2.0]octa-l,3,5-trien-2-ol

5- (5-hydroxy-3-methylbicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) -2-methylbenzaldehyde 14B (0.37 g, 1.47 mmol) was dissolved in methanol (30 mL), sodium borohydride (277 mg, 7.3 mmol) was added slowly and portionwise at 0 ℃ and stirred at room temperature for 1 hour, water (50 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure to give a white floc, which was filtered under suction, dissolved in ethyl acetate (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 5- (3- (hydroxymethyl) -4-methylphenyl) -4-methylcylocyclo [4.2.0] oct-1, 3, 5-trien-2-ol 14C (320 mg, yield 85%) was used directly in the next reaction.

The third step: (2-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) phenyl) methanol (14D)

(2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l,3,5-trien-2-yl)phenyl )methanol

Dissolving 5- (3- (hydroxymethyl) -4-methylphenyl) -4-methylbicyclo [4.2.0] octa-1, 3, 5-trien-2-ol 14C (315 mg, 1.24 mmol) in N, N-dimethylformamide (25 mL), adding 3-methylsulfamoylpropyl-4-methylbenzenesulfonic acid 1C (436 mg, 1.49 mmol) and cesium carbonate (513 mg, 1.73 mmol), heating to 80 ℃ and stirring for 3 hours, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (petroleum ether/ethyl acetate i N, =3:2) to obtain (2-methyl-5-P-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octa-1 as a pale yellow oil, 3, 5-Trien-2-yl) phenyl) methanol 14D (0.4 g, 86.0% yield)

The fourth step: (S) -methyl 2- (6- ((2-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octa-1, 3, 5-trien-2 yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (14E)

(S)-methyl2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-1 ,5 rien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate

Dissolving 14D (350 mg, 0.93 mmol) of (2-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octan-1, 3, 5-trien-2-yl) phenyl) methanol and 2D (214 mg, 1.03 mmol) of (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 2D (214 mg, 1.03 mmol, and 2 intermediate) in a dichloromethyl (10mL), sequentially adding tributylphosphine (0.68 mL, 2.74 mmol) and gamma, azodicarbonyl dipiperidine (0.69 g, 2.74 mmol) under the protection of nitrogen, stirring at room temperature for 3 hours, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1: 1) methyl (S) -2- (6- ((2-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] oct-1, 3, 5-trien-2 yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 14E (430 mg, 82%) was obtained as a yellow oil.

¾ NMR (400 MHz, CDC1₃) δ 7.30 (s, 1Η), 7.23 (d, 1H), 7.16 (dd, 1H), 7.03 (d, 1H), 6.60 (s, 1H), 6.52 - 6.46 (m, 2H), 5.02 (s, 2H), 4.75 (t, 1H), 4.29 - 4.21 (m, 3H), 3.81 (ddd, 1H), 3.72 (s, 3H)_:3.29― 3.17 (m, 4H), 3.08― 3.01 (m, 2H), 2.96 (s, 3H), 2.75 (dd, 1H), 2.55 (dd, 1H), 2.38 (s, 3H), 2.31 (dt, 2H), 2.21 (s, 3H).

The fifth step: (S) -2- (6- ((2-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] octa-1, 3, 5-trien-2 yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (compound 14)

(S)-2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l,3,5-trien-2- yl)benzyl)oxy)-2,3-dihy

Methyl (S) -2- (6- ((2-methyl-5- (3- (methylsulfonyl) propoxy) bicyclo [4.2.0] oct-1, 3, 5-trien-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 14E (390 mg, 0.69 mmol) was dissolved in a mixed solution of methanol (5 mL) and tetrahydrofuran (5 mL), a 2M sodium hydroxide solution (2 mL) was added thereto, the mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, water (25 mL) was added to the reaction solution, 1M dilute hydrochloric acid was added dropwise until the reaction solution had a pH of 1, and extraction was performed with ethyl acetate (25 mL. times.3), the organic phases were combined, 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) = 1: 3) to obtain (S) -2- (6-; 2-methyl-5- (3- (methylsulfonyl;) propoxy) bicyclo [4.2.0] oct-1, 3, 5-trien-2 yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid compound 14 (251 mg, 66% yield) as a white flocculent

MS: 549.0[M-1]— .

¾ NMR (400 MHz, CDC1₃) δ 7.30 (d, 1H), 7.23 (d, 1H), 7.17 (dd, 1H), 7.07 (d, 1H), 6.60 (s, 1H), 6.53-6.47 (m, 2H), 5.03 (s, 2H), 4.76 (t, 1H), 4.33-4.21 (m, 3H), 3.82 (ddd, 1H), 3.29-3.16 (m, 4H), 3.09-3.01 (m, 2H), 2.95 (s, 3H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.39 (s, 3H), 2.31 (ddd, 2H), 2.21 (s, 3H). biological test example

GPR40 luciferase reporter assay

The activity of the compounds prepared in the examples of the present invention was tested using the GPR40 luciferase reporter assay, which was performed as follows:

compounds were prepared in 10mM stock in DMSO and diluted in 3-fold gradients until use. The stably expressed strain HEK293/GPR40/5x Gal4UAS-Luc +/Gal4-Elkl was inoculated in a 96-well plate at an appropriate density. The next day, when the confluency of cells reached about 70%, the cells were replaced with serum-free medium and starved overnight. On the third day, test compounds at various concentrations were added

DMEM medium, 200. mu.1 per well, was placed in a cell incubator and incubated for 5 hours. Luciferase activity was detected using the Luciferase Assay System kit. Fluorescence data were subjected to fitting analysis using Origin 7 software, and EC of each compound was calculated_5QThe test results are shown in Table 1.

TABLE 1 luciferase reporter Gene assay results

And (4) conclusion: compared with a positive control, the compound of the invention has more excellent pharmacodynamic activity as a GPR40 agonist. 2. Oral glucose tolerance test

The glucose lowering effect of the compounds prepared in the examples of the present invention in glucose-loaded mice was evaluated using the Oral Glucose Tolerance Test (OGTT). The test procedure was as follows:

the used animals are SPF grade ICR mice, 18-22g, female, purchased from Beijing Huafukang Biotech GmbH, and the animal production certification number: SCXK (Jing) 2009-. Purchased mice were induced with high fat diet for 25 days and fasted overnight. The groups were 10 per group based on the fasting basal blood glucose values. Test compounds were formulated as 2mg/ml suspensions in 5% DMSO-15% solutol-80% normal saline. The administration amount is 20 mg/kg. Blank control group was given 5% DMSO-15% solutol-80% normal saline. After administration for 15 min, 20% aqueous glucose solution (lg/kg) was administered, and the blood glucose level of each mouse was measured at 0, 15, 30, 45, 60, and 120 min using a Qiangshenghuo blood glucose meter, and the percentage of decrease in area under the drug-time curve (AUC) was calculated. The test results are shown in Table 2.

TABLE 2 results of oral glucose tolerance test

And (4) conclusion: the compound has better hypoglycemic effect.

Claims

Claims

1. A compound shown in a general formula (I) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,

wherein:

r is selected from H or d-₈A alkyl group;

ring A is selected from 5-to 8-membered carbocyclyl or 5-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 4 substituents selected from N, 0 or 3(=0)₁₁The carbocyclyl or heterocyclyl group may optionally be further substituted with 0 to 4 atoms or groups selected from F, Cl, Br, I, =0, hydroxy, nitro, cyano, d \u₈Alkyl radical, d _₈Alkyl radical, C₂_₈Alkenyl radical, C₂_₈Alkynyl, -0-C (=0) -OR⁷、 -(CH₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷Or- (CH)₂)_m-NR⁷R^7aSubstituted with the substituent(s);

ring B, including the atoms attached to the benzene ring together form a four-membered ring, and ring B may optionally be further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, nitro, cyano, d —)₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷Or- (CH)₂)_m-NR⁷R^7aSubstituted with the substituent(s); r¹And R⁴Each independently selected from F, Cl, Br, I, hydroxyl, amino, nitro, cyano, carboxyl and d-₈Alkyl or d-₈Alkyl, said amino, alkyl or alkyl is further selected from 0 to 4 selected from F, Cl, Br, I, hydroxyl, cyano, Ci _₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7aOr- (CH)₂)_m-C(=0)-NR⁷R^7aSubstituted with the substituent(s); r²And R³Each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, d-₈Alkyl or d-₈Alkanyl, said amino, alkanyl or alkanyl group optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, cyano, Ci —)₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7aOr- (CH)₂)_m-C(=0)-NR⁷R^7aSubstituted with the substituent(s); r⁵And R⁶Each independently selected from H, F, Cl, Br, I, hydroxyl, nitro, cyano and d-₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7a、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-R⁷3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy, or 4-to 10-membered heterocyclyloxy, said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy, or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, cyano, d —, and₈radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷,

-(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7a、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-R⁷3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or 3(=0)₁₁An atom or group of (a);

alternatively, R⁵And R⁶A 4 to 8 membered carbocyclic or 5 to 8 membered heterocyclic ring may be formed, which carbocyclic or heterocyclic ring may optionally be further substituted by 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, nitro, cyano, d —₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷Or- (CH)₂)_m-NR⁷R^7aAnd said heterocycle contains 1 to 4 substituents selected from N, 0 or S (=0)_nAn atom or group of (a);

y is selected from the group consisting of a single bond, -0-, -NR⁷-、 -S(=0)_n-、 -C(=0)-、 -d_₈An alkyl-sub-base or-O-Cu alkyl-sub-base, said alkyl-sub-base being optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-₈Alkyl radical, Ci \₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、-(CH₂)_m-C(=0)-0-R⁷、-(CH₂)_m-C(=0)-NR⁷R^7a、 -(CH₂)_m-S(=0)_n-R⁷、 -0-C(=0)-0-R⁷or-NR⁷R^7aSubstituted with the substituent(s);

x is selected from H, F, Cl, Br, I, hydroxyl, nitro, cyano and d-₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7a、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-R⁷、 -(CH₂)_n-3 to 10 membered carbocyclyl, - (CH)₂)_n-4 to 10 membered heterocyclyl, - (CH)₂)_n-0-3 to 10 membered carbocyclyl or 4 to 10 membered heterocyclyloxy, said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, nitro, cyano, d — ]₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, - (CH)₂)_m-C(=0)-R⁷、 -(CH₂)_m-C(=0)-OR⁷、 -0-C(=0)-OR⁷、 -(CH₂)_m-S(=0)_n-R⁷、 -(CH₂)_m-NR⁷R^7a、 -(CH₂)_m-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-NR⁷R^7a、 -N(R^7b)-C(=0)-R⁷3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or 3(= 0;)₁₁An atom or group of (a);

R⁷1 and R^7bEach independently selected from H, hydroxy, amino, carboxy, d-₈Radix Et rhizoma Rhei₈Alkyl radical, C₂—₈An alkenyl group,

C₂.₈Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy, or 4-to 10-membered heterocyclyloxy, said amino, alkanyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy, or heterocyclyloxy being optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, hydroxy, amino, nitro, cyano, carboxy, d —, n₈Alkyl radical, d _₈Alkyl radical, C₂—₈Alkenyl radical, C₂—₈Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy or 4-to 10-membered heterocyclyloxy, and said heterocyclyl contains 1 to 4 substituents selected from N, 0 or S (=0)_nAn atom or group of (a);

p is selected from 0, 1,2 or 3, q is selected from 0, 1,2,3 or 4;

t is selected from 0, 1 or 2;

m is selected from 0, 1,2,3,4 or 5;

n is selected from 0, 1 or 2.
2. The compound of claim 1, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein the compound is selected from compounds represented by the general formula (II):

wherein-

R H or d-₄Alkyl base

Ring B, including the atoms to which the phenyl rings are attached together to form a four-membered ring;

R¹and R⁴Each independently selected from F, Cl, Br or d _₄A alkyl group;

R⁵and R⁶Each independently selected from H, F, Cl, Br or d _₄A alkyl group;

y is selected from the group consisting of a single bond, -0-or-O-d —₄An alkyl-sub-group, said alkyl-sub-group being optionally further selected from 0 to 4 groups- (CH)₂)_m-S(=0)_n-R⁷Substituted with the substituent(s);

x is selected from H, d \ u₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 8 membered carbocyclyl, said alkanyl, carbocyclyl or heterocyclyl optionally further substituted with 0 to 4 substituents selected from hydroxy or d —)₄Alkyl substituted by substituent (S) of alkyl, and said heterocyclic radical contains 1 to 4 substituents selected from N, 0 or S (=0)_nAn atom or group of (a);

R⁷selected from H or d \u₄A alkyl group;

p is selected from 0, 1 or 2;

q is selected from 0, 1 or 2;

m is selected from 0, 1,2,3,4 or 5;

n is selected from 0, 1 or 2.
3. The compound of claim 2, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein the compound is selected from compounds represented by the general formula (III):

wherein:

ring B, including the atoms to which the phenyl rings are attached together to form a four-membered ring;

R⁵and R⁶Each independently selected from H, F, Cl, Br or d _₄A alkyl group;

y is selected from-O-or-O-CM alkyl;

x is selected from H, d \ u₄Alkyl radical, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-3 to 8 membered carbocyclyl, - (CH)₂)_n-4 to 8 membered heterocyclyl or- (CH)₂)_n-a 0-3 to 8 membered carbocyclyl, said alkanyl, carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 substituents selected from hydroxyl or CM alkanyl;

R⁷is selected from H or d-₄A alkyl group;

m is selected from 0, 1,2,3 or 4;

n is selected from 0, 1 or 2.
4. The compound according to claim 3, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal thereof, wherein the compound is selected from compounds represented by the general formula (IV):

wherein-

R⁵Is selected from H or d-₄A alkyl group;

R⁶is H;

x is selected from H, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-4 to 6 membered carbocyclyl, - (CH)₂)_n-5 to 8 membered heterocyclyl or

-(CH₂)_n-0-3 to 5 membered carbocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 2 substituents selected from hydroxy or d —)₄Alkyl substituted by substituent of alkyl;

R⁷is selected from d-₄A alkyl group;

m is selected from 2,3 or 4;

n is selected from 0, 1 or 2.
5. The compound of claim 4, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

R⁵selected from H, methyl, ethyl, n-propyl or isopropyl; r⁶Is H;

x is selected from H, - (CH)₂)₃-S(=0)₂-R⁷、

R⁷Selected from methyl, ethyl, n-propyl or isopropyl.
6. The compound of claim 5, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

R⁵selected from H, methyl or ethyl;

R⁶is H;

x is selected from H, - (CH)₂)₃-S(=0)₂-R⁷、；

R⁷Is methyl.
7. The compound of claim 2, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein the compound is selected from compounds represented by the general formula (V):

wherein:

R⁴selected from H, F, CI or methyl;

R⁵is selected from H or d-₄A alkyl group;

x is selected from H, - (CH)₂)_m-S(=0)_n-R⁷、 -(CH₂)_n-4 to 6 membered carbocyclyl, - (CH)₂)_n-5 to 8 membered heterocyclyl or- (CH)₂)_n-0-3 to 5 membered carbocyclyl, said carbocyclyl or heterocyclyl being optionally further substituted with 0 to 2 substituents selected from hydroxy or d —)₄Alkyl substituted by substituent of alkyl;

R⁷is selected from H or d-₄A alkyl group;

m is selected from 0, 1,2,3 or 4;

n is selected from 0, 1 or 2.
8. The compound of claim 7, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

R⁴selected from H, F, CI or methyl;

R⁵is H or methyl;

x is selected from H, - (CH)₂)₃-S(=0)₂-CH₃、Or

Η 。
9. A compound according to claim 1 or a stereoisomer, hydrate, ester, metabolite, solvate, thereof,
10. A compound according to claim 9, or a stereoisomer, hydrate, ester, metabolite, solvate, thereof,
11. The compound according to any one of claims 1-10, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein the salt in the pharmaceutically acceptable salt thereof is selected from the group consisting of sodium salt, potassium salt, aluminum salt, lithium salt, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylammonium salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridine salt, picoline salt, 2, 6-dimethylpyridine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, purine salt, piperazine salt, piperidine salt, and a pharmaceutically acceptable salt, co-crystal, or prodrug thereof, N-ethylpiperidinium salt, polyamine resin salt, phentermine salt, or a combination thereof.
12. The compound of claim 11, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein the salt is selected from the group consisting of a sodium salt, a potassium salt, an ammonium salt, a triethylamine salt, an ethanolamine salt, a diethanolamine salt, or a combination thereof.
13. A process for the preparation of a compound according to any one of claims 1 to 10, which process may be selected from process one or process two comprising the steps of:

the method comprises the following steps:

compounds of general formula (I-aO are reduced by Climerson, modified Climerson reduction, Walff-Kacherner reduction, Huangming Long reduction or with a reducing agent-Lewis acid group I-a);

b human R⁹

(l-c) carrying out a suzuki coupling reaction on the compound with the general formula (I-a) and the compound with the general formula (I-b), and further carrying out hydrogenation reduction on the obtained product under the action of a reducing agent to obtain a compound with the general formula (I-c);

(l-ai) (l-a₂)

the general formula (I-aO is reduced into hydroxyl under the action of a reducing agent to obtain the general formula (I-a)₂) A compound; or the general formula (I-aO is reduced into hydroxyl under the action of a reducing agent and then undergoes nucleophilic substitution reaction to obtain a compound with the general formula (1-);

general formula (I-a)₂) Reducing hydroxyl by the compound to obtain a compound of a general formula (I-a); or the compound of the general formula (1-) reduces halogen to obtain a compound of the general formula (I-a);

(l-a) (l-c)

carrying out suzuki coupling reaction on the compound with the general formula (I-a) and the compound with the general formula (I-b), and further carrying out hydrogenation reduction on the obtained product under the action of a reducing agent to obtain a compound with the general formula (I-c);

carrying out Mistimobu reaction on the compound with the general formula (I-d) and the compound with the general formula (I-e) to obtain a product, and further hydrolyzing to obtain the compound with the general formula (I); 0. wherein R⁹Or R¹²Each independently selected from H, F, Cl, Br, I, hydroxy, ^ a,O' ， R^1QSelected from H, F, Cl, Br, I, hydroxy, d \ u₆Alkyl radical or d \ u₆Alkanyloxy, X, Y, ring B, R, R¹, R²、 R³、 R⁴、 R⁵、 R⁶P, q and t are as defined in any one of claims 1 to 10.
14. A pharmaceutical composition, said composition comprising: an effective dose of a compound according to any one of claims 1-12, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient;

the composition may further comprise one or more additional therapeutic agents.
15. The pharmaceutical composition of claim 14, wherein the additional therapeutic agent comprises:

(a) a GPR40 agonist or a pharmaceutically acceptable salt, and/or (b) a DPP-IV inhibitor or a pharmaceutically acceptable salt, and/or

(c) SGLT-2 inhibitor or pharmaceutically acceptable salt, and/or

(d) PPAR_TAgonists or Pp Α I_γPartial agonists or pharmaceutically acceptable salts, and/or

(e) PPAR dual agonists or pharmaceutically acceptable salts, and/or

(f) PPAR_sAn agonist or a pharmaceutically acceptable salt, and/or

(g) Insulin or insulin mimetic or pharmaceutically acceptable salt, and/or

(h) A protein tyrosine phosphatase- Α (Ρ Α) inhibitor or a pharmaceutically acceptable salt, and/or

(i) Sulfonylurea inhibitors or pharmaceutically acceptable salts, and/or

(D a-glucosidase inhibitor or pharmaceutically acceptable salt, and/or

(k) GLP-K GLP-1 analog, GIP-1, HSD-1 or a pharmaceutically acceptable salt, and/or

(1) A glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or

(m) an anti-inflammatory agent, and/or

(n) an ileal bile acid transporter inhibitor or a pharmaceutically acceptable salt, and/or

(0) An anti-obesity agent, and/or

(p) an agent that improves lipid profile in a patient, the agent selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, nicotinic acid or salts thereof? Is there a I! ^ agonists, cholesterol absorption inhibitors, acyl-CoA (cholesterol acyltransferase (ACAT)) inhibitors, CETP inhibitors or phenolic antioxidants or pharmaceutically acceptable salts, and/or

(q) biguanides, thiazole alkadiones, glinides or pharmaceutically acceptable salts or prodrugs thereof.
16. The pharmaceutical composition according to claim 15, wherein the GPR40 agonist is selected from the group consisting of fabuli & m hemihydrates (TAK-875) or a pharmaceutically acceptable salt or prodrug thereof.
17. The pharmaceutical composition of claim 15, wherein the DDPIV inhibitor is selected from linagliptini, linagliptin, omarigitin (MK-3102), sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (alogliptin), saxagliptin (saxagliptin), denagliptin (digagliptin), Carmegliptin (cartagliptin), Melogliptin (melaliptin), Dutogliptin (dulagliptin), Teneligliliptin (terliptin), Gemigliptin (digagliptin), or Trelagliptin (tregliptin); said SGLT-2 inhibitor is selected from Dapagliflozin (Dapagliflozin), Canagliflozin (Canagliflozin), Atigliflozin (aloglipzin), Empagliflozin (Empagliflozin), Ipagliflozin (Empagliflozin), Tofogliflozin (Tovogliflozin), Luseogliflozin (Lupulzin), Remogliflozin (regagliflozin), Sergliflozin (sergelliflozin), or Ertugliflozin (Etorizin); PPAR (PPAR) device_YAgonists include Ciglitazone (Ciglitazone), Troglitazone (Troglitazone), Pioglitazone (Pioglitazone), Rosglitazone (Rosiglitazone), Englitazone (Englitazone), Darglitazone C dapagliflozin, and PPAR dual agonists include muraglitazar (mogentazole) or aleglitazar (Alglitazar), which PPAR are_SAgonists include pioglitazone or rosiglitazone.
18. The pharmaceutical composition of claim 15, wherein the biguanide therapeutic agent is selected from metformin or diguanidine, the thiazoledione therapeutic agent is selected from Ciglitazone, Pioglitazone, Rosiglitazone, Troglitazone, Farglitazar or Darglitazone, the sulfonylurea inhibitor is selected from Glimepiride, Tolglybutramide, Glibornuride, Glibenclamide, Gliquidone, Glipipride or Gliclazipide, the canolide therapeutic agent is selected from Nateglinade, Gliglinide or Mitiglinide, the Mitiglinide α, the Gligosazide or the Gligosazide (Gligosazone) or the gliclazide analog, the glimepiridide therapeutic agent is selected from Cigliclazide or the Gligosazone (Gligosazone), the gliclazide inhibitor is selected from Gluconamide, Gligosazide, Gligosazone (gliclazone), the Gligosazide or the gliclazide.
19. Use of a compound according to any one of claims 1 to 12 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof or of a pharmaceutical composition according to any one of claims 14 to 18 for the preparation of a G protein-coupled receptor 40 agonist, in particular as a G protein-coupled receptor 40 agonist for the preparation of a pharmaceutical formulation, preferably for the treatment and/or prevention of a metabolic disorder.
20. The use of claim 19, wherein the metabolic disease comprises diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disorders, cardiovascular disease, renal disease, ketoacidosis, elevated levels of fatty acids or glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, syndrome X, insulin resistance, insulin allergy, glucose intolerance, skin disorders, atherosclerosis and its sequelae angina, angina pectoris, diabetes mellitus, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperlipidemia, elevated levels of fatty acids or glycerol, lipodystrophy, obesity, metabolic syndrome, syndrome X, insulin resistance, glucose intolerance, skin disorders, atherosclerosis and its sequelae, diabetes mellitus, diabetic nephropathy, diabetic neuropathy, or its sequelae, or hypertension, or a, One or more of lameness, heart attack, or stroke.
21. The use according to claim 20, wherein the metabolic disease comprises type II diabetes.
22. A method of treating and/or preventing a metabolic disease, comprising administering to a subject an effective amount of a compound of any one of claims 1-12, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of any one of claims 14-18.
23. The method of claim 22, wherein the metabolic disease comprises diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, renal disease, ketoacidosis, elevated levels of fatty acids or glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, syndrome X, insulin resistance, amylin allergy, glucose intolerance, skin disease, diabetes mellitus, hypertension, hyperlipidemia, obesity, diabetes mellitus, Atherosclerosis and its sequelae such as angina pectoris, claudication, heart attack or stroke.