CN104870429A

CN104870429A - Benzofuran derivative, preparation method therefor, and medical application thereof

Info

Publication number: CN104870429A
Application number: CN201480003531.4A
Authority: CN
Inventors: 张晨; 王健民; 何平; 雷鸣; 叶飞; 魏用刚; 邓炳初
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2013-05-22
Filing date: 2014-05-22
Publication date: 2015-08-26
Anticipated expiration: 2034-05-22
Also published as: WO2014187343A1; CN104870429B

Abstract

Disclosed are a benzofuran derivative, a preparation method therefor, and a medical application thereof, specifically relating to a compound represented by general formula (I), a stereoisomer thereof, a hydrate thereof, a solvate thereof, an eutecticum thereof, a pharmaceutically accepted salt or prodrug thereof, a preparation method therefor, a pharmaceutical composition comprising the benzofuran derivative, and a medical application of the compound or pharmaceutical composition, especially as a GPR40 receptor (G-protein coupled receptor) agonist, wherein definitions of substituent groups in general formula (I) are the same as definitions in the specification (img file='DDA0000739175360000011. TIF' wi='784' he='394' /).

Description

Benzofuran derivative, preparation method therefor, and medical application thereof

Benzofuran derivatives, preparation method and application technical field thereof in medicine

The invention relates to a benzofuran derivative, a preparation method and application thereof in medicines, in particular to a novel benzofuran derivative with a function regulation effect on a G protein-coupled receptor 40(GPR40) receptor, or a stereoisomer, hydrate, solvate, co-crystal, pharmaceutically acceptable salt or prodrug thereof, a preparation method and a pharmaceutical composition containing the same, and application thereof in medicines. 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, occurring mainly in the adult stage, and mainly manifested as insulin resistance due to insufficient secretion or insulin resistance (i.e. body tissues cannot effectively respond to endogenous insulin), genetics 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. The oral hypoglycemic agents which are approved to be on the market at present comprise sulfonylureas, biguanides and thiazole alkadione CTZD_SA-glucosidase inhibitor, dextrin analogue, dipeptidyl peptidase inhibitor (DPP-IV), sodium-glucose cotransporter 2 GLT-2) inhibitor and the like. However, all of these hypoglycemic agents have side effects such as hypoglycemia, weight gain, cardiovascular risk and urogenital infection (Vinod S. Deshmukh et al (2013). International Journal of Basic)&Clinical Pharmacology 2, 4-11), which further burden diabetic patients, and therefore, development of a new generation of hypoglycemic agents having a novel mechanism of action is required.

G protein-coupled receptor 40(GPR40) is a novel target with hypoglycemic potential and is highly expressed in pancreatic islet β cells.GPR40 is also called fatty acid receptor 1(FFAR1), is a membrane receptor belonging to a superfamily of homologous G protein-coupled receptors, which is highly conserved in various species, the G protein-coupled receptor has a 7-degree transmembrane structure, can sense extracellular signals, activate intracellular signal transduction pathways and finally cause cell response, GPR40 can be activated by medium-long chain free fatty acid CFFAs (Itoh Y et al (2003), Nature, 422, 173-containing 176). FFAs is also an important signal molecule besides being an energy source and can promote insulin secretion, and the function is mainly realized through GPR40, after the interaction between FFAs and GPR40, PLC in islet β cells or L-type Ca²⁺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 agonizing 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-. Fasiglifam hemihydrate (TAK-875) is a GPR40 agonist that has currently entered three phase clinics and has been shown to be effective. The research shows that: in diabetic animal models, the fastigifam hemihydrate (TAK-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); and in clinical trials, the fastigifam hemihydrate eCRAK-875) also shows obvious blood sugar reduction effect and has lower blood sugar risk (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.

(1) US2006258722 describes GPR40 receptor modulators useful as insulin secretion promoters and preventive and/or therapeutic agents for diabetes, having a structural formula as follows:

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.

(2) CN101616913 describes fused ring compounds having GPR40 receptor function modulating action useful as insulin secretion promoters and preventive and/or therapeutic agents for diabetes, the structural formula of which is as follows:

wherein R is¹Is selected from-S0₂-R⁶，， R⁶Is selected from d-₆Alkyl or optionally substituted 1, 1-dioxotetrahydrothiopyranyl, 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 R⁵Is selected from ^ substituted by hydroxyl₆A alkyl group; a is selected from a benzene ring, B is selected from a 5-to 7-membered ring, Y is selected from a bond or CH2, and R is selected from hydroxyl. The specific description in this patent is not considered to be part of the present invention.

(3) US7786165 describes GPR40 receptor function modulators of 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-N = N-group, W is selected from a bond or

₆Alkyl, X, Xa is selected from CH or N, Y is selected from 0 or CR⁶R⁷， R¹And R^laSelected from H, halogen, d-₆Alkyl or d-₆Alkyl radical, R²Is selected from H, d-₆Alkyl or optionally substituted acyl, R³And R⁴Selected from H or halogen, R⁵Selected from substituted hydroxyl or substituted amine groups, the compounds specifically described in US7786165 are not considered to be part of the present invention.

(4) 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 d₆Alkyl 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 provides a compound with a novel structure shown as a general formula omega, and researches show that the compound has excellent pharmacodynamic activity when being used as a GPR40 agonist.

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

wherein:

r is selected from H, d-₈Alkyl or PEG, preferably H or d-₆Alkyl, more preferably 11 or —₄Alkyl, further preferably H, ring Q is selected from 5-to 8-membered carbocyclyl or heterocyclyl, preferably 5-to 6-membered carbocyclyl or heterocyclyl, more preferably 5-membered carbocyclyl or heterocyclyl, further preferably 5-membered heterocyclyl, said heterocyclyl containing 1 to 4N, 0 or 3(=0)₁₁An atom or group (wherein when containing a plurality of N, 0 or S (=0)_nWhen an atom or group is used, each heteroatom may be the same or different, and the similar descriptions hereinafter have the same meanings and are not repeated), preferably 1 to 3 ^, 0 or 3(=0)₁₁An atom or group, more preferably 1 to 2N, 0 or S (=0)_nAn atom or group, said carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 groups selected from F, Cl, Br, I, =0, cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-R¹²、-(CH₂)_m-S(=0)_n-R¹²or-NR¹³R^13aWherein when a plurality of substituents are present, each substituent may be the same or different, and the similar descriptions hereinafter have the same meaning and are not repeated, preferably 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, =0, cyano, isocyano, amino, nitro, hydroxyl, carboxyl, d \\u₆Alkyl radical, d _₆Alkyl-oxy, -0-C (=0) -0-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-S(=0)_n-R¹²or-NR¹³R^13aMore preferably 0 to 3 substituents selected from F, Cl, Br, I, =0, cyano, and,Isocyano, amino, nitro, hydroxy, carboxy, d —₆Alkyl or d-₆Alkanyl, more preferably 0 to 2 alkyl groups selected from F, Cl, Br, I, =0, cyano, isocyano, amino, nitro, hydroxy, carboxy, d —)₄Alkyl radical or C_MAlkyl oxy, further preferably F, d —₃Alkyl or d-₃A alkyl group;

R¹, R²、 R³and R⁴Independently selected from H, F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxyl, carboxyl,₈Alkyl or d-₈Alkyl, preferably H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d —)₆Alkyl or d-₆Alkanyloxy, more preferably H, F, Cl, Br, I, cyano, hydroxy, d —₄Alkyl or d-₄Alkanyloxy, more preferably H, F, Cl, cyano, hydroxy, d —₃Alkyl or d-₃An alkyl group, further preferably H, F, Cl, d-2 alkyl or d-2 alkyl, further preferably H, F or Cl, wherein the alkyl, alkyl or amino groups are each independently optionally further selected from the group consisting of F, Cl, Br, I, -CH, and 0 to 4₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_m-S(=0)_n-R¹²、 -0-C(=0)-0-R¹²or-NR¹³R^13aPreferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, nitro, hydroxy, d-₆Alkyl radical or d \ u₆An alkyl group, more preferably 0 to 3 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical or d \ u₄Alkyl substituted by substituent(s) of alkyl, further preferably 0 to 2 substituents selected from F, Cl, -CF₃D-3 alkyl group or ^ -3 alkyl group, more preferably F, d \ u₂Alkyl or d-₂A alkyl group;

R⁵、 R⁶、 R⁷、 R⁸、 R⁹、 R¹. And R¹¹Each independently selected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxyl, C alkyl, d —₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group), - (CH)₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 10-membered heterocyclic group), preferably H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-₆A alkyl base,₆Alkyl-oxy- "alkyl₆alkyl-O-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3-to 6-membered carbocyclic group), - (CH)₂)_m- (3-to 6-membered heterocyclic group), -0- (CH)₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), more preferably F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-₄Radix Et rhizoma Rhei₄Alkyl radical, -d-₄alkyl-O-d-₄Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3-to 6-membered carbocyclic group), - (CH)₂)_m- (3-to 6-membered heterocyclic group), -0- (CH)₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), further preferably H, F, Cl, Br, hydroxyl, cyano, d-4 alkyl, -d —₄alkyl-O-d-₄Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), further preferably H, F, Cl, Br, hydroxyl, cyano, d —)₄Radix Et rhizoma Rhei₄Alkyl radical, -d-₄alkyl-O-d-₄Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 4-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 4-membered heterocyclic group), further preferably H, F, Cl, Br, hydroxyl, cyano, d —)₄Radix Et rhizoma Rhei₄Alkyl-oxygen base, -CM alkyl-O-CM alkyl base or- (CH)₂)_mS(=0)_nR¹²Further preferably H, d u₄Alkyl radical, d _₄Alkyl radical or-d \u₄alkyl-O-d-₄An alkyl group, said heterocyclic group containing 1 to 4N, 0 or 3(= 0;)₁₁An atom or group, preferably 1 to 3 heteroatoms selected from N, 0 or S, more preferably 1 to 2 heteroatoms selected from N, 0 or S, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 heteroatoms selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group), - (CH)₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-CKCH₂)_mSubstituted by (3-to 10-membered heterocyclyl), preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, amino, nitroHydroxy, carboxy, d-₆Radix Et rhizoma Rhei₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13aOr- (CH)₂)_mS(=0)_nR¹²More preferably 0 to 3 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-4 alkyl or-4 alkyl, more preferably 0 to 2 alkyl groups selected from F, Cl, Br, -CF₃Cyano, hydroxy, d-₃Alkyl radical or₃Alkanyloxy, further preferably 0 to 1, selected from F, Cl, cyano, hydroxy, d —)₂Alkyl or d-₂Alkyl oxygen radical, further preferably 0 to 1 selected from F, d-₂Root of Chinese Yak₂A alkyl group;

alternatively, R⁶And R⁷Can form (=0; > CR = CR)¹²R^12bPreferably (=0);

alternatively, R⁸And R⁹Can form (=0; > CR = CR)¹²R^12bPreferably (=0);

alternatively, R⁶And R⁷R and R⁸R and R⁹、 R⁷And R⁸、 R⁷And R⁹、 R⁸And R⁹May form a 3-to 8-membered carbocyclic ring or a 3-to 8-membered heterocyclic ring, preferably form a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring, more preferably R⁶And R⁷、 R⁸And R⁹May form a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring, further preferably a 3-to 4-membered carbocyclic ring or a 3-to 4-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring, said heterocyclic ring containing 1 to 4N, 0 or 3(=0)₁₁An atom or group, preferably 1 to 3 atoms selected from N, 0 or S (=0)_nAtom or radicalA group, more preferably 1 to 2 groups selected from N, 0 or 3(=0)₁₁An atom or group, said carbocyclic or heterocyclic ring being optionally further substituted by 0 to₄An_RWherein each R is substituted with a substituent of (wherein when having multiple Ri ^ s, each R is^12aMay be the same or different within the range, preferably 0 to 3R are selected from 0 to 3^12aMore preferably 0 to 2R^12a;R^12aSelected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano group, isocyano group, amino group, nitro group, hydroxyl group, carboxyl group, Ci-8 sintered foundation-O-Ci-8 sintered foundation₂)_m-j is a Hichiyl-R¹²、 -(CH₂)_m-a block radical-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group), - (CH)₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-0- (CH)₂)_m- (3 to 10 membered heterocyclyl), preferably F, Cl, Br, I, =0, hydroxy, peaceful radical, Ci —)₆A sintered body,₆A sintered body,₆Brick base-0-₆Sintered brick base- (C microspheres)_m-a rare radical-R¹²、 -(C¾)_m-a block radical-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_mC(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3-to 6-membered carbocyclyl) or- (CH)₂)_m- (3-to 6-membered heterocyclic group), more preferably F, Cl, Br, I, =0, hydroxyl, cyano, d —)₆Radix Et rhizoma Rhei₆Alkyl radical, d-₆Alkyl-0-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_mC(=0)-NR¹³R^13aOr- (CH)₂)_mS(=0)_nR¹²Further preferred are F, Cl, Br, =0, hydroxy and d —₄Radix Et rhizoma Rhei₄Alkyl radical, d-₄alkyl-O-d-₄Alkyl radical or- (CH)₂)_mS(=0)_nR¹²Further preferred are F, Cl, Br, =0, hydroxy and d —₄Radix Et rhizoma Rhei₄An alkyl group or a CM alkyl group O-d-4 alkyl group, preferably F, =0, a hydroxyl group, a d-3 alkyl group or a d-alkyl group₃Alkyl O-d-₃Alkyl group, preferably F, d-₂Radix Et rhizoma Rhei₂Alkyl radical or d-₂Alkyl O-d-₂Alkyl radical, the heterocycle contains 1 to 4 ^, 0 or 3(=0)₁₁An atom or group, preferably 1 to 3 heteroatoms selected from N, 0 or S, more preferably 1 to 2 heteroatoms selected from N, 0 or S, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl group optionally further substituted with 0 to 4 heteroatoms selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d \u₈Radix Et rhizoma Rhei₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group), - (CH)₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-CCH₂)_mSubstituted by (3-to 10-membered heterocyclyl), preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₆Radix Et rhizoma Rhei₆Alkyl-oxy-group, -d-₆alkyl-O-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²Or- (CH)₂)_mS(=0)_nR¹²More preferably 0 to 3 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical, d _₄Alkanyloxy, further preferably 0 to 3 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃CM-alkyl or CM-alkyl-oxy, more preferably 0 to 2 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or d-₄An alkyl group, further preferably 0 to 1 selected from F, Cl, Br, -CF₃、 d—₃Alkyl or d-₃An alkyl group, preferably 0 to 1, selected from F, d-2 alkyl or this-2 alkyl;

alternatively, when two R are present^12aWhen attached to the same atom, may form together with the atom to which they are attached a 3-to 8-membered carbocyclic ring or a 3-to 8-membered heterocyclic ring, preferably a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring, more preferably a 3-to 6-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 ^, 0 or 3(=0)₁₁An atom or group, preferably 1 to 3 heteroatoms selected from N, 0 or S, more preferably 1 to 2 heteroatoms selected from N, 0 or S, said carbocyclic or heterocyclic ring being optionally further substituted by 0 to 4 heteroatoms selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group), - (CH)₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-CKCH₂)_m- (3-to 10-membered heterocyclic group), preferably 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, cyano, d-₆Radix Et rhizoma Rhei₆Alkyl radical or-C ^ C-d-₄Alkanyl, more preferably 0 to 2, selected from F, Cl, Br, hydroxy, cyano, d —₄Root of Chinese Yak₄Alkyl radical, furtherPreferably 0 to 2 are selected from F, d —₃Alkyl or ^ - -₃Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Root of Chinese Yak₂A alkyl group;

_Ri2、_Ri2b, Ri3 and_Ri3a is selected from_H、 F、 Cl、 Br、 I、 -CH₂F、 -CHF₂、 -CF₃Cyano, mercapto, isocyano, amino, nitro, hydroxy, carboxyl, d-₈Radix Et rhizoma Rhei₈Alkanyl, 3-to 10-membered carbocyclyl or 3-to 10-membered heterocyclyl, preferably H, F, Cl, Br, I, hydroxy, mercapto, cyano, amino, d —₆Radix Et rhizoma Rhei₆Alkanyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, more preferably H, F, Cl, Br, hydroxy, mercapto, cyano, amino, d —₄Radix Et rhizoma Rhei₄Alkanyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, further preferably H, F, Cl, Br, d \u₄Alkyl radical, d _₄Alkanyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, further preferably H, F, Cl, Br, d \u₄Alkyl radical, d _₄Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, further preferably d — (R) —)₃Radix Et rhizoma Rhei₃Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclic group, preferably d — (R) —₂Alkyl or d-₂Alkyl-oxy, the heterocyclic radical containing 1 to 4 ^, 0 or 3(=0)₁₁An atom or group, preferably 1 to 3 atoms selected from N, 0 or S (=0)_nAn atom or group, more preferably 1 to 2 atoms selected from N, 0 or S (=0)_nAn atom or group, said alkyl, carbocyclyl or heterocyclyl group optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkanyl, -CLS alkanyl-O-d-₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group), - (CH)₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-CKCH₂)_mSubstituted by (3-to 10-membered heterocyclyl), preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₆Radix Et rhizoma Rhei₆Alkyl radical, -Ci _₆alkyl-O-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²Or- (CH)₂)_mS(=0)_nR¹²More preferably 0 to 3 groups selected from F, Cl, Br, I, -CH₂F、-CHF₂、 -CF₃、 d—₄Alkyl, CM alkyl, more preferably 0 to 3 selected from F, Cl, Br, -CH₂F、 -CHF₂、

-CF₃、 d_₄Alkyl radical or d \₄An alkyl group, further preferably 0 to 2 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃CM alkyl or d-₄Alkyl radicalFurther preferably 0 to 1 selected from F, Cl, Br, -CF₃、 d—₃Alkyl or d-₃Alkyl, preferably 0 to 1 selected from F, d-₂Radix et rhizoma Rhei₂A alkyl group;

alternatively, R¹²And R^12b、 R¹³And 1^1¾A 3 to 8-membered carbocyclic ring or a 3 to 8-membered heterocyclic ring may be formed, preferably a 3 to 6-membered carbocyclic ring or a 3 to 6-membered heterocyclic ring, more preferably a 3 to 6-membered heterocyclic ring, which contains 1 to 4N, 0 or S (= C)_nAn atom or group, preferably 1 to 3 atoms selected from N, 0 or 3(=0)₁₁An atom or group, more preferably 1 to 2 atoms selected from N, 0 or 3(=0)₁₁An atom or group, said carbocyclic or heterocyclic ring being optionally further substituted by 0 to 4 atoms selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group), - (CH)₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-CKCH₂)_mSubstituted by (3-to 10-membered heterocyclyl), preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, aminoNitro, hydroxy, carboxyl, d-₆Radix Et rhizoma Rhei₆Alkyl radical, -Ci _₆alkyl-O-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²Or- (CH)₂)_mS(=0)_nR¹²More preferably 0 to 3 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical, d _₄Alkanyloxy, further preferably 0 to 3 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃CM alkyl or d₄An alkyl group, further preferably 0 to 2 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃CM alkyl or d-₄An alkyl group, further preferably 0 to 1 selected from F, Cl, Br, -CF₃、 d—₃Alkyl or d-₃An alkyl group, preferably 0 to 1, selected from F, d-2 alkyl or this-2 alkyl;

p is selected from 0,1, 2 or 3, preferably 0,1 or 2, more preferably 0 or 1, further preferably 0;

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

t is selected from 0,1 or 2, preferably 0 or 1, more preferably 1;

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

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.

A preferred embodiment of the present invention comprises a compound represented by the general formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

R¹, R²、 R³and R⁴Each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d-₆Alkyl or d-₆Alkanyloxy, preferably H, F, Cl, Br, I, cyano, hydroxy, d —)₄Alkyl or d-₄An alkyl group, more preferably H, F, cyano, hydroxy, d-3 alkyl or d-3 alkyl, further preferably H, d —₂Alkyl or d-₂Alkanyl, further preferably H, wherein the alkanyl, alkanyl or amino groups are each independently optionally further 0 to 3 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, nitro, hydroxy, d-₆Alkyl or d-₆Alkyl substituted by substituent(s) of alkyl, preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical or d \ u₄Alkyl substituted by substituent(s) of alkyl, more preferably 0 to 2 substituents selected from F, Cl, -CF₃、 d—₃Alkyl or d-₃Alkyl oxy, further preferably F, d —₂Alkyl or d-₂Alkyl oxy, further preferred₂A alkyl group;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d-₆Radix Et rhizoma Rhei₆Alkyl radical or alkyl radical₆alkyl-O-d-₆Alkyl, preferably H, F, Cl, Br, I, d-₄Alkyl or d-₄Alkyl oxy, more preferably H, F, d —₃Alkyl or d-₃Alkyl oxy, further preferably H, F, d —₂Alkyl or d-₂Alkyl oxy, further preferably H or d-₂A alkyl group, the alkyl group and the alkyl group are independently optional furtherIs substituted by 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃6 alkyl or d-₆Alkyl substituted by alkyl, preferably 0 to 2 substituents selected from F, Cl, Br, I, d —)₄Alkyl or ^ - -₄Alkyl substituted by alkyl, more preferably 0 to 2 substituents selected from F, d —)₃Root of Chinese Yak₃Alkyl group, more preferably F, 2 alkyl group or —₂Alkyl oxy, further preferably d —)₂An alkyl group.

A preferred embodiment of the present invention comprises a compound represented by the general formula (I) or all stereoisomers, hydrates, esters, solvates, pharmaceutically acceptable salts or prodrugs thereof, wherein:

R¹, R²、 R³and R⁴Each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d-₄Alkyl or d-₄Alkanyloxy, preferably H, F, cyano, hydroxy, d —₃Alkyl or d-₃Alkyl oxy, more preferably H, d —₂Alkyl or d-₂An alkyl group, further preferably H, wherein the alkyl or alkyl group is each independently optionally further 0 to 3 selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or ^ - -₄Alkyl substituted by substituent(s) of alkyl, preferably 0 to 2 substituents selected from F, Cl, -CF₃、 d—₃Alkyl or ^ - -₃Alkyl oxy, more preferably F, d —₂Alkyl or ^ - -₂Alkyl oxy, further preferably d —)₂A alkyl group;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, I, d \ u₄Alkyl radical or d \₄Alkanyl radical, preferably H, F, 3 alkanyl or d —₃Alkyl oxy, more preferably H, F, d —₂Alkyl or d-₂Alkyl oxy, further preferably H or d-₂Alkanyl, said alkanyl or alkanyl each independently optionally further 0 to 2 are selected from F, Cl, Br, I, d —)₄Alkyl or d-₄Alkyl substituted by alkyl, preferably 0 to 2 substituents selected from F, d —)₃Root of Chinese Yak₃Alkyl oxy, more preferably F, d —₂Radix et rhizoma Rhei-₂Alkyl oxy, further preferably d —)₂An alkyl group.

R¹, R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably H, F, methyl, ethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, more preferably H, methyl, ethyl, methoxy or ethoxy, even more preferably H or methyl. A preferred embodiment of the present invention comprises a compound represented by the general formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, Ci₆Brick foundation and Ci₆Sintered body oxygen radical-Ci₆Sintered foundation-O-Ci-6 sintered foundation- (CH)₂)_m-j is a Hichiyl-R¹²、 -(CH₂)_m-a block radical-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3 to6-membered carbocyclic group), - (CH)₂)_m- (3-to 6-membered heterocyclic group), -0- (CH)₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), preferably H, F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxyl, d-4 alkyl, -d-4 alkyl-O-d-4 alkyl, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3-to 6-membered carbocyclic group), - (CH)₂)_m- (3-to 6-membered heterocyclic group), -0- (CH)₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), more preferably H, F, Cl, Br, hydroxyl, cyano, d \ u₄Alkyl radical, d _₄Alkyl radical, -d-₄alkyl-O-d-₄Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), preferably H, F, Cl, Br, hydroxyl, peaceful base, Ci-4 sintered oxygroup, Ci-4 sintered foundation-O-Ci-4 sintered foundation₂)_m-j is a Hichiyl-R¹²、 -(CH₂)_m-a block radical-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 4-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 4-membered heterocyclic group), further preferably H, F, Cl, Br, hydroxyl, cyano, d-4 alkyl, -d —₄alkyl-O-d-₄Alkyl radical or- (CH)₂)_mS(=0)_nR¹²Further preferably H, d —₄Radix Et rhizoma Rhei₄Alkyl radical or-d-₄alkyl-O-d-₄An alkyl group, said heterocyclic group containing 1 to 3 heteroatoms selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclic group each independently optionally further being 0 to 3 heteroatoms selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, amino, nitro, hydroxy, carboxy, d —₆Radix Et rhizoma Rhei₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13aOr is- (CH)₂)_mS(=0)_nR¹²Preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-₄Alkyl or ^ - -₄An alkyl group, more preferably 0 to 2 groups selected from F, Cl, Br, -CF₃Cyano, hydroxy, 3-alkyl or d —₃Alkanyloxy, further preferably 0 to 1, selected from F, Cl, cyano, hydroxy, d —)₂Alkyl or d-₂Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Alkyl or d-₂A alkyl group;

alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁶And R⁸、 R⁶And R⁹、 R⁷And R⁸、 R⁷And R⁹、 R⁸And R⁹May form a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring, preferably R⁶And R⁷、 R⁸And R⁹May form a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring, more preferably a 3-to 4-membered carbocyclic ring or a 3-to 4-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring, said heterocyclic ring containing 1 to 3 ^, 0 or S atoms, preferably 1 to 2 heteroatoms selected from N, 0 or S, said carbocyclic or heterocyclic ring optionally being further substituted with 0 to 3R^12aIs preferably 0 to 2R^12aSelected from F, Cl, Br, I, =0, hydroxyl, cyano and d-₆Radix Et rhizoma Rhei₆Alkyl radical, d-₆alkyl-O-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_mC(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3-to 6-membered carbocyclyl) or- (CH)₂)_mSubstituted with a substituent of (3-to 6-membered heterocyclyl); preferred are F, Cl, Br, I, =0, hydroxy, cyano, d \u₆Alkyl radical, d _₆Alkyl radical, d-₆Alkyl-0-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_mC(=0)-NR¹³R^13aOr- (CH)₂)_mS(=0)_nR¹²More preferably!⁷Cl, Br, =0, hydroxy, d —₄Radix Et rhizoma Rhei₄Alkyl-oxy, d-4 alkyl-0-d-4 alkyl or- (CH)₂)_mS(=0)_nR¹²Further preferred are F, Cl, Br, =0, hydroxyl, d-4 alkylAlkyl group or d-4 alkyl group 0-d-4 alkyl group, and further preferably F, =0, hydroxyl group, d —)₃Radix Et rhizoma Rhei₃Alkyl radical or d-₃Alkyl 0-d-₃Alkyl group, more preferably F, d-₂Alkyl radical, d _₂Alkyl radical or d-₂Alkyl radical O-d-₂An alkyl, said heterocycle containing 1 to 3 ^0 or S atoms, preferably 1 to 2 heteroatoms selected from N, 0 or S, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally further substituted with 0 to 3 heteroatoms selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxyl,₆Radix Et rhizoma Rhei₆Alkyl radical, -d-₆Alkyl-0-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²Or- (CH)₂)_mS(=0)_nR¹²Is preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical, d _₄Alkanyloxy, more preferably 0 to 3 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or d-₄An alkyl group, further preferably 0 to 2 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical or d \₄An alkyl group, further preferably 0 to 1 selected from F, Cl, Br, -CF₃D-3 alkyl or ^ -3 alkyl, further preferably 0 to 1 selected from F, d ^ -3 alkyl₂Alkyl or d-₂A alkyl group; alternatively, when two R are present^12aIs connected toOn the same atom, may form together with the atom to which they are attached a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 6 membered heterocyclic ring, containing 1 to 3 heteroatoms selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, said heterocyclic or carbocyclic ring being optionally further substituted by 0 to 3 heteroatoms selected from F, Cl, Br, I, hydroxy, cyano, d —, N₆Radix Et rhizoma Rhei₆Alkyl radical or-Q ^ C-d-₄Alkyl, preferably 0 to 2 substituents selected from F, Cl, Br, hydroxy, cyano, d —₄Alkyl or d-₄Alkyl, more preferably 0 to 2 selected from F, d —₃Root of Dingji₃Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Alkyl or d-₂A alkyl group;

R¹²、 R¹³and R^13aSelected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano, amino and d-₆Radix Et rhizoma Rhei₆Alkanyl, (3-to 6-membered carbocyclyl) or 3-to 6-membered heterocyclyl, preferably H, F, Cl, Br, hydroxy, mercapto, cyano, amino, d \u₄Alkanyl, CM alkanyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, more preferably H, F, Cl, Br, d —₄Radix Et rhizoma Rhei₄Alkanyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, further preferably H, F, Cl, Br, d \u₄Alkyl radical, d _₄Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, more preferably d — (d —)₃Radix Et rhizoma Rhei₃Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, further preferably d — (d —)₂Alkyl or d-₂A alkyl group; m is selected from 0,1, 2,3 or 4, preferably 0,1, 2 or 3, more preferably 0,1 or 2;

n is selected from 0,1 or 2.

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, F, Cl, Br, I, hydroxy, cyano, d \u₄Alkyl radical, d _₄A alkyl group,

-CM alkyl-O-CM alkyl or- (CH)₂)_mS(=0)_NR¹²Preferably H, d u₄Alkyl radical, d _₄Alkyl radical or-d \u₄alkyl-O-CM alkyl, more preferably H, d —₃Radix Et rhizoma Rhei₃Alkyl radical or-d-₃alkyl-O-d-₃Alkyl group, more preferably H, d-₃The alkyl group is preferably an alkyl group or a-Cw alkyl group-O-Cw alkyl group, and more preferably H, d u \ alkyl group₂Alkyl radical or-d \u₂The alkyl-O-Cw alkyl is further selected from 0 to 3-CH groups which are independent of each other₂F、 -CHF₂、 -CF₃Cyano, amino, nitro, hydroxy, carboxy or d-₄Substituted with an alkyl group, preferably 0 to 2 substituents selected from F, Cl, Br, -CF₃Cyano, hydroxy, d-₃Alkyl or ^ -3 alkyl, more preferably 0 to 1 selected from F, Cl, cyano, hydroxy, d-₂Alkyl or ^ - -₂Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Root of Chinese Yak₂A alkyl group;

alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁸And R⁹Any of which may form a 3 to 6 membered carbocyclic ring or 3 to 6 membered heterocyclic ring, preferably a 3 to 4 membered carbocyclic ring or 3 to 4 membered heterocyclic ring, more preferably a 3 membered carbocyclic ring or 3 membered heterocyclic ring, even more preferably a 3 membered carbocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may optionally be further interrupted by 0 to 3R^12aIs preferably 0 to 2R^12a _;

R^12aSelected from F, Cl, Br, I, =0, hydroxyl, cyano and d-₄Radix Et rhizoma Rhei₄Alkyl radical, d-₄Alkyl oxygen-0-d-₄Alkyl radical or- (CH)₂)_mS(=0)_nR¹²F, Cl, Br, =0, hydroxy, d \uare preferable₄Alkyl radical, d _₄Alkyl radical or d \ u₄Alkyl O-C alkyl, more preferably F, =0, hydroxy, d-)₃Radix Et rhizoma Rhei₃Alkyl radical or d-₃Alkyl O-d-₃A alkyl group, preferably F,

₂Radix Et rhizoma Rhei₂Alkyl radical or d-₂Alkyl O-d-₂Alkyl group, more preferably F, d-₂Alkyl radical or d-₂Alkyl O-d-₂An alkyl group, said alkyl or alkyl group being optionally further substituted by 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, amino, nitro, hydroxy, carboxy, d —₄Alkyl or ^ - -₄Alkyl substituted by substituent(s) of alkyl, preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl, CM alkyl, more preferably 0 to 3 selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or CM alkyl, further preferably 0 to 2 selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or CM alkyl, further preferably 0 to 1 selected from F, Cl, Br, -CF₃、 d—₃Alkyl or d-₃Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Radix et rhizoma Rhei₂A alkyl group;

n is selected from 0,1 or 2.

The preferable scheme of the invention comprises the compound shown in the general formula (I) or a stereoisomer, hydrate, ester, solvate, thereof,A co-crystal, metabolite, pharmaceutically acceptable salt or prodrug, wherein: r⁶、 R⁷、 R⁸And R⁹Each independently selected from H, F, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl, more preferably H, methoxy, ethoxy, methoxymethyl or ethoxymethyl, further preferably H;

alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁸And R⁹Any of the groups may form a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring, preferably a 3 membered carbocyclic ring or a 3 membered heterocyclic ring, more preferably a 3 membered carbocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms of 0, N or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may optionally be further substituted with 0 to 3 substituents selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably 0 to 2 substituents selected from F, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, methoxy, ethoxy, methyl, ethoxy, N, Ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, more preferably 0 to 1 selected from the group consisting of F, methyl, ethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, further preferably methoxy, ethoxy, methoxymethyl, methoxyethyl or ethoxymethyl.

The preferable scheme of the invention comprises the compound shown in the general formula (I) or the stereoisomer, hydrate, ester, solvate, co-crystal and substituent thereof

And ring Q may be further substituted by 0 to 3 groups selected from F, Cl, Br, I, =0, amino, hydroxy, d —)₆Alkyl or d-₆Alkyl-substituted, preferably 0 to 3, optional g F, Cl, =0, d-4 alkyl or d-4 alkyl, more preferably 0 to 2, optional F, Cl, =0, d —₃Alkyl or d-₃Alkanyloxy, further preferably 0 to 2 are optionally from F, Cl, =0, d —₂Alkyl or d-₂Alkanyloxy, further preferably 0 to 2 are optionally from F, =0 or d —₂An alkyl group.

A preferred embodiment of the present invention comprises a compound of formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolically acceptable salt or prodrug thereof, wherein:

ring Q is selected from。

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

wherein-

R is selected from H or d \u₆Alkyl radical, preferably H or d \ u₄Alkyl, more preferably H;

l 、>。、 Α ,Ν. i -s.>。、

or, preferably or more preferably ^ and ring Q may be further substituted by 0 to 3 groups selected from F, Cl, Br, I, =0, amino, hydroxy, d ^ -3₆Alkyl or d-₆Alkyl-oxy, preferably 0 to 3, optional g F, Cl, =0, d \\ \ u₄Alkyl radical or d \₄Alkyl oxy, more preferably 0 to 2 optional g F, Cl, =0, d —₃Alkyl or d-₃Alkanyloxy, further preferably 0 to 2 are optionally from F, Cl, =0, d —₂Alkyl or d-₂Alkanyloxy, further preferably 0 to 2, optionally from F, =0 or ^ -C₂A alkyl group;

R¹selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxyl and d-₆Alkyl or d-₆Alkanyloxy, preferably H, F, Cl, Br, cyano, amino, hydroxy, d —)₄Alkyl or d-₄Alkyl oxy, more preferably H, F, Cl, Br, cyano, amino, hydroxy,₃Alkyl or d-₃Alkyl oxy, further preferably H, F, d —₂Alkyl or d-₂Alkanyl, further preferably H, wherein the alkanyl, alkanyl or amino groups are each independently optionally further 0 to 3 groups selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, nitro, hydroxy, d-₆Alkyl or d-₆Substituted with alkyl-oxy substituents, preferably 0 to 3 substituents selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, nitro, hydroxy, d \_₄Alkyl radical or d \ u₄An alkyl group, more preferably 0 to 2 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, nitro, hydroxy, d-₃Alkyl or d-₃Alkyl, further preferably 0 to 2 groups selected from F, -CF₃D-2 alkyl or-2 alkyl;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d-₆Radix Et rhizoma Rhei₆Alkyl radical or alkyl radical₆alkyl-O-d-₆Alkyl, preferably H, F, Cl, Br, d-₄Alkyl or d-₄Alkanyloxy, more preferably H, F, Cl, Br, d —₃Alkyl or d-₃Alkyl oxy, more preferably H, F, Cl, Br, d-₂Alkyl radical or d—₂Alkyl oxy group, more preferably H, F, d u₂An alkyl or d-2 alkyl, each independently optionally further substituted by 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d—₆Alkyl or d-₆Alkyl substituted by substituent(s) of alkyl, preferably 0 to 3 substituents selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical or d \ u₄Alkyl, more preferably 0 to 2 substituents selected from F, Cl, Br, d-4 alkyl or ^ -4 alkyl, and still more preferably 0 to 2 substituents selected from F, Cl, Br, d-₃Alkyl or d-₃Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Alkyl or d-₂A alkyl group;

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, or a salt thereof,

Ci_₆Brick foundation and Ci₆Sintered body oxygen radical-Ci₆Sintered foundation-O-Ci-6 sintered foundation- (CH)₂)_m-j is a Hichiyl-R¹²、 -(CH₂)_m-a block radical-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3-to 6-membered carbocyclic group), - (CH)₂)_m- (3-to 6-membered heterocyclic group), -0- (CH)₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), preferably H, F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, CM alkyl, d-4 alkyl, -d-4 alkyl-O-d-4 alkyl, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、

-(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3-to 6-membered carbocyclic group), - (CH)₂)_m- (3-to 6-membered heterocyclic group), -0- (CH)₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), more preferably H, F, Cl, Br, hydroxyl, cyano, d \ u₄Alkyl radical, d _₄Alkyl radical, -d-₄alkyl-O-d-₄Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), preferably H, F, Cl, Br, hydroxyl, peaceful base, Ci-4 sintered oxygroup, Ci-4 sintered foundation-O-Ci-4 sintered foundation₂)_m-j is a Hichiyl-R¹²、 -(CH₂)_m-a block radical-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 4-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 4-membered heterocyclic group), further preferably H, F, Cl, Br, hydroxyl, cyano, d-4 alkyl, -d —₄alkyl-O-d-₄Alkyl radical or- (CH)₂)_mS(=0)_nR¹²Further preferably H, d —₄Radix Et rhizoma Rhei₄Alkyl radical or-d-₄alkyl-O-d-₄An alkyl group, said heterocyclic group containing 1 to 3 heteroatoms selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclic group each independently optionally further comprising 0 to 3 heteroatoms selected from F, N,Cl、 Br、 I、 -CH₂F、 -CHF₂、 -CF₃Cyano, amino, nitro, hydroxy, carboxy, d —₆Radix Et rhizoma Rhei₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13aOr- (CH)₂)_mS(=0)_nR¹²Preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-₄Alkyl or d-₄An alkyl group, more preferably 0 to 2 groups selected from F, Cl, Br, -CF₃Cyano, hydroxy, d-₃Alkyl or d-₃Alkanyloxy, further preferably 0 to 1, selected from F, Cl, cyano, hydroxy, d —)₂Alkyl radical or ^₂Alkyl, further preferably 0 to 1 selected from F, d u₂Alkyl radical or d \ u₂A alkyl group;

alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁷And R⁸、 R⁸And R⁹、 R⁶And R⁸、 R⁶And R⁹May form a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring, preferably R⁶And R⁷、 R⁸And R⁹May form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring, further preferably a 3 membered carbocyclic ring or a 3 membered heterocyclic ring, further preferably a 3 membered carbocyclic ring, said heterocyclic ring containing 1 to 3N, 0 or S atoms, preferably 1 to 2 heteroatoms selected from N, 0 or S, said carbocyclic or heterocyclic ring optionally being further interrupted by 0 to 3R^12aIs substituted by the substituent(s) of (a),preferably 0 to 2

_R12a;

R^12aSelected from F, Cl, Br, I, =0, hydroxyl, cyano and d-₆Radix Et rhizoma Rhei₆Alkyl radical, d-₆Alkyl-0-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_mC(=0)-NR¹³R^13aOr- (CH)₂)_mS(=0)_nR¹²Substituted with the substituent(s); preferred are F, Cl, Br, =0, hydroxy, and d \ u₄Alkyl radical, d _₄Alkyl radical, d \u₄alkyl-O-CM alkyl or- (CH)₂)_mS(=0)_nR¹²More preferably? Cl, Br, =0, hydroxy, d —₄Radix Et rhizoma Rhei₄Alkyl radical or d-₄Alkyl O-d-₄A alkyl group, preferably F,

=0, hydroxy, d —₃Radix Et rhizoma Rhei₃Alkyl radical or d-₃Alkyl O-d-₃Alkyl group, more preferably F, d-₂Radix Et rhizoma Rhei₂Alkyl radical or₂Alkyl O-d-₂Alkyl group, more preferably F, d-₂Alkyl radical or d-₂Alkyl 0-d-₂The alkyl, alkenyl and alkynyl are further selected from 0 to 3 selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxyl,₆Radix Et rhizoma Rhei₆Alkyl radical, -d-₆alkyl-O-d-₆Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²Or is- (CH)₂)_mS(=0)_nR¹²Preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃CM-alkyl, CM-alkyl-oxy, more preferably 0 to 3 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or CM alkyl, further preferably 0 to 2 selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical or d \₄An alkyl group, further preferably 0 to 1 selected from F, Cl, Br, -CF₃、 d—₃Alkyl or d-₃An alkyl group, further preferably 0 to 1 alkyl group selected from F, d-2 alkyl or this-2 alkyl group;

alternatively, when two R are present^12aWhen attached to the same atom, may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 6 membered heterocyclic ring, containing 1 to 3 heteroatoms selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, said heterocyclic or carbocyclic ring being optionally further substituted by 0 to 3 heteroatoms selected from F, Cl, Br, I, CF₃A hydroxyl group, a cyano group,₆Alkyl or ^ - -₆Alkyl substituted by substituent(s) of alkyl, preferably 0 to 2 substituents selected from F, Cl, Br, CF₃Hydroxy, cyano, d-₄Alkyl or ^ - -₄Alkyl, more preferably 0 to 2 selected from F, d —₃Alkyl or d-₃Alkyl, further preferably 0 to 1 is selected from F, d \ u₂Alkyl radical or d \ u₂A alkyl group;

R¹²、 R¹³and R^13aSelected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano, amino and d-₆Radix Et rhizoma Rhei₆Alkyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, preferably H, F, Cl, Br, hydroxy,Mercapto, cyano, amino, d-₄Alkyl, CM alkyl, 3 to 6 membered carbocyclyl or 3 to 6 membered heterocyclyl, more preferably H, F, Cl, Br, d \\ u₄Alkyl radical, d _₄Alkanyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, further preferably H, F, Cl, Br, d —₄Radix Et rhizoma Rhei₄Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, further preferably d — (d —)₃Radix Et rhizoma Rhei₃Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, further preferably d — (d —)₂Alkyl or d-₂A alkyl group;

p is selected from 0,1 or 2, preferably 0 or 1, more preferably 0;

n is selected from 0,1 or 2.

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

r is selected from 11 and ring Q is selected from0 to 3 substituents optionally selected from F, Cl, =0, d-4 alkyl or d-4 alkyl, preferably 0 to 2 optional substituents g F, Cl, =0, d —₃Radix et rhizoma Rhei-₃Alkyl oxy, more preferably 0 to 2 optional g F, Cl, =0, d —₂Alkyl or d-₂Alkyl oxy, further preferably 0 to 2 optional g F, =0 or ^ -i₂A alkyl group; r¹Selected from H, F, Cl, Br, cyano, amino, hydroxy, d-₄Alkyl or d-₄An alkyl group, preferably H, F, Cl, Br, cyano, amino, hydroxyl, d-3 alkyl or d-3 alkyl, more preferably H, F, d-2 alkyl or d-2 alkyl, further preferably H, wherein the alkyl, alkyl or amino are each independently selected from the group consisting of F, Cl, Br, -CH, and further preferably H, wherein the alkyl, alkyl or amino is further optionally selected from the group consisting of 0 to 3₂F、 -CHF₂、 -CF₃Cyano, nitro, hydroxy, d-₄Alkyl or ^ - -₄Substituted with a substituent of the alkyl group, preferably 0 to 2 substituents selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, nitro, hydroxy, d-₃Alkyl or d-₃Alkyl-oxy, more preferably 0 to 2 groups selected from F, -CF₃D-2 alkyl or ^ -2 alkyl;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, d \u₄Alkyl radical or d \ u₄Alkyl oxy, preferably H, F, Cl, Br, d-₃Alkyl or d-₃Alkanyloxy, more preferably H, F, Cl, Br, d —₂Alkyl or d-₂Alkyl oxy, further preferably H, F, d —₂Alkyl or d-₂An alkanyl group, said alkanyl or alkanyl group each independently optionally further 0 to 3 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or d-₄Alkyl, preferably 0 to 2 substituents selected from F, Cl, Br, d-4 alkyl or ^ -4 alkyl, more preferably 0 to 2 substituents selected from F, Cl, Br, d-₃Alkyl or d-₃Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Alkyl or d-₂A alkyl group;

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano-group, hydroxyl-group, Ci-4 sintered foundation-O-Ci-4 sintered foundation₂)_m-j is a Hichiyl-R¹²、 -(CH₂)_m-a block radical-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_mS(=0)_nR¹²、 -(CH₂)_m- (3-to 6-membered carbocyclic group), - (CH)₂)_m- (3-to 6-membered heterocyclic group), -0- (CH)₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), preferably H, F, Cl, Br, hydroxyl, cyano, d \ u₄Alkyl radical, d _₄Alkyl radical, -d-₄alkyl-O-d-₄Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), more preferably H, F, Cl, Br, hydroxyl, cyano, d \ u₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-CM alkyl- (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 4-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 4-membered heterocyclic group), further preferably H, F, Cl, Br, hydroxyl, cyano, d-4 alkyl, -d —₄alkyl-O-d-₄Alkyl radical or- (CH)₂)_mS(=0)_nR¹²Further preferably H, d —₄Radix Et rhizoma Rhei₄Alkyl radical or-d-₄alkyl-O-d-₄An alkyl group, said heterocyclic group containing 1 to 3 heteroatoms selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclic group each independently optionally further substituted by 0 to 3 heteroatoms selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-4 alkyl or ^ -4 alkyl, preferably 0 to 2 substituents selected from F, Cl, Br, -CF₃Cyano, hydroxy, d-3 alkyl or-3 alkyl, more preferably 0 to 1 alkyl selected from F, Cl, cyano, hydroxy、 d—₂Root of Chinese Yak₂Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Alkyl or ^ - -₂A alkyl group;

alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁸And R⁹May form a 3-to 6-membered carbocyclic ring or a 3-to 6-membered heterocyclic ring, preferably a 3-to 4-membered carbocyclic ring or a 3-to 4-membered heterocyclic ring, more preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, even more preferably a 3-membered carbocyclic ring, said heterocyclic ring containing 1 to 3 ^, 0 or S atoms, preferably 1 to 2 heteroatoms selected from N, 0 or S, said carbocyclic or heterocyclic ring optionally being further substituted with 0 to 3R^12aIs preferably 0 to 2R^12a _;

R^12aSelected from F, Cl, Br, =0, hydroxyl and d-₄Radix Et rhizoma Rhei₄Alkyl radical, d-₄alkyl-O-d-₄Alkyl radical or- (CH)₂)_mS(=0)_nR¹²Preferred substituents of (1) are F, Cl, Br, =0, hydroxy, d —)₄Radix Et rhizoma Rhei₄Alkyl radical or

A 4-alkyl group 0-d-4-alkyl group, more preferably F, =0, hydroxyl, d-3-alkyl group, or d-3-alkyl group 0-d-3-alkyl group, and further preferably F, d-alkyl group₂Radix Et rhizoma Rhei₂Alkyl radical or d-₂Alkyl O-d-₂Alkyl group, more preferably F, d-₂The alkaxy or Ci-2 sintered foundation O-Ci-2 sintered foundation;

R¹²、 R¹³and R^13aSelected from H, F, Cl, Br, hydroxyl, sulfhydryl, cyano, amino and d-₄Radix Et rhizoma Rhei₄Alkanyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, preferably H, F, Cl, Br, d —₄Radix Et rhizoma Rhei₄Alkanyloxy, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, morePreferably H, F, Cl, Br, d —₄Radix Et rhizoma Rhei₄Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, further preferably d — (d —)₃Radix Et rhizoma Rhei₃Alkanyloxy, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, further preferred₂Alkyl or d-₂A alkyl group;

p is selected from 0,1 or 2, preferably 0 or 1, more preferably 0;

n is selected from 0,1 or 2.

Preferred embodiments of the present invention include compounds represented by the general formula (III) or stereoisomers, hydrates, esters, solvates, co-crystals, metabolites, pharmaceutically acceptable salts or prodrugs thereof:

wherein-

R⁵、 R^1UAnd R¹¹Each independently selected from H, F, Cl, Br, d \u₄Alkyl radical or d \₄Alkyl oxy, preferably H, F, Cl, Br, d-₃Alkyl or d-₃Alkanyloxy, more preferably H, F, Cl, Br, d —₂Alkyl or d-₂An alkyl group, further preferably H, F, d-2 alkyl or d-2 alkyl, each independently optionally further substituted with 0 to 2 substituents selected from F, Cl, Br, d-4 alkyl or ^ -4 alkyl, preferably 0 to 2 substituents selected from F, Cl, Br, d-4 alkyl₃Alkyl or 3 alkyl, more preferably 0 to 1 selected from F, d —₂Root of Chinese Yak₂A alkyl group;

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, F, Cl, Br, hydroxyl, cyano, d \u₄Alkyl radical, d _₄Alkyl-oxy, -CM alkyl-O-d-₄Alkyl radical, - (CH)₂)_m-alkenyl -R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), preferably H, F, Cl, Br, hydroxyl, cyano, d \ u₄Alkyl, CM alkyl-d-₄alkyl-O-d-₄Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 4-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 4-membered heterocyclic group), more preferably H, F, Cl, Br, hydroxyl, cyano, C_MAlkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-CM alkyl or- (CH)₂)_mS(=0)_nR¹²Further, H, d.4-alkyl, CM-alkyl, or-d-4-alkyl-O-d-4-alkyl is preferable, and H, d-alkyl is more preferable₃Radix Et rhizoma Rhei₃Alkyl radical or-d-₃alkyl-O-d-₃An alkyl group, said heterocyclic group containing 1 to 3 heteroatoms selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclic group each independently optionally further comprising 0 to 3 heteroatoms selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-₄Alkyl or d-₄Substituted with substituents of the alkyl radical, preferably 0 to 2 substituents selected from F, Cl, Br, -CF₃Cyano, hydroxy, d-₃Alkyl or d-₃Alkyl, more preferably 0 to 1 selected from F, Cl, cyano, hydroxy, d —₂Alkyl or d-₂Alkanyloxy, further preferably 0 to 1 member selected from the group consisting of F, d —₂Alkyl or ^ - -₂A alkyl group;

alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁸And R⁹Any of which may form a 3 to 4 membered carbocyclic ring or 3 to 4 membered heterocyclic ring, preferably a 3 membered carbocyclic ring or 3 membered heterocyclic ring, more preferably a 3 membered carbocyclic ring, which heterocyclic ring contains 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may optionally be further substituted by 0 to 2R^12aSubstituted with the substituent(s);

R^12aselected from F, Cl, Br, =0, hydroxyl and d-₄Radix Et rhizoma Rhei₄Alkyl radical or d-₄Alkyl O-d-₄Alkyl, preferably F, =0, hydroxy, d-)₃Radix Et rhizoma Rhei₃Alkyl radical or d-₃Alkyl O-d-₃Alkyl group, more preferably F, d-₂Radix Et rhizoma Rhei₂Alkyl radical or d-₂Alkyl O-d-₂Alkyl group, more preferably F, d-₂Alkyl radical or d-₂Alkyl O-d-₂A alkyl group; the alkyl or alkyl group is further selected from 0 to 3 selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃、 d_₄Alkyl radical or d \₄Substituted with alkyl-oxy substituents, preferably 0 to 3 substituents selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or d-₄An alkyl group, more preferably 0 to 2 groups selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or d-₄An alkyl group, further preferably 0 to 1 selected from F, Cl, Br, -CF₃、 d_₃Alkyl radical or d \ u₃Alkyl, further preferably 0 to 1 alkyl selected from F, d u₂Alkyl radical or this d \₂A alkyl group;

R¹²selected from H, F, Cl, Br, d-₄Radix Et rhizoma Rhei₄Alkanyl, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, preferably H, F, Cl, Br, d \\ u₄Alkyl radical, d _₄An alkanyl group, a 3-to 5-membered carbocyclyl group, or a 3-to 5-membered heterocyclyl group,more preferably d \u₃Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, more preferably d — (d —)₂Alkyl or d-₂A alkyl group;

n is selected from 0,1 or 2.

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

R⁵、 R^1Qand R¹¹Each independently selected from H, F, methyl or ethyl.

The preferable scheme of the invention comprises the compound shown in the general formula (IV) or stereoisomer, hydrate, ester, solvate, co-crystal, metabolite and pharmacy thereofWherein:

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, F, Cl, Br, hydroxyl, cyano, d \u₄Alkyl radical, d _₄Alkyl-oxy, -CM alkyl-O-d-4 alkyl, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -0-(CH₂)_m- (3-to 6-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 6-membered heterocyclic group), preferably H, F, Cl, Br, hydroxyl, cyano, d —)₄Radix Et rhizoma Rhei₄Alkyl radical, -d-₄alkyl-O-d-₄Alkyl radical or- (CH)₂)_mS(=0)_nR¹²More preferably H, d —₄Radix Et rhizoma Rhei₄A alkyl group, a-CM alkyl group, an-O-CM alkyl group, and more preferably H, d u₃Alkyl radical, d _₃Alkyl radical or-d \u₃alkyl-O-Cw alkyl, more preferably 11, d-₃Alkyl radical or-d-₃alkyl-O-d-₃An alkyl group, said heterocyclic group containing 1 to 3 heteroatoms selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclic group each independently optionally further comprising 0 to 3 heteroatoms selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-4 alkyl or-4 alkyl, preferably 0 to 2 substituents selected from F, Cl, Br, -CF₃Cyano, hydroxy, d-3 alkyl or ^ -3 alkyl, more preferably 0 to 1 selected from F, Cl, cyano, hydroxy, d ^ -3 alkyl, more preferably₂Root of Chinese Yak₂Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Alkyl or d-₂A alkyl group;

alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁸And R⁹Any of which may form a 3 to 4 membered carbocyclic ring or 3 to 4 membered heterocyclic ring, preferably a 3 membered carbocyclic ring or 3 membered heterocyclic ring, more preferably a 3 membered carbocyclic ring, which heterocyclic ring contains 1 to 3 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may optionally be further substituted by 0 to 3R^12aSubstituted with the substituent(s);

R^12aselected from F, Cl, Br, =0, hydroxyl and d-₄Radix Et rhizoma Rhei₄Alkyl radical or d-₄Alkyl O-d-₄Alkyl, preferably F, =0, hydroxy, d-)₃Radix Et rhizoma Rhei₃Alkyl radical or d-₃Alkyl O-d-₃Alkyl group, more preferably F, d-₂Radix Et rhizoma Rhei₂Alkyl radical or d-₂Alkyl O-d-₂Alkyl group, more preferably F, d-₂Alkyl radical or d-₂Alkyl O-d-₂A alkyl group; the alkyl and alkyl groups are further selected from 0 to 3 groups,Cl、 Br、 -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or d-₄Substituted with an alkyl group, preferably 0 to 2 substituents selected from F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or d-₄An alkyl group, more preferably 0 to 1 selected from F, Cl, Br, -CF₃、 d—₃Alkyl or d-₃Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Radix et rhizoma Rhei₂A alkyl group;

R¹²selected from H, F, Cl, Br, d-₄Radix Et rhizoma Rhei₄Alkanyloxy, 3-to 6-membered carbocyclyl or 3-to 6-membered heterocyclyl, preferably

H. F, Cl, Br, CM alkyl, d-₄Alkanyloxy, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, more preferably d — (d —)₃Radix Et rhizoma Rhei₃Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, further preferably d — (d —)₂Alkyl or d-₂A alkyl group;

n is selected from 0,1 or 2.

A preferred embodiment of the present invention includes a compound represented by the general formula 0V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, F, Cl, Br, hydroxyl, cyano, d \u₄Alkyl radical, d _₄Alkyl-oxy, -CM alkyl-O-CM alkyl or- (CH)₂)_mS(=0)_NR¹²Preferably H, d u₄Alkyl radical, d _₄Alkyl radical or-d \u₄A alkyl-O-CM alkyl, more preferably H, d-3 alkyl, d-3 alkyl, or-d-3 alkyl-O-d-3 alkyl, and even more preferably H, d-alkyl₃The alkyl group is preferably an alkyl group or a-Cw alkyl group-O-Cw alkyl group, and more preferably H, d u \ alkyl group₂Alkyl radicalOr-d \u₂An alkyl-O-Cw alkyl, the alkyl or the alkyl being each independently optionally further selected from 0 to 3 of F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃Cyano, hydroxy, d-4 alkyl or-4 alkyl, preferably 0 to 2 substituents selected from F, Cl, Br, -CF₃Cyano, hydroxy, 3-alkyl or d —₃Alkyl, more preferably 0 to 1 selected from F, Cl, cyano, hydroxy, d —₂Alkyl or d-₂Alkanyloxy, further preferably 0 to 1 is selected from F, d —₂Root of Chinese Yak₂A alkyl group;

alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

R^12aselected from F, Cl, Br, =0, hydroxyl and d-₄Radix Et rhizoma Rhei₄Alkyl radical or d-₄alkyl-O-d-₄Alkyl, preferably F, =0, hydroxy, d-)₃Radix Et rhizoma Rhei₃Alkyl radical or d-₃alkyl-O-d-₃Alkyl group, more preferably F, d-₂Radix Et rhizoma Rhei₂Alkyl radical or d-₂alkyl-O-d-₂Alkyl group, more preferably F, d-₂Alkyl radical or d-₂alkyl-O-d-₂The alkyl or alkyl-radical of the alkyl-microp is further selected from 0 to 2 of F, Cl, Br, -CH₂F、 -CHF₂、 -CF₃、 d—₄Alkyl or d-₄Alkyl substituted by a substituent, preferably 0 to 1, selected from F, Cl, Br, -CF₃、 d—₃Alkyl or d-₃Alkyl oxy, more preferably 0 to 1, is selected from F, d u₂Alkyl radical or this d \₂A alkyl group;

R¹²selected from H, F, Cl, Br, d \u₄Alkyl radical, d _₄Alkanyl, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, preferably d —)₃Radix Et rhizoma Rhei₃Alkanyloxy, 3-to 5-membered carbocyclyl or 3-to 5-membered heterocyclyl, more preferably d — (d —)₂Alkyl or d-₂A alkyl group; m is selected from 0,1, 2,3 or 4, preferably 0,1, 2 or 3, more preferably 0,1 or 2;

n is selected from 0,1 or 2.

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

R⁶、 R⁷each independently selected from H, d \ u₄Alkyl radical, d _₄Alkyl radical or-d \u₄alkyl-O-CM alkyl, preferably H, d u₃A alkyl base,₃Alkyl radical or-d-₃alkyl-O-d-₃Alkyl group, more preferably H, d-₃Alkyl radical or-d-₃alkyl-O-d-₃Alkyl group, more preferably H, d-₂Alkyl radical or-d-₂alkyl-O-d-₂Alkyl, further preferably H;

alternatively, R⁶And R⁷Can be formed (=0);

R⁸and R⁹Each independently selected from H, d —₄Radix Et rhizoma Rhei₄Alkyl radical or-d-₄alkyl-O-d-₄Alkyl radical, preferably H, d u₃Radix Et rhizoma Rhei₃Alkyl-oxy or-d-3 alkyl-O-d-₃Alkyl radical, more preferably H, d u₂Radix Et rhizoma Rhei₂An alkyl group or-d-2 alkyl-O-Cw alkyl group, more preferably H, d u \ alkyl₂Alkyl radical or-d \u₂alkyl-O-Cw alkyl;

as an alternative to this, the first and second, R⁸and R⁹A 3-membered carbocyclic ring may be formed. A preferred embodiment of the present invention comprises a compound of formula v) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

R⁶、 R⁷respectively and independently select g H and d \u₃Alkyl radical, d _₃Alkyl radical or-d \u₃alkyl-O-Cw alkyl, preferably H, d u₃Alkyl-oxy or-3 alkyl-O-d-3 alkyl, more preferably H, d-alkyl₂Alkyl radical or-d-₂alkyl-O-d-₂Alkyl, further preferably H;

alternatively, R⁶And R⁷Can be formed (=0);

R⁸and R⁹Each independently selected from H, d.3 alkyl,₃Alkyl radical or-d-₃alkyl-O-d- (O-D) -O₃Alkyl base, preferably H, alkyl base, d \ u₂Alkyl radical or-d \u₂alkyl-O-Cw alkyl, more preferably H, d \ u₂Alkyl radical or-d \u₂An alkyl-O-Cw sintered body;

alternatively, R⁸And R⁹A 3-membered carbocyclic ring may be formed.

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

R⁶and R⁷Each independently selected from H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl, preferably H, methoxy or ethoxy, more preferably H;

alternatively, R⁶And R⁷Can be formed (=0);

R⁸and R⁹Each independently selected from H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl or methoxyethyl, preferably H, methyl, methoxymethyl or ethoxymethyl, more preferably H,methoxymethyl or ethoxymethyl; alternatively, R⁸And R⁹A 3-membered carbocyclic ring may be formed.

r and R⁷Selected from H, or R⁶And R⁷One =0 can be formed;

R⁸and R⁹Each independently is selected from H, methoxymethyl or ethoxymethyl; or, alternatively, R⁸And R⁹A 3-membered carbocyclic ring may be formed.

In a preferred embodiment of the present invention, there is provided a compound represented by the general formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, thereof,

Wherein:

r is selected from 11 or-₈A alkyl group;

ring Q is selected from 5-to 8-membered carbocyclyl or heterocyclyl containing 1 to 4 Ν,0 or S (=0)_nAn atom or a group, wherein the carbocyclyl or heterocyclyl is optionally further substituted with 0 to 4 atoms selected from the group consisting of F, Cl, Br, I, =0, cyano, isocyano, amino, nitro, hydroxy, carboxy, alkanyl, d — -)₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、

-0-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-S(=0)_n-R¹²or-NR¹³R^13aSubstituted with the substituent(s);

R¹and R⁴Each independently selected from F, Cl, Br, I,Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Alkyl or d-₈Alkanyl, wherein the alkanyl, alkanyl or amino groups are each independently optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_m-S(=0)_n-R¹²、 -0-C(=0)-0-R¹²or-NR¹³R^13aSubstituted with the substituent(s); r²And R³Each independently selected from H, F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxyl, carboxyl and d-₈Alkyl or d-₈Alkanyl, wherein the alkanyl, alkanyl or amino groups are each independently optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Alkyl or C alkyl substituent;

R⁵、 R⁶、 R⁷、 R⁸、 R⁹、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, alkanyl, d-)₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group), - (CH)₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 10-membered heterocyclic group) containing 1 to 4 of N, 0 or 3(=0)₁₁An atom or group, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl group optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, alkanyl, d-)₈Alkyl radical or-d-₈alkyl-O-d-₈A substituent of the alkyl group;

alternatively, R⁶And R⁷Can form (^ a or two ^ a)¹²!^²¹⁵;

As an alternative to this, the first and second,

alternatively, R⁶And R⁷R and R⁸R and R⁹、 R⁷And R⁸、 R⁷And R⁹、 R⁸And R⁹May form a 3-to 8-membered carbocyclic ring or a 3-to 8-membered heterocyclic ring containing 1 to 4N, 0 or S (= C)_nAn atom or group, said carbocyclic or heterocyclic ring being optionally further substituted by 0 to 4R^12aSubstituted with the substituent(s);

R^12aselected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro,Hydroxy, carboxy, Ci-₈Brick foundation C₈Sintered body or C₈Sintered foundation-O-C₈A foundation;

R¹²and R^12bSelected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, mercapto, isocyano, amino, nitro, hydroxy, carboxyl, d-₈Radix Et rhizoma Rhei₈Alkyl, 3 to 10 membered carbocyclyl or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 40 or 3(=0)₁₁An atom or group, said alkyl, carbocyclyl or heterocyclyl group optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical or-d-₈alkyl-O-d- (O-D) -O₈Alkyl substituent;

R¹³and R^13aSelected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, mercapto, isocyano, amino, nitro, hydroxy, carboxyl, alkyl, d —₈Alkanyl, 3-to 10-membered carbocyclyl or 3-to 10-membered heterocyclyl, said heterocyclyl containing 1 to 4N, 0 or 3(=0)₁₁An atom or group, said alkyl, carbocyclyl or heterocyclyl group optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy,₈Radix Et rhizoma Rhei₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical or- (CH)₂)_mS(=0)_nR¹²Substituted with the substituent(s);

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 or 4;

n is selected from 0,1 or 2.

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

R¹and R⁴Each independently selected from F, Cl, Br or d _₄Alkyl, preferably F or CI;

R²and R³Each independently selected from H, F, Cl, Br or d \u₄Alkyl, preferably H;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, I or d _₄Alkyl, preferably H, F or methyl.

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-C alkyl- (CH)₂)_m-NR¹³R^13aPreferably H, -CH₂OH, methyl, methoxy, ethoxy, "< lambda > O </lambda >, 0,' \\ - -y^QOr is

Alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁶And R⁸、 R⁶And R⁹、 R⁷And R⁸、 R⁷And R⁹、 R⁸And R⁹May form a 3 to 6 membered carbocyclic ring, preferably a 3 to 4 membered carbocyclic ring, more preferably a 3 membered carbocyclic ring;

R¹³and R^13aIs selected from H or d-₆Alkyl, preferably 11 or ^ -alkyl₄The alkyl can be further selected from 0 to 2 g- (CH)₂)_mS(=0)_nR¹²Substituted with the substituent(s);

R¹²is selected from 11 or ^ -11 ^ -3₆Alkyl, preferably H or methyl;

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 represented by formula ω, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: ring Q is selected from ^ b,-, -Y, preferably Y and ring Q may further be replaced by 0-3 of any of F, Cl, Br, I, =0, amino, hydroxyl, d \\/u₆Alkyl radical or d \₆Alkyl group.

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

wherein-

R is selected from 11 or-4 alkyl, preferably H:

and (4) Y.

Ring Q is \ and ring Q may be further substituted by 0 to 3 groups selected from F, =0, amino, hydroxy, d —)₄Alkyl radical or d \₄Alkyl substituted by substituent of alkyl;

R¹selected from F, C1 or Br, preferably F or C1;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br or d \u₄Alkyl, preferably H, F or methyl;

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-CM alkyl- (CH)₂)_m-NR¹³R^13aPreferably H, -CH₂OH, methyl, methoxy, ethoxy, C , 0, C ^QOr is

Alternatively, R⁶And R⁷Can be formed (=0);

R¹³and R^13aSelected from H or d \u₄An alkyl group, which may be further selected from- (CH) by 0 to 2₂)_mS(=0)_nR¹²Substituted with the substituent(s);

R¹²is selected from 11 or ^ -11 ^ -3₄Alkyl, preferably H or methyl;

p is selected from 0,1 or 2;

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 represented by the general formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof is a compound represented by the general formula (in) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereofThe above acceptable salts or prodrugs:

wherein-

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-C- (CH)₂)_m-NR¹³R^13aPreferably H, -CH₂OH, methyl, methoxy, ethoxy, 0

Alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹May form a 3-membered carbocyclic ring with the carbon atom to which it is attached;

R¹²selected from H or d \u₄Alkyl, preferably H or methyl;

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 represented by formula ω, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, is a compound represented by formula (IV), or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein-

R⁶、 R⁷、 R⁸And R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-0-C-1-4- (CH)₂)_m-NR¹³R^13aPreferably H, -CH₂OH, methyl, methoxy, ethoxy, 0

Alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹May form a water 3-membered carbocyclic ring with the carbon atom to which it is attached;

R¹³and R^13aSelected from H or d \u₄An alkyl group, which may be further selected from- (CH) by 0 to 2₂)_mS(=0)_nR is substituted by a substituent; r¹²Selected from 11 or ^ -4 alkyl, preferably H or methyl;

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 represented by the general formula (IV) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

R⁶and R⁷Each independently selected from H, methyl, methoxy, ethoxy, W or^N、〜S\_;

Alternatively, R⁶And R⁷Can be formed (=0);

R⁸and R⁹Each independently selected from H and-CH₂OH, methyl,Or 0;

alternatively, R⁸And R⁹May form a 3-membered carbocyclic ring with the carbon atoms to which it is attached.

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

(V)

wherein-

R⁴Selected from H, F or Cl, preferably H or F;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, CI or d \u₄Alkyl, preferably H, F or methyl;

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-CM- (CH)₂)_m-NR¹³R^13aPreferably H, -CH₂OH, methyl, methoxy, ethoxy. , -⁰、

Alternatively, R⁶And R⁷Can be formed (=0);

12

R¹³and R^13aIs selected from H or d-₄An alkyl group, which may be further selected from- (CH) by 0 to 2₂)_mS(=0)_nR is substituted by a substituent;

R¹²is selected from 11 or ^ -11 ^ -3₄Alkyl, preferably H or methyl;

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 (V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: r⁴Selected from H, F or Cl, preferably H or F;

R⁵and R¹¹Is methyl;

R^1Qselected from H or F, preferably H;

R⁶and R⁷Each independently selected from H, methyl, methoxy, ethoxy, \\ y \, or ^ though \/A⁵\, or R⁶And R⁷Form (=0), preferably H or R⁶And R⁷Form (=0), more preferably R⁶And R⁷Forming (=0);

R⁸and R⁹Each independently selected from H and-CH₂OH, methyl and ^ a. Or ^ a. ^, or R⁸And R⁹The carbon atom to which it is attached forms a 3-membered carbocyclic ring, preferably R⁸And R⁹The carbon atom to which it is attached forms a 3-membered carbocyclic ring; in a preferred embodiment of the present invention, the compound of formula (V) or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

r and R⁷Is H or R⁶And R⁷Form (=0), preferably R⁶And R⁷Forming (=0);

R⁸and R⁹May form a 3-membered carbocyclic ring with the carbon atoms to which it is attached.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, hydrate, solvate, ester thereof

Suitable pharmaceutically acceptable salts of the compounds of formula omega include, but are not limited to, sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, barium, ammonium, trimethylamine, tetramethylammonium, diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2, 6-lutidine, caffeine, procaine, choline, betaine, theobromine, purines, piperazine, piperidine, Ν -ethylpiperidine, polyamine, penicillin, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, calcium, magnesium, barium, ammonium, triethylamine, dicyclohexylamine, pyridine, picoline, choline, betaine, theobromine, purine, piperazine, piperidine, Ν -ethylpiperidine, polyamine, penicillin, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, sulfate, picloram, etc, Formate, acetate, glycolate, propionate, 2-hydroxypropionate, malonate, trifluoroacetate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, ethenesulfonate, benzenesulfonate, p-toluenesulfonate, benzoate, phenylacetate, alginate, anthranilate, camphorate, maleate, tartrate, citrate, succinate, mandelate, fumarate, malate, oxalate, salicylate, glucuronate, galacturonate, citrate, aspartate, glutamate, cinnamate, combinations thereof. Preferably sodium salt, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochloride salt, hydrobromide salt, sulfate salt, phosphate salt, trifluoroacetate salt, acetate salt, maleate salt, aspartate salt, glutamate salt, malate salt or their combination.

The invention also relates to a method for preparing the compound shown in the general formula (I), and a person skilled in the art knows that the compound can be synthesized by various preparation 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. Specifically, the preparation method of the compound of the general formula (I) is selected from one of the following methods:

the method comprises the following steps:the compound of the general formula (I-a) is converted into the compound of the general formula (I-b) through a Homer-Wadsworth-Emmons reaction (or wittig reaction), a reduction reaction and an alkanisation reaction in sequence; or the compound of the general formula (I-a) is converted into the compound of the general formula (I-b) through reduction elimination reaction;

l-b l-c

converting the compound of the general formula (I-b) into a compound of the general formula (I-c) through a suzuki coupling reaction and a reduction reaction;

the compound of the general formula (I-c) is converted into the compound of the general formula (I) through a Mitsunobu condensation reaction and a hydrolysis reaction; converting the compound of the general formula (I-c) into the compound of the general formula (I) through a Mitsunobu condensation reaction;

the second method comprises the following steps:

l-d l-e

the compound of the general formula (I-d) is converted into the compound of the general formula (I-e) through nucleophilic substitution reaction and claisen rearrangement reaction_t"

l-f

Converting the compound of the general formula (I-e) into a compound of the general formula (I-f) through epoxidation reaction and ring opening reaction; or the compound of the general formula (I-e) is converted into the compound of the general formula (I-f) through nucleophilic substitution reaction;

l-f l-c

carrying out Suzuki coupling reaction on the compound of the general formula (I-f) to obtain a compound of the general formula (l-c); or the compound of the general formula (I-f) is converted into the compound of the general formula (l-c) through suzuki coupling reaction and hydrogenation reduction reaction;the compound of the general formula (I-c) is converted into the compound of the general formula (I) through a Mitsimobu condensation reaction and a hydrolysis reaction; converting the compound of the general formula (I-c) into the compound of the general formula (I) through a Mitsimobu condensation reaction;

the third method comprises the following steps:

l-g 1-3

the compound of the general formula (I-g) is converted into a compound of the general formula (I-a) by an Adol reaction; or the compound of the general formula (I-g) is converted into the compound of the general formula (I-a) through nucleophilic substitution reaction;

l-a l-f

converting the compound of the general formula (I-a) into a compound of the general formula (I-f) through reduction reaction; or the compound of the general formula (I-a) is converted into the compound of the general formula (I-f) through reduction reaction and dehydroxylation reaction;

l-f l-c

the compound of the general formula (I-f) is prepared by carrying out suzuki coupling reaction on the compound of the general formula (I-c); or the compound of the general formula (I-f) is converted into the compound of the general formula (I-c) through a suzuki coupling reaction and a hydrogenation reduction reaction

The compound of the general formula (I-c) is converted into the compound of the general formula (I) through a Mitsimobu condensation reaction and a hydrolysis reaction; converting the compound of the general formula (I-c) into the compound of the general formula (I) through a Mitsimobu condensation reaction; the method four comprises the following steps:

l-a |-h

converting the compound of the general formula (I-a) into a compound of the general formula (I-h) through a suzuki coupling reaction; or the compound of the general formula (I-a) is converted into the compound of the general formula (I-h) through a suzuki coupling reaction and a hydrogenation reduction reaction;

the compound of the general formula (I-h) is converted into the compound of the general formula (1-I) by reductive amination;

the compound of the general formula (1-I) is converted into the compound of the general formula (I) through nucleophilic substitution reaction, Mitsimobu condensation reaction and hydrolysis reaction, or the compound of the general formula (1-I) is converted into the compound of the general formula (I) through Mitsimobu condensation reaction; wherein:

l is selected from F, Cl, Br or I;

R、 R¹, R²、 R³、 R⁴、 R⁵、 R⁶、 R⁷、 R⁸、 R⁹、 R¹⁰、 R^uq, p, Q and t are as defined in the invention, R¹⁶、 R¹⁷And R¹⁸Selected from H, hydroxy, methyl or ethyl.

More specifically, the preparation method of the compound of the general formula (I) of the present invention is selected from one of the following methods:

method 1

Reacting a compound of a general formula (I-a) with diethoxy cyanomethyl phosphate by using tetrahydrofuran as a solvent under an alkaline condition, reducing a cyano group into an aldehyde group by using diisobutylaluminum hydride, further reacting with a reducing agent, and further reacting with an alkyl-based reagent under an alkaline condition to obtain a compound of a general formula (I-b); or the compound of the general formula (I-a) reacts with a reducing agent, and then further undergoes an elimination reaction in the presence of concentrated sulfuric acid to obtain a compound of the general formula (I-b); wherein the base is selected from sodium hydrogen, sodium amide, potassium tert-butoxide, butyllithium or lithium diisopropylamide; the reducing agent is selected from sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium sulfoborohydride or lithium tri-sec-butylborohydride; the alkanylating reagent is selected from iodomethyl alkanyl, methyl p-toluenesulfonate, dimethyl sulfate, bromoethyl alkanyl, ethyl p-toluenesulfonate or diethyl sulfate;

toluene/ethanol/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 the action of a palladium catalyst, the compound of the general formula (I-b) and 3-formylphenylboronic acid undergo suzuki coupling reaction, and then under the action of a reducing agent, the compound of the general formula (I-c) is obtained through hydrogenation reduction; the palladium catalyst is selected from [ I, gamma-bis (; diphenylphosphino) ferrocene ] palladium dichloride, [ I, gamma-bis (diphenylphosphino) ferrocene ] palladium dichloride-methyl-alkanyl chloride complex, tetrakis (triphenylphosphine) palladium, palladium dichloride, palladium acetate or bis (triphenylphosphine) palladium dichloride, and the reducing agent is as described above;

carrying out Mitsunobu reaction on a compound in a general formula (I-c) and 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) ethyl acetate in the presence of diisopropyl azodicarboxylate or 1,1- (azodicarbonyl) dipiperidine in a solvent of dichloromethane or tetrahydrofuran under the condition of tri-tert-butylphosphine to obtain a compound in a general formula (1); or the compound of the general formula (I-c) is reacted by Mitsimobu condensation under the above conditions

Reacting a compound of a general formula (I-d) with 3-bromopropylene in the presence of potassium carbonate by using acetonitrile, tetrahydrofuran, toluene or 1, 2-dichloroalkyl as a solvent for nucleophilic substitution, and then obtaining a compound of a general formula (I-e) through claisen rearrangement at 180 ℃;

the method comprises the steps of taking a dichloro-methyl-alkyl or a1, 2-dichloro-ethyl-alkyl as a solvent, carrying out an epoxidation reaction on a compound of the general formula (I-e) and m-chloroperoxybenzoic acid, and then heating and refluxing the compound of the general formula (I-f) by taking the 1, 2-dichloro-methyl-alkyl as the solvent; or taking the dichloromethy or 1, 2-dichloromethy as a solvent, and carrying out nucleophilic substitution reaction on the compound of the general formula (I-e) in the presence of trifluoromethanesulfonic acid to obtain a compound of the general formula (I-f);

toluene/ethanol/water, acetonitrile/water, 1, 4-dioxane/water or tetrahydrofuran/water are used as a solvent, a compound of a general formula (I-f) and 3-hydroxymethylphenylboronic acid are subjected to a suzuki coupling reaction under the action of a palladium catalyst in the presence of potassium carbonate, sodium carbonate or potassium phosphate to obtain a compound of a general formula (I-c), or toluene/ethanol/water, acetonitrile/water, 1, 4-dioxane/water or tetrahydrofuran/water are used as a solvent, and the compound of the general formula (I-f) and 3-formylphenylboronic acid are subjected to a suzuki coupling reaction under the action of the palladium catalyst in the presence of potassium carbonate, sodium carbonate or potassium phosphate, and then under the action of a reducing agent, hydrogenation reduction to give a compound of general formula (I-c) wherein the palladium catalyst and the reducing agent are as defined above;

carrying out Mitsunobu reaction on a compound in a general formula (I-c) and 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) ethyl acetate in the presence of diisopropyl azodicarboxylate or 1,1- (azodicarbonyl) dipiperidine in a solvent of dichloromethane or tetrahydrofuran under the condition of tri-tert-butylphosphine to obtain a compound in a general formula (I); or the compound of the general formula (I-c) is converted into the compound of the general formula omega through a Mitsimobu condensation reaction and a hydrolysis reaction under the conditions;

taking methanol and water as solvents, and carrying out Add reaction on the compound with the general formula (I-g) and formaldehyde in the presence of potassium carbonate to obtain a compound with the general formula (I-a); or taking tetrahydrofuran, N-dimethylformamide as a solvent, and carrying out nucleophilic substitution reaction on the compound of the general formula (I-g) and the iodomethane-alkyl or the 1, 2-dibromoethane-alkyl in the presence of sodium hydrogen to obtain a compound of the general formula (I-a);

reacting a compound of a general formula (I-a) with lithium aluminum hydride in the presence of aluminum trichloride by using tetrahydrofuran as a solvent to obtain a compound of a general formula (I-f); or the compound of the general formula (I-a) is hydrogenated and reduced under the action of a reducing agent, and then the hydroxyl group is further removed to obtain the compound of the general formula (I-f), wherein the hydroxyl-removing agent is selected from triethyl alkanyl, palladium/carbon, TMSCl/Nal or CS₂The term "TMSC 1" refers to a trimethyl chlorosilicon alkyl, wherein the reducing agent is as described above;

using dichloromethyl alkyl or tetrahydrofuran as solvent, in the presence of diisopropyl azodicarboxylate or 1,1- (azodicarbonyl) dipiperidine, reacting the compound of general formula (I-c) with 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) ethyl acetate

Carrying out Mitsunobu reaction to obtain a compound shown as a general formula (I); or the compound of the general formula (I-c) is converted into the compound of the general formula omega through a Mitsimobu condensation reaction and a hydrolysis reaction under the conditions;

toluene/ethanol/water, acetonitrile/water, 1, 4-dioxane/water or tetrahydrofuran/water are taken as a solvent, a compound of a general formula (I-a) and 3-hydroxymethylphenylboronic acid are subjected to a suzuki coupling reaction under the action of a palladium catalyst in the presence of potassium carbonate, sodium carbonate or potassium phosphate to obtain a compound of a general formula (I-h), or toluene/ethanol/water, acetonitrile/water, 1, 4-dioxane/water or tetrahydrofuran/water are taken as a solvent, and the compound of the general formula (I-a) and 3-formylphenylboronic acid are subjected to a suzuki coupling reaction under the action of the palladium catalyst in the presence of potassium carbonate, sodium carbonate or potassium phosphate, and then under the action of a reducing agent, hydrogenation reduction to give compounds of general formula (I-h), wherein the palladium catalyst and the reducing agent are as defined above;

the compound of the general formula (1-I) is prepared by condensing the general formula (I-h) with hydroxylamine hydrochloride by using methanol/water, ethanol/water and isopropanol/water as solvents and in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide, and then carrying out hydrogenation reduction under the action of reducing agents such as lithium aluminum hydride and boron alkyl or under the action of Raney nickel and palladium carbon.

Taking acetonitrile, N-dimethylformamide as a solvent, and under the existence of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, N-diisopropylethylamine, carrying out nucleophilic substitution reaction on the general formula (1-I), and then under the existence of diisopropyl azodicarboxylate or 1,1- (azodicarbonyl) dipiperidine, carrying out Mitsimobu reaction on ethyl acetate to obtain a compound of the general formula (I); or the compound of the general formula (I-I) is further hydrolyzed under the above conditions to be converted into the compound of the general formula (I). Wherein L is selected from F, Cl, Br or I;

R、 R\ R²、 R³、 R⁴、 R⁵、 R⁶、 R⁷、 R⁸、 R⁹、 R¹⁰、 R^uthe definitions of Q, p, Q and t are consistent with those described herein; r¹⁶、 R¹⁷、 R¹⁸Selected from H, hydroxyl, methyl or ethyl.

The invention also relates to a pharmaceutical composition comprising: an effective dose of a compound of formula (I) or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient. The composition may further comprise one or more additional 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

((1)

(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) Protein tyrosine phosphatase-1 BCPTP-1B) inhibitor or 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, thiazolyldiketones, glinides or pharmaceutically acceptable salts or prodrugs thereof, and/or

(r) PARP inhibitors.

In a preferred embodiment of the invention, the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrate or a pharmaceutically acceptable salt or prodrug thereof. The DDPIV inhibitor is selected from linagliptin (linagliptin), omarigliptin (MK-3102), sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (alogliptin), saxagliptin (saxagliptin), denagliptin (digagliptin), Carmegliptin, Melogliptin (meroliptin), Dutogliptin, Teneligliliptin (terliptin), Gemigliptin or Trelagliptin. The SGLT-2 inhibitor is selected from dapagliflozin, propanediol, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, canagliflozin or eogliflozin. The PARP inhibitor is selected from the group consisting of benzafibrate, fenofibrate rate, pioglitazone, azelaic acid ^ rosiglitazone and saroglitazar. 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 the group consisting of glimepiride, Tolglybutamide, glibornuride, glyburide, gliquidone, glipizide, and gliclazide. The glinide therapeutic agent is selected from nateglinide, repaglinide or mitiglinide. The (X-glucosidase inhibitor is selected from acarbose, voglibose or miglitol, and the GLP-1 analogue is selected from exenatide or liraglutide.

The invention also relates to the medical application of the compound shown in the general formula (I) or the stereoisomer, hydrate, solvate, ester, metabolite, cocrystal, pharmaceutically acceptable salt or prodrug thereof as a G protein-coupled receptor 40 agonist, also relates to the application of the pharmaceutical composition comprising the compound shown in the general formula (I) or the stereoisomer, hydrate, solvate, ester, metabolite, cocrystal, pharmaceutically acceptable salt or prodrug thereof in medicine, preferably, the compound shown in the general formula (I) or a stereoisomer, a hydrate, a solvate, an ester, a metabolite, a co-crystal, a pharmaceutically acceptable salt or a prodrug thereof is used as a G protein-coupled receptor 40 agonist for preparing a pharmaceutical preparation for treating and/or preventing metabolic diseases. The metabolic disease may for example include 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 pectoris, claudication, diabetes mellitus, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperlipidemia, elevated levels of fatty acids or glycerol, lipodystrophy, obesity, metabolic syndrome, syndrome X, insulin resistance, insulin allergy, glucose intolerance, skin diseases, atherosclerosis and its sequelae, One or more of a heart attack or stroke. Further preferably, the compound of the general formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof is used as a G protein-coupled receptor 40 agonist for preparing a pharmaceutical preparation for treating and/or preventing type II diabetes.

The present invention also relates to a method for treating and/or preventing said metabolic diseases, which comprises administering to a subject an effective amount of a compound represented by the general formula ω of the present invention or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, or said pharmaceutical composition comprising the same.

Unless stated to the contrary, the terms used in the present invention 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, mercapto, -SR¹⁴、 -S(=0)R¹⁴、-S(=0)₂R¹⁴Nitro, cyano, isocyano, aldehyde, carboxyl, amino, alkanyl, amido, alkenyl, alkynyl, alkanyl, hydroxyalkyl, alkanyl, carbocyclyl, heterocyclyl, carboxylate, carboxyl, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_m-S(=0)_n-R¹²、 -0-C(=0)-0-R¹²or-NR¹³R^13aWherein R is substituted by a substituent of (1)¹⁴Selected from alkyl of 1 to 8 carbon atoms, carbocyclyl of 3 to 10 carbon atoms or heterocyclyl of 3 to 10 carbon atoms, R¹²、 R¹³And 1^1¾An alkyl, as defined in claim 1, appearing herein, is defined as described 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. The alkyl group can be further selected from 0 to 5 groups selected from F, Cl, Br, I, =0 and-CH₂F、 -CHF₂、 -CF₃Hydroxy, mercapto, -SR¹⁴、 -S(=0)R¹⁴、 -S(=0)₂R¹⁴Nitro, cyano, isocyano, aldehyde, carboxyl, amino, alkanamido, amido, alkenyl, alkanamido,Alkynyl, alkanyl, hydroxyalkyl, alkanyl, carbocyclyl, heterocyclyl, carboxylate, carboxyl, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_m-S(=0)_n-R¹²、 -0-C(=0)-0-R¹²or-NR¹³R^13aWherein R is substituted by a substituent of (1)¹⁴As defined above, R¹²、 R¹³And R^13aAs defined in claim 1.

"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, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-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 a bridged or spiro ring may be attached, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, phenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, ^ B, F, W. The carbocyclyl may optionally be further substituted by 0 to 8 substituents selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Hydroxy, mercapto, -SR¹⁴、 -S(=0)R¹⁴, -S(=0)₂R¹⁴Nitro, cyano, isocyano, aldehyde, carboxyl, amino, alkanyl, amido, alkenyl, alkynyl, alkanyl, hydroxyalkyl, alkanyl, carbocyclyl, heterocyclyl, carboxylate, carboxyl, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_m-S(=0)_n-R¹², -0-C(=0)-0-R¹²or-NR¹³R^13aWherein R is substituted by a substituent of (1)¹⁴As defined above, R¹²、 R¹³And 1^1¾As defined in claim 1.

"Heterocyclyl" refers to 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 contains 1 to 4A heteroatom selected from N, 0 or S, preferably a 3 to 8 membered heterocyclyl group, the optionally substituted N, S in the ring of which may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom to which the heterocyclic group may be attached a bridge or spiro ring, non-limiting examples include epoxyethyl, epoxypropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, oxepinyl, thiepinyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkanylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, perzin, morpholinyl, thiomorpholinyl, etc, . Thioxanthyl, 1, 3-dithiayl, dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, dihydrothienyl, pyrazolidinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 3-azabicyclo [3 brake 0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 3H-indolylquinozinyl, N-pyridylurea, 1-dioxothiomorpholinyl, azabicyclo [3.2.1]Alkanyl, azabicyclo [5.2.0 ]]Alkyl, oxa-tricyclo [5.3.1.1 ]]Alkyl, aza-adamantyl and oxaspiro [3.3 ]]The alkyl group is the alkyl group. The heterocyclic group can be optionally further substituted by 0 to 8 groups selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Hydroxy, mercapto, -SR¹⁴、 -S(=0)R¹⁴、 -S(=0)₂R¹⁴Nitro, cyano, isocyano, aldehyde, carboxyl, amino, alkanyl amineAlkyl, carbocyclyl, heterocyclyl, carboxylate, carboxyl, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹², -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_m-S(=0)_n-R¹²、 -0-C(=0)-0-R¹²or-NR¹³R^13aWherein R is substituted by a substituent of (1)¹⁴As defined above.

"PEG" refers to a polymer containing ^ where n is an integer in the 2-about 1000 range, preferably 2-large-about 500, more preferably 2-about 250, more preferably 2-about 125, more preferably 2-about 50, further preferably 2-about 25. "amino" means-NH₂。

The "alkanyl group" refers to an amino group having one or two alkanyl substituents.

"cyano" means ^ a^N。

"isocyano" means^≡e_。

"Nitro" means-N0₂。

"hydroxy" means-OH.

"mercapto" means-SH.

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

"carboxyl" means-COOH.

"Carboxylic acid ester" means COOR¹⁵Wherein R is¹⁵The alkyl is the base.

"amido" means-CONR¹³R^13a， R¹³And 1^1¾As defined in claim 1.

"=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.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid. 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; non-limiting examples of the inorganic and organic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, glycolic acid, propionic acid, 2-hydroxypropionic acid, malonic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, vinylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, phenylacetic acid, alginic acid, anthranilic acid, camphoric acid, maleic acid, tartaric acid, citric acid, succinic acid, mandelic acid, fumaric acid, malic acid, oxalic acid, salicylic acid, glucuronic acid, galacturonic acid, citric acid, aspartic acid, glutamic acid, cinnamic acid, acetic acid, salicylic acid, malic acid, citric acid, glutamic acid, tartaric acid, citric acid, malic acid,

"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 a hydroxy, amino, or sulfhydryl group is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, compounds of the present invention wherein a hydroxy or amino functional group is bonded to formic, acetic or benzoic acid.

"cocrystal" refers to a crystal in which the Active Pharmaceutical Ingredient (API) and the cocrystal former (CCF) are both solid in pure form at room temperature and a fixed stoichiometric ratio exists between the components, combined by hydrogen bonding or other non-covalent bonding. 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 example co-crystal formers 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, maleic acid, malic acid, glutamic acid, citric acid, malic acid, citric acid, formic acid, nitric acid, hydrobromic acid, hydrochloric acid, benzoic 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 trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzinum-penicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, succinic acid, fumaric acid, maleic acid, fumaric acid, 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.

In the present invention, the structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) by 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-C18100x4.6 mm).

The thin-layer chromatography silica gel plate adopts 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 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel 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:

single peak of s

d doublet peak

t is triplet

q is quartet

m is multiplet

br, broad peak

J coupling constant Hz

Bn is benzyl

Me is methyl

Et ethyl

TBS-tert-butyl dimethylsilyl group

Intermediate 1 methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (IE)

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

The first step is as follows: 4- (chloromethyl) -7-hydroxy-2H-benzopyran-2-one (1B)

4-(chloromethyl)-7-hydroxy-2H-chromen-2-one

Resorcinol 1A (17.62 g, 160.02 mmol) was added in small portions to concentrated sulfuric acid (60 mL) in which ethyl chloroformylacetate (28.00 g, 170.12 mmol) was dissolved at 0 ℃ and the reaction was stirred at room temperature for 2 hours. The reaction was poured into ice water, the mixture was filtered, and the filter cake was washed with water (100 mL x3) and dried to give the crude product as a beige solid which was used directly in the next reaction. The second step is that: 2- (6-hydroxybenzofuran-3-yl) acetic acid (1C)

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

The crude 4- (chloromethyl;) -7-hydroxy-2H-benzopyran-2-one IB was dissolved in aqueous sodium hydroxide (1000 mL, 1M) and heated under reflux for 2 hours. After the reaction was completed, the reaction solution was acidified with concentrated sulfuric acid, extracted with ethyl acetate (250 mL × 3), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 1C as a brown solid (16.00 g, yield 52%).

The third step: 2- (6-hydroxybenzofuran-3-yl;) methyl acetate (ID)

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

2- (6-hydroxybenzofuran-3-yl) acetic acid 1C (16.00 g, 83.26 mmol) was dissolved in methanol (75 mL), concentrated sulfuric acid (8 mL; i) was added dropwise, the mixture was heated under reflux for 4 hours-after the reaction was complete, the reaction solution was concentrated and spin-dried, dissolved with a dichloromethane-containing bath (30 mL), washed with water (100 mL x3) and saturated saline (100 mL > <3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure-the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give compound 1D as a pale yellow solid (8.37 g, 48% yield).

The fourth step: 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester (1E)

methyl 2-(6-hydroxy-2,3-dihydrobenzo

Palladium on carbon (1.38 g, 3.60 mmol, 10%) was added to a solution of methyl 2- (6-hydroxybenzofuran-3-yl) acetate 1D (7.38 g, 35.79 mmol) in methanol (65 mL), the reaction system was replaced with hydrogen gas for 3 times, hydrogen gas was introduced, and the reaction was stirred for 18 hours. The reaction solution was filtered and dried by spin-drying under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1), whereby compound 1E (4.50 g, yield 60.4%) was obtained as a white solid.

Intermediate 2 5-bromo-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-3-ol (2G)

5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3-ol

The first step is as follows: 4-bromo-3, 5-dimethylphenylacetic acid ester (2B)

4-bromo-3 ,5-dimethylphenyl acetate

Acetic anhydride (12.10 g, l 19 mmol) and triethylamine (12.00 g, l 19 mmol) were added to a solution of 4-bromo-3, 5-xylenol 2A (20.00 g,99 mmol) in a dichloroakkyne (50 mL) and the reaction was stirred at room temperature for 2 hours. Adding ice water (100 mL) into the reaction solution to quench the reaction, extracting by using a dichloromethane alkyl (100 mL x3), combining organic phases, washing by using a saturated sodium chloride solution (100 mL x3), drying the organic phase by using anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain a brown liquid-shaped crude product which is directly used in the next step: 1- (3-bromo-6-hydroxy-2, 4-dimethyl-benzene) ethanone (2C)

l-(3-bromo-6-hydroxy-2,4-dimethylphenyl)

Adding the 4-bromo-3, 5-dimethylphenyl acetate crude product 2B and aluminum trichloride (19.7 g,148.1 mmol) into a1, 2-dichloroethylene alkyl (200 mL), heating to reflux, stirring for reacting for 2.5 hours, and enabling the color of a reaction system to become dark. The mixture was cooled to 0 ℃ with an ice-water bath, 1M HC1 was slowly added dropwise to stop the reaction, water (100 mL) was added to dilute, extracted with a dichloromethane (100 mL x3), the organic phases were combined, washed with saturated aqueous sodium chloride (200 mL x3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized from petroleum ether/methylene chloride to give 2C C16.0.0 g of white floc with 66% yield over two steps).

MS m/z(ESI):241.0,243.0[M-l]

^ NMR (300 MHz, CDC13) δ 10.99 (s, 1H), 6.77 (s, 1H), 2.61 (s, 6H), 2.40 (s, 3H).

The third step: 2-bromo-, (³Bromine-⁶-hydroxy-²,⁴-dimethyl-acetophenone (²D)

2-bromo- 1 -(3-bromo-6-hydroxy-2,4-dimethylphenyl)ethanone

1- (3-bromo-6-hydroxy-2, 4-dimethylbenzene) ethanone 2C (10.0 g, 41.14 mmol) and copper bromide (15.6 g,69.85 mmol) were dissolved in a mixed solvent of chloroform (100 mL) and ethyl acetate (50 mL), and the reaction was stirred under reflux for 4 hours. After the reaction, the reaction mixture was cooled to room temperature in an ice-water bath and filtered. The filtrate was diluted with water (100 mL), extracted with ethyl acetate (100 mL x3;, the organic phases were combined, washed with saturated aqueous sodium chloride (200 mL x l), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was used directly in the next reaction.

The fourth step: 5-bromo-4, 6-dimethylbenzofuran-3 (2H) -one (2E)

5-bromo-4,6-dimethylbenzofuran-3(2H)-one

Sodium acetate (10.1 g,123.3 mmol) was added to a solution of the crude 2D product of the above step in methanol (150 mL) and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched by adding water (50 mL), the mixture was concentrated under reduced pressure to remove part of methanol, diluted to lloo mL with water, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride (200 mL × 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give compound 2E as a pale yellow solid (5.4 g, 55% yield in two steps). Ή NMR (300 MHz in DMSO). delta.7.22 (s, 1H), 4.83 (s, 2H), 2.61 (s, 6H).

¹³C NMR (75 MHz, CDC1₃) δ 199.31, 172.98, 148.75, 139.18, 121.13, 118.19, 112.51, 75.11 25.54, 17.64.

The fifth step: 5-bromo-2, 2,4, 6-tetramethylbenzofuran-3 (2H) -one (2F)

5-bromo-2,2,4,6-tetramethylbenzofuran-3( -one

Sodium hydride (125 mg, 5.21 mmol) was added to a solution of 5-bromo-4, 6-dimethylbenzofuran-3 (2H) -one 2E (500 mg, 2.07 mmol) in dry tetrahydrofuran (20 mL) at-30 ℃ in the absence of oxygen and water, and the mixture was stirred for 20 minutes. To the mixture was added the iodomethyl alkyl (1.5 g, 10.57 mmol) and the reaction was allowed to warm to room temperature for 3 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride (50 mL), diluted with water (10 mL), extracted with ethyl acetate (100 mL x3), and the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1), whereby compound 2F (482 mg, yield 85%) was obtained as a pale yellow solid.

¾ NMR (300 MHz, CDC13) δ 6.83 (s, 1H), 2.67 (s, 3H), 2.48 (s, 3H), 1.43 (s, 6H).

And a sixth step: 5-bromo-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-3-ol (2G)

5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobe

5-bromo-2, 2,4, 6-tetramethylbenzofuran-3 (2H) -one 2F (482 mg, 1.79 mmol) was dissolved in a mixed solvent of methanol (4mL) and tetrahydrofuran (16 mL), and sodium borohydride (339 mg, 8.96 mmol) was added in small portions under ice bath, followed by stirring at room temperature for 0.5 hour. After the reaction was completed, the reaction was quenched by adding water (15 mL), concentrated to remove a part of the reaction solution, acidified by adding hydrochloric acid (10 mL, 1M), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/dikyaku =2/1), yielding compound 2G as a white solid (450 mg, yield 92%).

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

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

The first step is as follows:

(S)2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid (R) phenethylamine salt (3B)

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

2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid 3A (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 addition was completed, the heating was turned off, and the temperature was slowly decreased to room temperature and stirred overnight. Filtered and the precipitate washed with a small amount of acetone. Adding 1N diluted hydrochloric acid, adjusting pH to 2, extracting with ethyl acetate, and concentrating. The concentrate was dissolved in acetone (35 mL) and heated to reflux, and a solution of R-phenylethylamine in acetone (1.53 g, 12.7 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the heating was turned off and allowed to slowly cool to room temperature, and stirred overnight. Filtration, washing of the precipitate with a small amount of acetone, and dissolving the precipitate in acetone (25 mL) and recrystallization afforded Compound 3B (600 mg, 60%).

The second step is that: (S)2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid (3C)

(S)-2-(6-hydroxy-2,3-dihydrobenzofuran- -yl)acetic acid

Dissolving (S)2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid (R) phenethylamine salt 3B in 1M hydrochloric acid aqueous solution, adding ethyl acetate (50mLx3) for extraction, combining organic layers, drying with anhydrous sodium sulfate, and concentrating to obtain compound 3C (370 mg, 99%; mobile phone, third step (S)2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) methyl acetate (3D)

(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzo

Dissolving (S)2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid 3C in methanol at room temperature, dropwise adding concentrated sulfuric acid 0.2 mL, heating to 50 ℃ for reaction for 2 hours, adding saturated aqueous sodium bicarbonate solution to stop the reaction, adding ethyl acetate (50mLx3) for extraction, combining organic layers, drying over anhydrous sodium sulfate, concentrating, and eluting by column chromatography (silica gel 6.0 g, petroleum ether/ethyl acetate = 5/1) to obtain a white solid compound 3D (317 mg, 80%, ee% = 99%).

The absolute configuration of the product is determined from the literature (ACS med. chem. lett. 2010,1, 290-.

Example 1

₂- (6- ((3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 1)

2-(6-((3-(3-methoxy-2,2,4,6 etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzof uran-3-yl)acetic acid

Sodium hydride (48 mg, 1.99 mmol) was added to a solution of 5-bromo-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-3-ol 2G (450 mg, 1.66 mmol) in dry tetrahydrofuran (15 mL) in an anhydrous oxygen-free atmosphere in an ice-water bath and stirred for 20 minutes. The iodomethane-alkyl (471 mg,3.32 mmol) was added to the mixture and the reaction was allowed to warm to room temperature for 1 hour. After the reaction was complete, the reaction was quenched by addition of saturated aqueous ammonium chloride (15 mL), water (25 mL) was added and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, washed with saturated brine (30 mL × l), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound la as a pale yellow oily liquid (360 mg, yield 77%).

¾ NMR (300 MHz, CDC1₃) δ 6.56 (s, 1Η), 4.44 (s, 1H), 3.38 (s, 3H), 2.38 (d, 6H), 1.53 (s, 3H)_:1.33 (s, 3H).

The second step is that: 3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzaldehyde (lb)

3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde

5-bromo-3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran la (350 mg, 1.30 mmol) and 3-formylphenylboronic acid (210 mg, 1.40mmol) were dissolved in aqueous sodium carbonate (10 mL, 1M), and toluene (15 mL) and ethanol (5 mL) were added. The reaction system was replaced with nitrogen, and tetrakis (triphenylphosphine;) palladium (81 mg, 0.07 mmol) was added. The reaction was carried out at 80 ℃ for 15 hours while maintaining the nitrogen atmosphere. After completion of the reaction, water (5 mL) and ethyl acetate (40 mL) were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was washed with a saturated aqueous solution of sodium chloride (20 mL X3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate =14/1), whereby compound lb (335 mg, yield 83%) was obtained as a pale yellow oily liquid. The third step: (3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) phenyl) methanol (lc)

(3-(3-methoxy-2,2,4,6-tetramethyl-2, -dihydrobenzofuran-5-yl)phenyl)methanol

3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzaldehyde lb (335 mg, 1.08 mmol) is dissolved in a mixed solution of methanol (4mL) and tetrahydrofuran (16 mL), sodium borohydride (204 mg, 5.40 mmol) is added to the mixture in small portions under ice bath, and the mixture is warmed to room temperature for reaction for 1 hour. After completion of the reaction, water (10 mL) was added to the reaction mixture to quench the reaction, and a part of the reaction mixture was removed by concentration under reduced pressure. Hydrochloric acid (6 mL, 1M) was added to the mixture, extracted with ethyl acetate pO mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give lc as a pale yellow viscous solid (322 mg, yield 95%).

¾ NMR (400 MHz, CDC1₃) δ 7.41 (t, 1Η), 7.34 (d, 1H), 7.13 (s, 1H), 7.07 (dd, 1H), 6.54 (s,

1H) 4.73 (d, 2H), 4.45 (d, 1H), 3.49 (s, 1H), 3.41 (d, 3H), 1.98 (d, 6H), 1.57 (s, 3H), 1.39 (s, 3H). 2- (6- ((3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl;) acetic acid methyl ester (Id)

methyl 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) benzyl)oxy)-2,3 -dihydrobenzofuran-3-yl)acetat

(3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) phenyl) methanol lc (130 mg,0.4 mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 1E (100 mg, 0.48 mmol) were dissolved in a dichlorome (15 mL). The reaction system was replaced with nitrogen, tributylphosphine (178 mg, 0.88 mmol) and l, Γ - (azodicarbonyl) dipiperidine (222 mg, 0.88 mmol) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. Adding a small amount of n-hexyl alkyl into the reaction solution, filtering, and concentrating the filtrate. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 8/1) to obtain Id (165 mg, yield 82.1%) as a pale yellow viscous solid.

The fifth step: 2- (6- ((3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 1)

A sodium hydroxide solution (1 mL, 2M) was added to methyl 2- (6- ((3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl;) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate Id (200 mg,0.40 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4mL) and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was diluted with water (20 mL), acidified to pH 1 with 1M aqueous hydrochloric acid, extracted with ethyl acetate (30 mL x3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate =2/1) to give compound 1 (178 mg, yield 91.3%) as a white solid.

MS m/z(ESI):487.0[M-l]

^ NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 7.44 (td, 1H), 7.38 (d, 1H), 7.14 (s, 1H), 7.08 (dd, 2H), 6.52 (s, 1H), 6.50 - 6.41 (m, 2H), 5.10 (d, 2H), 4.68 (t, 1H), 4.47 (s, 1H), 4.23 - 4.10 (m, 1H), 3.75― 3.55 (m, 1H), 3.36 (s, 3H), 2.70 (dd, 1H), 2.46 (d, 1H), 1.90 (dd, 6H), 1.46 (s, 3H), 1.31 (s, 3H).

Example 2

2- (6- ((3- (3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 2)

2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofur an-3-yl)acetic acid

The first step is as follows: 5-bromo-3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran (2 a)

5-bromo-3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran

Sodium hydride (80 mg,3.32 mmol) was added to a solution of 5-bromo-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-3-ol 2G (750 mg, 2.76 mmol) in dry tetrahydrofuran (20 mL) under anhydrous and oxygen-free atmosphere and ice-bath, and the reaction was stirred for 20 minutes. The mixture was added to iodoethane (0.45 mL, 3.52 mmol), warmed to room temperature for 5 hours, and heated to reflux for 2 hours to complete the reaction. The reaction mixture was diluted with water (20 mL), and a saturated aqueous ammonium chloride solution (10 mL) was added, followed by extraction with ethyl acetate (30 mLx 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1), to give compound 2a as a pale yellow liquid (532 mg, yield 64.4%).

¾ NMR (400 MHz, CDC1₃) δ 6.55 (s, IH), 4.51 (s, IH), 3.56 (q, 2H), 2.37 (d, 6H), 1.52 (s, 3H) 1.34 (s, 3H), 1.22 (t, 3H).

The second step is that: 3- (3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzaldehyde (2 b)

3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde

5-bromo-3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran 2a (500 mg, 1.67 mmol) and 3-formylphenylboronic acid (334 mg, 2.23 mmol) were dissolved in a mixed solvent of sodium carbonate solution (11 mL, 1M), toluene (15 mL) and ethanol (4 mL). The reaction system was replaced with nitrogen, tetrakis (triphenylphosphine) palladium (127 mg, 0.11 mmol) was added to the mixture, and the mixture was stirred at 80 ℃ for 21 hours while maintaining a nitrogen atmosphere. After completion of the reaction, water (10 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was washed with a saturated aqueous solution of sodium chloride (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain compound 2b (435 mg, yield 80.1%) as a pale yellow viscous solid.

The third step: 3- (3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl alcohol (2 c)

(3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol

Sodium borohydride (254 mg, 6.70 mmol) was added in portions to 3- (3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzaldehyde 2b (435 mg, 1.34 mmol) in a mixed solvent of methanol (5 mL) and tetrahydrofuran (10 mL) under ice water, and the reaction was stirred at room temperature for 0.5 hour. After completion of the reaction, water (10 mL) was added to the reaction mixture to quench the reaction, and the reaction mixture was concentrated under reduced pressure to remove a part of the reaction mixture, and a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate (30 mL x3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 8/1) to give 2c (400 mg, yield 91.5%) as a white viscous solid.

^ NMR (400 MHz, DMSO) δ 7.38 (td, IH), 7.28 (d, IH), 7.04 (d, IH), 7.00― 6.93 (m, IH), 6.51 (s, IH), 5.21 (dd, IH), 4.55 (d, 2H), 4.53 (s, IH), 3.59 (tt, 2H), 1.91 (d, 6H), 1.45 (s, 3H), 1.31 (s_:3H), 1.12 (t, 3H).

The fourth step: methyl 2- (6- ((3- (3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (2 d)

methyl 2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3- dihydrobenzofuran-3-yl)acetate

3- (3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl alcohol 2c (150 mg, 0.46 mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 1E (115 mg, 0.55 mmol) were dissolved in a dichlorome (15 mL). The reaction system was replaced with nitrogen, tributylphosphine (202 mg, 1.00 mmol) and l, Γ - (azodicarbonyl) dipiperidine (252 mg, 1.00 mmol) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. Adding a small amount of n-hexyl alkyl into the reaction solution, filtering, and concentrating the filtrate under reduced pressure. The residue was subjected to separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate = 8/1) to give colorless transparent oily liquid 2d (185 mg, yield 77.9%).

The fifth step: 2- (6- ((3- (3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 2)

An aqueous solution of sodium hydroxide (0.9 mL, 2M) was added to methyl 2- (6- ((3- (3-ethoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 2d (185 mg,0.36 mmoL) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4mL), and the reaction was stirred at room temperature for 1.5 hours. After the reaction, the reaction mixture was quenched with water (20 mL), acidified to pH 1 with 1M aqueous hydrochloric acid, extracted with ethyl acetate (30 mL x3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1.5/1) to obtain compound 2 (150 mg, yield 83.4%) as a white solid.

MS m/z(ESI):501.2[M-l]

^ NMR (400 MHz, CDC1₃) δ 7.40 (dt, 2H), 7.18 (s, 1H), 7.08 (dd, 2H), 6.55― 6.41 (m, 3H),

5.06 (s, 2H), 4.76 (t, 1H), 4.53 (d, 1H), 4.29 (dd, 1H), 3.91― 3.74 (m, 1H), 3.67― 3.48 (m, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 1.97 (dd, 6H), 1.55 (s, 3H), 1.39 (s, 3H), 1.24 (t, 3H).

Example 3

2- (6- ((3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (; Compound 3)

2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydroben zofuran-3 -yl)acetic acid

The first step is as follows: 2- (5-bromo-4, 6-dimethylbenzofuran-3-yl) acetonitrile (3 a)

2-(5-bromo-4,6-dimethylbenzofuran-3-yl)

Diethoxy cyanomethyl phosphate (1.1 g, 6.22 mmol) was slowly added dropwise to a solution of sodium hydride (149 mg, 6.22 mmol) in tetrahydrofuran (20 mL) under an anhydrous oxygen-free atmosphere at 0 ℃ for 10 minutes with stirring, a solution of 5-bromo-4, 6-dimethylbenzofuran-3 (2H) -one 2E (1.0 g, 4.15 mmol) in tetrahydrofuran was slowly added dropwise to the mixture, and the reaction was allowed to continue stirring up to 35 ℃ for 3 hours. To the reaction solution were added a saturated ammonium chloride solution (20 mL) and water (20 mL), extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with a saturated brine (50 mL. times.l), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and washed with petroleum ether. The residue was recrystallized from ethyl acetate to give compound 3a (870 mg, yield 82.9%) as a pale yellow solid.

¾ NMR (300 MHz, DMSO) δ 7.95 (s, 1H), 7.52 (s, 1H), 4.26 (s, 2H), 2.68 (s, 3H), 2.46 (s,

3H).

The second step is that: 2- (5-bromo-4, 6-dimethylbenzofuran-3-yl) acetaldehyde (3b)

2-(5-bromo-4,6-dimethylbenzofuran-3-yl)acetaldehyde

Diisobutylaluminum hydride (434 mg, 3.05 mmol) was slowly added dropwise to a solution of 2- (5-bromo-4, 6-dimethylbenzofuran-3-yl) acetonitrile 3a (0.73 g, 2.78 mmol) in toluene (30 mL) under nitrogen at 0 ℃ and the reaction was stirred for 1.5 hours. After the reaction, diethyl ether (10 mL) and water (0.12 mL) were added to the reaction mixture, followed by addition of sodium hydroxide solution (0.12 mL, 15%) and stirring was continued for 15 minutes. Water (3 mL) was added again and stirring was continued for 15 min. The mixture was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/macak =2/1), yielding reddish viscous material 3b (400 mg, yield 52.6%).

¾ NMR (300 MHz, DMSO) δ 9.79 (s, 1Η), 7.86 (s, 1H), 7.49 (s, 1H), 4.06 (s, 2H), 2.50 (s,

6H).

The third step: 2- (5-bromo-4, 6-dimethylbenzofuran-3-yl) ethanol (3c)

2-(5-bromo-4,6-dimethylbenzofuran-3-yl)ethanol

2- (5-bromo-4, 6-dimethylbenzofuran-3-yl) acetaldehyde 2b was dissolved in a mixed solvent of methanol (3 mL) and tetrahydrofuran (10 mL), and sodium borohydride (124 mg, 3.28 mmol) was added to the mixture at 0 ℃ and the reaction was stirred for 0.5 hour. After the reaction was completed, water (5 mL) was added to the reaction solution to quench the reaction, and the reaction solution was concentrated to remove a part of the organic solvent. Water (10 mL) was added for dilution, extracted with ethyl acetate (10 mL x3), the organic phases were combined, washed with saturated brine (30 mL x l), dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography for separation and purification (petroleum ether/ethyl acetate = 9/1) to give 3c as a pale yellow solid (251 mg, yield 71.3%).

The fourth step: 5-bromo-3-methoxyethyl-4, 6-dimethylbenzofuran (3d)

5-bromo-3-(2-methoxyethyl)-4,6-dimethylbenzofuranUnder a nitrogen atmosphere, iodomethyl alkanyl (198 mg, 1.40mmol) was added to a solution of 2- (5-bromo-4, 6-dimethylbenzofuran-3-yl) ethanol 3c (251 mg, 0.93 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred for 20 minutes. Sodium hydride (34 mg, 1.40mmol) was added to the mixed solution, heated to 40 ℃ and stirred for reaction for 5 hours, heated to reflux and reacted for 2 hours. After completion of the reaction, a saturated ammonium chloride solution (mL) and water (10 mL) were added to the reaction mixture, and the mixture was extracted with petroleum ether (30 mL. times.3), the organic phases were combined, washed with a saturated brine (30 mL. times.l), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/macadamia = 3/1), and compound 3d was obtained as a pale yellow solid (260 mg, yield 98%).

¾ NMR (400 MHz, DMSO) δ 7.71 (s, 1H), 7.43 (s, 1H), 3.60 (t, 2H), 3.28 (s, 3H), 3.00 (t, 2H),

2.64 (s, 3H), 2.44 (s, 3H).

The fifth step: 3- (3- (2-methoxyethyl) -4, 6-dimethylbenzofuran-5-yl;) benzaldehyde (3 e)

3-(3-(2-methoxyethyl)-4,6-dimethylb

^ 5-bromo-3-methoxyethyl-4, 6-mg, l.Olmmol) was dissolved in aqueous sodium carbonate (2.8 mL, 1M), and toluene (5 mL) and ethanol (5 mL) were added. The reaction system was replaced with nitrogen, and tetrakis (triphenylphosphine) palladium (53 mg, 0.045 mmol) was added to the mixture. The temperature was raised to 80 ℃ and the reaction was stirred for 24 hours while maintaining the nitrogen atmosphere. After completion of the reaction, a saturated ammonium chloride solution (20 mL) and water (5 mL) were added to the reaction mixture, and extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with a saturated saline solution (30 mL × l), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate =14/1), whereby compound 3e (170 mg, yield 60%) was obtained as a colorless viscous substance.

¾ NMR (400 MHz, DMSO) δ 10.07 (s, 1Η), 7.94 (d, 1H), 7.74― 7.68 (m, 3H), 7.52 (dd, 1H), 7.35 (s, 1H), 3.62 (t, 2H), 3.29 (s, 3H), 3.02 (t, 2H), 2.23 (s, 3H), 2.01 (s, 3H).

And a sixth step: (3- (3- (2-methoxyethyl) -4, 6-dimethylbenzofuran-5-yl) phenyl) methanol (3 f)

(3-(3-(2-methoxyethyl)-4,6- ethanol

Sodium borohydride (42 mg, 1.10 mmol) was added to a solution of 3- (3- (2-methoxyethyl) -4, 6-dimethylbenzofuran-5-yl) benzaldehyde 3e (170 mg, 0.55 mmol) in a mixed solvent of tetrahydrofuran (5 mL) and methanol (2 mL) under ice-bath conditions, and the reaction was stirred for 0.5 hour. The reaction mixture was quenched by adding water (13 mL), extracted with ethyl acetate (10 mL × 3), and the organic layer was washed with saturated brine (30 mL × l), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1), whereby compound 3f (151 mg, yield 88%) was obtained as a colorless viscous substance.

The seventh step: (3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol (3 g)

(3-(3-(2-methoxyethyl)-4,6-dimethyl- -dihydrobenzofuran-5-yl)phenyl)methanol

(3- (3- (2-methoxyethyl) -4, 6-dimethylbenzofuran-5-yl) phenyl) methanol 3f (151 mg,0.49 mmol) was dissolved in a mixed solvent of methanol (6 mL) and tetrahydrofuran (3 mL), and palladium on carbon (30 mg, palladium content w/w =10%) was added to the mixture. The reaction system was replaced with hydrogen, stirred at room temperature for 1 hour, and heated to 55 ℃ for further reaction for 7 hours. The reaction mixture was diluted with ethyl acetate (15 mL), filtered through celite, and water (10 mL) was added to the filtrate. Extracted with ethyl acetate (10 mL × 3), and the organic layer was washed with saturated brine (30 mL × l), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/methylene chloride =1/1), and 3g (91 mg, yield 59%) of a colorless oily compound was obtained.

¾ NMR (400 MHz, DMSO) δ 7.38 (t, 1H), 7.28 (d, 1H), 7.08― 6.91 (m, 2H), 6.55 (s, 1H), 5.20 (t, 1H), 4.53 (dd, 2H), 4.42 (d, 2H), 3.47― 3.36 (m, 4H), 3.24 (s, 3H), 1.89 (s, 6H).

Eighth step: methyl 2- (6- ((3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (3 h) methyl 2- (6- ((3- (3- (2-methoxy) -4, 6-dimethyl-2-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Under nitrogen atmosphere, 3g (82 mg, 0.26 mmoL) of (3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol, 3g (66 mg, 0.26 mmoL), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate, 1E (66 mg, 0.32mmoL) was dissolved in a dried solution of a dichlorosilane (10 mL), tributylphosphine (115 mg, 0.57 mmoL), li, Γ - (azodicarbonyl) dipiperidine (144 mg, 0.57 mmoL) was added to the mixture, the mixture was stirred at room temperature for 6 hours, the TLC plate followed the reaction to the end, the reaction solution was concentrated under reduced pressure, and the residue was analytically purified by silica gel column chromatography (petroleum ether/ethyl acetate = 6/1), this gave a colourless oil for 3h (92 mg, yield 70.2%).

The ninth step: 2- (6- ((3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 3)

Aqueous sodium hydroxide (1 mL, 1M) was added to a solution of methyl 2- (6- ((3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate in tetrahydrofuran (5 mL) for 3h (92 mg, 0.18 mmoL), and the reaction was stirred at room temperature for 1 hour. Concentrating the reaction solution to remove part of solvent, adjusting pH to be less than or equal to 3 with 1M hydrochloric acid solution, extracting with ethyl acetate (10 mL x2), combining organic phases, washing with saturated saline (10 mL x 1), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (diackthol/methanol = 10/1) to obtain compound 3 as a white solid (71 mg, yield 79%).

ESIMS [M+H]⁺: 489.0.

¾ NMR (400 MHz, DMSO) δ 12.36 (s, 1Η), 7.44 (t, 1H), 7.37 (d, 1H), 7.08 (dt, 3H), 6.55 (s, 1H), 6.46 (t, 2H), 5.09 (s, 2H), 4.68 (t, 1H), 4.42 (d, 2H), 4.18 (dd, 1H), 3.71 - 3.60 (m, 1H), 3.48 - 3.36 (m, 3H), 3.24 (s, 3H), 2.70 (dd, 1H), 2.46 (d, 1H), 1.86 (s, 6H), 1.90― 1.78 (m, 1H), 1.63 (m, 1H).

Example 4

2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (; Compound 4)

2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

The first step is as follows: 5-bromo-4, 6-dimethyl-2, 3-dihydrobenzofuran-3-ol (4 a)

5-bromo-4,6-dimethyl-2,3-dihydrobenzofur -3-ol

Sodium borohydride (0.24 g, 6.22 mmol) was added in portions to a mixed solution of 5-bromo-4, 6-dimethylbenzofuran-3 (2H) -one 2E (0.50 g, 2.07 mmol) in a mixed solvent of tetrahydrofuran (10 mL) and methanol (2 mL) under ice bath, and the reaction was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (20 mL × 3), and the organic layer was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 6/1) to give compound 4a as a white solid (400 mg, yield 79%). The second step is that: 5-bromo-4, 6-dimethylbenzofuran (4 b)

5-bromo-4,6-dimethylbenzofuran

P-toluenesulfonic acid (568 mg, 3.30 mmol) was added to a solution of 5-bromo-4, 6-dimethyl-2, 3-dihydrobenzofuran-3-ol 4a (400 mg, 1.65 mmol) in toluene (20 mL), and the reaction was stirred under reflux for 15 minutes, thereby completing the reaction. The reaction solution was cooled to room temperature, diluted with water (15 mL), extracted with petroleum ether (10 mL × 3), washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether) to give compound 4b (363 mg, yield 97%) as a colorless liquid.

¾ NMR (400 MHz, DMSO) δ 7.96 (d, 1Η), 7.49 (s, 1H), 7.07 (d, 1H), 2.54 (s, 3H), 2.46 (s,

3H).

The third step: 3- (4, 6-Dimethylbenzofuran-5-yl) benzaldehyde (4 c)

3-(4,6-dimethylbenzofuran-5-yl)benzaldehyde

Toluene (10 mL) and ethanol (5 mL) were added to a solution of 5-bromo-4, 6-dimethylbenzofuran 4b (363 mg, 1.61 mmol) and 3-formylphenylboronic acid (266 mg, 1.77 mmol) in sodium carbonate (4.8 mL, 1M). The reaction system was purged with nitrogen, and tetrakis (triphenylphosphine) palladium (93 mg, 0.08 mmol) was added to the mixture. The reaction was stirred for 24 hours while maintaining the nitrogen atmosphere and increasing the temperature to 80 ℃. After the reaction was completed, the mixture was filtered, the filtrate was diluted with water (10 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (50mL × l), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 8/1) to give 4c (249mg, yield 61.8%) as a colorless oil.

¾ NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 7.94 (t, 2H), 7.74― 7.69 (m, 2H), 7.54 (d, 1H), 7.40 (s, 1H), 7.02 (d, 1H), 2.13 (s, 3H), 2.05 (s, 3H).

The fourth step: (3- (4, 6-dimethylbenzofuran-5-yl;) phenyl;) methanol (4 d)

(3-(4,6-dimethylbenzofuran-5-yl)phenyl)methanol

Sodium borohydride (112 mg, 2.96 mmol) was added to a mixed solvent of 3- (4, 6-dimethylbenzofuran-5-yl) benzaldehyde 4c (247 mg, 0.99 mmol) and tetrahydrofuran (10 mL) and methanol (3 mL) under ice-bath conditions, and the reaction was stirred for 0.5 hour. The reaction was quenched by adding water (15 mL), extracted with ethyl acetate (10 mL × 3), and the organic layer was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4d (241 mg, 96% yield) as a colorless oil.

ESIMS [M+H]⁺: 255.1.

The fifth step: (3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol (4 e)

(3-(4,6-dimethyl-2,3-dihydrobenzofura -5-yl)phenyl)methanol

(3- (4, 6-Dimethylbenzofuran-5-yl) phenyl) methanol 4d (241 mg, 0.96 mmol) was dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (5 mL), and palladium on carbon (48 mg, 10%) was added to the mixture. The reaction system was replaced with hydrogen, stirred at 35 ℃ for 24 hours, and heated to 55 ℃ for further reaction for 48 hours. The reaction mixture was diluted with ethyl acetate (15 mL), filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give 4e (190 mg, yield 78%) as a colorless oil.

And a sixth step: 2- (6- ((3- (4,6-dimethyl-2, 3-dihydrobenzofuran-5-yl;) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl;) Methyl acetate (4 f) Methyl 2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate

Under nitrogen atmosphere, at 0 ℃ (4 e (130 mg,0.51mmoL), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate lE (128 mg, 0.61 mmoL) and tributylphosphine (227 mg, 1.12 mmoL), l, Γ - (azodicarbonyl) dipiperidine (283 mg, 1.12 mmoL) were dissolved in dry dichloromethyl alkyl (10 mL), and the mixture was heated to room temperature for 2 hours. The reaction solution was filtered to remove insoluble substances, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 7/1) to give 4f (190 mg, yield 84%) as a pale yellow oil.

The seventh step: 2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 4)

Aqueous sodium hydroxide (5 mL, 2M) was added to a solution of methyl 2- (6- ((; 3- (4,6-dimethyl-2, 3-dihydrobenzofuran-5-yl;) benzyl;) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 4f (190 mg, 0.43 mmoL) in tetrahydrofuran (5 mL) and the reaction was stirred at room temperature overnight. Adjusting pH of the reaction solution to 2 or less with dilute hydrochloric acid, extracting with ethyl acetate (10 mL x3), combining organic phases, washing with saturated saline (50mL x l), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1.5/1) to obtain compound 4 (170 mg, yield 92.4%) as a white solid.

ESIMS [M-H]": 429.1.

¾ NMR (400 MHz, DMSO) δ 12.35 (s, IH), 7.44 (t, IH), 7.37 (d, IH), 7.16― 7.01 (m, 3H), 6.53 (s, IH), 6.47 (m, 2H), 5.09 (s, 2H), 4.68 (t, IH), 4.52 (t, 2H), 3.66 (m, IH), 3.34 (s, 2H), 3.09 (t, 2H), 2.69 (dd, IH), 1.87 (s, 3H), 1.83 (s, 3H).

Example 5

2- (6- ((3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 5)

2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofUran-5-yl)benzyl)oxy)-2,3-dihydro benzofuran-3 -yl)acetic acid

Potassium carbonate (1.2 g, 8.69 mmol), methanol (20 mL) and water (20 mL) were added to a solution of 5-bromo-4, 6-dimethylbenzofuran-3 (2H) -one 2E (1.0 g, 4.16 mmol) in tetrahydrofuran (40 mL), and a formaldehyde solution (0.85 g, 10.41 mmol, 37.6%) was added to the mixture, and the reaction was stirred at room temperature for 0.5 hour. The reaction was concentrated to remove some of the solvent, diluted with water (50 mL), extracted with ethyl acetate (60 mL x3), and the organic phases combined and washed successively with saturated brine (100 mL x2) and water (100 mL x 2). Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure and spin dry to give compound 5a as a white solid (1.18g, 94% yield).

MS m/z(ESI):252.9,255.0[M-31]

¾ NMR (300 MHz, DMSO) δ 7.15 (s, 1H), 5.08 (t, 2H), 3.67 (d, 4H), 2.57 (s, 3H), 2.45 (s,

3H).

Tetra A .,2008,19,2497-2507

The second step is that: 5-bromo-2, 2-bis (methoxymethyl) -4, 6-dimethyl-benzofuran-3 (2H) -one (5 b)

5-bromo-2,2-bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one

Sodium hydride (0.5 g, 12.45 mmol, 60%) was added in portions to a solution of 5-bromo-2, 2-bis (hydroxymethyl) -4, 6-dimethylbenzofuran-3 (2H) -one 5a (1.59 g, 4.98 mmol) in dry tetrahydrofuran (38 mL) under an anhydrous oxygen-free atmosphere on an ice bath, the reaction was stirred for 20 minutes, and iodomethane-soluble (1.5 mL, 24.90 mmol) was added to the mixture. The reaction was continued for 3 hours with stirring after warming to room temperature, and the reaction was terminated. To the reaction mixture were added water (25 mL) and saturated ammonium chloride solution (25 mL), extracted with ethyl acetate (50mLx3), and the organic phases were combined and washed with saturated brine (100 mL x 2). Dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate =14/1) to give compound 5b (734 mg, yield 46%) as a white solid.

MS m/z(ESI):329.0,330.9[M+l]

¾ NMR (400 MHz, DMSO) δ 7.18 (s, 1H), 3.65 (s, 4H), 3.17 (s, 6H), 2.57 (s, 3H), 2.44 (s,

3H).

The third step: 5-bromo-2, 2-bis (methoxymethyl) -4,6-dimethyl-2, 3-dihydrobenzofuran-3-ol (5 c)

5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofumn-3-ol

Sodium borohydride (328 mg, 8.66 mmol) was added in small portions to a mixed solution of 5-bromo-2, 2-bis (methoxymethyl) -4, 6-dimethyl-benzofuran-3 (2-azulenone 513 (5701 ^ 1.731 ^1) in methanol (5 mL) and tetrahydrofuran (10 mL) under ice-bath, warmed to room temperature for 0.5 hour, the reaction was quenched by adding water (10 mL), a saturated ammonium chloride solution (15 mL) was added, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined and washed with water (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, the reaction was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1), this gave colorless transparent liquid 5c (572 mg, yield 99%).

The fourth step: 5-bromo-2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran (5 d)

5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2 -dihydrobenzofuran

Under anhydrous and oxygen-free atmosphere and ice bath, adding the triethylhydrosilane alkyl (16.3 mL, 102.10 mmol) into 5-bromo-2, 2-bis (methoxymethyl) -4,6-dimethyl-2, 3-dihydrobenzofuran-3-ol 5c (573 mg, 1.73 mmol) of dry dichlorosilane (20 mL), slowly adding trifluoroacetic acid (1.03 mL, 13.80 mmol) dropwise, and stirring for reacting for 2 hours. To the reaction solution, a solution of dichloromethane (20 mL) and saturated sodium bicarbonate (20 mL) was added, followed by stirring for 10 minutes, followed by addition of water (10 mL) and liquid separation. The aqueous layer was extracted with ethyl acetate (30 mL x2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1) to give 5d (480 mg, yield 88%) as a white solid.

^ NMR (400 MHz, DMSO) δ 6.61 (s, 1Η), 3.46 (d, 4H), 3.28 (s, 6H), 3.01 (s, 2H), 2.27 (s, 3H), 2.22 (s, 3H)

The fifth step: 3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde (5 e)

3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde3-Formylphenylboronic acid (247.4 mg, 1.65 mmol) and sodium carbonate solution (6.5 mL, 1M) were added to a solution of 5-bromo-2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran 5d (510 mg, 1.62 mmol) in toluene (15 mL), followed by ethanol (3 mL). Tetrakis (triphenylphosphine) palladium (93.6 mg, 0.08 mmol) was added to the reaction system under nitrogen, the temperature was raised to 80 ℃ and the reaction was stirred for 18 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and ethyl acetate (50 mL). Filter through celite, wash the organic layer with brine (20 mL x3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Residue is remainedThe product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 12/1) to give 5e (410 mg, yield 74%) as a colorless transparent oily liquid.

And a sixth step: (3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl alcohol (5 f)

(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol

Sodium borohydride (228 mg, 6.03 mmol) was added portionwise to a mixed solvent of 3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde 5e (410 mg, 1.20 mmol) in tetrahydrofuran (8 mL) and methanol (4mL) under ice-bath conditions. The reaction was stirred at room temperature for 15 minutes. The reaction was quenched by adding water (10 mL), part of the solvent was removed, saturated ammonium chloride solution (15 mL) was added, extraction was performed with ethyl acetate (25 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1), yielding colorless transparent oily liquid 5f (380 mg, yield 92%).

¾ NMR (400 MHz, DMSO) δ 7.37 (t, 1H), 7.27 (d, 1H), 7.02 (s, 1H), 6.95 (d, 1H), 6.49 (s, 1H), 5.19 (t, 1H), 4.53 (d, 2H), 3.57― 3.42 (m, 4H), 3.31 (s, 6H), 2.95 (s, 2H), 1.88 (s, 3H), 1.81 (s, 3H).

The seventh step: 2- (6- ((3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl;) methyl acetate (5 g)

Methyl2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)2,3-^ ihydrobenzofuran-3-yl)acetate

Adding methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 1E (110 mg, 0.53 mmol) to a solution of (3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl alcohol 5f (150 mg, 0.44 mmol) in dry dichlorojian (15 mL), adding tributylphosphine (0.24 mL, 0.97 mmol) and azobisformyldipiperidine (245 mg, 0.97 mmol) to the mixture under nitrogen atmosphere, stirring the mixture at room temperature for 2 hours, adding a small amount of n-hexyl cutter to the reaction solution, filtering the mixture, concentrating the filtrate under reduced pressure, performing flash column chromatography (petroleum ether/ethyl acetate = 6/1) to obtain a crude product and using the crude product directly in the next reaction. 2010,1, 290-: 2- (6- ((3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 5)

2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3- dihydrobenzofuran-3-yl)acetic acid

Cl. mL of aqueous sodium hydroxide solution, 2M) was added to the mixed solvent of methanol (2 mL) and tetrahydrofuran (4mL) of the crude product of the above reaction, and the reaction was stirred at room temperature for 1.5 hours. The reaction was concentrated under reduced pressure, diluted with water (20 mL), acidified to pH 1 with 1M hydrochloric acid, extracted with ethyl acetate (30 mL x3), the organic phases combined and dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (diketackol/methanol = 40/1) to give compound 5 as a white solid (168 mg, 73% yield over two steps).

MS m/z(ESI):517.2[M-l]

¾ NMR (400 MHz, CDC1₃) δ 7.45― 7.33 (m, 2H), 7.16 (s, 1H), 7.06 (t, 2H), 6.57 (s, 1H), 6.53 ― 6.42 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.28 (dd, 1H), 3.81 (dt, 1H), 3.68― 3.51 (m, 4H), 3.44 (s, 6H), 3.00 (s, 2H), 2.89― 2.74 (m, 1H), 2.61 (dd, 1H), 1.91 (d, 6H).

Example 6

2- (6- (3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 6)

2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenz

The first step is as follows: 5-allyloxy-2-bromo-1, 3-dimethylbenzene (6 a)

-(allyloxy)-2-bromo- 1 ,3-dimethylbenzen

Potassium carbonate (20.6 g, 0.15 mol) and 3-bromopropene (8.6 mL, 0.10 mol) were added to a solution of 4-bromo-3, 5-xylenol 2A (10.0 g, 0.05 mol) in acetonitrile (200 mL), and the reaction was stirred under reflux for 6 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 50/1) to obtain 6a (10.9 g, yield 90%) as a pale yellow oily liquid.

¾ NMR (400 MHz, CDC1₃) δ 6.66 (s, 2Η), 6.03 (ddd, 1H), 5.33 (dd, 2H), 4.48 (d, 2H), 2.37 (s,

6H).

The second step is that: 2-allyl-4-bromo-3, 5-dimethylphenol (6 b)

2-allyl-4-bromo-3,5-dimethylphenol

5-allyloxy-2-bromo-1, 3-dimethylbenzene 6a (7.5 g, 0.03 mol) was heated to 180 ℃ in an anhydrous and oxygen-free atmosphere for 6 hours. The reaction was cooled to room temperature, a dichloromethane (50 mL) was added, the solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1) to give compound 6b as a pale yellow solid (1.94 g, 25% yield).

¾ NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 6.68 (s, 1H), 5.82 (dt, 1H), 5.00― 4.79 (m, 2H), 3.38 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H).

The third step: (5-bromo-4, 6-dimethyl-2, 3-dihydrobenzofuran-2-yl) methanol (6 c)

(5-bromo-4,6-dimethyl-2,3-dihydrobenzo l

M-chloroperoxybenzoic acid (538 mg, 3.11 mol) was added to a solution of 2-allyl-4-bromo-3, 5-dimethylphenol 6b (500 mg, 2.07 mol) in 1, 2-dichloroethylene (20 mL) and the reaction was stirred for 4 hours at 70 ℃. After the reaction, the reaction solution was cooled to room temperature, and a saturated sodium thiosulfate solution (10 mL) was added and stirred for 15 minutes. To the mixture was added a saturated sodium carbonate solution (30 mL), and stirring was continued for 30 minutes. Extraction with ethyl acetate (40 mL x3), combining the organic phases, washing with saturated sodium carbonate solution (30 mL x2), drying over anhydrous sodium sulfate, filtration and concentration of the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1-6/1) to give compound 6c (286 mg, 53% yield) as a white solid.

¾ NMR (400 MHz, DMSO) δ 6.61 (s, 1H), 4.99 (t, 1H), 4.84― 4.73 (m, 1H), 3.60― 3.48 (m, 2H), 3.16 (dd, 1H), 2.93 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H).

The fourth step: 5-bromo-2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran (6 d)

5-Bromo-2- (Methoxymethyl) -4, 6-dimethyl-2-dihydrobenzofurans sodium hydride (40 mg, 1.67 mmol) was added in portions to a solution of (5-bromo-4, 6-dimethyl-2, 3-dihydrobenzofuran-2-yl) methanol 6c (286 mg, 1.11 mmol) in dry tetrahydrofuran (20 mL) under ice-bath in an anhydrous oxygen-free atmosphere, and stirred for 20 minutes. The iodomethane alkyl (788 mg, 5.55 mmol) was added to the mixture, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by addition of water (10 mL), saturated ammonium chloride solution (15 mL) was added, extraction was performed with ethyl acetate (25 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1), to give colorless transparent oily liquid 6d (270 mg, yield 89%).

¾ NMR (400 MHz, DMSO) δ 6.62 (s, 1Η), 4.93 (ddt, 1H), 3.50 (dd, 2H), 3.29 (s, 3H), 3.21 (dd, 1H), 2.90 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H).

The fifth step: 3- (2- (methylmethoxy) -4,6-dimethyl-2, 3-dihydrobenzofuran-5-yl;) benzaldehyde (6 e)

3-(2-(methoxymethyl)-4,6-dimethyl- -dihydrobenzofuran-5-yl)benzaldehyde

Sodium carbonate solution (4.8 mL, 1M) and ethanol (2.5 mL) were added to a solution of 5-bromo-2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran 6d (260 mg, 0.96 mmol) and 3-formylphenylboronic acid (159 mg, 1.06 mmol) in toluene (10 mL), the mixture was bubbled with nitrogen for 30 minutes while maintaining a nitrogen atmosphere, and tetrakis (triphenylphosphine) palladium (58 mg, 0.05 mmol) was added to the mixture. The reaction solution was heated to 80 ℃, stirred for 18 hours, and cooled to room temperature. To the mixture were added water (8 mL) and ethyl acetate (40 mL), filtered over celite, the filtrate was partitioned, the organic layer was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate =14/1) to give 6e (260 mg, yield 91%) as a pale yellow oily liquid.

And a sixth step: (3- (2- (methylmethoxy) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl alcohol (6 f)

(3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofumn-5-yl)phenyl)methanol

Sodium borohydride (134 mg, 3.55 mmol) was added portionwise to a mixed solution of 3- (2- (methylmethoxy) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde 6e (260 mg, 0.71 mmol) in tetrahydrofuran (6 mL) and methanol (3 mL) under ice-bath conditions, and the reaction was stirred at room temperature for 0.5 h. The reaction mixture was quenched by adding water (5 mL), part of the solvent was removed, and a saturated ammonium chloride solution (15 mL) was added. Extract with ethyl acetate (20 mL x3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give colorless transparent oily liquid 6f (255 mg, yield 97%).

The seventh step: 2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl;) acetic acid methyl ester (6 g)

methyl 2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetate

Tributylphosphine (0.13 mL, 0.52 mmol) and azobisformyldipiperidine (130.9 mg, 0.52 mmol) were added to a solution of (3- (2- (methylmethoxy) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl alcohol 6f (70.0 mg, 0.23 mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate IE (58.9 mg, 0.28 mmol) in dry dichloromethyl-bowl (8 mL) under nitrogen atmosphere, the reaction was warmed to room temperature, stirred for 2 hours, a small amount of n-hexyl-bowl was added to the reaction, the mixture was filtered to remove insolubles, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 6/1), yield 6g (90mg, 78% yield) of compound as a white solid.

¾ NMR (400 MHz, DMSO) δ 7.44 (t, IH), 7.37 (d, IH), 7.16― 6.99 (m, 3H), 6.51 (s, IH), 6.47 (d, 2H), 5.09 (s, 2H), 4.98― 4.89 (m, IH), 4.67 (t, IH), 4.20 (dd, IH), 3.77― 3.66 (m, IH), 3.63 (s, 3H), 3.53 (d, 2H), 3.32 (s, 3H), 3.16 (dd, IH), 2.84 (dd, IH), 2.77 (dd, IH), 2.59 (dd, IH), 1.86 (s, 3H), 1.80 (s, 3H).

Eighth step: 2- (6- ((3- (2- (methoxymethyl) - (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 6)

2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenz ofuran-3-yl)acetic acid

Sodium hydroxide solution (0.87 mL, 2M) was added to 2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2, 3-dihydrobenzofuran)

-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester 6g (170 mg, 0.35 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL). The reaction mixture was stirred at room temperature for 1.5 hours, and water (20 mL) was added to the reaction mixture to adjust the pH to 1 with 1M hydrochloric acid. Extract with ethyl acetate (30 mL x3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. The residue was separated and purified by silica gel column chromatography (diackthol/methanol = 50/1), and compound 6 was obtained as a white solid (155 mg, yield 93%).

MS m/z(ESI):473.2[M-l]

¾ NMR (400 MHz, CDC1₃) δ 7.40 (dd, 2H), 7.16 (d, IH), 7.06 (dd, 2H), 6.59 (s, IH), 6.53-6.43 (m, 2H), 5.05 (s, 2H), 5.02-4.91 (m, IH), 4.76 (t, IH), 4.29 (dd, IH), 3.81 (td, IH), 3.63 (ddd, 2H), 3.46 (s, 3H), 3.19 (dd, dd), 2.89 (dd, IH), 2.81 (dd, IH), 2.62 (dd, IH), 1.95 (s, 3H), 1.88 (s, 3H). example 7

(3S) 2- (6- ((3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 7)

-(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-

The first step is as follows: (3S) methyl 2- (6- ((3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl;) acetate

(3S) methyl 2-(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetate(7a)

(3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) phenyl) methanol lc (100 mg, 0.32mmol) and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (80 mg, 0.38 mmol) were dissolved in a dichlorome (10 mL). The reaction system was purged with nitrogen, tributylphosphine (142 mg, 0.70 mmol) and 1, Γ - (azodicarbonyl) dipiperidine (178 mg, 0.70 mmol) were added to the mixture, and the reaction was stirred at room temperature for 2 hours. Adding a small amount of n-hexyl alkyl into the reaction solution, filtering, and concentrating the filtrate under reduced pressure. The residue was subjected to silica gel flash column chromatography (petroleum ether/ethyl acetate = 8/1) to give a crude colorless transparent oily liquid. The second step is that: (3S) 2- (6- ((3- (3-methoxy-2, 2,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 7)

(3S) 2-(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran -5-yl)benzyl)oxy)- 2,3- dihydrobenzofuran-3 -yl)acetic acid

Sodium hydroxide solution (0.8mL, 2M) was added to the crude mixture of methanol (2 mL) and tetrahydrofuran (4mL) from the previous reaction and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was diluted with water (20 mL), acidified to pH 1 with 1M aqueous hydrochloric acid, extracted with ethyl acetate (30 mL. times.3), and combined withThe organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (diackthol/methanol = 70/1), yielding compound 7 as a white solid (130 mg, two-step yield 83.3%).

MS m/z(ESI):487.2[M-l]

¾ NMR (400 MHz, CDC1₃) δ 7.47― 7.33 (m, 2H), 7.17 (d, 1H), 7.08 (dd, 2H), 6.54 (s, 1H), 6.51 - 6.40 (m, 2H), 5.06 (s, 2H), 4.76 (t, 1H), 4.46 (d, 1H), 4.29 (dd, 1H), 3.86 - 3.75 (m, 1H), 3.42 (s, 3H), 2.81 (dd, 1H), 2.61 (dd, 1H), 1.96 (dt, 6H), 1.56 (s, 3H), 1.39 (s, 3H).

Example 8

(S)2- (6- (3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenethyl) -2, 3-dihydrobenzofuran-3-yl;) acetic acid (; Compound 8)

(S)-2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofUran-5-yl)phenethyl)-2,3-dihyd robenzofuran-3-yl)acetic acid

The first step is as follows: (S) methyl 2- (6- (3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenethyl) -2, 3-dihydrobenzofuran-3-yl) acetate 8a

(S)-methyl 2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenet hyl)-2,3-dihydrobenzofuran-3-yl)acetate

Dissolving (3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl alcohol 5f (120 mg, 0.35 mmol) and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (87 mg, 0.42 mmol) in a dichloromethyl-alkan (10 mL), and carrying out nitrogen gas replacement reaction on tributylphosphine (156 mg, 0.77 mmol) and a mixture of I, gamma- (azodicarbonyl) dipiperidine

(192 mg, 0.77 mmol) was added to the mixture, and the reaction was stirred at room temperature for 2 hours. Adding a small amount of n-hexyl alkyl into the reaction solution, filtering, and concentrating the filtrate under reduced pressure. The residue was subjected to silica gel flash column chromatography (petroleum ether/ethyl acetate = 6/1) to give a crude colorless transparent oily liquid, which was used directly in the next step.

The second step is that: (S)2- (6- (3- (2, 2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenethyl) -2, 3-dihydrobenzofuran-3-yl;) acetic acid (; Compound 8)

Sodium hydroxide solution (0.9 mL, 2M) was added to the crude mixture of methanol (2 mL) and tetrahydrofuran (4mL) and the reaction was stirred at room temperature for 1.5 h. After the reaction was complete, the reaction was quenched with water (20 mL), acidified to pH 1 with 1M aqueous hydrochloric acid, extracted with ethyl acetate (25 mL x3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (diackthol/methanol = 60/1) to obtain compound 8 as a white vesicular solid (140 mg, two-step yield 77.6%).

MS m/z(ESI):5172[M-l]

¾ NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 7.43 (t, 1H), 7.37 (d, 1H), 7.16 - 7.01 (m, 3H), 6.54― 6.42 (m, 3H), 5.09 (s, 2H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.76― 3.59 (m, 1H), 3.54― 3.43 (m, 4H), 3.30 (s, 6H), 2.95 (s, 2H), 2.69 (dd, 1H), 2.49― 2.41 (m, 1H), 1.86 (s, 3H), 1.79 (s, 3H).

Example 9

2- (6- ((3- (4, 6-dimethyl-3-oxo-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (; Compound 9)

2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)a cetic acid

The first step is as follows: 5- (3-Hydroxymethylphenyl) -4, 6-dimethyl-benzofuran-3 (2H) -one (9a)

5-(3-(hydroxymethyl)phenyl)-4,6-dimethylbenzofuran-3(2H)-one

3-Hydroxymethylbenzeneboronic acid (2.8 g, 18.3 mmol) and sodium carbonate solution (83.0 mL, 1M) were added to a solution of 5-bromo-4, 6-dimethylbenzofuran-3 (2H) -one 2E (4.0 g, 16.6 mmol) in toluene (100 mL), followed by ethanol (40 mL). Tetrakis (triphenylphosphine) palladium (1.0 g, 0.8 mmol) was added to the reaction under nitrogen atmosphere and the temperature was raised to 80 deg.C. And C, stirring and reacting for 24 hours. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and ethyl acetate (200 mL). Filter through celite, wash the organic layer with saturated brine (50mL x3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 6/1-4/1) to obtain 9a (3.3 g, yield 74%) as a pale yellow oily liquid.

^ NMR (400 MHz, CDC1₃) δ 7.44 (t, 1Η), 7.38 (d, 1H), 7.11 (s, 1H), 7.03 (d, 1H), 6.87 (s, 1H)_:4.75 (s, 2H), 4.61 (s, 2H), 2.28 (s, 3H), 2.07 (s, 3H)

The second step is that: methyl 2- (6- ((3- (4, 6-dimethyl-3-oxo-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (9b)

Methyl 2-(6-((3 -(4,6-dimethyl-3 -oxo-2,3 -dihydrobenzofuran-5-yl)benzyl)oxy)-2 ,3 - dihydrobenzofuran-3-yl)acetate

Tributylphosphine (0.41 mL, 1.64 mmol) and azobisformyldipiperidine (413.8 mg, 1.64 mmol) were added to a solution of 5- (3-hydroxymethylphenyl) -4, 6-dimethyl-benzofuran-3 (2H) -one 9a (200 mg, 0.75 mmol) and methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 1E (186.1 mg, 0.89 mmol) in dry methylene dichloride (15 mL) under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 hours. Adding a small amount of n-hexyl alkyl into the reaction solution, filtering to remove insoluble substances in the mixture, and concentrating the filtrate under reduced pressure. The residue was subjected to silica gel flash column chromatography (petroleum ether/ethyl acetate = 6/1) to give crude product 9b as a pale yellow transparent oily liquid.

The third step: 2- (6- ((3- (4, 6-dimethyl-3-oxo-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 9)

2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)a

Adding sodium hydroxide solution (1.9 mL, 2M) to a mixed solvent of 2- (6- ((3- (4, 6-dimethyl-3-oxo-2, 3-dihydrobenzofuran-5-yl;) benzyl;) oxy; 1-2, 3-dihydrobenzofuran-3-yl;) methyl acetate 9b in methanol (2 mL) and tetrahydrofuran (4mL) and stirring at room temperature for 1.5 hours, after the reaction is completed, adding water (20 mL) to dilute the reaction, acidifying with 1M aqueous hydrochloric acid to pH 1, extracting with ethyl acetate (30 mL x3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (dichloromethane/methanol = 60/1), compound 9 was obtained as a pale yellow solid (140 mg, 36.4% yield over two steps).

MS m/z(ESI):443.1 [M-l]

¾ NMR (400 MHz, CDC1₃) δ 7.49― 7.39 (m, 2H), 7.13 (s, 1H), 7.05 (d, 2H), 6.86 (s, 1H), 6.47 (ddd, 2H), 5.07 (s, 2H), 4.76 (t, 1H), 4.61 (s, 2H), 4.29 (dd, 1H), 3.81 (td, 1H), 2.80 (dd, 1H), 2.62 (dd, 1H), 2.26 (s, 3H), 2.06 (s, 3H).

Example 10

(S)2- (6- ((3- (4, 6-dimethyl-3-oxo-3-hydro-2, 1' -cyclopropylbenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 10)

(S)-2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)-2,3-diliyd robenzofuran-3-yl)acetic acid

The first step is as follows: 5- (3- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4, 6-dimethyl-2-hydrobenzofuran-3-one (10a)

-(3-(((tert-bu1yldimethylsilyl)oxy)methyl)phenyl)-4,6-dimethylbenzofuran-3(2H)-one

In a single-neck flask were added 5- (3-hydroxymethylphenyl) -4, 6-dimethyl-benzofuran-3 (2H) -one 9a (3.3 g, 12.3 mmol), t-butyldimethylsilicone-base (3.71 g, 24.6 mmol), imidazole (2.51 g, 36.9 mmol), and a dichlorome-base (40 mL) and stirred at room temperature for 40 minutes. After the reaction was completed, 70 mL of water was added to quench the reaction. After adding 250 mL of ethyl acetate, the layers were separated and the organic layer was taken. The organic layer was washed with water (100 mLx2), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (petroleum ether/dichloromethane alkyl =2/1) to give a pale yellow oily liquid 10a (4.68 g, 99% yield). The second step is that: 5- (3- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4, 6-dimethyl-3H-spiro- [ benzofuran-2, 1' -cyclopropyl ] -3-one (10b)

-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4,6-dimethyl-3H-spiro[benzofuran-2,r-cycloprop

In anhydrous and oxygen-free atmosphere, under-30' C, 5- (3-W tert-butyl dimethyl silicon base;) oxyl is added; ) A methyl group; ) Phenyl, 1-4, 6-dimethyl-2-hydro-benzofuran-3-one 10a (2.5g,6.54 mmol) was added to lOOmL of dry tetrahydrofuran. 60% sodium hydride (1.31 g,32.68 mmol) was added and stirred for 20 minutes. Slowly adding 1, 2-dibromo-ethylene-alkyl (3.68 g, 19.6 mmol) dropwise, and heating to 50 ℃ after adding for reaction for 16 hours. After the reaction was completed, it was cooled to 0 ℃, 25 mL of water was slowly added to quench the reaction, 75 mL of saturated aqueous ammonium chloride solution was added, and extraction was performed with ethyl acetate (100 mLx 3;. mobile phone, combined organic layers, dried with anhydrous sodium sulfate, and concentrated) by silica gel column chromatography (petroleum ether/dichloro-methyl-alkyl =1/1) to obtain a brown oily liquid 10b (1.08 g, 40% yield).

^ NMR (400 MHz, DMSO) δ 7.49 (t, 1H), 7.38 (d, 1H), 7.13 (d, 2H), 7.07 (d, 1H), 4.81 (s, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 1.78 (dd, 2H), 1.44 (dd, 2H), 0.91 (s, 9H), 0.10 (s, 6H).

The third step: 5- (3-Hydroxymethylphenyl) -4, 6-dimethyl-3H-spiro [ benzofuran-2, 1' -cyclopropyl ] -3-one (10c)

5-(3-(hydroxymethyl)phenyl)-4,6-dimethyl-3H-spiro[benzoftiran-2,r-cyclopropan|-3-one

A single vial was charged with 5- (3-W-tert-butyldimethylsilyl) oxy) methyl) phenyl, 1-4, 6-dimethyl-3H-spiro- [ benzofuran-2, Γ -cyclopropyl ] -3-one 10b (449 mg, 1.1 mmol), tetrahydrofuran solvent 10mL, and tetrabutylammonium fluoride (863 mg,3.3 mmol), and stirred at room temperature for 30 minutes. The reaction was quenched by addition of 10mL of water, stirring for 10 min, extraction with ethyl acetate (15 mLx3), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. Silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) gave 10c as a white foamy solid (270 mg, 84% yield).

The fourth step: (S) methyl 2- (6- ((3- (4, 6-dimethyl-3-oxo-3H-spiro- [ benzofuran-2, 1' -cyclopropyl ] -5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl;) acetate (1 Od)

(S)-methyl 2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl) benzyl )oxy)-2,3-dihydrobenzofuran-3-yl)acetate

Tributylphosphine (0.3 mL, 1.20 mmoL) and azobisformyldipiperidine (302 mg, 1.20 mmoL) were added to a solution of 5- (3-hydroxymethylphenyl) -4, 6-dimethyl-3H-spiro [ benzofuran-2, Γ -cyclopropyl ] -3-one 10c (160 mg, 0.54 mmoL) and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (136 mg, 0.65 mmoL) in dry methylene dichloride (15 mL) under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 hours. Adding a small amount of n-hexyl alkyl into the reaction solution, filtering to remove insoluble substances in the mixture, and concentrating the filtrate under reduced pressure. The residue was subjected to silica gel flash column chromatography (petroleum ether/ethyl acetate = 6/1) to give crude product 10d as a pale yellow transparent oily liquid.

The fifth step: (S)2- (6- ((3- (4, 6-dimethyl-3-oxo-3H-spiro [ benzofuran-2, 1' -cyclopropyl ] -5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 10)

(S)-2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)-2,3-dihy- drobenzofuran-3 -yl)acetic acid

Adding sodium hydroxide solution (1.4 mL, 2M) to a mixture of (S)2- (6- ((3- (4, 6-dimethyl-3-oxo-3H-spiro- [ benzofuran-2, gamma-cyclopropyl ] -5-yl;) benzyl;) oxy; 1-2, 3-dihydrobenzofuran-3-yl;) methyl acetate 10d in methanol (3 mL) and tetrahydrofuran (6 mL) and stirring at room temperature for 2 hours, after the reaction is complete, diluting the reaction with water (20 mL), acidifying with 1M aqueous hydrochloric acid to pH 1, extracting with ethyl acetate (25 mL x3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (diketackol/methanol = 70/1) to give compound 10 as a white vesicular solid (215 mg, 84% yield over two steps).

MS m/z(ESI):469.1 [M-l]

¾ NMR (400 MHz, DMSO) δ 12.35 (s, 1Η), 7.55― 7.40 (m, 2H), 7.18 (d, 1H), 7.11 (d, 3H),

6.47 (d, 2H), 5.06 (s, 2H), 4.68 (t, 1H), 4.23― 4.11 (m, 1H), 3.74― 3.61 (m, 1H), 2.70 (dd, 1H), 2.50

― 2.41 (m, 1H), 2.21 (s, 3H), 2.03 (s, 3H), 1.75 (dd, 2H), 1.41 (q, 2H).

Example 11

(S)2- (6- ((3- (2, 2-bis (methoxymethyl) -4, 6-dimethyl-3-oxo-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 11)

(S)-2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetic acid

The first step is as follows: 5- (3- (hydroxymethyl) phenyl) -2, 2-bis (methoxymethyl) -4, 6-dimethylbenzofuran-3 (2H) -one (11a)

-(3-(hydroxymethyl)phenyl)-2,2-bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one

Adding 3-hydroxymethylphenylboronic acid (150 mg, 0.97 mmol) and sodium carbonate solution (8.1 mL, 1M) to a toluene (10 mL) solution of 4,6-dimethyl-2, 2-bis (methoxymethyl) -5-bromo-benzofuran-3 (2H) -one 5b (265 mg, 0.81mmol), adding ethanol (4mL under nitrogen), adding tetrakis (triphenylphosphine) palladium (46 mg, 0.04 mmol) to the reaction system, heating to 80 ℃, stirring for reaction for 42 hours, diluting the reaction solution with water (10 mL), adding ethyl acetate (50 mL), diluting with celite, washing the organic layer with saturated saline (10 mL x3), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 6/1-5/1) to obtain 11a (240 mg, yield 83%) as a pale yellow oily liquid.

^ NMR (400 MHz, DMSO) δ 7.43 (t, 1H), 7.34 (d, 1H), 7.08 (s, 1H), 7.02 (d, 2H), 5.23 (t, 1H), 4.55 (d, 2H), 3.66 (s, 4H), 3.21 (s, 6H), 2.03 (s, 3H), 1.99 (s, 2H).

The second step is that: (S) methyl 2- (6- ((3- (2, 2-bis (methoxymethyl) -4, 6-dimethyl-3-oxo-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (l ib)

(S)-methyl 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5- yl)benzyl)oxy)-2,3-dihy

Under a nitrogen atmosphere, tributylphosphine (0.34 mL, 1.36 mmol) and azobisformyldipiperidine (343 mg, 1.36 mmol) were added to a solution of 5- (3- (hydroxymethyl) phenyl) -2, 2-bis (methoxymethyl) -4, 6-dimethylbenzofuran-3 (2H) -one 11a (220 mg, 0.62 mmol) and methyl (S)2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (154 mg, 0.74 mmol) in dry dichloromethyl alkan (15 mL). The reaction solution was stirred at room temperature for 1 hour. Adding a small amount of n-hexane to the reaction solution, filtering to remove insoluble substances in the mixture, and concentrating the filtrate under reduced pressure. The residue was subjected to silica gel flash column chromatography (diketankaryne/ethyl acetate = 60/1) to give crude lb as a colorless transparent oily liquid.

The third step: (S)2- (6- ((3- (2, 2-bis (methoxymethyl) -4, 6-dimethyl-3-oxo-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 11)

Adding sodium hydroxide solution (1.5 mL, 2M) into (S)2- (6- ((3- (2, 2-bis (methoxymethyl) -4, 6-dimethyl-3-oxo-2, 3-dihydrobenzofuran-5-yl;) benzyl;) oxy; 1-2, 3-dihydrobenzofuran-3-yl;) methyl acetate kib in a mixed solvent of methanol (4mL) and tetrahydrofuran (8 mL) and stirring at room temperature for 1.5 hours, quenching the reaction with water (20 mL), acidifying with 1M hydrochloric acid aqueous solution to pH 1, extracting with ethyl acetate (25 mL x3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (diackthol/methanol = 80/1), yielding white vesicular solid compound 11(160 mg, two-step yield 49%).

MS m/z(ESI):533.2[M+l]

¾ NMR (400 MHz, CDC1₃) δ 7.48― 7.37 (m, 2H), 7.14 (s, IH), 7.08― 7.03 (m, 2H), 6.91 (s, IH), 6.47 (ddd, 2H), 5.07 (s, 2H), 4.76 (t, IH), 4.29 (dd, IH), 3.81 (dd, 3H), 3.70 (dd, 2H), 3.36 (s, 6H), 2.81 (dd, IH), 2.62 (dd, IH), 2.24 (s, 3H), 2.05 (s, 3H).

Example 12

(S)2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 12)

(3S) 2-(-6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2, 3-dihydrobenzofuran-3- l acetic acid

The first step is as follows: (S) methyl 2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (12a)

(3S) methyl 2- (-6- ((3- (2- (methoxymymethyl) -4,6-dimethyl-2, 3-dihydrobenzofuranyl-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuranyl-3-yl) acetate Nitrogen atmosphere Tributylphosphine (0.33 mL, 1.33 mmol) and azobisformyldipiperidine (336 mg, 1.33 mmol) were added to a solution of (3- (2- (methylmethoxy) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl alcohol 6f (180 mg, 0.60 mmol) and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (150 mg, 0.72 mmol) in dry Dichloromethane (15 mL) the reaction solution was stirred at room temperature For 2 hours. Adding a small amount of n-hexyl alkyl into the reaction solution, filtering to remove insoluble matters in the mixture, and concentrating the filtrate under reduced pressure. The residue was subjected to silica gel flash column chromatography (petroleum ether/ethyl acetate = 6/1) to give crude product 12a as a pale yellow transparent oily liquid.

The second step is that: (S)2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 12)

(3S) 2-(-6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3

-dihydrobenzofuran-3 -yl)acetic acid

Adding sodium hydroxide solution (1.5 mL, 2M) into (S)2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2, 3-dihydrobenzofuran-5-yl;) benzyl) oxy; 1-2, 3-dihydrobenzofuran-3-yl) methyl acetate 12a in a mixed solvent of methanol (3 mL) and tetrahydrofuran (6 mL), stirring at room temperature for 1.5 hours, adding water (20 mL) to quench the reaction, acidifying with 1M aqueous hydrochloric acid to pH 1, extracting with ethyl acetate (25 mL x3), 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 (dichloromethane/methanol = 60) 1) Compound 11 was obtained as a white foamy solid (215 mg, 75.4% yield in two steps).

MS m/z(ESI):473.1 [M-l]

¾ NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.1 1 (t, 2H), 7.04 (t, 1H)_:

6.51 (s, 1H), 6.47 (d, 2H), 5.09 (s, 2H), 5.00― 4.87 (m, 1H), 4.68 (t, 1H), 4.28― 4.12 (m, 1H), 3.76― 3.60 (m, 1H), 3.53 (d, 2H), 3.32 (s, 3H), 3.16 (dd, 1H), 2.84 (dd, 1H), 2.69 (dd, 1H), 2.49 - 2.41 (m, 1H), 1.83 (d, 6H).

Example 13

(3S) 2- (6- ((3- (2,4, 6-trimethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 13)

(3S) 2-(-6-((3-(2,4,64rimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n -3-yl)acetic acid

The first step is as follows: 2,4,5, 6-tetramethyl-2, 3-dihydrobenzofuran (13a)

2,4,5,6-tetramethyl-2,3-dihydrobenzofura

Dissolving trifluoromethanesulfonic acid C32mg, 0.2 mmol) into a 5mL dichloroalkyl, slowly dropwise adding the solution into a 15mL dichloroalkyl solution dissolved with 2-allyl-4-bromo-3, 5-dimethylphenol 6b (480 mg,2.0 mmol), and heating to 60 ℃ for reaction for 3 hours after finishing addition. After the reaction was complete, the temperature was reduced to room temperature, 15mL of saturated aqueous sodium bicarbonate solution and 5mL of water were added, extracted with a dichloromethane (20 mL x2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Column chromatography of the residue on silica gel (petroleum ether/methylene chloride = 4/1) gave 13a (360 mg, 75% yield) as a pale yellow transparent oily liquid.

^ NMR (400 MHz, DMSO) δ 6.60 (s, 1Η), 5.02― 4.80 (m, 1H), 3.28 (dd, 1H), 2.73 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 1.36 (d, 3H).

The second step is that: 3- (2,4, 6-trimethyl-2, 3-dihydrobenzofuran-5-yl) benzaldehyde (13b)

3-(2,4,6-trimethyl-2,3-dihydrobenzofur -5-yl)benzaldehyde

Toluene (20 mL) and ethanol (5 mL) were added to a solution of 2,4,5, 6-tetramethyl-2, 3-dihydrobenzofuran 13a (350 mg, 1.45 mmol) and 3-formylphenylboronic acid (253 mg, 1.60 mmol) in sodium carbonate (14.5 mL, 1M). The reaction system was purged with nitrogen, and tetrakis (triphenylphosphine;) palladium (173 mg, 0.10 mmol) was added to the mixture. The reaction was stirred for 15 hours while maintaining the nitrogen atmosphere and increasing the temperature to 80 ℃. After the reaction was completed, the mixture was filtered, the filtrate was diluted with water (10 mL), 50mL of ethyl acetate was added, the mixture was washed with saturated brine (20 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was flash column chromatographed on silica gel (petroleum ether/ethyl acetate = 20/1) to give crude 13b as a yellow oil.

The third step: (3- (2,4, 6-trimethyl-2, 3-dihydrobenzofuran-5-yl) phenylmethanol (13c)

(3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol

Sodium borohydride (275 mg, 7.25 mmol) was added to the crude product of 3- (2,4, 6-trimethyl-2, 3-dihydrobenzofuran-5-yl) benzaldehyde 13b in a mixed solvent of tetrahydrofuran (12 mL) and methanol (3 mL) under ice-bath conditions, and the reaction was stirred at room temperature for 0.5 hour. The reaction mixture was quenched by adding water (10 mL), and 20 mL of a saturated aqueous ammonium chloride solution and 35 mL of ethyl acetate were added. After separation, the aqueous phase was extracted with ethyl acetate (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give 13c (315 mg, 81% yield in two steps) as a pale yellow oil.

MS m/z(ESI):269.1 [M+l]

The fourth step: (3S) methyl 2- (6- ((3- (2,4, 6-trimethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (Compound 13d)

(3S) methyl 2-(6-((3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- 2,3-dihydrobe nzo- furan-3-yl)acetate

Tributylphosphine (0.3 mL, 1.23 mmol) and azobisformyldipiperidine (317 mg, 1.23 mmol) were added to a solution of (3- (2,4, 6-trimethyl-2, 3-dihydrobenzofuran-5-yl) phenylmethanol (13c) (150 mg, 0.56 mmol) and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (129 mg, 0.62 mmol) in dry dichloromethyl-alkyl (12 mL) under a nitrogen atmosphere, the reaction solution was stirred at room temperature for 1.5 hours, a small amount of n-hexyl-cutter was added to the reaction solution, the mixture was filtered to remove insoluble material, the filtrate was concentrated under reduced pressure, and the product was directly subjected to the next reaction.

The fifth step: (3S) 2- (6- ((3- (2,4, 6-trimethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 13)

Sodium hydroxide solution (1.4 mL, 2M) was added to methyl (3S) 2- (6- ((3- (2,4, 6-trimethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 13d (235 mg,0.51mmol) in a mixed solvent of methanol (3 mL) and tetrahydrofuran (6 mL), and the reaction was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction was quenched with water (25 mL), acidified to pH 1 with 1M aqueous hydrochloric acid, extracted with ethyl acetate (25 mL x3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (diackthol/methanol = 60/1), yielding white vesicular solid compound 13(190 mg, 84% yield).

MS m/z(ESI):443.1 [M-l]

¾ NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.11 (t, 2H), 7.04 (t, 1H)_:6.47 (dd, 3H), 5.09 (s, 2H), 4.91 (dd, 1H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.74― 3.60 (m, 1H), 3.24 (dd, 1H), 2.71 (t, 1H), 2.68― 2.63 (m, 1H), 2.46 (dd, 1H), 1.83 (d, 6H), 1.39 (d, 3H).

Example 14

(3S) 2- (6- ((3- (2, 2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 14)

(S)-2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihyd robe

The first step is as follows: 5-bromo-2, 2-bis (ethoxymethyl) -4, 6-dimethyldihydrobenzofuran-3 (2H) -one (14a)

5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one

Sodium hydride (700 mg, 17.5 mmol, sodium hydride content w/w =60%) was added in portions to 5-bromo-2, 2-bis (hydroxymethyl) -4, 6-dimethylbenzofuran-3 (2H) -one 5a (2.11 g, 7.0 mmol) in dry n, n-dimethylformamide (50 mL) under ice-bath in an anhydrous oxygen-free atmosphere, the reaction was stirred for 20 minutes, and iodoethyl alcohol (2.8 mL, 25.0 mmol) was added to the mixture. The reaction was stirred at 0 ℃ for 0.5 hour to complete the reaction. To the reaction mixture were added water (50 mL) and saturated ammonium chloride solution (25 mL), extracted with ethyl acetate (80 mL. times.3), the organic phases combined and washed with saturated brine (100 mL. times.2). Dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was subjected to separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate = 16/1) to obtain oily liquid 14a (450 mg, yield 18%).

^ NMR (400 MHz, DMSO) δ 7.17 (s, 1H), 3.69 (s, 4H), 3.38 (q, 4H), 2.57 (s, 3H), 2.44 (s, 3H) 0.96 (t, 6H).

The second step is that: 5-bromo-2, 2-bis (ethoxymethyl) -4,6-dimethyl-2, 3-dihydrobenzofuran-3-ol (14b)

5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-3-ol

Sodium borohydride (238 mg, 6.30 mmol) was added in portions to a mixed solution of 5-bromo-2, 2-bis (ethoxymethyl) -4, 6-dimethyldihydrobenzofuran-3 (2H) -one 14a (450 mg, 1.26 mmol) in methanol (3 mL) and tetrahydrofuran (6 mL) under ice-cooling, and the mixture was warmed to room temperature for 1.5 hours. The reaction was quenched by adding water (5 mL), saturated ammonium chloride solution (15 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the reaction was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1), and colorless transparent liquid 14b was obtained (315 mg, yield 70%).

The third step: 5-bromo-2, 2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran (14c)

5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran

Under anhydrous and oxygen-free atmosphere and ice bath, adding a hydrogen-silane alkyl (7.7 mL, 48.2 mmol) into a dry dichloro-methane alkyl (10 mL) of 4,6-dimethyl-2, 2-diethoxymethyl-3-hydroxy-5-bromo-2, 3-dihydrobenzofuran 14b (315 mg, 0.88 mmol), slowly adding trifluoroacetic acid (0.52 mL, 7.0 mmol), and stirring for reacting for 2.5 hours. To the reaction solution, a solution of dichloromethane (10 mL) and saturated sodium bicarbonate (10 mL) was added, followed by stirring for 10 minutes, followed by addition of water (10 mL) and liquid separation. The aqueous layer was extracted with a dichloromethanone (20 mL x2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 40/1), and 14c was obtained as a colorless transparent liquid (210 mg, yield 70%).

The fourth step: 3- (2, 2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde (14d)

3-(2,2-bis(ethoxymethyl)-4,6-dimeth -2,3-dihydrobenzofuran-5-yl)benzaldehyde

3-Formylphenylboronic acid (106 mg, 0.67 mmol) and sodium carbonate solution (6.1 mL, 1M) were added to a solution of 5-bromo-2, 2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran 14c (210 mg, 061 mmol) in toluene (15 mL), followed by ethanol (3 mL). Tetrakis (triphenylphosphine;) palladium (70 mg, 0.1 mmol) was added to the reaction system under nitrogen atmosphere, heated to 80 ℃ and stirred for reaction for 18 hours. After completion of the reaction, the reaction mixture was quenched by adding water (10 mL) and diluted with ethyl acetate (50 mL). Filter through celite, wash the organic layer with brine (20 mL x3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain 14d (150 mg, yield 68%) as a pale yellow oily liquid.

The fifth step: 3- (2, 2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl alcohol (14e)

(3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol

Sodium borohydride (78 mg, 2.05 mmol) was added portionwise to a mixture of 3- (2, 2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde 14d (150 mg,0.4 mmol) in tetrahydrofuran (4mL) and methanol (2 mL) under ice-bath conditions. The reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water (5 mL), part of the solvent was removed, saturated ammonium chloride solution (15 mL) was added, extraction was performed with ethyl acetate (20 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1), yielding colorless transparent oily liquid 14e (140 mg, yield 93%).

MS m/z(ESI):371.3[M+l]

And a sixth step: (S) methyl 2- (6- ((3- (2, 2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl;) acetate (14f)

(S)-methyl 2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) oxy)- 2,3-dihydrobenzofuran- -yl)acetate

Tributylphosphine (0.21 mL, 0.83 mmoL) and azobisformyldipiperidine (214 mg, 0.83 mmoL) were added to a solution of 3- (2, 2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl alcohol 14e (140 mg, 0.38 mmoL) and methyl (S)2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (94 mg, 0.45 mmoL) in dry methylene dichloride (12 mL) under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 hours. Adding a small amount of n-hexyl alkyl into the reaction solution, filtering to remove insoluble substances in the mixture, and concentrating the filtrate under reduced pressure. The obtained product is directly used for the next reaction.

The seventh step: (3S) 2- (6- ((3- (2, 2-diethoxymethyl-4, 6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 14)

(S)-2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihyd robenzofuran-3-yl)acetic acid

Sodium hydroxide solution (0.8mL, 2M) was added to methyl (S)2- (6- ((3- (2, 2-diethoxymethyl-4, 6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 14f (180 mg, 0.32mmol) in a mixed solvent of methanol (3 mL) and tetrahydrofuran (6 mL), and the reaction was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction was quenched with water (20 mL), acidified to pH 1 with 1M aqueous hydrochloric acid, extracted with ethyl acetate (25 mL x3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate =1/1), whereby compound 14 (138 mg, yield 79%) was obtained as a white foamy solid.

MS m/z(ESI):545.3[M-l]

¾ NMR (400 MHz, CDC1₃) δ 7.44-7.32 (m, 2H), 7.16 (s, 1H), 7.06 (dd, 2H), 6.56 (s, 1H), 6.51-6.43 (m, 2H), 5.05 (s, 2H), 4.75 (t, 1H), 4.28 (dd, 1H), 3.80 (ddd, 1H), 3.69 (d, 2H), 3.66-3.48 (m, 6H), 2.99 (s, 2H), 2.80 (dd, 1H), 2.61 (dd, 1H), 1.94 (s, 3H), 1.87 (s, 3H), 1.21 (t, 6H). example 15

(S)2- (6- ((3- (4,6-dimethyl-3H-spiro [ benzofuran-2, Γ -cyclopropyl ] 5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 15)

(S)-2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2, -cyclopropan]-5-yl)benzyl)oxy)-2,3-dihydrobenz o

The first step is as follows: tert-butyl (3- (4,6-dimethyl-3H-spiro [ benzofuran-2, 1' -cyclopropyl)]-5-yl) phenyl) oxy) dimethylsiloxane (15 a) tert-bu1yl ((3- (4, 6-dimethyl-3H-spiro-5-yl) benzyl) oxy) dimethyl silane

Under an anhydrous and oxygen-free atmosphere, aluminum trichloride (420 mg,3.15 mmol) was added to 20 mL of dry tetrahydrofuran in an ice-water bath, and lithium aluminum hydride (114 mg, 3.0 mmol) was added thereto and stirred for 15 minutes. 4, 6-dimethyl-5- (3- (((; tert-butyldimethylsilyl) oxy) methyl) phenyl) -2-hydro-2, 1' -cyclopropylbenzofuran-3-one 10b (625 mg, 1.53 mmol) was prepared as a dry tetrahydrofuran (10 mL) solution, which was added dropwise to the reaction mixture, and then the temperature was raised to room temperature for 1 hour. After the reaction, the reaction mixture was cooled in an ice-water bath, 15mL of a 0.5N aqueous solution of sodium hydroxide was slowly added dropwise thereto, and the mixture was stirred for 10 minutes, followed by addition of 15mL of water. Extraction with ethyl acetate (30 mLx3), combining the organic phases, washing with saturated brine (30 mLx 3;. drying of the organic phase with anhydrous sodium sulphate, concentration. silica gel column chromatography of the residue (petroleum ether/dichloro-methyl-alka = 7/1) gave 15a as a colorless transparent oily liquid (450 mg, 76% yield).

^ NMR (400 MHz, DMSO) δ 7.40 (t, 1H), 7.27 (d, 1H), 7.04 (s, 1H), 6.98 (d, 1H), 6.52 (s, 1H) 4.75 (s, 2H), 3.23 (s, 2H), 1.89 (s, 3H), 1.84 (s, 3H), 1.08 (q, 2H), 0.88 (s, 9H), 0.77 (q, 2H), 0.06 (s, 6H).

The second step is that: (3- (4,6-dimethyl-3H-spiro [ benzofuran-2, Γ -cyclopropyl ] -5-yl) benzyl alcohol (15 b)

(3-(4,6-dimethyl-3H-spiro[benzofuran- -cyclopropan]-5-yl)phenyl)methanol

A single-necked flask was charged with tert-butyl (3- (4,6-dimethyl-3H-spiro [ benzofuran-2, 1' -cyclopropyl ] -5-yl;) phenyl) oxy) dimethylsiloxane 15a (500 mg,1.3mmol), tetrahydrofuran solvent 12 mL, and tetrabutylammonium fluoride (994 mg, 3.8 mmol), and stirred at room temperature for 30 minutes. The reaction was quenched by addition of 20 mL of water, stirring for 10 min, extraction with ethyl acetate (20 mLx4), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. Silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) gave 15b (353 mg, 99% yield) as a pale yellow oily liquid.

Microspheres NMR (400 MHz, DMSO). delta.7.38 (t, 1H), 7.28 (d, 1H), 7.04 (s, 1H), 6.96 (d, 1H), 6.51 (s, 1H), 5.17 (t, 1H), 4.54 (d, 2H), 3.22 (s, 2H), 1.90 (s, 3H), 1.84 (s, 3H), 1.08 (t, 2H), 0.80-0.74 (m, 2H). The third step: (S) methyl 2- (6- ((3- (4,6-dimethyl-3H-spiro [ benzofuran-2, Γ -cyclopropyl ] -5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (15 c)

(S)-methyl 2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)- 2,3- dihydrobenzofuran-3 -yl)acetate

Tributylphosphine (0.34 mL, 1.34 mmoL) and azobisformyldipiperidine (338 mg, 1.34 mmoL) were added to a solution of (3- (4,6-dimethyl-3H-spiro [ benzofuran-2, Γ -cyclopropyl ] -5-yl) benzyl alcohol 15b (170 mg, 0.61 mmoL) and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (139 mg, 0.67 mmoL) in dry methylene chloride (12 mL) under nitrogen atmosphere, the reaction solution was stirred at room temperature for 2 hours, a small amount of n-hexyl was added to the reaction solution, the mixture was filtered to remove insolubles, the filtrate was concentrated under reduced pressure, the residue was chromatographed on silica gel flash column (petroleum ether/ethyl acetate = 9/1), colorless, transparent oily liquid 15c (230 mg, 80%) was obtained. The fourth step: (S)2- (6- ((3- (4,6-dimethyl-3H-spiro [ benzofuran-2, Γ -cyclopropyl ] -5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 15)

(S)-2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2, -cyclopropan]-5-yl)benzyl)oxy)-2,3-dihydrobenz ofuran-3-yl)acetic acid

Sodium hydroxide solution (1.2 mL, 2M) was added to methyl (S)2- (6- ((3- (4,6-dimethyl-3H-spiro [ benzofuran-2, 1' -cyclopropyl ] -5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 15c (230 mg,0.49 mmol) in a mixed solvent of methanol (3 mL) and tetrahydrofuran (6 mL), and the reaction was stirred at room temperature for 1.0 hour. After the reaction was complete, the reaction was diluted with water (20 mL), acidified to pH 3 with 1M aqueous hydrochloric acid, extracted with ethyl acetate (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate =2/1) to obtain compound 15(200 mg, yield 90%) as a white foamy solid.

MS m/z(ESI):455.2[M-l]

^ NMR (400 MHz, DMSO) δ 12.30 (s, 1H), 7.44 (t, 1H), 7.38 (d, 1H), 7.13 (s, 1H), 7.07 (dd, 2H), 6.52 (s, 1H), 6.50― 6.44 (m, 2H), 5.10 (s, 2H), 4.67 (t, 1H), 4.18 (dd, 1H), 3.71― 3.63 (m, 1H), 3.22 (s, 2H), 2.68 (dd, 1H), 2.46 (d, 1H), 1.88 (s, 3H), 1.82 (s, 3H), 1.08 (t, 2H), 0.77 (t, 2H).

Example 16

(S)2- (6- ((3- (3,3,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 16)

(S)-2-(6-((3-(3,3,4,64etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3- yl)acetic acid

16e Compound 162-bromo-1, 3-dimethyl-5- ((2-methylallyl) oxybenzene (16 b)

2-bromo- 1 ,3-dimethyl-5-((2-methylallyl)oxy)benzene

4-bromo-3, 5-dimethylphenol 16a (8.04 g, 40mmol), 2-methyl-3-chloro-propene (3.62 g, 40mmol) and anhydrous potassium carbonate (11.06 g, 80 mmol) were added to acetonitrile (80 mL) at room temperature, the temperature was raised to 95 ℃ and the reaction was refluxed for 15 hours, and TLC showed completion of the reaction. Ethyl acetate (200 mL) and water (200 mL) were added to the reaction system, and the mixture was stirred for 10 minutes, separated, and the organic phase was dried over anhydrous sodium sulfate (10 g), concentrated, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 30/1) to obtain brown liquid 16b (8.0 g, yield 80%).

The second step is that: 5-bromo-3, 3,4, 6-tetramethyl-2, 3-dihydrobenzofuran (16c)

5-bromo-3,3,4,6-tetramethyl-2,3-dihydrobenzofuran

At room temperature, 2-bromo-1, 3-dimethyl-5- ((2-methylallyl) oxybenzene 16b (18.0 g, 31 mmol) was added to a double-chloro-alkyl (lioo mL), the temperature was reduced to 0 ℃, anhydrous aluminum trichloride (208 mg, 1.57 mmol) was added, the reaction was carried out after warming to room temperature, and the reaction was completed after 30 minutes.

The third step: (3- (3,3,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) methanol (16d)

(3-(3,3,4,6-tetramethyl-2,3-dihydrobenzo methanol

5-bromo-3, 3,4, 6-tetramethyl-2, 3-dihydrobenzofuran 16C (2.55 g, 10 mmol), 3-hydroxymethylphenylboronic acid (1.52 g, 10 mmol), palladium tetratriphenylphosphine (578 mg,0.5 mmol) and anhydrous sodium carbonate (3.18 g, 30 mmol) were added to toluene (50 mL) at room temperature, the temperature was raised to 100 ℃ for reaction, and the reaction was complete after 22 hours. Ethyl acetate (100 mL) and water (lloo mL) were added to the reaction system, and the mixture was separated, and the organic phase was washed with water (50mL × 3), dried over anhydrous sodium sulfate (10 g), concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain 16d as a white solid (565 mg, 20% yield).

¾ NMR (400 MHz, CDC1₃) δ 7.39 (t, 1H), 7.33 (d, 1H), 7.12 (s, 1H), 7.08 (d, 1H), 6.51 (s, 1H), 4.71 (s, 2H), 2.94 (s, 2H), 1.97 (s, 3H), 1.87 (s, 3H), 1.50 (s, 6H)。

The fourth step: (S) methyl 2- (6- ((3- (3,3,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (16 e)

(S)-methyl 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydro benzofuran-3-yl)acetate

At room temperature, (3- (3,3,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) methanol 16d (565 mg, 2mmol), (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3C (416 mg, 2mmol) and azobisformyldipiperidine (1.05 g, 4 mmol) were added to a dichloroformazan (30 mL) and tributylphosphine (809 mg, 4 mmol) was added dropwise. After the completion of the dropping, the reaction was completed in 2 hours. The reaction was concentrated to dryness and isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1). White solid 16e was obtained (472 mg, 50% yield).

The fifth step: (S)2- (6- ((3- (3,3,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 16)

Methyl (S)2- (6- ((3- (3,3,4, 6-tetramethyl-2, 3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 16e (472 mg, 1mmol) was suspended in methanol (10 mL) at room temperature, and a solution of sodium hydroxide (800 mg, 20 mmol) in water (l mL) was added to conduct a reaction at room temperature for 15 hours. The reaction was concentrated to 2mL, water (10 mL) was added, PH was adjusted to <4 with hydrochloric acid, extracted with ethyl acetate (10 mLx3), the organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate (1 g), concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2). Compound 16 was obtained as a white solid (220 mg, 48% yield, 97.96% HPLC purity).

MS m/z(ESI):459.3[M+l]

¾ NMR (400 MHz, CDC1₃) δ 7.37 (m, 2H), 7.18 (s, IH), 7.06(m, 2H), 6.50(m, 3H), 5.06(s, 2H), 4.76 (t, IH), 4.28 (dd, IH), 3.80 (m, IH), 2.94 (s, 2H), 2.83 (dd, IH), 2.63 (dd, IH), 1.96 (s, 3H)_:1.86 (s, 3H), 1.50 (s, 6H)。

Example 17

(S)2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 17)

(S)-2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acet ic acid

One step: (S) Ethyl 2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) carboxylate (17 a)

(S)-methyl 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzo furan-3-yl)acetate

Under a nitrogen atmosphere, 4e (180 mg, 0.71 mmol) of (3- (4,6-dimethyl-2, 3-dihydrobenzofuran-5-yl;) phenyl) methanol and 3D (162 mg, 0.78 mmol) of (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate were dissolved in dry dichloro-methyl alkyl (10 mL), tributylphosphine (315 mg, 1.56 mmol), li, Γ - (azodicarbonyl) dipiperidine (393 mg, 1.56 mmol) were added to the mixture, and the mixture was warmed to room temperature for 2 hours. The reaction mixture was filtered to remove insoluble substances, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 7/1) to give a pale yellow oil 17a (231 mg, yield 73%)

The second step is that: (S)2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 17)

Aqueous sodium hydroxide (5 mL, 2M) was added to a solution of methyl (S)2- (6- ((3- (4,6-dimethyl-2, 3-dihydrobenzofuran-5-yl;) benzyl;) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate 17a (231 mg, 0.52 mmol) in tetrahydrofuran (5 mL) and the reaction was stirred at room temperature overnight. Adjusting pH of the reaction solution to 2 or less with dilute hydrochloric acid, extracting with ethyl acetate (10 mL x3), combining organic phases, washing with saturated saline (50mL x l), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1.5/1) to obtain compound 17 (175 mg, yield 78%) as a white solid.

MS m/z(ESI):[M-l]": 429.3.^ NMR (400 MHz, CDC1₃) δ 12.22 (s, IH), 7.35 (t, IH), 7.29 (d, IH), 7.06― 6.98 (m, 2H), 6.95 (d, IH), 6.44 (s, IH), 6.41― 6.34 (m, 2H), 5.01 (s, 2H), 4.59 (t, IH), 4.44 (t, 2H), 4.10 (dd, IH), 3.59 (td, IH), 3.00 (t, 2H), 2.60 (dd, IH), 2.37 (d, IH), 1.79 (s, 3H), 1.74 (s, 3H).

Example 18

2- [ (3S) -6- [ [3- (7-fluoro-4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropan ] -5-yl;) phenyl ] methoxy ] -2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 18)

2-[(3 S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2, 1 '-cyclopropane]-5-yl)phenyl]methox y]- -dihydrobenzofuran-3-yl]acetic acid

The first step is as follows: 4-bromo-2-fluoro-3, 5-dimethylphenol (18 b)

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

4-bromo-3, 5-dimethylphenol 2A (5.0 g,24.8 mmol) and N-pyridine trifluoromethanesulfonate (15.3 g, 62.0 mmol) were added to a1, 2-dichloroethylene-base (50 mL) and reacted under reflux for 24 hours under a nitrogen atmosphere. After completion of the reaction, a saturated aqueous solution (50 mL) of sodium thiosulfate was added and the mixture was stirred for 5 minutes. The aqueous layer was extracted with a dichlorome alkyl (50 mi x2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to separate and purify (petroleum ether/dichlorome (v/v) = l/l) to obtain 4-bromo-2-fluoro-3, 5-dimethylphenol 18b as a yellow solid (2.1 g, yield 38.7%). The second step is that: 4-bromo-2-fluoro-3, 5-dimethylphenolacetate (18 c)

4-bromo-2-fluoro-3,5-dimethylphenyl ac

4-bromo-2-fluoro-3, 5-dimethylphenol (2.0 g, 9.1 mmol), acetic anhydride (1.4 g,1.37 mmol), triethylamine (1.39 g,1.37 mmol), and a dichlorosilane (30 mL) were sequentially added to a reaction flask and stirred at room temperature for 2 hours. After the reaction, water (50 mL) was added, the aqueous layer was extracted with a dichloroalkyl (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography for separation and purification (petroleum ether/dichloroalkyl (v/v) =10/l) to obtain 4-bromo-2-fluoro-3, 5-dimethylphenol acetate 18c as a pale yellow oil (2.4 g, yield 100%).

The third step: 1- (3-bromo-5-fluoro-⁶-hydroxy-²,⁴-dimethylphenyl) ethanone (18 d)

l-(3-bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl)ethanone

4-bromo-2-fluoro-3, 5-dimethylphenolacetate (2.35 g, 9.0 mmol), aluminum trichloride (3.6 g, 27.0 mmol) and 1, 2-di-chloroethyl (25 mL) were added to the reaction flask in this order, and the reaction was refluxed for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into ice water (200 mL), acidified to pH 3 with 6N hydrochloric acid, and the aqueous layer was extracted with a dichloromethane (200 mL > < 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/dichloroalkyl (v/v) =1/1) to give 1- (3-bromo-5-fluoro-6-hydroxy-2, 4-dimethylphenyl) ethanone 18d (0.91 g, 38% yield) as a yellow solid

¾ NMR (400 MHz, DMSO) δ 10.23 (t, 1Η), 2.45 (s, 3H), 2.29 (d, 3H), 2.14 (s, 3H).

The fourth step: 2-bromo-l- (3-bromo-5-fluoro-6-hydroxy-2, 4-dimethylphenyl) ethanone (18 e)

2-bromo-l-(3-bromo-5-fluoro-6-hydroxy-2, -dimethylphenyl)ethanone

1- (3-bromo-5-fluoro-6-hydroxy-2, 4-dimethylphenyl) ethanone 18d (900 mg, 3.45 mmol), copper bromide (1.15 g,5.17 mmol), chloroform (15 mL) and ethyl acetate (10 mL) were added to a reaction flask in this order, and the reaction was refluxed for 18 hours. After the reaction was completed, it was cooled to room temperature, filtered, washed with water (15 mL 1), the filtrate was collected, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Separating and purifying the residue by silica gel column chromatography (petroleum ether/dichloro-methyl-alkyl (v/v) = l/l) to obtain a brownish red solid crude product (1.17 g) of 2-bromo-1- (3-bromo-5-fluoro-6-hydroxy-2, 4-dimethylphenyl) ethanone 18e, and directly feeding the crude product to the next step for reaction. The fifth step: 5-bromo-7-fluoro-4, 6-dimethyl-benzofuran-3-one (18 f)

5-bromo-7-fluoro-4,6-dimethyl-benzofuran-3-one

To a reaction flask were added crude 2-bromo-1- (3-bromo-5-fluoro-6-hydroxy-2, 4-dimethylphenyl) ethanone 18e (1.17 g, 3.45 mmol), sodium acetate (848 mg, 10.34 mmol) and methanol (15 mL) in that order, and the mixture was stirred at room temperature for 3 days. After the reaction was completed, water (15 mL) was added, extraction was performed with ethyl acetate (15 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/diketazine (v/v) =2/l) to obtain 5-bromo-7-fluoro-4, 6-dimethyl-benzofuran-3-one 18f as a yellow solid (530 mg, total yield of the fourth step and the fifth step 59%).

And a sixth step: 5-bromo-7-fluoro-4, 6-dimethyl-spiro [ benzofuran-2, 1' -cyclopropan ] -3-one (18 g)

5-bromo-7-fluoro-4,6-dimethyl-spiro[b ropane]-3-one

Under the protection of anhydrous and oxygen-free nitrogen, 5-bromo-7-fluoro-4, 6-dimethyl-benzofuran-3-one 18f (530 mg,2.0 mmol) and anhydrous tetrahydrofuran (15 mL) are sequentially added into a reaction flask, sodium hydride (410 mg, 10.2 mmol) is added at-30 ℃, and the mixture is stirred for 20 minutes. The mixture is heated to room temperature and stirred for 20 minutes, then heated to 35 ℃, and 1, 2-dibromo-ethylene-alkyl (0.53 ml, 6.1 mmol) is slowly added dropwise and stirred for 10 minutes after the addition. The temperature was raised to 45 ℃ for 30 hours. At the end of the reaction, cool to 0 ℃, slowly add saturated aqueous ammonium chloride (15 mL), extract the aqueous layer with ethyl acetate (15 mi x4), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether/dichloro-methyl-alkyl (v/v) =2/1) to obtain 18g of 5-bromo-7-fluoro-4, 6-dimethyl-spiro [ benzofuran-2, 1' -cyclopropyl-3-one as a pink solid (260 mg, 45% yield). The seventh step: 7-fluoro-5- [3- (hydroxymethyl) phenyl ] -4, 6-dimethyl-spiro [ benzofuran-2, 1' -cyclopropan-3-one (18 h)

-fluoro-5-[3-(hydroxymethyl)phenyl]- -dimethyl-spiro[benzofuran-2, -cyclopropane]-3-one

Mixing 5-bromo-7-fluoro-4, 6-dimethyl-spiro [ benzofuran-2, gamma-cyclopropanol]18g of (250 mg,0.88 mmol) of (E) -3-ketone, and 160 mg,1.05 mmol of (3-hydroxymethylphenylboronic acid) are added into N, N-dimethylformamide (5 mL), 2M potassium carbonate aqueous solution (1.75 mL) is added, nitrogen is substituted for reaction, and [ I, Γ -bis (diphenylphosphino) ferrocene is added]Palladium dichloride (32 mg, 0.04 mmol) was reacted at 90 ℃ for 1 hour. After the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (30 mL) was added, the mixture was filtered, the mixture was washed with water (10 mi 3), the organic layer was dried over anhydrous sodium sulfate, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate: (petroleum ether/ethyl acetate) (10 mi 3))_vV) =4/l) 7-fluoro-5- [3- (hydroxymethyl) phenyl giving a yellow oily liquid]-4, 6-dimethyl-spiro [ benzofuran-2, 1' -cyclopropanol]-3-one 18h (220 mg, 81% yield).

Eighth step: methyl 2- [ (3S) -6- [ [3- (7-fluoro-4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropan-alkyl)]-5-yl) phenyl]Methoxy radical]-²3-dihydrobenzofuran-3-yl]Acetic acid methyl ester (18 i)

methyl2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl]methoxy]-2,3-dihydrobenzofura -3-yl]acetate

7-fluoro-5- [3- (hydroxymethyl) phenyl ] -4, 6-dimethyl-spiro [ benzofuran-2, Γ -cyclopropal ] -3-one 18h (220 rag, 0.71 raranol) was added to the dichloroalkyl (15 mL), methyl (S) 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (162.4 mg, 0.78 mmol), nitrogen replaced. 0. Tributylphosphine (0.39 mL, 1.56 mmol) and l, Γ - (azodicarbonyl) dipiperidine (393 mg, 1.56 mmol) were added sequentially under C, and stirred at room temperature for 3 hours. Filtering, and concentrating the filtrate under reduced pressure to obtain a light yellow oil-shaped crude product of methyl 2- [ (3S) -6- [ [3- (7-fluoro-4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cycloprophos-5-yl) phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid methyl ester 18i, which is directly used for the next step of reaction.

The ninth step: 2- [ (3S 6- [ [3- (7-fluoro-4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropalkan ] -5-yl;) phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid (compound 18)

2-[(3 S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2, 1 '-cyclopropane]-5-yl)phenyl]methox y]-2,3-dihydrobenzofuran-3-yl]acetic acid

Dissolving the crude methyl 2- [ (3S) -6- [ [3- (7-fluoro-4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropalkan ] -5-yl) phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid methyl ester 18i in a mixed solution of methanol (2 mL) and tetrahydrofuran (5 mL), adding 2M sodium hydroxide solution (1.7 mL; i, stirring at room temperature for 2 hours, concentrating under reduced pressure, adding water (10 mL) to the reaction solution, dropwise adding 1M dilute hydrochloric acid until the pH of the reaction solution is 3, extracting with ethyl acetate (15 mL x 3), combining organic phases and drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichlorosilane/methanol (v/v) =100/1) to obtain 2- [ (3S) -6- [ [3- (7-fluoro-4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cycloprophor ] -5-yl) phenyl ] methoxy ] -2-2, 3-dihydrobenzofuran-3-yl ] acetic acid compound 18 (225 rag, 65% total yield of eighth and ninth steps, 97.39%)

MS: 487.2[M-1]

¾ NMR (400 MHz, DMSO) δ 12.28 (s, 1H), 7.50 (m, 2H), 7.21 (s, 1H), 7.11 (m, 2H), 6.47 (dt, 2H),5.12 (s, 2H), 4.68 (t, IH), 4.18 (dd, IH), 3.67 (m, IH), 2.69 (dd, IH), 2.46 (m, IH), 2.18 (s, 3H), 1.97 (d, 3H), 1.86 (dd, , 2H), 1.47 (q, 2H).

Example 19

2- [ (3S) -6- [ [3- [2, 2-bis (hydroxymethyl) -4, 6-dimethyl-3-oxo-benzofuran-5-yl)]Phenyl radical]Methoxy radical]-2,3-dihydrobenzofuran pyridine-³-radical]Acetic acid (Compound I)⁹)

2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-di hydr

The first step is as follows: 5-bromo-2,2-bis [ [ tert-butyl (dimethyl) silylalkyl group]Oxymethyl radical]-4, 6-dimethyl-benzofuran-3-one (19a) 5-bromo-2,2-bis [ [ tert-butyl (dimethyl) lysine]oxymethyl]-4,6-dimethyl-benzofuran-3-one

To a reaction flask were added 5-bromo-2,2-bis (hydroxymethyl) -4, 6-dimethylbenzofuran-3 (2H) -one 5a (603 mg,2.0 mmol), methyl t-butylchlorosilicon alkyl (1.2 g, 8.0 mmol), imidazole (816 mg, 12.0 mmol), and Ν, Ν -dimethylformamide (8 mL) in that order, and stirred at room temperature for 30 minutes. After the reaction was completed, water (10 mL) and ethyl acetate (50 mL) were added, the layers were separated, the organic layer was washed with water p 0mL × 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 5-bromo-2,2-bis [ [ tert-butyl (dimethyl) silylalkanyl ] oxymethyl ] -4, 6-dimethyl-benzofuran-3-one 19a (1.05 g, 99% yield) as a pale yellow oil.

The second step is that: 2,2-bis [ tert-butyl (dimethyl) silylalkanyl ] oxymethyl ] -5- [3- (hydroxymethyl) phenyl ] -4, 6-dimethyl-benzofUran-3-one (19b)2,2-bis [ [ tert-butyl (dimethyl) lysine ] oxymethyl ] -5- [3- (hydroxymethyl) phenyl ] -4, 6-dimethyl-benzouran-3-one

5-bromo-2,2-bis [ [ tert-butyl (dimethyl) silylalkyl ] oxymethyl ] -4, 6-dimethyl-benzofuran-3-one 19a (1.0 g, 1.89 mmol), 3-hydroxymethylphenylboronic acid (344 mg, 2.27 mmol) were added to Ν, Ν -dimethylformamide (15 mL), 2M aqueous potassium carbonate solution (3.78 mL) was added, nitrogen substitution was performed, [ ih, Γ -bis (; diphenylphosphino) ferrocene ] palladium dichloride (69 mg,0.05 mmol) was added, and reaction was performed at 90 ℃ for 1 hour. After the reaction was completed, the reaction was cooled to room temperature, ethyl acetate (50 mL) was added, the mixture was filtered, the filtrate was washed with water (20 mL X3), the organic layer was dried over anhydrous sodium sulfate, 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) =10/1) to obtain 2,2-bis [ tert-butyl (dimethyl;) silylalkanyl ] oxymethyl ] -5- [3- (hydroxymethyl;) phenyl ] -4, 6-dimethyl-benzofuran-3-one 19b (1.03 g, 99% yield) as a yellow oil.

Microspheres NMR (400 MHz, DMSO). delta.7.45 (d, IH), 7.34 (s, IH), 7.03 (s, IH), 7.02 (s, IH), 6.92 (d, IH), 5.22 (t, IH), 4.57 (d, 2H), 3.92 (d, 4H), 2.16 (s, 3H), 2.04 (s, 3H), 0.72 (d, 18H), -0.00 (t, 12H). The third step: methyl-2- [ (3S) -6- [ [3- [2, 2-bis [ [ tert-butyl (dimethyl) silylalkanyl ] oxymethyl ] -4, 6-dimethyl-3-oxo-benzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid (19 c)

Methyl 2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-4,6-dimethyl-3-oxo-benzofumn

-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate

2,2-bis [ tert-butyl (dimethyl) silyl alkyl]Oxymethyl radical]-5- [3- (hydroxymethyl) phenyl]-4, 6-dimethyl-benzofuran-3-one 19b (105 g)_?1.88 mmol) was added to a double-barreled alkyl (20 mL), and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (396.4 mg,1.9 mmol), nitrogen substitution, 0, was added. Adding tributylphosphine (1.04 ml, 4.15 mmol) and I, gamma- (azodicarbonyl) dipiperidine (1.05 g, 4.15 mmol) in sequence under the condition of C, stirring at room temperature for 3 hours, filtering, concentrating the filtrate under reduced pressure, separating and purifying residues by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to obtain methyl-2- [ (3S) -6- [ [3- [2, 2-bis [ [ tert-butyl (dimethyl) silyl alkyl group ] of yellow oil]Oxymethyl radical]-4, 6-dimethyl-3-oxo-benzofuran-5-yl]Phenyl radical]Methoxy radical]-2,3-dihydrobenzofuran-3-yl]Acetic acid 19c (1.2 g, 87% yield).

The fourth step: 2- [ (3S) -6- [ [3- [2, 2-bis [ [ tert-butyl (dimethyl) silylalkanyl ] oxymethyl ] -4, 6-dimethyl-3-oxo-benzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid (19 d)

2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-4,6-dimethyl-3-oxo-benzoftiran-5-yl]phe nyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

Dissolving methyl-2- [ (3S) -6- [ [3- [2, 2-bis [ [ tert-butyl (dimethyl) silylalkanyl ] oxymethyl ] -4, 6-dimethyl-3-oxo-benzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid 19c (1.2 g, 1.6 mmol) in a mixed solution of methanol (3 mL) and tetrahydrofuran (9 mL), adding a 2M sodium hydroxide solution (2.2 mL), stirring at room temperature for 2 hours, concentrating under reduced pressure, adding water (10 mL) to the reaction solution, dropwise adding 1M dilute hydrochloric acid (5 mL), extracting with ethyl acetate (15 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2- [ pS) -6- [ [3- [2, 2-bis [ [ tert-butyl (dimethyl) silylalkanyl ] oxymethyl ] -4, 6-dimethyl-3-oxo-benzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid 19d (1.08 g) as a pale yellow oil.

The fifth step: 2- [ (3S) -6- [ [3- [2, 2-bis (hydroxymethyl) -4, 6-dimethyl-3-oxo-benzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid (Compound 19)

2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-di hydrobenzofuran-3-yl]acetic acid

The crude product of step 2- [ (3S) -6- [ [3- [2, 2-bis [ [ tert-butyl (dimethyl) silylalkanyl ] oxymethyl ] -4, 6-dimethyl-3-oxo-benzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid 19d (1.08 g, 1.47 mmol) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride trihydrate (2.32 g, 7.35 mmol) was added and stirred at room temperature for 45 minutes. After the reaction was complete, the reaction was quenched by addition of water (20 mL), the aqueous layer was extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1/1) to give pale yellow foamy 2- [ (3S) -6- [ [3- [2, 2-bis (hydroxymethyl) -4, 6-dimethyl-3-oxo-benzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid compound 19 (470 mg, total yield in the fourth and fifth steps 63.4%, HPLC: 96.33%)

MS m/z(ESI): 527.3[M+23];503.2[M-1].

¾ NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.19 (s, 1H), 7.09 (m, 2H), 7.01 (d, 1H), 6.47 (dt, 2H), 5.10 (s, 2H), 5.03 (s, 2H), 4.67 (d, 1H), 4.18 (dd, 1H), 3.68 (m, 5H), 2.69 (dd, 1H), 2.46 (d, 1H), 2.14 (s, 3H), 2.01 (s, 3H).

Example 20

2- [ (3S) -6- [ [3- [4,6-dimethyl-3- (3-methanesulfonylpropylamino) -2,3-dihydrobenzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid (Compound 20)2- [ (3S) -6- [ [3- [4,6-dimethyl-3- (3-methylenepropyl) -2,3-dihydrobenzofuran-5-yl ] phenyl ] m ethoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid

The first step is as follows: 4, 6-dimethyl-5- [3- (tetrahydropyran-2-yloxymethyl) phenyl ] benzofuran-3-one (20 a)

4,6-dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]benzofuran-3-one

4, 6-dimethyl-5- (3-hydroxymethylphenyl) benzofuran-3-one 9a (1.30 g,4.8 mmol) was dissolved in a dichloroalkyl (20 mL), 3, 4-dihydropyran (0.5 mL, 5.8 mmol) and pyridinium p-toluenesulfonate (125 mg, 0.5 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (20 mL) was added, the aqueous layer was extracted with a dichloromethane (20 mL X3), 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) =5/1) to give 4, 6-dimethyl-5- [3- (tetrahydropyran-2-yloxymethyl;) phenyl ] benzofuran-3-one 20a as a pale yellow oil (1.59 g, 94% yield).

The second step is that: 4, 6-dimethyl-5- [3- (tetrahydropyran-2-yloxymethyl) phenyl ] -2, 3-dihydrobenzofuran-3-amine (20 b)

4,6-dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydrobenzofuran-3-amine

4, 6-dimethyl-5- [3- (tetrahydropyran-2-yloxymethyl) phenyl ] benzofuran-3-one 20a (563 mg, 1.6 mmol) and hydroxylamine hydrochloride (333 mg, 4.8 mmol) were added to methanol (10 mL), a solution of sodium hydroxide (211 mg, 5.28 mmol) in water (3 mL) was added to the reaction flask, and the mixture was reacted at 80 ℃ for 4 hours, concentrate under reduced pressure, add water (20 mL) and a dichloromethane (50 mL) to the residue, wash the organic layer with water (10 mL x 2), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, dissolve the residue again in methanol (10 mL), add nickel (120 mg), stir at room temperature for 24 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 (dichloromethane/methanol (v/v) =50/l) to give 4, 6-dimethyl-5- [3- (tetrahydropyran-2-yloxymethyl;) phenyl ] -2, 3-dihydrobenzofuran-3-amine 20b (240 mg, yield 68%) as a pale yellow oil.

The third step: 4, 6-dimethyl-N- (3-methanesulfonylpropyl) -5- [3- (tetrahydropyran-2-yloxymethyl) phenyl ] -2, 3-dihydrobenzofuran-3-amine (20 c)

4,6-dimethyl-N-(3-methylsulfonylpropyl)-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydro benzofuran-3 -amine

4, 6-dimethyl-5- [3- (tetrahydropyran-2-yloxymethyl) phenyl ] -2, 3-dihydrobenzofuran-3-amine 20b (240 mg, 0.68 mmol), 3- (methylsulfonyl) propyl 4-methylbenzenesulfonic acid (226 mg,0.82 mmol), and potassium carbonate (188 mg,1.36 mmol) were added to acetonitrile (10 mL) and reacted at 90 ℃ for 48 hours. After the reaction is finished, filtering, and concentrating the filtrate under reduced pressure to obtain a light yellow oily 4, 6-dimethyl-N-P-methylsulfonylpropyl) -5- [3- (tetrahydropyran-2-yloxymethyl) phenyl ] -2, 3-dihydrobenzofuran-3-amine 20c crude product which is directly used for the next reaction.

The fourth step: (3- (4, 6-dimethyl-3- ((3- (methylsulfonyl) propyl) amino) -2, 3-dihydrobenzofuran-5-yl;) phenyl) methanol (20d)

[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofumn-5-yl]phenyl]methanol

The crude product of the above step 4, 6-dimethyl-N-P-methanesulfonylpropyl) -5- [3- (tetrahydropyran-2-yloxymethyl) phenyl ] -2, 3-dihydrobenzofuran-3-amine 20c was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (3 mL), and 12N hydrochloric acid (1 mL) was added thereto, followed by stirring at room temperature for 30 minutes. Saturated sodium bicarbonate solution (15 mL) was added, extracted with ethyl acetate (15 mL x 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 (dichloromethy =60/l) (3- (4, 6-dimethyl-3- ((3- (methylsulfonyl) propyl) amino) -2, 3-dihydrobenzofuran-5-yl;) phenyl) methanol 20d (175 mg, 66% total yield in the third and fourth steps) as a pale yellow oil.

The fifth step: methyl 2- [ (3S) -6- [ [3- [4,6-dimethyl-3- (3-methanesulfonylpropylamino) -2,3-dihydrobenzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetate (20 e)

methyl2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]ph enyljmethoxy]-2,3-dihydrobe

(3- (4, 6-dimethyl-3- ((3- (methylsulfonyl) propyl) amino) -2, 3-dihydrobenzofuran-5-yl) phenyl) methanol 20D (167 rag, 43 mrnol) was added to the dichloro-methyl-alkyl (10 mL), methyl (S) 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (98.3 mg, 0.47 mmol), nitrogen substitution, 0. Under C, tributylphosphine (0.24mL, 0.94 mmol) and I, Γ - (azodicarbonyl) dipiperidine (238 mg, 0.94 mmol) were added sequentially and stirred at room temperature for 2 hours. Filtering, and concentrating the filtrate under reduced pressure to obtain a light yellow oily methyl 2- [ (3S) -6- [ [3- [4,6-dimethyl-3- (3-methylsulfonylpropylamino) -2, 3-dihydrobenzofuran-5-yl: phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetate 20e crude product which is directly used for the next reaction.

And a sixth step: 2- [ (3S) -6- [ [3- [4,6-dimethyl-3- (3-methanesulfonylpropylamino) -2,3-dihydrobenzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid (Compound 20)

2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]phenyl]m ethoxy]-2,3-dihydrobenzofura -3-yl]acetic acid

Adding the crude methyl 2- [ (3S) -6- [ [3- [4,6-dimethyl-3- (3-methanesulfonylpropylamino) -2,3-dihydrobenzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran pyridin-3-yl ] acetic acid methyl ester 20e obtained in the above step to tetrahydrofuran (6 mL) and methanol (3 mL), adding 2M sodium hydroxide solution (1.05 mL), stirring at room temperature for 2 hours, completing the reaction, adding 2M hydrochloric acid (1.5 mL), adding potassium phosphate to adjust pH to 6-7, adding water (10 mL), extracting with ethyl acetate (15 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue by silica gel column chromatography (dichloro-methyl-alkyl/methanol (v/v) =50/1) to obtain 2- [ (3S) -6- [ [3- [4,6-dimethyl-3- (3-methylsulfonylpropyl amino; 1-2, 3-dihydrobenzofuran-5-yl ] phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid compound 20 (170 mg, total yield of the fifth step and the sixth step 70%, HPLC:99.75

MS m/z(ESI):564.3[M-l].

¾ NMR (400MHz, DMSO) 57.44 (td,lH), 7.38 (d, IH), 7.08 (m,3H), 6.57 (s, IH), 6.47 (ddd,

2H) 5.09 (s, 2H), 4.67 (t, 1H),4.38 (m,3H), 4.18 (t, IH), 3.67 (m, IH), 3.13(dd, 2H), 2.92 (s, 3H), 2.69 (dd, IH), 2.59 (m, 2H), 2.46 (d, IH), 1.95 (d, 3H), 1.88 (s, 3H), 1.80 (m, 2H). example 21

2- [ (3S) -6- [ [5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropalkan ] -5-yl) -2-fluoro-phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid (Compound 21)

2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho -2,3-dihydrobenzofuran-3-yl]acetic acid

Under the protection of anhydrous and anaerobic nitrogen, 5-bromo-4, 6-dimethylbenzofuran-3 (2H) -ketone 2E (12.05 g and 50 mmol) is added into tetrahydrofuran (150 mL), sodium hydride (10 g and 60 percent wt and 250 mmol) is added at the temperature of-30 ℃, stirring is carried out for 30 minutes, the temperature is slowly increased to 35 ℃, stirring is carried out for 30 minutes, 1, 2-dibromoethane (13 mL and 150 mmol) is dropwise added, and the temperature is increased to 45 ℃ after the addition, and reaction is carried out for 24 hours. After the reaction was complete, it was cooled to-20 ℃ and quenched by slow addition of water (50 mL). Saturated aqueous ammonium chloride (50 mL) was added, extracted with ethyl acetate (80 mL x 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/macak (v/v) =1/1) to give 5-bromo-4, 6-dimethyl-spiro [ benzofuran-2, Γ -cyclopropyl-alkan ] -3-one 21a as a pink solid (8.78g, 65.8% yield).

Microspheres NMR (400 MHz, DMSO) δ 7.23 (s, 1 Η), 2.62 (s, 3H), 2.46 (s, 3H), 1.77 (q, 2H), 1.43 (q, 2H). 4, 6-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) spiro [ benzofuran-2, 1' -cyclopropan-3-one (21b)

4,6-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[benzofuran-2,l'-cyclopropane]-3- one

Adding 5-bromo-4, 6-dimethyl-spiro [ benzofuran-2, gamma-cyclopropanol ] -3-one 21a (5.34 g,20 mmol), diboronic acid pinacol ester (5.59 g, 22 mmol), [ I, gamma-bis (diphenylphosphino) ferrocene ] palladium dichloride-palladium-dichloro-methyl-alkyl complex (818 mg,1 mmol) and potassium acetate (5.89 g, 60 mmol) into an ethanol solution (100 mL), performing nitrogen substitution, and performing reflux reaction for 16 hours. After the reaction was completed, the reaction solution was slightly concentrated, water (100 mL) was added, and extraction was performed with a dichloromethane (100 mL × 3;, organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/dichloromethane (v/v) =1/1) to obtain 4, 6-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl;) spiro [ benzofuran-2, 1' -cyclopropane-3-one 21b (3.7 g, yield 59%) as a pale yellow solid.

¾ NMR (400 MHz, DMSO) δ 6.94 (s, 1Η), 2.60 (s, 3H), 2.42 (s, 3H), 1.71 (q, 2H), 1.37 (dd, 2H), 1.34 (s, 12H).

Third step 5-bromo-2-fluorobenzyl alcohol (2 Id)

(5-bromo-2-fluorophenyl)methanol

5-bromo-2-fluorobenzaldehyde 21C (1.015 g, 5.0 mmol) was dissolved in a mixed solution of methanol (5 mL) and tetrahydrofuran (10 mL), and sodium borohydride (378 mg, 10 mmol) was added at 0 ℃ and stirring was continued for 15 minutes after the addition. The reaction was quenched by the addition of water (10 mL). Slightly concentrating the reaction solution, adding saturated aqueous ammonium chloride (10 mL), extracting with ethyl acetate (20 mL x3;, combining the organic phases, sequentially washing with saturated aqueous ammonium chloride (50 mL x l), water (50 mL x l), combining the organic phases, and concentrating under reduced pressure to obtain 5-bromo-2-fluorobenzyl alcohol 21d (1.1 g, yield 99%) as a white solid, fourth step 5- [ 4-fluoro-3- (hydroxymethyl) phenyl ] -4, 6-dimethyl-spiro [ benzofuran-2, 1' -cyclopropyl-alkan ] -3-one (21e)

-[4-fluoro-3-(hydroxymethyl)pheny -4,6-dimethyl-spiro[benzofuran-2, -cyclopropane]-3-one

Adding 4, 6-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolane-2-yl) spiro [ benzofuran-2, Γ -cyclopropal ] -3-one 21b (628 mg,2.0 mmol) and 5-bromo-2-fluorobenzyl alcohol 21d (615 mg, 3.0 mmol) into Ν, Ν -dimethylformamide (5 mL), adding 2M potassium carbonate solution (5 mL), carrying out nitrogen substitution reaction, adding [ ih, Γ -bis (; diphenylphosphine;) ferrocene ] palladium dichloride (73 mg, 0.1 mmol), reacting at 90 ℃ for 1 hour, adding ethyl acetate, filtering, washing the filtrate with water (10 mL x 3), 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 5- [ 4-fluoro-3- (hydroxymethyl) phenyl ] -4, 6-dimethyl-spiro [ benzofuran-2, 1' -cyclopropal ] -3-one 21e (462 mg, 74% yield) as a yellow oil.

¾ NMR (400 MHz, DMSO) δ 7.23 (ddd , 2H), 7.11 (s, 1H), 7.10― 7.05 (m, 1H), 5.28 (t, 1H), 4.60 (d, 2H), 2.24 (s, 3H), 2.06 (s, 3H), 1.74 (q, 2H), 1.41 (q, 2H).

The fifth step: methyl 2- [ (3S) -6- [ [5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropal ] -5-yl) -2-fluoro-phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid methyl ester (21 f)

Methyl

2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho xy]-2,3-dihydrobenzofuran-3-yl]acetate

Adding 5- [ 4-fluoro-3- (hydroxymethyl) phenyl ] -4, 6-dimethyl-spiro [ benzofuran-2, 1' -cyclopropan-3-one into a reaction bottle in sequence

21e (300 rag, 0.96 ramoI), dichloromethyl alkyl (15 mL) and (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (210 mg, 1.01 mmol), under nitrogen protection, 0. And C, sequentially adding tributylphosphine (0.53 mL, 2.11 mmol) and I, gamma- (azodicarbonyl) dipiperidine (532 mg, 2.11 mmol), stirring at room temperature for 3 hours, filtering, and concentrating the filtrate under reduced pressure to obtain a light yellow oily methyl 2- [ (3S) -6- [ [5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropyl ] -5-yl ] -2-fluoro-phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid methyl ester 21f crude product which is directly used for the next step of reaction.

The sixth step 2- [ (3S) -6- [ [5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropan ] -5-yl;) -2-fluoro-phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid (Compound 21)

2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho xy]-2,3-dihydrobenzofuran-3-yl]acetic acid

Dissolving the crude methyl 2- [ (3S) -6- [ [5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropalkan ] -5-yl) -2-fluoro-phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid methyl ester 21f in a mixed solution of methanol (5 mL) and tetrahydrofuran (10 mL), adding 2M sodium hydroxide solution C2.4 mL, stirring at room temperature for 2 hours, concentrating under reduced pressure, adding water (10 mL) to the reaction solution, dropwise adding 1M dilute hydrochloric acid until the pH of the reaction solution is 1, extracting with ethyl acetate (15 mL x 3), combining organic phases and 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) =4: 1-dichloro-methyl-alkan/methanol (hi, =70: 1) to obtain a yellow vesicular 2- [ (3S) -6- [ [5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropyl-5-yl ];) -2-fluoro-phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid compound 21 (366 mg, 78% of the total yield of the fifth step and the sixth step), MS M/z (esi): 487.1M-lj.

Microsphere NMR (400 MHz, DMSO). delta.12.29 (s, 1H), 7.39-7.27 (m, 2H), 7.23-7.15 (m, 1H), 7.11 (t, 2H), 6.49 (dd, 2H), 5.14 (s, 2H), 4.68 (t, 1H), 4.19 (dd, 1H), 3.73-3.61 (m, 1H), 2.69 (dd, 1H), 2.47 (dd, 1H), 2.20 (s, 3H), 2.02 (s, 3H), 1.74 (dd, 2H), 1.41 (q, 2H). Example 22

2- [ (3S) -6- [ [ 2-chloro-5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropalkan ] -5-yl) phenyl ] methoxy ] -2-2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 22)

2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl]metho -2,3-dihydrobenzofuran-3-yl]acetic acid

22b 22c

The first step is as follows: (5-bromo-2-chlorophenyl) methanol (22 b)

(5-bromo-2-chlorophenyl)methanol

5-chloro-2-fluorobenzaldehyde (1.10 g, 5.0 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (10 mL), and sodium borohydride (378 mg, 10 mmol) was added at 0 ℃ and stirring was continued for 15 minutes after the addition. The reaction was quenched by addition of water (10 mL), the reaction was slightly concentrated, saturated ammonium chloride solution (10 mL) was added, extraction was performed with ethyl acetate (20 mL x 3), the organic phases were combined, washed successively with saturated ammonium chloride solution (50 mL x L) and water (50 mL x L), and the organic phase was concentrated under reduced pressure to give (5-bromo-2-chlorophenyl) methanol 22b as a white solid (1.15 g, 99% yield).

The second step is that: 5- (4-chloro-3- (hydroxymethyl) phenyl) -4, 6-dimethyl-3H-spiro [ benzofuran-2, 1' -cyclopropan ] -3-one (22 c)

5-(4-chloro-3-(hydroxymethyl)phenyl)- -dimethyl-3H-spiro[benzofuran-2,l'-cyclopropan]-3-one

Adding 4, 6-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolane-2-yl) spiro [ benzofuran-2, gamma-cyclopropa ] -3-one 21b (628 mg,2.0 mmol) and (5-bromo-2-chlorophenyl) methanol 22b (615 mg, 3.0 mmol) into N, N-dimethylformamide (5 mL), adding 2M potassium carbonate solution (5 mL), carrying out nitrogen substitution reaction, adding [ I, gamma-bis (; diphenylphosphine;) ferrocene ] palladium dichloride (73 mg, 0.1 mmol), reacting at 90 ℃ for 2 hours, adding ethyl acetate, filtering, washing the filtrate with water (lO mL x 3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate i N, =5/1) to obtain 5- (4-chloro-3- (hydroxymethyl;) phenyl group, 1-4, 6-dimethyl-3H-spiro [ benzofuran-2, 1' -cyclopropyl-3-one 22c (500 mg, 76% yield) as a yellow oil.

MS m/z(ESI):331.1 [M+]].

The third step: methyl 2- [ (3S) -6- [ [ 2-chloro-5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cycloprophos ] -5-yl) phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetic acid methyl ester (22 d)

methyl2-[(3S)-6-[ [2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,l'-cyclopropane]-5-yl)phenyl jmethoxy]-2,3-dihydro benzo

Adding 5- (4-chloro-3- (hydroxymethyl) phenyl) -4, 6-dimethyl-3H-spiro [ benzofuran-2, gamma-cycloproparaffin ] -3-one 22c (49() mg,1.49 rasanol) dichloro-methyl-alkan (15 mL), adding (S) methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate 3D (326 mg, 1.57 mmol, intermediate), adding tributylphosphine (0.82 mL, 3.28 mmol) and gamma, gamma- (azodicarbonyl) dipiperidine (828 mg, 3.28 mmol) under nitrogen protection and 0 ℃, stirring for 3 hours at room temperature, filtering, concentrating the filtrate under reduced pressure to obtain pale yellow oily methyl 2- [ (3S) -6- [ [ 2-chloro-5- ] Methyl (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropal-5-yl) phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetate 22d crude product, which is directly used for the next reaction.

And a sixth step: 2- [ (3S) -6- [ [ 2-chloro-5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cycloprophos ] -5-yl) phenyl ] methoxy ] -2-2, 3-dihydrobenzofuran-3-yl ] acetic acid (Compound 22)

2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl]metho xy]-2,3-dihydrobenzofuran-3-yl]acetic acid

Dissolving the crude product of methyl (methyl 2- [ (3S) -6- [ [ 2-chloro-5- (4, 6-dimethyl-3-oxo-spiro [ benzofuran-2, 1' -cyclopropalkan ] -5-yl) phenyl ] methoxy ] -2,3-dihydrobenzofuran-3-yl ] acetate 22d in a mixed solution of methanol (5 mL) and tetrahydrofuran (10 mL), adding 2M sodium hydroxide solution C3.7 mL, stirring at room temperature for 2 hours, concentrating under reduced pressure, adding water (10 mL) to the reaction solution, dropwise adding 1M dilute hydrochloric acid until the pH of the reaction solution is 1, extracting with ethyl acetate (15 mL x 3), combining organic phases and 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) =4: 1-dichloroalkan/methanol (v/v) =70: 1) to obtain the 2- [ (3S) -6- [ [ 2-chloro-5- (4, 6-dimethyl-3-oxo-spiro [ benzofurane-2, 1' -cyclopropane-5-yl) phenyl ] methoxy ] -2-2, 3-dihydrobenzofuran-3-yl ] acetic acid compound 22 (595 mg, 79% of the total yield of the fifth step and the sixth step) in yellow bubble shape.

MS m/z(ESI): 506,0! M+1],

^ NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 7.60 (d, 1H), 7.33 (s, 1H), 7.18 (dd, 1H), 7.11 (t,

2H) Biological test examples 6.47 (d, 2H), 5.16 (s, 2H), 4.68 (t, 1H), 4.24-4.16 (m, 1H), 3.75-3.60 (m, 1H), 2.69 (dd, 1H), 2.50-2.42 (m, 1H), 2.19 (s, 3H), 2.00 (s, 3H), 1.74 (dd, 2H), 1.41 (dd, 2H)

GPR40 luciferase reporter assay

The activity of the compounds of the invention was tested using the GPR40 luciferase reporter assay as follows: compounds were prepared in 10mM stock in DMSO and diluted in 3-fold gradients until use. Will stably express the strain

HEK293/GPR40/5x Gal4UAS-Luc +/Gal4-Elkl in the appropriate density inoculated in 96 well plate. The next day, when the cell confluence reaches about 70%, the medium is replaced by serum-free medium, and starvation is carried out overnight. On the third day, DMEM medium containing different concentrations of the test compound was added at 200. mu.1 per well and placed in a cell culture incubator 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: the compounds of the invention have significant agonist activity on human GPR 40. 2. Oral glucose tolerance test

The glucose lowering effect of the compounds of the present invention in glucose-loaded mice was evaluated using the Oral Glucose Tolerance Test (OGTT). The test procedure is 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 (Kyoto) 2009-0004. 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 reduction ratio of the 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 good hypoglycemic effect.

Claims

Claims

1. A compound shown in general formula (I) or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite and pharmaceutically acceptable salts

Wherein:

r is selected from 11 or-₈A alkyl group;

ring Q is selected from 5-to 8-membered carbocyclyl or heterocyclyl containing 1 to 4 Ν,0 or S (=0)_nAn atom or a group, wherein the carbocyclyl or heterocyclyl is optionally further substituted with 0 to 4 atoms selected from F, Cl, Br, I, =0, cyano, isocyano, amino, nitro, hydroxyl, carboxyl, alkyl, d — -)₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-S(=0)_n-R¹²or-NR¹³R^13aSubstituted with the substituent(s);

R¹and R⁴Each independently selected from F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxyl, carboxyl and d-₈Alkyl or C-alkyl(iii) oxo, wherein the alkyl, or amino groups are each independently optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -(CH₂)_m-S(=0)_n-R¹²、 -0-C(=0)-0-R¹²or-NR¹³R^13aSubstituted with the substituent(s); r²And R³Each independently selected from H, F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxyl, carboxyl and d-₈Alkyl or d-₈Alkanyl, wherein the alkanyl, alkanyl or amino groups are each independently optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Alkyl radical or d \₈Alkyl substituted by substituent of alkyl;

R⁵、 R⁶、 R⁷、 R⁸、 R⁹、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, alkanyl, d-)₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical, - (CH)₂)_m-alkenyl-R¹²、 -(CH₂)_m-alkynyl-R¹²、 -(CH₂)_m-NR¹³R^13a、 -(CH₂)_m-C(=0)-R¹²、 -(CH₂)_m-C(=0)-0-R¹²、 -(CH₂)_m-C(=0)-NR¹³R^13a、 -0-C(=0)-NR¹³R^13a、 -0-C(=0)-R¹²、 -0-C(=0)-0-R¹²、 -(CH₂)_mS(=0)_nR¹²、 -N(R^12b)C(=0)NR¹³R^13a、 -N(R^12b)C(=0)R¹²、 -N(R^12b)C(=0)OR¹²、 -(CH₂)_m- (3-to 10-membered carbocyclic group),

-(CH₂)_m- (3-to 10-membered heterocyclic group), -0- (CH)₂)_m- (3-to 10-membered carbocyclic group) or-0- (CH)₂)_m- (3-to 10-membered heterocyclic group) containing 1 to 4 of N, 0 or 3(=0)₁₁An atom or group, said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl group optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, alkanyl, d-)₈Alkyl radical or-d-₈alkyl-O-d-₈Alkyl substituent;

alternatively, R⁶And R⁷Can form (^ a or two ^ a)¹²!^²¹⁵;

As an alternative to this, the first and second,

alternatively, R⁶And R⁷、 R⁶And R⁸、 R⁶And R⁹、 R⁷And R⁸、 R⁷And R⁹、 R⁸And R⁹Can form a 3-to 8-membered carbocyclic ring or a 3-to 8-membered heterocyclic ring containing 1 to 4N, 0 or S (=0)_nAn atom or group, said carbocyclic or heterocyclic ring being optionally further substituted by 0 to 4R^12aSubstituted with the substituent(s);

R^12aselected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, Ci —₈Brick foundation, Ci—₈The foundation is an oxygen or Ci-₈Brick foundation-O-Ci₈A foundation;

R¹²and R^12bSelected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, mercapto, isocyano, amino, nitro, hydroxy, carboxyl, d-₈Radix Et rhizoma Rhei₈Alkyl, 3 to 10 membered carbocyclyl or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 40 or 3(=0)₁₁An atom or group, said alkyl, carbocyclyl or heterocyclyl group optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy, d —₈Radix Et rhizoma Rhei₈Alkyl radical or-d-₈alkyl-O-d-₈Alkyl substituent;

R¹³and R^13aSelected from H, F, Cl, Br, I, -CH₂F、 -CHF₂、 -CF₃Cyano, mercapto, isocyano, amino, nitro, hydroxy, carboxyl, d-₈Radix Et rhizoma Rhei₈Alkyl, 3 to 10 membered carbocyclyl or 3 to 10 membered heterocyclyl, said heterocyclyl containing 1 to 40 or 3(=0)₁₁An atom or group, said alkyl, carbocyclyl or heterocyclyl group optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, =0, -CH₂F、 -CHF₂、 -CF₃Cyano, isocyano, amino, nitro, hydroxy, carboxy,₈Radix Et rhizoma Rhei₈Alkyl radical, -d-₈alkyl-O-d-₈Alkyl radical or- (CH)₂)_mS(=0)_nR¹²Substituted with the substituent(s);

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 or 4;

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

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

R²and R³Each independently selected from H, F, Cl, Br or d \u₄A alkyl group;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br, I or d _₄And (5) priming.
3. The compound of claim 1, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein:

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-C alkyl or- (CH)₂)_m-NR¹³R^13a _;

Alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹Can be formed (=0);

alternatively, R⁶And R⁷、 R⁶And R⁸、 R⁶And R⁹、 R⁷And R⁸、 R⁷And R⁹、 R⁸And R⁹May form a 3 to 6 membered carbocyclic ring;

R¹³and R^13aIs selected from H or d-₆An alkyl group, which may be further selected from- (CH) by 0 to 2₂)_mS(=0)_nR¹²Substituted with the substituent(s);

R¹²is selected from 11 or-₆A alkyl group;

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

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

And ring Q may be further substituted by 0 to 3 groups selected from F, Cl, Br, I, =0, amino, hydroxy, d —)₆Alkyl or d-₆Alkyl group.
5. The compound according to claim 1, which is a compound represented by the following general formula (II) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein-

R is selected from 11 or ^ -11₄A alkyl group: ring Q is ^ and ring Q may be further substituted by 0 to 3 groups selected from F, =0, amino, hydroxy, d ^ -3₄Alkyl or CM alkyl substituent;

R¹selected from F, C1 or Br;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br or d \u₄A alkyl group;

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, -CH₂0H、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-C alkylOr- (CH)₂)_m-NR¹³R^13a;

Alternatively, R⁶And R⁷Can be formed (=0); alternatively, R⁶And R⁷、 R⁶And R⁸、 R⁶And R⁹、 R⁷And R⁸、 R⁷And R⁹、 R⁸And R⁹May form a 3 to 6 membered carbocyclic ring;

R¹³and R^13aSelected from H or d \u₄An alkyl group, which may be further selected from- (CH) by 0 to 2₂)_mS(=0)_nR¹²Substituted with the substituent(s);

R¹²is selected from 11 or-₄A alkyl group;

p is selected from 0, 1 or 2;

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

n is selected from 0, 1 or 2.
6. The compound according to claim 1, which is a compound represented by the general formula (in) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof

Wherein:

R⁵、 R^1Qand R¹¹Each independently selected from H, F, Cl, Br or d \u₄A alkyl group;

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-C alkyl or- (CH)₂)_m-NR¹³R^13a;

Alternatively, R⁶And R⁷Can form (= n)0);

Alternatively, R⁸And R⁹May form a 3-membered carbocyclic ring with the carbon atom to which it is attached;

R¹³and R^13aSelected from H or d \u₄An alkyl group, which may be further selected from- (CH) by 0 to 2₂)_mS(=0)_nR¹²Substituted with the substituent(s);

R¹²is selected from 11 or-₄A alkyl group;

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

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

wherein-R⁶、 R⁷、 R⁸And R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-C alkyl or- (CH)₂)_m-NR¹³R^13a;

Alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹May form a 3-membered carbocyclic ring with the carbon atom to which it is attached;

R¹³and R^13aSelected from H or d \u₄An alkyl group, which may be further selected from- (CH) by 0 to 2₂)_mS(=0)_nR¹²Substituted with the substituent(s);

R¹²is selected from 11 or ^ -11 ^ -3₄A 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, solvate, co-crystal, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein:

R⁶and R⁷Each independently selected from H, methyl, methoxy, ethoxy, -y^υOr is^N〜^S\_;

Alternatively, R⁶And R⁷Can be formed (=0);

R⁸and R⁹Each independently selected from H and-CH₂OH, methyl, or 0;

alternatively, R⁸And R⁹May form a 3-membered carbocyclic ring with the carbon atoms to which it is attached.
9. The compound according to claim 1, which is a compound represented by the general formula (V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:

(V)

wherein:

R⁴selected from H, F or C1;

R⁵、 R^1Qand R¹¹Each independently selected from H, F, CI or d \u₄A alkyl group;

R⁶、 R⁷、 R⁸and R⁹Each independently selected from H, -CH₂OH、 d_₄Alkyl radical, d _₄Alkyl radical, -d \u₄alkyl-O-d alkyl or- (CH)₂)_m-NR¹³R^13a;

Alternatively, R⁶And R⁷Can be formed (=0);

alternatively, R⁸And R⁹May form a 3-membered carbocyclic ring with the carbon atom to which it is attached;

R¹³and R^13aSelected from H or d \u₄An alkyl group, which may be further selected from- (CH) by 0 to 2₂)_mS(=0)_nR is substituted by a substituent; r¹²Selected from 11 or ^ -4 alkyl;

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

n is selected from 0, 1 or 2.
10. The compound of claim 9, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein:

R⁴selected from H, F or C1;

R⁵and R¹¹Is methyl;

R^1Qselected from H or F;

R⁶and R⁷Each independently selected from H, methyl, methoxy, ethoxy,' \ or⁵\, or R⁶And R⁷Forming (=0);

R⁸and R⁹Each independently selected from H and-CH₂OH, methyl,Or 0;

alternatively, R⁸And R⁹May form a 3-membered carbocyclic ring with the carbon atoms to which it is attached.
11. The compound according to claim 10, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

r and R⁷Is H or R⁶And R⁷Forming (=0);

R⁸and R⁹The carbon atom to which it is attached forms a 3-membered carbocyclic ring.
12. The compound of claim 1 or a stereoisomer, hydrate, ester, solvate, co-crystal, or salt thereof
13. A compound according to any one of claims 1 to 12, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the salt 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, 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, piperidine salt, N-ethylpiperidine salt, acetic acid salt, polyamine resin salts, phentermine salts, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, formates, acetates, glycolates, propionates, 2-hydroxypropionates, malonates, trifluoroacetates, methanesulfonates, ethanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, benzoate, phenylacetate, alginate, anthranilate, camphorate, maleate, tartrate, citrate, succinate, mandelate, fumarate, malate, oxalate, salicylate, glucuronate, galacturonate, citrate, aspartate, glutamate, cinnamate, or combinations thereof.
14. The compound of claim 13, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein the salt is selected from the group consisting of sodium salt, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochloride salt, hydrobromide salt, sulfate salt, phosphate salt, trifluoroacetate salt, acetate salt, maleate salt, aspartate salt, glutamate salt, malate salt, or a combination thereof.
15. A process for preparing a compound according to any one of claims 1 to 14, which process may be selected from process one, process two, process three or process four comprising the steps of:

the method comprises the following steps:the compound with the general formula (I-a) is converted into the compound with the general formula (I-b) through a Horner-Wadsworth-Emmons reaction or a wittig reaction, a reduction reaction and an alkanisation reaction in sequence; or the compound of the general formula (I-a) is converted into a compound of the general formula (I-b) through reduction elimination reaction;

l-b l-c

converting the compound of the general formula (I-b) into a compound of the general formula (I-c) through a suzuki coupling reaction and a reduction reaction;

the compound of the general formula (I-c) is converted into the compound of the general formula (I) through a Mitsunobu reaction and a hydrolysis reaction; or compounds of the general formula (I-c) are converted by the Mitsunobu reactionIs a compound of the general formula (I);

the second method comprises the following steps:

l-d l-e

the compound of the general formula (I-d) is converted into a compound of the general formula (I-e) through nucleophilic substitution reaction and claisen rearrangement reaction;

l-e l-f

converting the compound of the general formula (I-e) into a compound of the general formula (I-f) through epoxidation reaction and ring opening reaction; or compounds of the general formula (l-e) are reacted with I-f) compounds by nucleophilic substitution;

l-f compounds of general formula (I-f) are prepared by a suzuki coupling reaction of compounds of general formula (I-c); or the compound of the general formula (I-f) is converted into the compound of the general formula (I-c) through a suzuki coupling reaction and a hydrogenation reduction reaction;

the compound of the general formula (I-c) is converted into the compound of the general formula (I) through a Mitsimobu condensation reaction and a hydrolysis reaction; or the compound of the general formula (I-c) is converted into the compound of the general formula (I) through a Mitsimobu condensation reaction;

the third method comprises the following steps:

1-9 l-a

the compound of the general formula (I-g) is converted into a compound of the general formula (I-a) by an Adol reaction; or compounds of the general formula (I-g) by nucleophilic substitutionThe reaction is converted into a compound of the general formula (I-a);

radish a l-f

Converting the compound of the general formula (I-a) into a compound of the general formula (I-f) through reduction reaction; or the compound of the general formula (I-a) is converted into the compound of the general formula (I-f) through reduction reaction and dehydroxylation reaction;

l-f l-c

the compound of the general formula (I-f) is prepared by carrying out suzuki coupling reaction on the compound of the general formula (I-c); or the compound of the general formula (I-f) is converted into the compound of the general formula (I-c) through a suzuki coupling reaction and a hydrogenation reduction reaction

The compound of the general formula (I-c) is converted into the compound of the general formula (I) through a Mitsimobu condensation reaction and a hydrolysis reaction; or the compound of the general formula (I-c) is converted into the compound of the general formula (I) through a Mitsimobu condensation reaction;

the method four comprises the following steps:

l-a

converting the compound of the general formula (I-a) into a compound of the general formula (I-h) through a suzuki coupling reaction; or the compound of the general formula (I-a) is converted into the compound of the general formula I-h) through suzuki coupling reaction and hydrogenation reduction reaction;

the compound of the general formula (I-h) is converted into the compound of the general formula (1-I) by reductive amination;

the compound of the general formula (1-I) is converted into the compound of the general formula (I) through nucleophilic substitution reaction, Mitsimobu condensation reaction and hydrolysis reaction, or the compound of the general formula (I-I) is converted into the compound of the general formula (I) through Mitsimobu condensation reaction; wherein:

l is selected from F, Cl, Br or I;

R、 R¹, R²、 R³、 R⁴、 R⁵、 R⁶、 R⁷、 R⁸、 R⁹、 R¹⁰、 R^uq, p, Q and t are as defined in any one of claims 1 to 14;

R¹⁶、 R¹⁷and R¹⁸Selected from H, OH, methyl or ethyl.
16. A pharmaceutical composition, said composition comprising: an effective amount of a compound according to any one of claims 1 to 14, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, in combination with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient; may further comprise one or more other therapeutic agents.
17. The pharmaceutical composition of claim 16, 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) Is there a Is there a | A ^ agonists and partial agonists or pharmaceutically acceptable salts, and/or

(e PPAR ^ dual agonist or pharmaceutically acceptable salt, 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) Protein tyrosine phosphatase-1 BCPTP-1B) inhibitor or pharmaceutically acceptable salt, and/or

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

G) a-glucosidase inhibitor or a 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, thiazolyldiketones, glinides or pharmaceutically acceptable salts or prodrugs thereof, and/or

(r) PARP inhibitors.
18. The pharmaceutical composition of claim 17, wherein the GPR40 agonist is selected from fasiglifam hemihydrate (TAK-875) or a pharmaceutically acceptable salt or prodrug thereof.
19. The pharmaceutical composition of claim 17, wherein the DDP-IV inhibitor is selected from the group consisting of linagliptin (; linagliptin), omarigliptin (MK-3102), sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (alogliptin), saxagliptin (saxagliptin), denaglliptin (digagliptin), Carmegliptin, Melogliptin (Melogliptin), Dutogliptin, Teneligliptin (Trigliptin), Gemigliptin, or Trelagliptin, and the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, nonprolidek empagliflozin, ugliflozin, ipragliflozin, tolgliflogliflozilon; the PARP inhibitor is selected from the group consisting of benzafibrate, fenofibrate rate, pioglitazone, azelaic acid, rosiglitazone and saroglitazar.
20. The pharmaceutical composition of claim 17, wherein the biguanide therapeutic is selected from metformin or metformin; the therapeutic agent of the thiazole dione group is selected from Ciglitazone, Pioglitazone and Pioglitazone,

Rosiglitazone, Troglitazone, Farglitazar or Darglitazone, a sulfonylurea therapeutic agent selected from Glimepiride, Tolglybutamide, gliomuride, Glibenclamide, Gliquidone, Glipizide or gliclazide, a glinide therapeutic agent selected from Nateglinide, Repagide or Mitiglinid mitiglinide, a α -glucosidase inhibitor selected from Acarbose, Miglitoligold or Migliquid mitide, a GLP-1 analogue selected from Exendide or Liraglutide.
21. Use of a compound according to any one of claims 1 to 14 or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to any one of claims 16 to 20 for the preparation of a G protein-coupled receptor 40 agonist, in particular for the preparation of a pharmaceutical formulation for the treatment and/or prevention of a metabolic disease.
22. The use of claim 21, 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, 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, insulin allergy, glucose intolerance, skin disorders, atherosclerosis and its sequelae, diabetes mellitus, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or its sequelae, or hyperlipidemia, One or more of lameness, heart attack, or stroke.
23. The use of claim 22, wherein the metabolic disease comprises type II diabetes.
24. 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 1-14, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of any one of claims 16-20.
25. The method of claim 24, 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, 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, insulin allergy, glucose intolerance, skin disorders, atherosclerosis and its sequelae, diabetes mellitus, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or its sequelae, or hyperlipidemia, One or more of lameness, heart attack, or stroke.