Dihydrofuro-indole compound or derivative thereof and application of dihydrofuro-indole compound or derivative thereof

Abstract

The invention provides a dihydrofuro-indole compound with a structure as shown in a formula I, or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof, and application of the dihydrofuro-indole compound or the derivative thereof, or the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, or the solvate thereof, or the prodrug molecule thereof, or the deuteride thereof, or the tritide thereof. The dihydrofuro-indole compound or the derivative thereof provided by the invention is a compound with a novel structure, and the compound has relatively good inhibitory activity on urate oxidase and urate transporter protein, realizes XOR / URAT1 dual inhibition, has a good uric acid reducing effect, is good in safety, has a very good pharmacokinetic property, and can be used for preparing a medicine for treating uric acid. The compound is high in druggability, can be used for preparing uric acid reducing medicines, and is used for preventing and / or treating gout or hyperuricemia. # imgabs0 #

Description

[0001] This invention claims the priority of a Chinese patent application titled "Dihydrofuroindole Compounds or Their Derivatives and Their Applications" with the application number 2024101275857, which was filed with the Chinese Patent Office on January 30, 2024. The entire content of this application is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, and specifically relates to a class of dihydrofuroindole compounds or their derivatives and their applications. Background Art

[0003] Uric acid is the end product of purine metabolism in humans and non-human primate mammals, formed by the catalysis of xanthine by xanthine oxidase. Humans do not have uricase, and uric acid can only be excreted from the body through the intestines and kidneys in the end. Due to the popularity of Western diets, excessive purine intake through diet, a large number of cell deaths occurring in a short time (tumor lysis syndrome), and inefficient uric acid excretion pathways caused by genetic or environmental factors may all lead to hyperuricemia. A large amount of basic medical and clinical data shows that hyperuricemia itself is an independent high-risk factor, regardless of whether uric acid crystals are formed, and is related to the pathogenesis of various diseases in the body (such as diabetic nephropathy, other chronic kidney diseases, cardiovascular and cerebrovascular diseases). The normal value range of human blood uric acid is 3 - 6.0 mg / dl (180 - 360 μmol), and the solubility of uric acid is < 6.5 mg / dl (37 °C, pH 7.0). Exceeding this concentration may form crystals, and a decrease in pH value and temperature both promote crystal formation, depositing in the joints at the distal extremities of the limbs or other parts of the body (such as blood vessels, kidneys), causing damage to cells and inflammation, bringing great pain to patients and seriously affecting the quality of life of patients. Hyperuricemia accounts for 8% of the total population, and gout patients account for 4% of the total population. Among people over 60 years old, more than 10% of them will have gout attacks.

[0004] Currently, the main drugs used for reducing uric acid are as follows: allopurinol or febuxostat inhibits xanthine oxidase to reduce the production of uric acid; benzbromarone interferes with the reabsorption of uric acid in the kidneys to promote the excretion of uric acid; or for patients with refractory hyperuricemia, exogenous recombinant and modified uricase (even in combination with immunosuppressants) is used to degrade uric acid; or some single-target drugs targeting uric acid transporters, such as Lesinurad, which was approved in the United States in 2015 and withdrawn from the market in 2019, and Dotinurad, which is on the market in Japan.

[0005] Existing drugs and treatment methods all have their limitations. There is a huge unmet clinical need among the vast number of patients with hyperuricemia and gout. Therefore, it is necessary to develop new, safe and effective drugs for reducing uric acid. From the perspective of mechanism of action and pharmacokinetics, using a single molecule to simultaneously target the pathways of uric acid production (xanthine oxidase) and uric acid reabsorption (uric acid transporter URAT1, gene name SLC22A12) has more advantages than the strategy of targeting them separately. Pfizer developed an XOR / URAT1 dual inhibitor, namely the dual-target molecule PF-06743649, but it stalled at the first phase of clinical trials due to acute kidney injury in a small number of patients. Therefore, it is necessary to develop a new dual-target drug for reducing uric acid to benefit patients with high uric acid and relieve the burden on national medical payments. Summary of the Invention

[0006] In view of the above problems, the present invention provides a dihydrofuroindole compound or its derivative, which has good inhibitory activity against uricase and uric acid transporter, is an XOR / URAT1 dual inhibitor, and has a good effect on reducing uric acid.

[0007] The present invention includes the following technical solutions:

[0008] A dihydrofuroindole compound or its derivative having the structure shown in Formula I, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide,

[0009]

[0010] wherein, X is selected from: O, S, C(R 1 )2, NR 2 ;

[0011] Z and W are each independently selected from: CR 3 , N;

[0012] m and n are each independently selected from: 0, 1, 2, 3, and m + n is 2, 3 or 4;

[0013] Q is selected from: hydrogen, a C1-C6 alkyl group substituted or unsubstituted with one or more R 4 , a C1-C6 alkoxy group substituted or unsubstituted with one or more R 4 , a C1-C6 alkylthio group substituted or unsubstituted with one or more R 4 , halogen, cyano, aldehyde group, carboxyl group, nitro group, hydroxyl group, a C3-C8 cycloalkyl group substituted or unsubstituted with one or more R 5 , a C3-C8 cycloalkyl group substituted or unsubstituted with one or more R 5a substituted or unsubstituted 3-8 membered heterocyclic group, one or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 substituted or unsubstituted 5-10 membered heteroaryl,

[0014] L is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C6 alkyl, one or more R 4 Substituted or unsubstituted C1-C6 alkoxy, one or more R 4 Substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C8 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-8 membered heterocyclic group, one or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 substituted or unsubstituted 5-10 membered heteroaryl,

[0015] X 1 、X 2 are independently selected from: O, S, C(R 1 )2、NR 2 ;

[0016] Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N;

[0017] Each R 1 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen;

[0018] Each R 2 are independently selected from: hydrogen, C1-C6 alkyl;

[0019] Each R 3 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen;

[0020] Each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;

[0021] Each R 5Independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde group, carboxyl group, nitro, hydroxyl group;

[0022] Each R 6 Independently selected from: hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxyl group, mercapto group, amino group, R 5 Substituted or unsubstituted C6-C 10 Aryl, R 5 Substituted or unsubstituted 5-10-membered heteroaryl;

[0023] Each R is independently selected from: hydrogen, hydroxyl group, hydroxyamino group, amino group, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino group.

[0024] In some embodiments, the dihydrofuroindole compounds or their derivatives have the structure shown in Formula II:

[0025]

[0026] In some embodiments, the dihydrofuroindole compounds or their derivatives have the structures shown in Formula III-1, Formula III-2, Formula III-3, Formula III-4, Formula III-5, Formula III-6, Formula III-7, Formula III-8, Formula III-9, Formula III-10, Formula III-11, Formula III-12, Formula III-13, Formula III-14, Formula III-15, Formula III-16, Formula III-17 or III-18:

[0027]

[0028] In some embodiments, each R in Formula III-1 1 Is independently selected from: hydrogen, C1-C3 alkyl, halogen; each R in Formula III-8, Formula III-9, Formula III-10 2 Is independently selected from: hydrogen, C1-C3 alkyl.

[0029] In some embodiments, each R in Formula III-1 1 Is independently selected from: hydrogen, methyl, ethyl, fluorine, chlorine, bromine; each R in Formula III-8, Formula III-9, Formula III-10 2 Is independently selected from: hydrogen, methyl, ethyl.

[0030] In some embodiments, X1 , X 2 are each independently selected from: O, S, C(R 1 )2, NR 2 ;

[0031] Z 1 , Z 2 and Z 3 are each independently selected from: CR 3 , N;

[0032] Each R 1 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, bromine;

[0033] Each R 2 is each independently selected from: hydrogen, C1-C3 alkyl;

[0034] Each R 3 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen.

[0035] In some embodiments, X 1 is selected from: O, S, and X 2 is NR 2 , and R 2 is selected from: hydrogen, methyl, ethyl, propyl;

[0036] Z 1 , Z 2 and Z 3 One or two of them are N, and the others are CR 3 , and R 3 is selected from: hydrogen, methyl, ethyl, propyl. In some embodiments, each R 4 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group.

[0037] In some embodiments, each R 4 is each independently selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxanyl, pyrrolidinyl, thienyl.

[0038] In some embodiments, each R 5 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl.

[0039] In some of these embodiments, each R 5 is independently selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde group, carboxyl group, nitro group, hydroxyl group.

[0040] In some of these embodiments, each R 6 is independently selected from: hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, -C(=O)R, nitro group, hydroxyl group, mercapto group, amino group, R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl;

[0041] Each R is independently selected from: hydrogen, hydroxyl group, hydroxyamino group, amino group, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

[0042] In some of these embodiments, each R 6 is independently selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde group, carboxyl group, -C(=O)NHOH, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, nitro group, hydroxyl group, mercapto group, amino group, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furyl, thienyl, pyrrolyl, imidazolyl.

[0043] In some of these embodiments, Q is selected from: hydrogen, one or more R 4 substituted or unsubstituted C1-C3 alkyl, one or more R 4 substituted or unsubstituted C1-C3 alkoxy, one or more R 4 substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde group, carboxyl group, nitro group, hydroxyl group, one or more R 5 substituted or unsubstituted C3-C6 cycloalkyl, one or more R 5 substituted or unsubstituted 3-6 membered heterocyclic group, one or more R[[ID=|37]] 6 substituted or unsubstituted phenyl, one or more R 6Substituted or unsubstituted naphthyl, one or more Rs 6 Substituted or unsubstituted 5- or 6-membered heteroaryl,

[0044] X 1 , X 2 Are each independently selected from: O, S, C(R 1 )2, NR 2 ;

[0045] Z 1 , Z 2 And Z 3 Are each independently selected from: CR 3 , N;

[0046] Each R 1 Is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen;

[0047] Each R 2 Is each independently selected from: hydrogen, C1-C3 alkyl;

[0048] Each R 3 Is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen;

[0049] Preferably, each R 4 Is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy, C3-C6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0050] Preferably, each R 5 Is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy;

[0051] Preferably, each R 6 Is each independently selected from: hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5 Substituted or unsubstituted 5- or 6-membered heteroaryl;

[0052] Each R is independently selected from: hydrogen, hydroxy, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

[0053] In some of these embodiments, Q is selected from: hydrogen, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxanyl, pyrrolidinyl, tetrahydrothienyl, halogen-substituted pyrrolidinyl, hydroxy-substituted pyrrolidinyl, azetidinyl, halogen-substituted azetidinyl, hydroxy-substituted azetidinyl, one or more R 6 substituted or unsubstituted phenyl, one or more R 6 substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted pyridyl, one or more R 6 substituted or unsubstituted pyrazinyl, one or more R 6 substituted or unsubstituted pyridazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl,

[0054] Preferably, each R 6 is independently selected from: hydrogen, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, nitro, hydroxy, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl.

[0055] In some of these embodiments, Q is selected from: chlorine, bromine, aldehyde, cyano, difluoromethyl,

[0056] In some of these embodiments, Q is selected from: chlorine, bromine, aldehyde, cyano.

[0057] In some of these embodiments, Q is cyano.

[0058] In some of these embodiments, L is selected from: hydrogen, one or more R 4 substituted or unsubstituted C1-C3 alkyl, one or more R 4 substituted or unsubstituted C1-C3 alkoxy, one or more R4 Substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy, one or more R 5 Substituted or unsubstituted C3-C6 cycloalkyl, one or more R 5 Substituted or unsubstituted 3-6 membered heterocyclic group, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 Substituted or unsubstituted 5-6 membered heteroaryl,

[0059] X 1 、X 2 are each independently selected from: O, S, C(R 1 )2, NR 2 ;

[0060] Z 1 、Z 2 and Z 3 are each independently selected from: CR 3 、N;

[0061] Each R 1 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen;

[0062] Each R 2 is each independently selected from: hydrogen, C1-C3 alkyl;

[0063] Each R 3 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen;

[0064] Preferably, each R 4 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic group;

[0065] Preferably, each R 5 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy;

[0066] Preferably, each R 6 is each independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxy, mercapto, amino, R5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5 Substituted or unsubstituted 5- to 6-membered heteroaryl;

[0067] Each R is independently selected from: hydrogen, hydroxy, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

[0068] In some embodiments, L is selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxanyl, pyrrolidinyl, tetrahydrothienyl, halogen-substituted pyrrolidinyl, hydroxy-substituted pyrrolidinyl, azetidinyl, halogen-substituted azetidinyl, hydroxy-substituted azetidinyl, one or more Rs 6 Substituted or unsubstituted phenyl, one or more Rs 6 Substituted or unsubstituted naphthyl, one or more Rs 6 Substituted or unsubstituted pyridyl, one or more Rs 6 Substituted or unsubstituted pyrazinyl, one or more Rs 6 Substituted or unsubstituted pyridazinyl, one or more Rs 6 Substituted or unsubstituted pyrimidinyl,

[0069] Preferably, each R 6 is independently selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, nitro, hydroxy, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl.

[0070] In some embodiments, L is selected from:

[0071]

[0072] In some embodiments, L is selected from:

[0073]

[0074] In some embodiments, L is

[0075] In some embodiments, Q is selected from: halogen, aldehyde group, cyano group, oxygen-containing 3- to 5-membered heterocyclic group;

[0076] L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted pyridyl, one or more Rs 6 substituted or unsubstituted pyrazinyl, one or more Rs 6 substituted or unsubstituted pyrimidinyl, wherein each R 6 is independently selected from: hydrogen, methyl, ethyl, halogen, carboxyl group, hydroxyl group, tetrazolyl group, C(=O)NHOH.

[0077] In some embodiments, Q is selected from: chlorine, bromine, aldehyde group, cyano group,

[0078] L is selected from:

[0079] In some embodiments, Q is halogen, preferably chlorine or bromine;

[0080] L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted 5- to 6-membered heteroaryl,

[0081] each R 6 is independently selected from: hydrogen, hydroxyl group, carboxyl group, tetrazolyl group.

[0082] In some embodiments, Q is halogen, preferably chlorine or bromine; L is selected from: R 6 substituted or unsubstituted phenyl, R 6 substituted or unsubstituted pyridyl.

[0083] In some embodiments, Q is halogen, preferably chlorine or bromine; L is selected from:

[0084] In some embodiments, Q is a halogen, preferably chlorine or bromine; L is selected from:

[0085] In some embodiments, Q is a halogen, preferably chlorine or bromine; L is

[0086] In some embodiments, Q is a cyano group;

[0087] L is selected from: one or more R 6 substituted or unsubstituted phenyl, one or more R 6 .. substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted 5- or 6-membered heteroaryl,

[0088] Each R 6 is independently selected from: hydrogen, methyl, ethyl, hydroxy, carboxy, halogen, tetrazolyl, C(=O)NHOH.

[0089] In some embodiments, each R 6 is independently selected from: hydrogen, hydroxy, carboxy, tetrazolyl, C(=O)NHOH.

[0090] In some embodiments, Q is a cyano group; L is selected from: one or more R 6 substituted or unsubstituted phenyl, one or more R 6 substituted or unsubstituted pyridyl, one or more R 6 substituted or unsubstituted pyrazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl,

[0091] In some embodiments, Q is a cyano group; L is selected from: one or more R 6 substituted or unsubstituted pyridyl, one or more R 6 substituted or unsubstituted pyrazinyl,

[0092] In some embodiments, Q is a cyano group; L is selected from:

[0093] In some embodiments, Q is a cyano group; L is selected from:

[0094] In some embodiments, Q is an aldehyde group;

[0095] L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted 5- to 6-membered heteroaryl;

[0096] Each R 6 is independently selected from: hydrogen, hydroxyl, carboxyl, tetrazolyl.

[0097] In some embodiments, Q is an aldehyde group; L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted pyridyl, one or more Rs 6 substituted or unsubstituted pyrimidinyl.

[0098] In some embodiments, Q is an aldehyde group; L is selected from:

[0099] In some embodiments, Q is an aldehyde group; L is selected from:

[0100] The present invention also provides the use of the described dihydrofuroindole compounds or their derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, including the following technical solutions:

[0101] Use of the dihydrofuroindole compounds or their derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, or their deuterides, or their tritides described in the present invention in the preparation of XOR inhibitors and / or URAT1 inhibitors.

[0102] Use of the dihydrofuroindole compounds or their derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, or their deuterides, or their tritides described in the present invention in the preparation of anti-hyperuricemic drugs.

[0103] Use of the dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide of the present invention in the preparation of a drug for preventing and / or treating gout or hyperuricemia.

[0104] The present invention also provides an XOR / URAT1 dual inhibitor, the active ingredient of which contains the dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide of the present invention.

[0105] The present invention also provides a uric acid-lowering drug, which is characterized in that it is prepared from an active ingredient and a pharmaceutically acceptable carrier or excipient, and the active ingredient includes the dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide of the present invention.

[0106] The dihydrofuroindole compound or its derivative provided by the present invention is a novel class of compounds. This class of compounds has good inhibitory activities against both urate oxidase and urate transporter, is an XOR / URAT1 dual inhibitor, has a good uric acid-lowering effect, has good safety, has good pharmacokinetic properties, and has high drug-forming properties. It can be used to prepare uric acid-lowering drugs for preventing and / or treating gout or hyperuricemia. Description of the Drawings

[0107] Figure 1 Serum uric acid concentration in mice 8 hours after administration of Compound 4, Compound 12, and Compound 137-7. Detailed Description of the Invention

[0108] For the convenience of understanding the present invention, the present invention will be described more comprehensively below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the understanding of the disclosed content of the present invention more thorough and comprehensive.

[0109] The experimental methods without specific conditions noted in the following examples are generally in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. All kinds of commonly used chemical reagents used in the examples are commercially available products.

[0110] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the technical field to which the present invention pertains. The terms used in the description of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0111] In addition, as used in the present invention, the term "or" is an inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for other factors not described, unless the context clearly dictates otherwise. Further, throughout the specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in" includes "in" and "on".

[0112] In the compounds of the present invention, when any variable (e.g., R 4 、R 5 etc.) appears more than once in any component, its definition at each occurrence is independent of its definition at each other occurrence. Similarly, combinations of substituents and variables are permitted, provided that such combinations render the compound stable. The lines drawn from substituents into the ring system indicate that the indicated bond can be attached to any ring atom capable of substitution. If the ring system is polycyclic, it means that such a bond is attached only to any suitable carbon atom of an adjacent ring. It is to be understood that those of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by the techniques of the art and the methods set forth hereinafter. If a substituent itself is substituted by more than one group, it is to be understood that these groups can be on the same carbon atom or on different carbon atoms, provided that the structure is stable.

[0113] As used herein, the term "alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, the definition of "C1-C6 alkyl" for "C1-C6" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight-chain or branched-chain manner. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.

[0114] As used herein, the term "cycloalkyl" means a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon group whose ring atoms are composed of carbon atoms, and bicyclic or polycyclic includes spiro, fused, and bridged rings. For example: "cycloalkyl" includes, but is not limited to, the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0115] As used herein, the term "alkoxy" refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0116] As used herein, the term "heterocycloalkyl" or "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring substituent, wherein one or more ring atoms are heteroatoms selected from N, O or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Bicyclic or polycyclic rings include spiro rings, fused rings and bridged rings. For example: oxetanyl, azetidinyl, morpholinyl, piperidinyl, pyrrolidinyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and their N-oxides. The connection of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom.

[0117] As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S, and the aromatic ring can be monocyclic, bicyclic or polycyclic. For example, but not limited to: quinolinyl, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, etc.; "heteroaryl" is also understood to include any N-oxide derivative of a heteroaryl containing nitrogen. The connection of the heteroaryl can be achieved through a carbon atom or through a heteroatom.

[0118] As will be understood by those skilled in the art, as used herein, "halogen" or "halo" means chlorine, fluorine, bromine and iodine.

[0119] The present invention includes the free form of the compounds of formula I, as well as their pharmaceutically acceptable salts and stereoisomers. The pharmaceutically acceptable salts included not only include the exemplary salts of the specific compounds described herein, but also include the typical pharmaceutically acceptable salts of all free forms of the compounds of formula I. The free form of the specific salts of the compounds can be isolated using techniques known in the art. The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired salt form of an inorganic or organic acid in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0120] Accordingly, the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, trifluoroacetic acid, etc.

[0121] If the compound of the present invention is acidic, then the appropriate “pharmaceutically acceptable salts” refer to salts prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, said bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0122] Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.’ 1977:66:1-19 describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0123] Metabolites of the compounds and their pharmaceutically acceptable salts involved in the present invention, as well as prodrugs that can be converted in vivo into the structures of the compounds and their pharmaceutically acceptable salts involved in the present invention, are also included in the claims of the present invention.

[0124] The present invention also provides a pharmaceutical composition, which contains an active ingredient within a safe and effective amount range, as well as a pharmaceutically acceptable carrier or excipient.

[0125] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate.

[0126] "Safe and effective amount" means that: the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the active ingredient per dose, more preferably, it contains 10 - 200 mg of the active ingredient per dose. Preferably, the "per dose" is one tablet.

[0127] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage during administration is the pharmaceutically recognized effective dosage. For a person weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 20 - 500 mg. Of course, the specific dosage should also consider factors such as the administration route and the health condition of the patient, which are all within the scope of the skills of a skilled physician.

[0128] "Pharmaceutically acceptable carrier or excipient" means: one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0129] "Compatibility" here means that the components in the composition can be mixed with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0130] Some examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen - free water, etc.

[0131] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or polymer through non-bonding interactions. In another preferred embodiment, the compound of formula I of the present invention, as a small molecule, can also be connected to a macromolecular compound or polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0132] There is no particular limitation on the mode of administration of the active ingredient or pharmaceutical composition of the present invention. Representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0133] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0134] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or mixed with the following components:

[0135] (a) Fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0136] (b) Binders, such as hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0137] (c) Humectants, such as glycerol;

[0138] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0139] (e) Retardants, such as paraffin wax;

[0140] (f) Absorption accelerators, such as quaternary ammonium compounds;

[0141] (g) Wetting agents, such as cetyl alcohol and glycerol monostearate;

[0142] (h) Adsorbents, such as kaolin; and

[0143] (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form can also contain buffering agents.

[0144] The solid dosage forms can also be prepared with coatings and shell materials, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and the release of the active ingredient in such a composition can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances.

[0145] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweetening agents, flavoring agents and fragrances.

[0146] In addition to the active ingredient, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum monostearate and agar or mixtures of these substances, etc.

[0147] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0148] The compounds of the present invention can be administered alone, or in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I simultaneously. Drug combination also includes taking the compound of formula I and one or more other known drugs over overlapping time periods. When the compound of formula I is combined with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage when they are administered alone.

[0149] The present invention will be further illustrated below with reference to specific examples. It should be understood that these examples are only for illustrating the present invention and not for limiting the scope of the present invention. The experimental methods without specific conditions noted in the following examples are generally carried out under conventional conditions, or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0150] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the methods of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0151] The starting materials in the following examples can be obtained from commercial sources, or prepared by methods known in the art, or prepared according to the methods described herein.

[0152] Example 1 Preparation of Compound 1

[0153]

[0154] Step 1: Synthesis of 6-bromo-5-amino-1,3-dihydroisobenzofuran (Intermediate 1-1)

[0155] 5-Amino-1,3-dihydroisobenzofuran (20 g, 0.148 mol) and NBS (26.2 g, 0.148 mol) were added to acetonitrile (300 ml), and the mixture was stirred at 0°C for 4 hours. After concentration, water was added to the reaction mixture, and dichloromethane was added for extraction. The organic phase was dried and concentrated under reduced pressure to obtain an off-white solid product (30.6 g, 97%).

[0156] MS(ESI)calcd for C8H8BrNO:212.98; found:213.85, 215.85[M+1].

[0157] 1 H NMR (400MHz, CDCl3) δ7.28 (s, 1H), 6.64 (s, 1H), 4.97 (d, J = 1.2Hz, 2H), 4.99 (d, J = 1.2Hz, 2H), 4.08 (brs, 2H).

[0158] Step 2: Synthesis of 6-trimethylsilylene-5-amino-1,3-dihydroisobenzofuran (Intermediate 1-2)

[0159] 6-Bromo-5-amino-1,3-dihydroisobenzofuran (20 g, 93.9 mmol), trimethylsilylene (18.45 g, 187.8 mmol), CuI (894 mg, 4.7 mmol), and Pd(dppf)Cl2 (2.1 g, 2.82 mmol) were added to triethylamine (190 ml). The reaction was then allowed to react at 100°C for 12 hours. After concentration, the reaction mixture was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a yellow solid (17.4 g, 80.5%).

[0160] MS(ESI)calcd for C 13 H 17 NOSi:231.11; found:232.00[M+1].

[0161] 11H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 6.56 (s, 1H), 4.98 (s, 2H), 4.96 (s, 2H), 4.25 (brs, 2H), 0.26 (s, 9H).

[0162] Step 3: Synthesis of 5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 1-3)

[0163] In DMF (130 ml), 6-trimethylsilylethynyl-5-amino-1,3-dihydroisobenzofuran (15 g, 64.8 mmol) and CuI (24.7 g, 130 mmol) were added. Then the reaction was carried out at 120 °C for 1 hour. After concentration, the reaction was treated with water, extracted with dichloromethane, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a yellow solid product (5.2 g, 50.5%).

[0164] MS (ESI) calcd for C 10 H9NO: 159.07; found: 216.00 [M+1].

[0165] 1 1H NMR (400 MHz, CDCl3) δ 8.15 (brs, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 7.22 - 7.20 (m, 1H), 6.53 - 6.52 (m, 1H), 5.19 (s, 4H).

[0166] Step 4: Synthesis of 3-chloro-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 1-4)

[0167] In dichloromethane (10 ml), 5,7-dihydro-1H-furo[3,4-f]indole (400 mg, 2.5 mmol) and NCS (355 mg, 2.5 mmol) were added. Then the reaction was carried out at room temperature for 0.5 hour. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a yellow solid product (288 mg, 60%).

[0168] 1 1H NMR (400 MHz, CDCl3) δ 8.08 (brs, 1H), 7.45 (s, 1H), 7.19 (s, 1H), 7.17 (d, J = 2.8 Hz, 1H), 5.19 (s, 2H), 5.18 (s, 2H).

[0169] Step 5: Synthesis of Ethyl 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (Intermediate 1-5)

[0170] In DMF (5 ml), 3-chloro-5,7-dihydro-1H-furo[3,4-f]indole (230 mg, 1.2 mmol), Cs2CO3 (970 mg, 2.98 mmol), and ethyl 4-fluoro-2-(methoxymethyloxy)benzoate were added. Then the reaction was carried out at 80 °C for 12 h and cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a white solid product (430 mg, 89%).

[0171] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 7.31 (d, J = 2 Hz, 1H), 7.16 (dd, J = 8.4 and 2.0 Hz, 1H), 5.30 (s, 2H), 5.21 (s, 2H), 5.17 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.55 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[0172] Step 6: Synthesis of Ethyl 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (Intermediate 1-6)

[0173] In THF (4 ml), ethyl 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (430 mg, 1.2 mmol), EtOH (2 ml), and HCl (2.0 M, 2 ml) were added. Then the reaction was carried out at 65 °C for 1 h and cooled to room temperature. Filtration was carried out, and then it was washed with EtOH and H2O, and dried to obtain a white solid product (254 mg, 66%).

[0174] 1 H NMR (400 MHz, DMSO-D6) δ 10.85 (s, 1H), 7.98 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.51 (s, 1H), 7.25 - 7.22 (m, 2H), 5.09 (s, 2H), 5.08 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0175] Step 7: Synthesis of 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoic acid (Compound 1)

[0176] In THF (7 ml), ethyl 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (230 mg, 0.7 mmol), H2O (3.5 ml), and LiOH (298 mg, 7.1 mmol) were added. Then the reaction was carried out at room temperature for 48 hours, and then HCl (2.0 M) was added to acidify the pH of the reaction solution to 2. Ethyl acetate was added for extraction, the organic phase was washed with H2O, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid product (205 mg, 97%).

[0177] MS (ESI) calcd for C 17 H 12 ClNO4: 329.05; found: 328.05 [M - 1].[[]END]]

[0178] 1 H NMR (400 MHz, DMSO-D6) δ 7.99 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.22 - 7.19 (m, 2H), 5.09 (s, 4H).

[0179] Preparation of Compound 12 in Example 2

[0180]

[0181] Step 1: Synthesis of methyl 4-(3-cyano-......

[0182] For the synthesis of compound 3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 4-2), see Example 3.

[0183] In DMF (2.5 ml), 3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (80 mg, 0.43 mmol), Cs2CO3 (354 mg, 1.08 mmol), and methyl 4-fluoro-2-(methoxymethyloxy)benzoate (140 mg, 0.65 mmol) were added. Then the reaction was carried out at 85 °C for 12 hours and cooled to room temperature. Then the reaction was treated with water, ethyl acetate was added for extraction, the organic phase was dried and concentrated under reduced pressure, and then purified by column chromatography to obtain a white solid product (70 mg, 43%).

[0184] 1 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.4 and 2.0 Hz, 1H), 5.32 (s, 2H), 5.22 (s, 2H), 5.17 (s, 2H), 3.95 (s, 3H), 3.55 (s, 3H).

[0185] Step 2: Synthesis of methyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (Intermediate 12-2)

[0186] In THF (1 ml), methyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (65 mg, 0.17 mmol), EtOH (2 ml), and HCl (2.0 M, 0.5 ml) were added. Then the reaction was carried out at 70 °C for 4 h and cooled to room temperature. The mixture was filtered and then washed with EtOH and H2O, and dried to obtain a off-white solid product (40 mg, 70%).

[0187] 1 1H NMR (400 MHz, DMSO-D6) δ 10.80 (s, 1H), 8.64 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.65 (s, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.4 and 2.0 Hz, 1H), 5.09 (s, 2H), 5.06 (s, 2H), 3.92 (s, 3H).

[0188] Step 3: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoic acid (Compound 12)

[0189] In THF (15 ml), methyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (420 mg, 1.2 mmol), H2O (6.0 ml), and LiOH (506 mg, 12.1 mmol) were added. Then the reaction was carried out at room temperature for 48 h, and then HCl (2.0 M) was added to acidify the pH of the reaction mixture to 2. The resulting off-white solid product was filtered, washed with H2O and EtOH, and dried to obtain the target product (225 mg, 59%).

[0190] MS(ESI) calcd for C 18 H 12 N2O4: 320.08; found: 318.85 [M - 1].

[0191] 1 H NMR (400 MHz, DMSO - D6) δ 8.64 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.66 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 8.4 and 2.4 Hz, 1H), 5.10 (s, 2H), 5.07 (s, 2H).

[0192] Preparation of Compound 4 in Example 3

[0193]

[0194] Step 1: Synthesis of 3 - formyl - 5,7 - dihydro - 1H - furo[3,4 - f]indole (Intermediate 4 - 1)

[0195] In DMF (1.5 ml), 5,7 - dihydro - 1H - furo[3,4 - f]indole (131 mg, 0.82 mmol) and POCl3 (152 mg, 0.99 mmol) were added. Then the reaction was carried out at room temperature for 3 hours. Then an aqueous NaOH solution (2.0 M) was added to adjust the pH of the reaction solution to 11 - 12, and the mixture was heated to 70 °C and reacted for 0.5 hour. Ethyl acetate was added for extraction, and the organic phase was dried and concentrated under reduced pressure to dryness to obtain a red solid product (80 mg, 51%).

[0196] 1 H NMR (400 MHz, DMSO - D6) δ 12.11 (brs, 1H), 9.89 (s, 1H), 8.25 (d, J = 3.2 Hz, 1H), 7.95 (s, 1H), 7.39 (s, 1H), 5.05 (s, 4H).

[0197] Step 2: Synthesis of 3 - cyano - 5,7 - dihydro - 1H - furo[3,4 - f]indole (Intermediate 4 - 2)

[0198] In THF (1.5 ml), 3-formyl-5,7-dihydro-1H-furo[3,4-f]indole (80 mg, 0.42 mmol), hydroxylamine hydrochloride (60 mg, 0.84 mmol) and pyridine (0.2 ml) were added. Then the reaction was carried out at 80 °C for 4 hours. Then acetic anhydride (0.4 ml) was added and the reaction was carried out for 12 hours. Then an aqueous NaOH solution (2.0 M) was added at room temperature to adjust the pH of the reaction solution to 11 - 12, and ethyl acetate was added for extraction. The organic phase was dried and concentrated under reduced pressure to obtain a yellow solid product (70 mg, 90%).

[0199] Step 3: Synthesis of ethyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-benzoate (Intermediate 4-3)

[0200] In DMF (4 ml), 3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (200 mg, 1.1 mmol), Cs2CO3 (885 mg, 2.72 mmol), and ethyl 4-fluorobenzoate (274 mg, 1.63 mmol) were added. Then the reaction was carried out at 80 °C for 12 hours and cooled to room temperature. Then the reaction was treated with water, and ethyl acetate was added for extraction. After the organic phase was dried and concentrated under reduced pressure and then passed through a column, a white solid product (189 mg, 52%) was obtained.

[0201] MS(ESI) calcd for C 20 H 16 N2O3: 332.12; found: 333.00 [M + 1].[[]END]]

[0202] 1 H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.66 (s, 1H), 7.57 (d, J = 8.4 Hz 2H), 7.39 (s, 1H), 5.23 (s, 2H), 5.17 (s, 2H), 4.45 (q, J = 7.2 Hz, 2H), 1.4 (t, J = 7.2 Hz, 3H).

[0203] Step 4: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-benzoic acid (Compound 4)

[0204] In THF (2 ml), ethyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-benzoate (90 mg, 0.27 mmol), H2O (1.0 ml), and LiOH (68 mg, 1.63 mmol) were added. The reaction was then carried out at room temperature for 48 hours. Then, HCl (2.0 M) was added to acidify the pH of the reaction solution to 2. The resulting off-white solid product was filtered, washed with H2O and EtOH, and dried to obtain the target product (55 mg, 67%).

[0205] MS(ESI) calcd for C 18 H 12 N2O3: 304.08; found: 302.95 [M - 1].[[]END]]

[0206] 1 H NMR (400 MHz, DMSO - D6) δ 13.22 (brs, 1H), 8.66 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.64 (s, 1H), 5.11 (s, 2H), 5.07 (s, 2H).

[0207] Preparation of Compound 2 in Example 4

[0208]

[0209] Step 1: Synthesis of ethyl 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (Intermediate 2 - 1)

[0210] In DMF (3.0 ml), 3-formyl-5,7-dihydro-1H-furo[3,4-f]indole (200 mg, 1.07 mmol), Cs2CO3 (870 mg, 2.67 mmol), and ethyl 4-fluoro-2-(methoxymethyloxy)benzoate (366 mg, 1.6 mmol) were added. The reaction was then carried out at 80 °C for 12 hours and cooled to room temperature. Then, the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography (Hexane / EtOAc = 3 / 2) to obtain an off-white solid product (210 mg, 50%).

[0211] 11H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.23 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.37 (s, 1H), 7.22 (dd, J = 2.0 and 8.0 Hz, 1H), 5.32 (s, 2H), 5.22 (s, 2H), 5.17 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.55 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).

[0212] Step 2: Synthesis of methyl 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (Intermediate 2-2)

[0213] In THF (2 ml), ethyl 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (160 mg, 0.40 mmol), EtOH (1.0 ml), and HCl (2.0 M, 1.0 ml) were added. Then the reaction was carried out at 70 °C for 2 hours and cooled to room temperature. It was filtered, and then washed with EtOH and H2O, and dried to obtain a off-white solid product (108 mg, 76%).

[0214] 1 1H NMR (400 MHz, DMSO-D6) δ 10.87 (s, 1H), 10.03 (s, 1H), 8.66 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 2.0 and 8.4 Hz, 1H), 5.10 (s, 2H), 5.07 (s, 2H), 4.41 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0215] Step 3: Synthesis of 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoic acid (Compound 2)

[0216] In THF (4 ml), ethyl 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (250 mg, 0.71 mmol), H2O (2.0 ml), and LiOH (180 mg, 4.3 mmol) were added. The reaction was then carried out at room temperature for 48 hours. Then, HCl (2.0 M) was added to acidify the pH of the reaction solution to 2. The resulting off-white solid product was filtered, washed with H2O and EtOH, and dried to obtain the target product (219 mg, 95%).

[0217] MS (ESI) calcd for C 18 H 13 NO5: 323.08; found: 322.05 [M - 1].

[0218] 1 H NMR (400 MHz, DMSO-D6) δ 10.02 (s, 1H), 8.66 (s, 1H), 8.10 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.30 - 7.26 (m, 2H), 5.10 (s, 2H), 5.07 (s, 2H).

[0219] Preparation of Compound 21 in Example 5

[0220]

[0221] Step 1: Synthesis of 1-Boc-3-iodo-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 21-1)

[0222] In DMF (10 ml), 5,7-dihydro-1H-furo[3,4-f]indole (500 mg, 3.18 mmol), I2 (848 mg, 3.34 mmol), and KOH (268 mg, 4.77 mmol) were added. The reaction was then carried out at room temperature for 4 hours. Then, saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 were added to treat the reaction. Ethyl acetate was used for extraction. The organic phase was dried, concentrated under reduced pressure to dryness, and then dichloromethane (5 ml), DMAP (40.0 mg, 0.32 mmol), and Boc-anhydride (1.04 g, 4.77 mmol) were added. The reaction was then carried out at room temperature for 4 hours. Then, saturated aqueous NaHCO3 was added to treat the reaction. Ethyl acetate was used for extraction. The organic phase was dried, concentrated under reduced pressure to dryness, and then purified by column chromatography to obtain an off-white solid product (830 mg, 65%).

[0223] MS (ESI) calcd for C 15 H 16INO3: 385.02; found: 385.95 [M+1].

[0224] 1 H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.70 (s, 1H), 7.23 (s, 1H), 5.20 (s, 4H), 1.66 (s, 9H).

[0225] Step 2: Synthesis of methyl 4-(1-N-Boc-5,7-dihydro-1H-furo[3,4-f]indol-3-yl)-2-(methoxymethyloxy)benzoate (Intermediate 21-2)

[0226] In DMF (5 ml), 1-Boc-3-iodo-5,7-dihydro-1H-furo[3,4-f]indole (820 mg, 2.06 mmol), Na2CO3 (1.0 N, 4.2 ml, 4.2 mmol), Pd(PPh3)4 (238 mg, 0.21 mmol) and 3-(methoxymethyloxy)-4-methoxycarbonylphenylboronic acid pinacol ester (1.04 g, 3.08 mmol) were added. Then the reaction was carried out at 80 °C for 12 h and cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried by rotary evaporation, and then purified by column chromatography to obtain a white solid product (320 mg, 34%).

[0227] MS (ESI) calcd for C 25 H 27 NO7: 453.18; found: 454.10 [M+1].

[0228] 1 H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 5.33 (s, 2H), 5.23 (s, 2H), 5.20 (s, 2H), 3.93 (s, 3H), 3.56 (s, 3H), 1.70 (s, 9H).

[0229] Step 3: Synthesis of methyl 4-(5,7-dihydro-1H-furo[3,4-f]indol-3-yl)-2-(methoxymethyloxy)benzoate (Intermediate 21-3)

[0230] In MeOH (30 ml), methyl 4-(1-N-Boc-5,7-dihydro-1H-furo[3,4-f]indol-3-yl)-2-(methoxymethyloxy)benzoate (1.4 g, 3.09 mmol) and a methanol solution of KOH (0.1 M, 90 ml) were added. Then the reaction was carried out at 60 °C for 1 hour and cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure to dryness by rotary evaporation to obtain a brown solid product (1.05 g, 96%).

[0231] 1 H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.34 (dd, J = 1.6 and 8.0 Hz, 1H), 5.33 (s, 2H), 5.21 (s, 4H), 3.92 (s, 3H), 3.57 (s, 3H).

[0232] Step 4: Synthesis of methyl 4-{N-(oxetan-3-yl)-5,7-dihydro-1H-furo[3,4-f]indol-3-yl}-2-(methoxymethyloxy)benzoate (Intermediate 21-4)

[0233] In DMF (1.5 ml), methyl 4-(5,7-dihydro-1H-furo[3,4-f]indol-3-yl)-2-(methoxymethyloxy)benzoate (130 mg, 0.37 mmol), Cs2CO3 (300 mg, 0.92 mmol), and 3-iodooxetane (101 mg, 0.55 mmol) were added. Then the reaction was carried out at 80 °C for 12 hours and cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure to dryness by rotary evaporation and then purified by column chromatography to obtain an off-white solid (68 mg, 45%).

[0234] 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 5.62 - 5.55 (m, 1H), 5.34 (s, 2H), 5.24 - 5.20 (m, 6H), 5.15 - 5.11 (m, 2H), 3.92 (s, 3H), 3.57 (s, 3H).

[0235] Step 5: Synthesis of 4-{N-(oxetan-3-yl)-5,7-dihydro-1H-furo[3,4-f]indol-3-yl}-2-(methoxymethyloxy)benzoic acid (Compound 21)

[0236] In THF (1.0 ml), 4-{N-(oxetan-3-yl)-5,7-dihydro-1H-furo[3,4-f]indol-3-yl}-2-(methoxymethyloxy)benzoic acid methyl ester (35 mg, 0.08 mmol), H2O (0.5 ml), and LiOH (36 mg, 0.85 mmol) were added. Then the reaction was carried out at room temperature for 24 hours, and then HCl (2.0 M) was added to acidify the pH of the reaction solution to 2. Ethyl acetate was added for extraction, and the organic phase was dried and concentrated under reduced pressure to dryness to obtain the target product as a yellowish solid (25 mg, 76%).

[0237] MS(ESI) calcd for C 22 H 21 NO6: 395.14; found: 396.10 [M + 1].[[]END]]

[0238] 1 H NMR (400 MHz, DMSO-D6) δ 12.52 (brs, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.46 (dd, J = 1.6 and 8.0 Hz, 1H), 5.81 (pet, J = 7.2 Hz, 1H), 5.37 (s, 2H), 5.09 (s, 4H), 5.08 - 5.05 (m, 2H), 5.03 - 5.00 (m, 2H), 3.46 (s, 3H).

[0239] Preparation of Compound 24 in Example 6

[0240]

[0241] Step 1: Synthesis of ethyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (Intermediate 24-1)

[0242] In DMF (30 ml), 3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (2.0 g, 10.86 mmol), Cs2CO3 (8.8 g, 27.2 mmol), and ethyl 4-fluoro-2-(methoxymethyloxy)benzoate (3.7 g, 16.29 mmol) were added. Then the reaction was carried out at 85 °C for 12 hours and cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a off-white solid product (1.2 mg, 28%).

[0243] Step 2: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoic acid (Intermediate 24-2)

[0244] In THF (16 ml), ethyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (1.2 g, 3.06 mmol), H2O (8.0 ml), and LiOH (770 mg) were added. Then the reaction was carried out at room temperature for 48 hours, and then HCl (2.0 M) was added to acidify the pH of the reaction solution to 2. The resulting off-white solid product was filtered, washed with H2O and EtOH, and dried to obtain the target product (0.8 g, 72%).

[0245] Step 3: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3, 4-f]indol-1-yl)-2-(methoxymethyloxy)-N-(OTHP)benzamide (Compound 24-3)

[0246] In DMF (8 ml), 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoic acid (1.2 g, 3.3 mmol), DIPEA (1.28 g), HATU (2.5 g, 6.6 mmol), and NH2OTHP (580 mg, 4.95 mmol) were added. Then the reaction was carried out at room temperature for 20 hours, and then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a off-white solid product (1.1 g, 72%).

[0247] 11H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.38 (d, J = 8 Hz, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.4 and 2.0 Hz, 1H), 5.40 (s, 2H), 5.22 (s, 2H), 5.17 (s, 2H), 5.12 (d, J = 3.2 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.70 - 3.67 (m, 1H), 3.57 (s, 3H), 1.95 - 1.88 (m, 3H), 1.71 - 1.64 (m, 3H).

[0248] Step 4: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-N,2-dihydroxybenzamide (Intermediate 24-4)

[0249] 4-(3-Cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)-N-(OTHP)benzamide (1.1 g, 2.37 mmol), EtOH (6 ml), and HCl (2.0 M, 7 ml) were added to THF (12 ml). The mixture was then reacted at 70 °C for 4 h and cooled to room temperature. The resulting solid was filtered, washed with EtOH and H2O, and dried to obtain a white solid product (0.8 g, 99%).

[0250] MS (ESI) calcd for C 18 H 13 N3O4: 335.09; found: 333.90 [M - 1].[[]END]]

[0251] 1 1H NMR (400 MHz, DMSO-D6) δ 12.69 (brs, 1H), 11.58 (s, 1H), 8.59 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.19 - 7.16 (m, 2H), 5.08 (s, 2H), 5.06 (s, 2H).

[0252] Step 5: Synthesis of 1-(benzo[d]isoxazol-3(2H)-one-6-yl)-3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (Compound 24)

[0253] 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-N,2-dihydroxybenzamide (300 mg, 0.9 mmol) and CDI (218 mg) were added to THF (9 ml), and the reaction was carried out at 70 °C for 4 h. Then the reaction was quenched with water, extracted with ethyl acetate, washed with HCl (1 M), dried, concentrated under reduced pressure and dried by rotary evaporation, and then purified by column chromatography to obtain a pale white solid product (115 mg, 40%).

[0254] MS(ESI) calcd for C 18 H 11 N3O3: 317.08; found: 315.95 [M - 1].

[0255] 1 H NMR (400 MHz, DMSO - D6) δ 12.69 (brs, 1H), 11.29 (s, 1H), 8.59 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 2 Hz, 1H), 7.76 (dd, J = 8.4 and 2.0 Hz, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 5.10 (s, 2H), 5.07 (s, 2H).

[0256] Preparation of Compound 59 in Example 7

[0257]

[0258] Step 1: Synthesis of 5-iodo-6-amino-2,3-dihydrobenzofuran (Intermediate 59-1)

[0259] 6-Amino-2,3-dihydrobenzofuran (0.9 g, 6.66 mmol) and NIS (1.95 g, 8.66 mmol) were added to acetonitrile (12 ml), and the reaction was stirred at 0 °C for 4 h. After concentration, the reaction was quenched with water, extracted with dichloromethane, the organic phase was dried and concentrated under reduced pressure, and then purified by column chromatography to obtain a pale yellow solid product (1.47 g, 86%).

[0260] 1 H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 6.27 (s, 1H), 4.53 (t, J = 8.4 Hz, 2H), 4.01 (s, 2H), 3.10 (t, J = 8.4 Hz, 2H).

[0261] Step 2: Synthesis of 5-(trimethylsilyl)ethynyl-6-amino-2,3-dihydrobenzofuran (Intermediate 59-2)

[0262] In triethylamine (19 ml), 5-iodo-6-amino-2,3-dihydrobenzofuran (1.5 g, 5.75 mmol), trimethylsilylacetylene (2.8 g, 28.74 mmol), CuI (2.2 g, 11.5 mmol), and Pd(dppf)Cl2 (1.3 g, 1.73 mmol) were added. Then the reaction was carried out at 100 °C for 24 hours. After concentration, the reaction was treated with water, extracted with dichloromethane, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then passed through a column to obtain a yellow solid product (1.3 g, 98%).

[0263] 1 H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 6.15 (s, 1H), 4.53 (t, J = 8.4 Hz, 2H), 4.20 (s, 2H), 3.06 (t, J = 8.4 Hz, 2H), 0.24 (m, 9H).

[0264] Step 3: Synthesis of 3,7-dihydro-2H-furo[3,2-f]indole (Intermediate 59-3)

[0265] In DMF (26 ml), 5-trimethylsilylacetylene-6-amino-2,3-dihydrobenzofuran (1.3 g, 5.63 mmol) and CuI (1.6 g, 8.44 mmol) were added. Then the reaction was carried out at 120 °C for 2 hours. After concentration, the reaction was treated with water, extracted with dichloromethane, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then passed through a column to obtain a yellow solid product (292 mg, 32%).

[0266] 1 H NMR (400 MHz, CDCl3) δ 7.96 (brs, 1H), 7.39 (s, 1H), 7.06 - 7.04 (m, 1H), 6.79 (s, 1H), 6.44 - 6.42 (m, 1H), 4.60 (t, J = 8.4 Hz, 2H), 3.27 (t, J = 8.4 Hz, 2H).

[0267] Step 4: Synthesis of 5-formyl-3,7-dihydro-2H-furo[3,2-f]indole (Intermediate 59-4)

[0268] In DMF (1.5 ml), 3,7-dihydro-2H-furo[3,2-f]indole (80 mg, 0.5 mmol) and POCl3 (93 mg, 0.6 mmol) were added. Then the reaction was carried out at room temperature for 3 hours. Then an aqueous NaOH solution (2.0 M) was added to adjust the pH of the reaction solution to 11 - 12, and the mixture was heated to 70 °C and reacted for 0.5 hour. 2 M HCl was added to acidify the pH of the reaction solution to 2, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain a yellow solid product (55 mg, 59%).

[0269] LCMS calcd for C 11 H9NO2: 187.06; found: 188.00 [M + 1].

[0270] Step 5: Synthesis of 5-cyano-3,7-dihydro-2H-furo[3,2-f]indole (Intermediate 59-5)

[0271] In THF (1.0 ml), 5-formyl-3,7-dihydro-2H-furo[3,2-f]indole (55 mg, 0.29 mmol), hydroxylamine hydrochloride (41 mg, 0.59 mmol) and pyridine (0.1 ml) were added. Then the reaction was carried out at 80 °C for 4 hours. Then acetic anhydride (0.22 ml) was added and the reaction was carried out for 12 hours. Then an aqueous NaOH solution (2.0 M) was added at room temperature to adjust the pH of the reaction solution to 11 - 12, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain a yellow solid product (69 mg).

[0272] Step 6: Synthesis of tert-butyl 4-(5-cyano-2,3-dihydro-7H-furo[3,2-f]indol-7-yl)benzoate (Intermediate 59-6)

[0273] In DMF (7 ml), 5-cyano-3,7-dihydro-2H-furo[3,2-f]indole (250 mg, 1.36 mmol), Cs2CO3 (886 mg, 2.72 mmol) and tert-butyl 4-fluorobenzoate (293 mg, 1.49 mmol) were added. Then the reaction was carried out at 80 °C for 12 hours and cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure and purified by column chromatography to obtain a yellow solid product (184 mg, 38%).

[0274] MS(ESI) calcd for C 22 H 20 N2O3: 360.15; found: 361.25 [M + 1].

[0275] 11H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 2H), 7.67 (s, 1H), 7.57 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 6.90 (s, 1H), 4.65 (t, J = 8.4 Hz, 2H), 3.34 (t, J = 8.4 Hz, 2H), 1.63 (s, 9H).

[0276] Step 7: Synthesis of 4-(5-cyano-2,3-dihydro-7H-furo[3,2-f]indol-7-yl)benzoic acid (Compound 59)

[0277] To TFA (2 ml) was added tert-butyl 4-(5-cyano-2,3-dihydro-7H-furo[3,2-f]indol-7-yl)benzoate (90 mg, 0.25 mmol). The reaction was then carried out at room temperature for 2 hours, followed by concentration under reduced pressure and drying by washing with MeOH to obtain the target product (45 mg, 59%).

[0278] MS (ESI) calcd for C 18 H 12 N2O3: 304.08; found: 305.25 [M + 1].

[0279] 1 1H NMR (400 MHz, DMSO-D6) δ 8.47 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.57 (s, 1H), 7.00 (s, 1H), 4.60 (t, J = 8.4 Hz, 2H), 3.30 (t, J = 8.4 Hz, 2H).

[0280] Preparation of Compound 137 in Example 8

[0281]

[0282] Step 1: Synthesis of 6-bromo-5-amino-2,3-dihydrobenzofuran (Intermediate 137-1)

[0283] To acetonitrile (30 ml) was added 5-amino-2,3-dihydrobenzofuran (2.0 g, 14.8 mmol) and NBS (2.6 g, 14.8 mmol). The reaction was then stirred at 0 °C for 4 hours, concentrated, treated with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain a yellowish solid product (600 mg, 19%).

[0284] 11H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 6.68 (s, 1H), 4.50 (t, J = 8.4 Hz, 2H), 3.73 (brs, 2H), 3.10 (t, J = 8.4 Hz, 2H).

[0285] Step 2: Synthesis of 6-(trimethylsilylethynyl)-5-amino-2,3-dihydrobenzofuran (Intermediate 137-2)

[0286] To triethylamine (7 ml), 6-bromo-5-amino-2,3-dihydrobenzofuran (0.6 g, 2.8 mmol), trimethylsilylethyne (0.68 g, 7.01 mmol), CuI (534 mg, 2.8 mmol), and Pd(dppf)Cl2 (406 mg, 0.56 mmol) were added. Then the reaction was carried out at 80 °C for 48 h. After concentration, the reaction was treated with water, extracted with dichloromethane, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a white solid product (282 mg, 43%).

[0287] 1 1H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 6.60 (s, 1H), 4.47 (t, J = 8.8 Hz, 2H), 3.95 (brs, 2H), 3.12 (t, J = 8.4 Hz, 2H), 0.25 (s, 9H).

[0288] Step 3: Synthesis of 3,5-dihydro-2H-furo[2,3-f]indole (Intermediate 137-3)

[0289] To DMF (4 ml), 6-(trimethylsilylethynyl)-5-amino-2,3-dihydrobenzofuran (282 mg, 1.22 mmol) and CuI (465 mg, 2.44 mmol) were added. Then the reaction was carried out at 120 °C for 1 h. After concentration, the reaction was treated with water, extracted with dichloromethane, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a white solid product (170 mg, 87%).

[0290] 1 1H NMR (400 MHz, CDCl3) δ 7.97 (brs, 1H), 7.19 (s, 1H), 7.13 - 7.11 (m, 1H), 6.98 (s, 1H), 6.43 - 6.41 (m, 1H), 4.57 (t, J = 8.4 Hz, 2H), 3.29 (t, J = 8.4 Hz, 2H).

[0291] Step 4: Synthesis of 7-formyl-3,5-dihydro-2H-furo[2,3-f]indole (Intermediate 137-4)

[0292] In DMF (3 ml), 3,5-dihydro-2H-furo[2,3-f]indole (170 mg, 1.07 mmol) and POCl3 (197 mg, 1.28 mmol) were added. Then the reaction was carried out at room temperature for 3 hours. Then an aqueous NaOH solution (2.0 M) was added to adjust the pH of the reaction solution to 11 - 12, and the mixture was heated to 70 °C and reacted for 0.5 hour. 2 M HCl was added to acidify the pH of the reaction solution to 2, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain a red solid product (100 mg, 50%).

[0293] 1 H NMR (400 MHz, DMSO-D6) δ 11.92 (brs, 1H), 9.82 (s, 1H), 8.11 (d, J = 3.2 Hz, 1H), 7.32 (s, 2H), 4.51 (t, J = 8.4 Hz, 2H), 3.23 (t, J = 8.4 Hz, 2H).

[0294] Step 5: Synthesis of 7-cyano-3,5-dihydro-2H-furo[2,3-f]indole (Intermediate 137-5)

[0295] In THF (2.0 ml), 7-formyl-3,5-dihydro-2H-furo[2,3-f]indole (100 mg, 0.53 mmol), hydroxylamine hydrochloride (74 mg, 1.07 mmol) and pyridine (0.2 ml) were added. Then the reaction was carried out at 80 °C for 4 hours. Then acetic anhydride (0.4 ml) was added and the reaction was carried out for 12 hours. Then an aqueous NaOH solution (2.0 M) was added at room temperature to adjust the pH of the reaction solution to 11 - 12, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain a yellow solid product (98 mg, 99%).

[0296] 1 H NMR (400 MHz, DMSO-D6) δ 11.95 (brs, 1H), 8.05 (d, J = 3.2 Hz, 1H), 7.36 (s, 2H), 6.83 (s, 1H), 4.52 (t, J = 8.4 Hz, 2H), 3.24 (t, J = 8.4 Hz, 2H).

[0297] Step 6: Synthesis of tert-butyl 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)benzoate (Intermediate 137-6)

[0298] In DMF (4 ml), 7-cyano-3,5-dihydro-2H-furo[2,3-f]indole (300 mg, 1.63 mmol), Cs2CO3 (797 mg, 2.45 mmol), and tert-butyl 4-fluorobenzoate (384 mg, 1.96 mmol) were added. Then the reaction was carried out at 80 °C for 12 hours and cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a yellow solid product (400 mg, 68%).

[0299] 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.56 (s, 1H), 6.99 (s, 1H), 4.59 (t, J = 8.4 Hz, 2H), 3.27 (t, J = 8.4 Hz, 2H), 1.58 (s, 9H).

[0300] Step 7: Synthesis of 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid (Intermediate 137-7)

[0301] In TFA (2 ml), tert-butyl 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoate (130 mg, 0.36 mmol) was added. Then the reaction was carried out at room temperature for 2 hours, and then concentrated under reduced pressure and rotary evaporated, washed with H2O, and dried to obtain the target product (113 mg, 99%).

[0302] MS (ESI) calcd for C 18 H 12 N2O3: 304.08; found: 302.85 [M-1].

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.57 - 7.56 (m, 1H), 6.99 (s, 1H), 4.58 (t, J = 8.4 Hz, 2H), 3.27 (t, J = 8.4 Hz, 2H).

[0304] Step 8: Synthesis of 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid THP hydroxyamide (Intermediate 137-8)

[0305] In DMF (1 ml), 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid (50 mg, 0.16 mmol), HATU (125 mg, 0.33 mmol), DIPEA (64 mg, 0.49 mmol) and NH2OTHP (29 mg, 0.25 mmol) were added. Then the reaction was carried out at room temperature for 12 hours, and then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then passed through a column to obtain a pale white solid product (60 mg, 93%).

[0306] MS(ESI) calcd for C 23 H 21 N3O4: 403.15; found: 404.05 [M+1].[[]END]]

[0307] Step 9: Synthesis of 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzohydroxamic acid (Compound 137)

[0308] In AcOH (1.5 ml), 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid THP hydroxyamide (60 mg, 0.15 mmol), THF (0.5 ml) and water (0.5 ml) were added. Then the reaction was carried out at room temperature for 12 hours, filtered and washed with H2O and EtOH, and dried to obtain the target pale white solid product (40 mg, 84%).

[0309] MS(ESI) calcd for C 18 H 13 N3O3: 319.10; found: 320.00 [M+1].[[]END]]

[0310] 1 H NMR (400 MHz, DMSO-D6) δ 11.40 (s, 1H), 9.17 (s, 1H), 8.46 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.50 (s, 1H), 6.96 (s, 1H), 4.57 (t, J = 8.4 Hz, 2H), 3.26 (t, J = 8.4 Hz, 2H).

[0311] Preparation of Compound 22 in Example 9

[0312]

[0313] Step 1: Synthesis of 6-bromo-2,3-dihydro-1H-inden-5-amine (Intermediate 22-1)

[0314] In acetonitrile (30 mL), 2,3-dihydro-1H-inden-5-amine (2.0 g, 15 mmol) and NBS (2.67 g, 15 mmol) were added. Then the reaction mixture was stirred at 0 °C for 4 hours. After concentration, the reaction was treated with an aqueous solution of NaHCO3, extracted with dichloromethane, the organic phase was dried, concentrated under reduced pressure, and then purified by column chromatography to obtain a yellow solid product (1.38 g, 41%).

[0315] Step 2: Synthesis of 6-(trimethylsilylethynyl)-2,3-dihydro-1H-inden-5-amine (Intermediate 22-2)

[0316] In triethylamine (45 mL), 6-bromo-2,3-dihydro-1H-inden-5-amine (4.7 g, 20.98 mmol), trimethylsilylethyne (2.3 g, 23.08 mmol), CuI (400 mg, 2.1 mmol), and Pd(dppf)Cl2 (1.5 g, 2.1 mmol) were added. Then the reaction was carried out at 80 °C for 12 hours. After concentration, the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and evaporated to dryness, and then purified by column chromatography to obtain an off-white solid product (3.0 g, 62%).

[0317] 1 H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 6.59 (s, 1H), 4.10 (brs, 2H), 2.79 (t, J = 7.6 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.01 (pent, J = 7.6 Hz, 2H), 0.25 (s, 9H).

[0318] Step 3: Synthesis of 1,5,6,7-tetrahydrocyclopenta[f]indole (Intermediate 22-3)

[0319] In DMF (30 mL), 6-(trimethylsilylethynyl)-2,3-dihydro-1H-inden-5-amine (2.3 g, 10.09 mmol) and CuI (0.5 g) were added. Then the reaction was carried out at 120 °C for 2 hours. After concentration, the reaction was treated with water, extracted with dichloromethane, the organic phase was dried, concentrated under reduced pressure and evaporated to dryness, and then purified by column chromatography to obtain a yellow solid product (1.5 g, 73%).

[0320] 1 H NMR (400 MHz, CDCl3) δ 7.98 (brs, 1H), 7.45 (s, 1H), 7.23 (s, 1H), 7.13 - 7.12 (m, 1H), 6.47 - 6.46 (m, 1H), 3.00 - 2.96 (m, 4H), 2.12 (pent, J = 7.2 Hz, 2H).

[0321] Step 4: Synthesis of 3-formyl-1,5,6,7-tetrahydrocyclopenta[f]indole (Intermediate 22-4)

[0322] In DMF (10 ml), 1,5,6,7-tetrahydrocyclopenta[f]indole (700 mg, 4.46 mmol) and POCl3 (820 mg, 5.35 mmol) were added. Then the reaction was carried out at room temperature for 5 hours. Then an aqueous NaOH solution (2.0 M) was added to adjust the pH of the reaction solution to 11 - 12, and the mixture was heated to 70 °C and reacted for 0.5 hour. 2 M HCl was added to acidify the pH of the reaction solution to 2, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain a red solid product (700 mg, 85%).

[0323] MS (ESI) calcd for C 12 H 11 NO: 185.08; found: 185.85 [M+1].[[]END]]

[0324] 1 H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.76 (brs, 1H), 8.14 (s, 1H), 7.77 (d, J = 3.2 Hz, 1H), 7.26 (s, 1H), 3.03 - 2.97 (m, 4H), 2.13 (pent, J = 7.2 Hz, 2H).

[0325] Step 5: Synthesis of 3-cyano-1,5,6,7-tetrahydrocyclopenta[f]indole (Intermediate 22-5)

[0326] In THF (10.0 ml), 3-formyl-1,5,6,7-tetrahydrocyclopenta[f]indole (700 mg, 3.78 mmol), hydroxylamine hydrochloride (525 mg, 7.56 mmol) and pyridine (1.5 ml) were added. Then the reaction was carried out at 80 °C for 4 hours. Then acetic anhydride (2.0 ml) was added and the reaction was carried out for 12 hours. Then an aqueous NaOH solution (2.0 M) was added at room temperature to adjust the pH of the reaction solution to 11 - 12, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain a yellow solid product (700 mg, 99%).

[0327] 1 H NMR (400 MHz, DMSO-D6) δ 11.99 (brs, 1H), 8.10 (s, 1H), 7.41 (s, 1H), 7.35 (s, 1H), 2.93 (t, J = 7.2 Hz, 4H), 2.05 (pent, J = 7.2 Hz, 2H).

[0328] Step 6: Synthesis of Ethyl 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-(methoxymethyloxy)benzoate (Intermediate 22-6)

[0329] In DMF (10 ml), 3-cyano-1,5,6,7-tetrahydrocyclopenta[f]indole (700 mg, 3.84 mmol), Cs2CO3 (3.1 g, 9.6 mmol), and ethyl 4-fluoro-2-(methoxymethyloxy)benzoate (1.3 g, 5.77 mmol) were added. Then the reaction was carried out at 85 °C for 12 hours and cooled to room temperature. Then the reaction was treated with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a pale white solid product (600 mg, 40%).

[0330] MS (ESI) calcd for C 23 H 22 N2O4: 390.16; found: 391.00 [M+1].[[]END]]

[0331] 1 H NMR (400 MHz, DMSO-D6) δ 8.54 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.4 and 2.0 Hz, 1H), 5.38 (s, 2H), 4.32 (q, J = 6.8 Hz, 2H), 3.44 (s, 3H), 3.00 - 2.93 (m, 4H), 2.07 (pent, J = 7.6 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H).

[0332] Step 7: Synthesis of Ethyl 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-hydroxybenzoate (Intermediate 22-7)

[0333] In THF (1.5 ml), ethyl 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-(methoxymethyloxy)benzoate (300 mg, 0.77 mmol), EtOH (1 ml), and HCl (2.0 M, 1.5 ml) were added. Then the reaction was carried out at 70 °C for 1 hour and cooled to room temperature. The mixture was filtered, then washed with EtOH and H2O, and dried to obtain a pale white solid product (120 mg, 33%).

[0334] MS (ESI) calcd for C 21 H 18N2O3: 346.13; found: 346.85 [M+1].

[0335] 1 H NMR (400 MHz, DMSO-D6) δ 10.85 (s, 1H), 8.53 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.53 (s, 1H), 7.25 - 7.22 (m, 2H), 4.40 (q, J = 7.2 Hz, 2H), 2.98 - 2.93 (m, 4H), 2.06 (pent, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).

[0336] Step 8: Synthesis of 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-hydroxybenzoic acid (Compound 22)

[0337] In THF (1 ml), ethyl 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-hydroxybenzoate (100 mg, 0.27 mmol), H2O (0.5 ml), and LiOH (140 mg) were added. Then the reaction was carried out at room temperature for 72 hours. Then HCl (2.0 M) was added to acidify the pH of the reaction solution to 2. Ethyl acetate was added for extraction. The organic phase was washed with H2O, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid product (88 mg, 97%).

[0338] MS (ESI) calcd for C 19 H 14 N2O3: 318.10; found: 316.90 [M-1].

[0339] 1 H NMR (400 MHz, DMSO-D6) δ 8.52 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.53 (s, 1H), 7.21 - 7.18 (m, 2H), 2.98 - 2.93 (m, 4H), 2.09 - 2.02 (m, 2H).

[0340] Preparation of Compound 34 in Example 10

[0341]

[0342] Step 1: Synthesis of 3-bromo-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 34-1)

[0343] In dichloromethane (14 ml), 5,7-dihydro-1H-furo[3,4-f]indole (1.0 g, 6.37 mmol) and NBS (906 mg, 5.09 mmol) were added. Then the reaction was carried out at room temperature for 0.5 h. Then the reaction was quenched with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried by rotary evaporation, and then purified by column chromatography to obtain a off-white solid product (321 mg, 21%).

[0344] MS(ESI) calcd for C 10 H8BrNO: 236.98; found: 235.90, 237.90 [M - 1].

[0345] Step 2: Synthesis of ethyl 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (Intermediate 34-2)

[0346] In DMF (3 ml), 3-bromo-5,7-dihydro-1H-furo[3,4-f]indole (170 mg, 0.72 mmol), Cs2CO3 (584 mg, 1.79 mmol) and ethyl 4-fluoro-2-(methoxymethyloxy)benzoate (245 mg, 1.08 mmol) were added. Then the reaction was carried out at 80 °C for 12 h and cooled to room temperature. Then the reaction was quenched with water, extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure and dried by rotary evaporation, and then purified by column chromatography to obtain a off-white solid product (175 mg, 55%).

[0347] MS(ESI) calcd for C 21 H 20 BrNO5: 445.05; found: 446.00, 448.00 [M + 1].

[0348] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.4 and 2.0 Hz, 1H), 5.31 (s, 2H), 5.21 (s, 2H), 5.18 (s, 2H), 4.40 (q, J = 7.2 Hz, 1H), 3.54 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[0349] Step 3: Synthesis of ethyl 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (Intermediate 34-3)

[0350] In THF (3 ml), ethyl 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyloxy)benzoate (170 mg, 0.38 mmol), EtOH (2 ml), and HCl (2.0 M, 3 ml) were added. Then the reaction was carried out at 60 °C for 4 hours and cooled to room temperature. The mixture was filtered, then washed with EtOH and H2O, and dried to obtain a white solid product (150 mg).

[0351] MS(ESI)calcd for C 19 H 16 BrNO4: 401.03; found: 399.90, 401.90 [M - 1].

[0352] Step 4: Synthesis of 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoic acid (Compound 34)

[0353] In THF (2.3 ml), ethyl 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (100 mg, 0.25 mmol), H2O (1.0 ml), and LiOH (124 mg) were added. Then the reaction was carried out at room temperature for 72 hours, and then HCl (2.0 M) was added to acidify the pH of the reaction solution to 2. Ethyl acetate was added for extraction, the organic phase was washed with H2O, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a gray solid product (23 mg, 25%).

[0354] MS(ESI)calcd for C 17 H 12 BrNO4: 372.99; found: 371.85, 373.85 [M - 1].

[0355] 1 H NMR(400 MHz, DMSO - D6) δ 8.00 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 7.22 - 7.17 (m, 2H), 5.07 (s, 4H).

[0356] Preparation of Compound 35 in Example 11

[0357]

[0358] Step 1: Synthesis of 5-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-cyanopyridine (Intermediate 35 - 1)

[0359] In DMSO (10 ml), 3-formyl-5,7-dihydro-1H-furo[3,4-f]indole (500 mg, 2.67 mmol), 40% KF / Al2O3 (500 mg), 18-crown-6 (70 mg) and 5-fluoro-2-cyanopyridine (650 mg, 5.34 mmol) were added. Then the reaction was carried out in a sealed tube at 120 °C for 12 h and cooled to room temperature. Then water (30 ml) and ethyl acetate (10 ml) were added to treat the reaction. After filtration, it was washed with EtOH and dried to obtain a white solid product (550 mg, 71%).

[0360] MS (ESI) calcd for C 17 H 11 N3O2: 289.09; found: 287.95 [M-1].

[0361] Step 2: Synthesis of 1-(6-(tetrazol-1H-5-yl)pyridin-3-yl)-3-formyl-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 35-2)

[0362] In NMP (2.5 ml), 5-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-cyanopyridine (200 mg, 0.69 mmol), NaN3 (157 mg) and triethylamine hydrochloride (190 mg) were added. Then the reaction was carried out in a sealed tube at 120 °C for 12 h and cooled to room temperature. Then water was added to adjust the pH to 3.0, filtered, and then washed with MeOH and dried to obtain a brown solid product (100 mg, 43%).

[0363] MS (ESI) calcd for C 17 H 12 N6O2: 332.10; found: 330.90 [M-1].

[0364] 1 H NMR (400 MHz, DMSO-D6) δ 10.06 (s, 1H), 9.16 (brs, 1H), 8.77 (s, 1H), 8.47 (s, 2H), 8.12 (s, 1H), 7.62 (s, 1H), 5.11 (s, 2H), 5.07 (s, 2H).

[0365] Step 3: Synthesis of 1-(6-(tetrazol-1H-5-yl)pyridin-3-yl)-3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (Compound 35)

[0366] In HCO2H (1.0 ml), 1-(6-(tetrazol-1H-5-yl)pyridin-3-yl)-3-formyl-5,7-dihydro-1H-furo[3,4-f]indole (30 mg, 0.09 mmol), hydroxylamine hydrochloride (9 mg), and sodium formate (18 mg) were added. Then the reaction was carried out at 105 °C for 2 hours and cooled to room temperature. Then water was added, and the resulting brown solid product was filtered, recrystallized from DMF, and dried to obtain a light brown solid product (11 mg, 33%).

[0367] MS(ESI)calcd for C 17 H 11 N7O: 329.10; found: 327.90[M - 1].

[0368] 1 H NMR(400 MHz, DMSO - D6)δ9.13(s, 1H), 8.76(s, 1H), 8.44(s, 2H), 7.70 - 7.67(m, 2H), 5.10(s, 2H), 5.06(s, 2H).

[0369] Preparation of Compound 138 in Example 12

[0370]

[0371] Step 1: Synthesis of methyl 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)pyridine-2-carboxylate (Intermediate 138-1)

[0372] In DMF (2 ml), 7-cyano-3,5-dihydro-2H-furo[2,3-f]indole (200 mg, 1.09 mmol), Cs2CO3 (889 mg, 2.73 mmol), and methyl 5-fluoropyridine-2-carboxylate (253 mg, 1.63 mmol) were added. Then the reaction was carried out at 80 °C for 12 hours and cooled to room temperature. Then the reaction was treated with water, filtered, washed with H2O, and dried to obtain a yellow solid product (259 mg, 78%).

[0373] MS(ESI)calcd for C 18 H 13 N3O3: 319.10; found: 320.25[M + 1].

[0374] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.4 Hz, 1H), 8.62 (s, 1H), 8.34 (dd, J = 8.8 and 2.4 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.01 (s, 1H), 4.60 (t, J = 8.4 Hz, 2H), 3.94 (s, 3H), 3.27 (t, J = 8.4 Hz, 2H).

[0375] Step 2: Synthesis of 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylic acid (Intermediate 138-2)

[0376] To THF (1 ml) was added methyl 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylate (100 mg, 0.13 mmol) and LiOH (2.0 M, 1.9 ml). The reaction was then carried out at room temperature for 72 h, and then HCl (2.0 M) was added to acidify the reaction mixture to pH 2. The resulting off-white solid product was filtered, washed with H2O and EtOAc, and dried to obtain the target product (80 mg, 85%).

[0377] MS (ESI) calcd for C 17 H 11 N3O3: 305.08; found: 306.25 [M+1].

[0378] 1 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.4 Hz, 1H), 8.89 (s, 1H), 8.43 (dd, J = 8.8 and 2.4 Hz, 1H), 8.41 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 4.59 (t, J = 8.4 Hz, 2H), 3.31 (t, J = 8.4 Hz, 2H).

[0379] Step 3: Synthesis of 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)pyridine-2-carboxylic acid THP hydroxyamide (Intermediate 138-3)

[0380] In DMF (1 ml), 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylic acid (40 mg, 0.13 mmol), HATU (100 mg, 0.26 mmol), DIPEA (51 mg, 0.39 mmol) and NH2OTHP (23 mg, 0.20 mmol) were added. Then the reaction was carried out at room temperature for 12 hours, and then the reaction was quenched with water. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure and rotary evaporated, and then purified by column chromatography to obtain a yellow solid product (35 mg, 62%).

[0381] MS(ESI) calcd for C 22 H 20 N4O4: 404.15; found: 405.25 [M+1].

[0382] Step 4: Synthesis of 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)pyridine-2-carboxylic acid hydroxamic acid (Compound 138)

[0383] In AcOH (0.9 ml), 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylic acid THP hydroxamic acid (34 mg, 0.08 mmol), THF (0.3 ml) and water (0.3 ml) were added. Then the reaction was carried out at room temperature for 12 hours, concentrated under reduced pressure, and the reaction was quenched with water. After filtration, it was washed with H2O and EtOAc, and dried to obtain a white solid target product (18 mg, 70%).

[0384] MS(ESI) calcd for C 17 H 12 N4O3: 320.09; found: 321.25 [M+1].

[0385] 1 H NMR (400 MHz, DMSO-D6) δ 9.30 (s, 1H), 8.95 - 8.87 (m, 2H), 8.39 - 8.32 (m, 2H), 7.94 (d, J = 8.4 Hz, 1H), 6.97 (s, 1H), 4.61 (t, J = 8.0 Hz, 2H), 3.31 (t, J = 8.0 Hz, 2H).

[0386] Compounds 1 - 138 were prepared by referring to the preparation methods of Examples 1 - 12. The examples referred to in the preparation methods, as well as their structural formulas and characterization data, are shown in Table 1.

[0387] Table 1 Structural formulas, characterization data and preparation methods of Compounds 1 - 138

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399] Inhibition of the Activity of Xanthine Oxidase by the Compound of Example 13

[0400] Weigh 2 - 3 mg of the compound to be tested, including the positive control febuxostat, and dissolve it in DMSO to prepare a 10 mM stock solution. Then, perform gradient dilution to obtain 8 concentration gradients (500 μM, 50 μM, 5 μM, 500 nM, 250 nM, 50 nM, 5 nM, 0.5 nM) containing the same concentration of DMSO (5%).

[0401] The xanthine oxidase activity detection kit (MAK078 - 1KT) was purchased from the official website of the reagent supplier Merck. Homogenize mouse liver tissue (500 μl / 30 mg) with the detection buffer of this kit to obtain tissue homogenate containing mouse xanthine oxidase. After centrifugation at 10000 rpm for 10 min at 4°C, transfer the supernatant to a new centrifuge tube and place it on ice for later use.

[0402] Add 50 μl of tissue homogenate into a 96-well plate, add 2 μl of the test compound at the corresponding concentration, and then add 48 μl of the mixture containing other components of the kit. The total volume is 100 μl / well. Incubate at 25 °C for 3 minutes, excite at a wavelength of 535 nm, and read the excited fluorescence intensity at 587 nm (the more superoxide radicals generated due to the oxidation of hypoxanthine and xanthine by xanthine oxidase in the reaction system, the more Resorufin is generated through a chemical reaction with 10-acetyl-3,7-dihydroxyphenoxazine in the system, and the higher the excited fluorescence intensity, indicating the higher the activity of xanthine oxidase). Read dynamically every 3 minutes within 15 minutes at 25 °C. Use the wells without inhibitor as 100% xanthine oxidase activity, and the wells without enzyme as zero activity (background). After reading the plate, perform QC to confirm that the 12-minute point is within the linear range, analyze the inhibition efficiency at the 12-minute point, and obtain the IC of the test compound. 50 。

[0403] The test results are shown in Table 2: The dihydrofuroindole compounds or their derivatives of the present invention have a strong inhibitory effect on the activity of xanthine oxidase, and the inhibitory activities of some compounds are better than that of the positive drug febuxostat.

[0404] Table 2. Inhibitory results of compounds on xanthine oxidase activity

[0405]

[0406]

[0407] Inhibition of compound of Example 14 on urate transporter

[0408] Prepare concentration gradients of the test compound and the positive control (lesinurad) as in Example 13.

[0409] All cell culture media were purchased from Invitrogen, and plastic products were purchased from Corning. Since renal tubular epithelial cells express Urat1 and Glut9, such epithelial cells can be used for the detection of the activity of uric acid transporters. Mouse renal tubular epithelial cells were seeded on a cell culture transwell membrane with a pore size of 0.4 μm, and cultured until the cells completely covered the transwell, forming a monolayer cell membrane. Before detecting the test compound, the inner chamber of the transwell was replaced with DMEM basal medium containing a specific concentration of the test compound and 4.5 mg / dL uric acid. The bottom layer of the multi-well plate was replaced with DMEM basal medium without uric acid. Incubate at 37 °C for 60 min, remove 100 μL of the medium from the bottom layer of the multi-well plate, and read the uric acid concentration at 290 nm with an enzyme-linked immunosorbent assay reader. The wells without uric acid were used as blank controls, and the wells without the compound were used as 100% transport. The uric acid concentration in the wells corresponding to the test compound was compared with the concentration in the wells with 100% transport to obtain the inhibition efficiency.

[0410] The results showed that the inhibition rate of lesinurad on uric acid transporters at a concentration of 1000 nM was 23.63%; the inhibition rate of compound 12 on uric acid transporters at a concentration of 250 nM was 64.27%. It can be seen that the compounds of the present invention have good inhibitory activity on uric acid transporters, and their inhibitory activity on uric acid transporters at a concentration of 250 nM is higher than that of lesinurad at a concentration of 1000 nM.

[0411] Inhibition of Compounds in Example 15 on Uric Acid Transporters

[0412] In this example, a third party (Beijing ChemPartner Co., Ltd.) was commissioned to use HEK-293 cells (HEK293-hURAT1) that stably overexpressed human uric acid transporter (protein name URAT1, gene name SLC22A12) as a cell model for studying uric acid transport to determine the inhibitory activity of the compounds on human uric acid transporters. Prepare concentration gradients of the test compounds and positive controls (lesinurad) as in Example 13. All cell culture media were purchased from Invitrogen, and plastic products were purchased from Corning. C14-labeled uric acid was from VWR, USA. The specific operations are as follows:

[0413] Cells were pre-plated in 96-well plates. The next day, the medium was replaced with a medium pre-mixed with C14-labeled uric acid and different concentrations of positive controls or other test compounds. After incubation for 5 minutes, the medium was removed, and the cells were lysed with 0.1N NaOH. Then the supernatant was read using a Perkin Elmer liquid scintillation counter (model MicroBeta2). The reading of the wells with C14-labeled uric acid but without any compound added was defined as 100% uric acid transport, and the reading of the wells without C14-labeled uric acid added was the background reading. The inhibition efficiency of the positive control compounds or test compounds at different concentrations on the uric acid transporter was calculated to obtain the IC50.

[0414] The test results are shown in Table 3: The activity of compound 12 of the present invention in inhibiting the uric acid transporter was significantly higher than that of the positive control drug lesinurad. It can be seen that the compounds of the present invention have good inhibitory activity on the uric acid transporter.

[0415] Table 3 Inhibitory results of compounds on the uric acid transporter

[0416] Compound IC50 (nM) 12 8919 Lesinurad 48431

[0417] Pharmacodynamic test of compound in Example 16 for reducing uric acid in vivo

[0418] In this example, adult male Balb / c wild-type mice aged 8 - 12 weeks provided by Vital River Laboratories were divided into a control group (vehicle) and a dosing group (6 mice in each group) to test the pharmacodynamic effect of the compound in reducing uric acid in vivo. The specific experimental method is as follows:

[0419] Gavage administration was performed. The control group was given 0.5 ml of a solution of 1.2% 2-BP-β-CD (cyclodextrin) prepared with water, and the dosing group was given 0.5 ml of a solution containing 1.2% 2-BP-β-CD (cyclodextrin) and 1.6 mg / ml of the test compound prepared with water. After 7 hours, 15 hours, or 23 hours of dosing, 0.5 ml of a mixed solution containing 60 mg / ml of potassium oxonate (an inhibitor of uricase) and 6.67 mg / ml of hypoxanthine (a substrate of xanthine oxidase) prepared with 0.5% aqueous methylcellulose solution was orally administered to induce hyperuricemia. One hour later, 100 μl of peripheral blood was taken from the inner canthus of the eye, and the serum uric acid concentration was measured using the conventional phosphotungstic acid method.

[0420] The results are as Figure 1 shown. After 8 hours of dosing with compound 4, compound 12, and compound 137 - 7, compared with the control group, the serum uric acid concentration could be effectively reduced to approximately half.

[0421] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0422] The above-described embodiments merely represent several implementation manners of the present invention. The description thereof is relatively specific and detailed, but it should not be construed as a limitation to the scope of the patent for the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention shall be subject to the appended claims.

Claims

1. A dihydrofuroindole compound or its derivative having the structure shown in Formula I, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, Among them, X is selected from: O, S, C(R 1 )2, NR 2 ; Z and W are each independently selected from: CR 3 , N; m and n are each independently selected from: 0, 1, 2, 3, and m + n is 2, 3 or 4; Q is selected from: hydrogen, one or more Rs 4 substituted or unsubstituted C1-C6 alkyl, one or more Rs 4 substituted or unsubstituted C1-C6 alkoxy, one or more Rs 4 substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy, one or more Rs 5 substituted or unsubstituted C3-C8 cycloalkyl, one or more Rs 5 substituted or unsubstituted 3-8 membered heterocyclic group, one or more Rs 6 substituted or unsubstituted C6-C 10 aryl, one or more Rs 6 substituted or unsubstituted 5-10 membered heteroaryl L is selected from: hydrogen, one or more Rs 4 substituted or unsubstituted C1-C6 alkyl, one or more Rs 4 substituted or unsubstituted C1-C6 alkoxy, one or more Rs 4 substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy, one or more Rs 5 substituted or unsubstituted C3-C8 cycloalkyl, one or more Rs 5 substituted or unsubstituted 3-8 membered heterocyclic group, one or more Rs 6 substituted or unsubstituted C6-C 10 aryl, one or more Rs 6 substituted or unsubstituted 5-10 membered heteroaryl X 1 and X 2 are each independently selected from: O, S, C(R 1 )2, NR 2 ; Z 1 、Z 2 and Z 3 Independently selected from: CR 3 , N; Each R 1 is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen; Each R 2 is independently selected from: hydrogen, C1-C6 alkyl; Each R 3 is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen; Each R 4 is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group; Each R 5 is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl; Each R 6 is independently selected from: hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxy, mercapto, amino, R 5 substituted or unsubstituted C6-C 10 aryl, R 5 substituted or unsubstituted 5- to 10-membered heteroaryl; Each R is independently selected from: hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino.

2. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to claim 1, characterized in that, The dihydrofuroindole compound or its derivative has the structure shown in Formula II:

3. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to claim 1, characterized in that The dihydrofuroindole compound or its derivative has the structures shown in Formula III-1, Formula III-2, Formula III-3, Formula III-4, Formula III-5, Formula III-6, Formula III-7, Formula III-8, Formula III-9, Formula III-10, Formula III-11, Formula III-12, Formula III-13, Formula III-14, Formula III-15, Formula III-16, Formula III-17 or III-18:

4. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to claim 3, characterized in that Each R in formula III-1 1 is independently selected from: hydrogen, C1-C3 alkyl, halogen; Each R in Formula III-8, Formula III-9, and Formula III-10 2 is independently selected from: hydrogen, C1-C3 alkyl; Preferably, each R in formula III-1 1 is independently selected from: hydrogen, methyl, ethyl, fluorine, chlorine, bromine; Preferably, each R in Formula III-8, Formula III-9, and Formula III-10 2 is independently selected from: hydrogen, methyl, ethyl.

5. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-3, characterized in that, X 1 、 X 2 are each independently selected from: O, S, C(R 1 )2, NR 2 ; Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N; Each R 1 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, bromine; Each R 2 is independently selected from: hydrogen, C1-C3 alkyl; Each R 3 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen; Preferably, X 1 is selected from: O, S, X 2 is NR 2 , R 2 is selected from: hydrogen, methyl, ethyl, propyl; Preferably, Z 1 , Z 2 and Z 3 one or two of them are N, and the others are all CR 3 , R 3 is selected from: hydrogen, methyl, ethyl, propyl.

6. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-3, characterized in that Each R 4 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic group; Preferably, each R 4 is independently selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde group, carboxyl group, nitro group, hydroxyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, thietanyl.

7. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-3, characterized in that, Each R 5 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl; Preferably, each R 5 is independently selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxy.

8. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiated compound according to any one of claims 1-3, characterized in that, Each R 6 is independently selected from: hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxy, mercapto, amino, R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5- to 6-membered heteroaryl; Each R is independently selected from: hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino; Preferably, each R 6 is independently selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde group, carboxyl group, -C(=O)NHOH, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, nitro group, hydroxyl group, mercapto group, amino group, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl group, naphthyl group, pyridyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, triazolyl group, tetrazolyl group, furyl group, thienyl group, pyrrolyl group, imidazolyl group.

9. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-3, characterized in that, Q is selected from: hydrogen, one or more Rs 4 substituted or unsubstituted C1-C3 alkyl, one or more Rs 4 substituted or unsubstituted C1-C3 alkoxy, one or more Rs 4 substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxy, one or more Rs 5 substituted or unsubstituted C3-C6 cycloalkyl, one or more Rs 5 substituted or unsubstituted 3-6 membered heterocyclic group, one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted 5-6 membered heteroaryl, X 1 、X 2 are each independently selected from: O, S, C(R 1 )2, NR 2 ; Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N; Each R 1 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen; Each R 2 is independently selected from: hydrogen, C1-C3 alkyl; Each R 3 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen; Preferably, each R 4 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde group, carboxyl group, nitro group, hydroxyl group, C3-C6 cycloalkyl, 3-6 membered heterocyclic group; Preferably, each R 5 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl; Preferably, each R 6 is independently selected from: hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxy, mercapto, amino, R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5- to 6-membered heteroaryl; Each R is independently selected from: hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

10. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to claim 9, characterized in that, Q is selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde group, carboxyl group, nitro group, hydroxyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxanyl, pyrrolidinyl, tetrahydrothiophenyl, halogen-substituted pyrrolidinyl, hydroxyl-substituted pyrrolidinyl, azetidinyl, halogen-substituted azetidinyl, hydroxyl-substituted azetidinyl, one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted pyridyl, one or more Rs 6 substituted or unsubstituted pyrazinyl, one or more Rs 6 substituted or unsubstituted pyridazinyl, one or more Rs 6 substituted or unsubstituted pyrimidinyl Preferably, each R 6 is independently selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde group, carboxyl group, -C(=O)NHOH, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, nitro group, hydroxyl group, mercapto group, amino group, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl group, naphthyl group, pyridyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, triazolyl group, tetrazolyl group, furyl group, thienyl group, pyrrolyl group, imidazolyl group.

11. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiated compound according to claim 10, characterized in that Q is selected from: chlorine, bromine, aldehyde group, cyano group, difluoromethyl, Preferably, Q is selected from: chlorine, bromine, aldehyde group, cyano group, more preferably cyano group.

12. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to any one of claims 1-3, characterized in that L is selected from: hydrogen, one or more Rs 4 substituted or unsubstituted C1-C3 alkyl, one or more Rs 4 substituted or unsubstituted C1-C3 alkoxy, one or more Rs 4 substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde group, carboxyl group, nitro group, hydroxyl group, one or more Rs 5 substituted or unsubstituted C3-C6 cycloalkyl, one or more Rs 5 substituted or unsubstituted 3- to 6-membered heterocyclic group, one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted 5- to 6-membered heteroaryl X 1 and X 2 are each independently selected from: O, S, C(R 1 )2, NR 2 ; Z 1 、Z 2 and Z 3 Independently selected from: CR 3 , N; Each R 1 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen; Each R 2 is independently selected from: hydrogen, C1-C3 alkyl; Each R 3 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen; Preferably, each R 4 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group; Preferably, each R 5 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl; Preferably, each R 6 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxy, mercapto, amino, R 5 substituted or unsubstituted phenyl, R 5 substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl; Each R is independently selected from: hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

13. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiated compound according to claim 12, characterized in that, L is selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde group, carboxyl group, nitro group, hydroxyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, halogen-substituted tetrahydropyrrolyl, hydroxyl-substituted tetrahydropyrrolyl, azetidinyl, halogen-substituted azetidinyl, hydroxyl-substituted azetidinyl, one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted pyridyl, one or more Rs 6 substituted or unsubstituted pyrazinyl, one or more Rs 6 substituted or unsubstituted pyridazinyl, one or more Rs 6 substituted or unsubstituted pyrimidinyl, Preferably, each R 6 is independently selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde group, carboxyl group, -C(=O)NHOH, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, nitro group, hydroxyl group, mercapto group, amino group, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl group, naphthyl group, pyridyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, triazolyl group, tetrazolyl group, furyl group, thienyl group, pyrrolyl group, imidazolyl group.

14. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to claim 13, characterized in that, L is selected from: Preferably, L is selected from: More preferably, L is or 15. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to any one of claims 1-3, characterized in that, Q is selected from: halogen, aldehyde group, cyano group, oxygen-containing 3-5 membered heterocyclic group; L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted pyridyl, one or more Rs 6 substituted or unsubstituted pyrazinyl, one or more Rs 6 substituted or unsubstituted pyrimidinyl, wherein each R 6 is independently selected from: hydrogen, methyl, ethyl, halogen, carboxyl, hydroxyl, tetrazolyl, C(=O)NHOH.

16. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to claim 15, characterized in that, Q is selected from: chlorine, bromine, aldehyde group, cyano group, L is selected from:

17. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to any one of claims 1-3, characterized in that Q is halogen, preferably chlorine or bromine; L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted 5-6 membered heteroaryl, Each R 6 is independently selected from: hydrogen, hydroxyl, carboxyl, tetrazolyl; Preferably, L is selected from: R 6 substituted or unsubstituted phenyl, R 6 substituted or unsubstituted pyridyl; Preferably, L is selected from: More preferably, L is selected from: More preferably, L is or 18. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-3, characterized in that, Q is cyano group; L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted 5- to 6-membered heteroaryl Each R 6 is independently selected from: hydrogen, methyl, ethyl, hydroxyl, carboxyl, halogen, tetrazolyl, C(=O)NHOH; Preferably, each R 6 is independently selected from: hydrogen, hydroxyl, carboxyl, tetrazolyl, C(=O)NHOH.

19. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiated compound according to claim 18, characterized in that, L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted pyridyl, one or more Rs 6 substituted or unsubstituted pyrazinyl, one or more Rs 6 substituted or unsubstituted pyrimidinyl, More preferably, L is selected from: one or more Rs 6 substituted or unsubstituted pyridyl, one or more Rs 6 substituted or unsubstituted pyrazinyl, 20. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to claim 18, characterized in that L is selected from: Preferably, L is selected from:

21. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiated compound according to any one of claims 1-3, characterized in that, Q is aldehyde group; L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted naphthyl, one or more Rs 6 substituted or unsubstituted 5- to 6-membered heteroaryl; Each R 6 is independently selected from: hydrogen, hydroxyl, carboxyl, tetrazolyl; Preferably, L is selected from: one or more Rs 6 substituted or unsubstituted phenyl, one or more Rs 6 substituted or unsubstituted pyridyl, one or more Rs 6 substituted or unsubstituted pyrimidinyl; Preferably, L is selected from: More preferably, L is selected from:

22. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritiide according to claim 1, characterized in that, The dihydrofuroindole compound or its derivative is selected from the following compounds: Or, the dihydrofuroindole compound or its derivative is selected from the following compounds: Preferably, the dihydrofuroindole compound or its derivative is selected from the following compounds: Preferably, the dihydrofuroindole compound or its derivative is selected from the following compounds: Preferably, the dihydrofuroindole compound or its derivative is selected from the following compounds:

23. Use of the dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-22 in the preparation of an XOR inhibitor and / or a URAT1 inhibitor.

24. Use of the dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-22 in the preparation of a drug for reducing uric acid. Use of a dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-22 in the preparation of a drug for preventing and / or treating gout or hyperuricemia.

26. An XOR / URAT1 dual inhibitor, characterized in that, The active ingredient contains a dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-22.

27. A uric acid-lowering drug, characterized in that, Prepared from an active ingredient and a pharmaceutically acceptable carrier or excipient, wherein the active ingredient comprises a dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide according to any one of claims 1-22.

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