Indole saturated ring compound or derivative and application thereof

Abstract

The invention provides an indolo saturated ring compound with a structure as shown in a formula I or a formula II, 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 tritium thereof, and an application of the indolo saturated ring 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 tritium thereof. The indolo saturated ring 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, 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.

Description

[0001] The present invention claims priority to Chinese patent application No. 2024104935740, filed with the Patent Office of China on April 23, 2024, entitled “Indole and saturated cyclic compounds or their derivatives and their applications”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medicinal chemistry, and in particular to a class of indole saturated ring compounds or derivatives thereof and applications thereof. Background Art

[0003] Uric acid is the final product of purine metabolism in humans and non-human primates, and is formed from xanthine by xanthine oxidase. Humans do not have uricase, so uric acid can only be excreted from the body through the intestines and kidneys. Due to the popularity of the Western diet, excessive purine intake through the diet, massive cell death in a short period of 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 medical data shows that regardless of whether uric acid crystals are formed, high uric acid itself is an independent high-risk factor and is related to the pathogenesis of various diseases in the body (such as diabetic nephropathy, other chronic kidney diseases, and cardiovascular and cerebrovascular diseases). The normal range of uric acid in human blood 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 can lead to crystallization, and lower pH and temperature promote crystallization. Crystallization can deposit in distal joints or other parts of the body (such as blood vessels and kidneys), causing cell damage and inflammation, causing great pain to patients and seriously affecting their quality of life. Hyperuricemia affects 8% of the general population, and gout patients account for 4% of the total population. Among people over 60 years old, over 10% will experience gout attacks.

[0004] Currently, the main drugs used to lower uric acid are as follows: allopurinol or febuxostat are used to inhibit xanthine oxidase, thereby reducing the production of uric acid; benzbromarone is used to interfere with the reabsorption of uric acid in the kidneys, thereby promoting the excretion of uric acid; or for patients with refractory hyperuricemia, exogenous recombinant or 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 was launched in Japan.

[0005] Existing drugs and treatments have their limitations, and the vast majority of patients with hyperuricemia and gout have huge unmet clinical needs, so there is a need to develop safe and effective new uric acid-lowering drugs. From the perspective of mechanism of action and pharmacokinetics, using a single molecule to simultaneously attack the pathways of uric acid production (xanthine oxidase) and uric acid reabsorption (uric acid transporter URAT1, gene name SLC22A12) has more advantages than strategies that attack each pathway separately. Pfizer has developed a dual XOR / URAT1 inhibitor, the dual-target molecule PF-06743649, but it was stopped in Phase I clinical trials because a small number of patients developed acute kidney injury. Therefore, it is necessary to develop a new dual-target uric acid-lowering drug to benefit patients with hyperuricemia and reduce the burden on national medical payments. Summary of the Invention

[0006] To address the above problems, the present invention provides an indole-saturated ring compound or its derivatives, which has good inhibitory activity on both urate oxidase (XOR) and urate transporter (URAT1), is a XOR / URAT1 dual inhibitor, and has a good uric acid-lowering effect.

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

[0008] An indole-saturated ring compound having a structure as shown in Formula I or Formula II, 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 deuterated compound thereof, or a tritiated compound thereof,

[0009]

[0010] Wherein, X is selected from: -O-, -S-, -CH2-, -NR 2 -;

[0011] Y is selected from: -O-, -S-, -NR 2 -;

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

[0013] Z and W are independently selected from: CR 3 ;

[0014] Q 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;

[0015] 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,

[0016] X 1 、X 2 are independently selected from: -O-, -S-, -C(R 1 )2-、-NR 2 -;

[0017] Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N;

[0018] Each R 1 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen;

[0019] Each R 2 are independently selected from: hydrogen, C1-C6 alkyl;

[0020] Each R 3 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen;

[0021] 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;

[0022] Each R 5 are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl;

[0023] Each R 6are independently selected from the group consisting of 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 5-10 membered heteroaryl;

[0024] Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C1-C6 alkylamino.

[0025] In some embodiments, the indole saturated ring compound or its derivative has a structure as shown in Formula III or Formula IV:

[0026]

[0027] In some embodiments, the indole saturated ring compound or its derivative has a structure as shown in Formula V-1, Formula V-2, Formula V-3, Formula V-4, Formula V-5, Formula V-6, Formula V-7 or Formula V-8:

[0028]

[0029] In some embodiments, each R 2 Selected from: hydrogen, C1-C3 alkyl.

[0030] In some embodiments, each R 2 Selected from: hydrogen, methyl, ethyl.

[0031] In some embodiments, X 1 、X 2 are independently selected from: -O-, -S-, -C(R 1 )2-、-NR 2 -;

[0032] Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N;

[0033] Each R 1 Each is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, and bromine;

[0034] Each R 2 are independently selected from: hydrogen, C1-C3 alkyl;

[0035] Each R 3 Each is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen.

[0036] In some embodiments, X 1 Selected from: -O-, -S-, X 2 -NR 2 -, R 2 Selected from: hydrogen, methyl, ethyl, propyl.

[0037] In some embodiments, Z 1 , Z 2 and Z 3 0 or 1 of them are N, and the others are CR 3 , R 3 Selected from: hydrogen, methyl, ethyl, propyl.

[0038] In some embodiments, each R 4 Each of the following groups is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic group.

[0039] In some embodiments, each R 4 Each of the following groups is independently selected from the group consisting of 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, tetrahydropyrrolyl, and tetrahydrothiophenyl.

[0040] In some embodiments, each R 5 Each of the following is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

[0041] In some embodiments, each R 5 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

[0042] In some embodiments, each R 6are independently selected from the group consisting of 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 a substituted or unsubstituted 5-6 membered heteroaryl group;

[0043] Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

[0044] In some embodiments, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, 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, furyl, thienyl, pyrrolyl, and imidazolyl.

[0045] In some 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, carboxyl, nitro, hydroxyl.

[0046] In some embodiments, Q is selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

[0047] In some embodiments, Q is selected from the group consisting of chlorine, bromine, and cyano.

[0048] In some 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 R 4Substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C6 cycloalkyl, one or more R 5 a 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,

[0049] X 1 、X 2 are independently selected from: -O-, -S-, -C(R 1 )2-、-NR 2 -;

[0050] Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N;

[0051] Each R 1 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen;

[0052] Each R 2 are independently selected from: hydrogen, C1-C3 alkyl;

[0053] Each R 3 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen;

[0054] Each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl;

[0055] Each R 5 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl;

[0056] Each R 6 are independently selected from the group consisting of 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, R5 Substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl;

[0057] Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

[0058] 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, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, tetrahydropyrrolyl, tetrahydrothienyl, halogen-substituted tetrahydropyrrolyl, hydroxy-substituted tetrahydropyrrolyl, 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,

[0059] Among them, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, 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, furyl, thienyl, pyrrolyl, and imidazolyl.

[0060] In some embodiments, L is selected from:

[0061] In some embodiments, Q is selected from: halogen, cyano;

[0062] L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R6 Substituted or unsubstituted pyrazinyl, one or more R 6 substituted or unsubstituted pyridazinyl, Among them, each R 6 Each is independently selected from the group consisting of hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, and -C(=O)NHOH.

[0063] In some embodiments, Q is selected from: chlorine, bromine, cyano;

[0064] L is selected from:

[0065] In some embodiments, the indole saturated ring compound or its derivative has a structure as shown in Formula V-1,

[0066]

[0067] Wherein, Q is cyano;

[0068] L is selected from: 1 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 pyridazinyl; each R 6 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, -C(=O)NHOH;

[0069] Preferably, L is selected from:

[0070] More preferably, L is selected from:

[0071] In some embodiments, the indole saturated ring compound or its derivative has a structure as shown in Formula V-3,

[0072]

[0073] Wherein, Q is cyano;

[0074] L is selected from: 1 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 pyridazinyl; each R 6Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, -C(=O)NHOH;

[0075] Preferably, L is selected from:

[0076] More preferably, L is selected from:

[0077] In some embodiments, the indole saturated ring compound or its derivative has a structure as shown in Formula V-5,

[0078]

[0079] Wherein, Q is cyano;

[0080] L is selected from: 1 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 pyridazinyl; each R 6 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, -C(=O)NHOH;

[0081] Preferably, L is selected from:

[0082] More preferably, L is selected from:

[0083] In some embodiments, the indole saturated ring compound or its derivative has a structure as shown in Formula V-1,

[0084]

[0085] Wherein, Q is chlorine or bromine;

[0086] L is selected from: 1 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 pyridazinyl; each R 6 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, -C(=O)NHOH;

[0087] Preferably, L is selected from:

[0088] More preferably, L is selected from:

[0089] The present invention also provides the use of the indole saturated ring compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, including the following technical solutions:

[0090] Use of the indole-saturated ring compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product of the present invention in the preparation of XOR inhibitors and / or URAT1 inhibitors.

[0091] The indole saturated ring compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritium compound described in the present invention is used in the preparation of uric acid-lowering drugs.

[0092] Use of the indole-saturated ring 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 in the preparation of a drug for preventing and / or treating gout or hyperuricemia.

[0093] The present invention also provides an XOR / URAT1 dual inhibitor, the active ingredient of which contains the indole-saturated ring compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product according to the present invention.

[0094] The present invention also provides a uric acid-lowering drug, characterized in that it is prepared from active ingredients and pharmaceutically acceptable excipients, and the active ingredient includes the indole-saturated ring 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 described in the present invention.

[0095] The indole-saturated ring compounds or their derivatives provided by the present invention are a class of compounds with novel structures. These compounds have good inhibitory activity against both urate oxidase and urate transporter, are a type of XOR / URAT1 dual inhibitor, have good uric acid-lowering effects, are safe, have excellent pharmacokinetic properties, and are highly druggable. They can be used to prepare uric acid-lowering drugs for the prevention and / or treatment of gout or hyperuricemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 The blood uric acid concentration of mice 8 hours after administration of compound 1 and compound 6. DETAILED DESCRIPTION

[0097] To facilitate understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the present disclosure more thorough and comprehensive.

[0098] In the following examples, the experimental methods without specific conditions are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0099] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification are for the purpose of describing specific embodiments only and are not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0100] Furthermore, as used herein, the term "or" is inclusive and equivalent to the term "and / or," unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. Furthermore, throughout this specification, the meanings of "a," "an," and "the" include plural referents. The meaning of "in" includes "in" and "on."

[0101] In the compounds of the present invention, when any variable (such as R 4 、R 5 If a substituent (e.g., ) occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permissible so long as such combinations result in a stable compound. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds may be attached only to any suitable carbon atom in an adjacent ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns in the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0102] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0103] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon group whose ring atoms are composed of carbon atoms, and the bicyclic or polycyclic rings include spirocyclic, fused rings and bridged rings. For example, "cycloalkyl" includes but is not limited to the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0104] The term "alkoxy" used herein refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0105] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituent, wherein one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon, and the bicyclic or polycyclic rings include spirocyclic, fused and bridged rings. For example: oxetanyl, azetidinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and N-oxides thereof. Attachment of the heterocyclic substituents can be achieved via a carbon atom or via a heteroatom.

[0106] As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S. The aromatic ring may be monocyclic, bicyclic, or polycyclic, and includes, but is not limited to, quinolinyl, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, and pyridazinyl. "Heteroaryl" is also understood to include any nitrogen-containing heteroaryl N-oxide derivative. Attachment of the heteroaryl group may be through a carbon atom or a heteroatom.

[0107] As will be understood by those skilled in the art, "halo" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0108] The present invention includes the free forms of compounds of Formula I or Formula II, as well as pharmaceutically acceptable salts and stereoisomers thereof. Pharmaceutically acceptable salts encompassed include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of compounds of Formula I or Formula II. The free forms of specific salts of the compounds described can be isolated using techniques known in the art. Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Salts of basic compounds are typically prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or an excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0109] Therefore, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting an alkaline compound of this 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, and the like, 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, isethionic acid, trifluoroacetic acid, and the like.

[0110] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from 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, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic 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, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0111] 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.

[0112] The metabolites of the compounds of the present invention and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds of the present invention and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present invention.

[0113] The uric acid-lowering drug provided by the present invention, as well as the drug or method for preventing and / or treating gout or hyperuricemia, comprises (administered to a patient or subject) an active ingredient within a safe and effective amount (i.e., the indole and saturated cyclic 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) and a pharmaceutically acceptable adjuvant. When administering the drug, a safe and effective amount of the active ingredient is administered to a mammal (such as a human) in need of treatment, wherein the dosage at the time of administration is a pharmaceutically effective dosage. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, which are all within the skill of a skilled physician.

[0114] The "active ingredient" described in the present invention refers to the compound of formula I or formula II described in the present invention, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product.

[0115] A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one tablet.

[0116] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0117] "Pharmaceutically acceptable excipients" refer to: one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be sufficiently pure and have sufficiently low toxicity.

[0118] "Compatibility" herein means that the components in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0119] Examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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 (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0120] In another preferred embodiment, the compound of Formula I or Formula II of the present invention can form a complex with a macromolecular compound or polymer through a non-bonding interaction. In another preferred embodiment, the compound of Formula I or Formula II of the present invention, as a small molecule, can also be linked 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.

[0121] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0122] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0123] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with:

[0124] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0125] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0126] (c) humectants, for example, glycerin;

[0127] (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0128] (e) buffering solvents, such as paraffin;

[0129] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0130] (g) wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0131] (h) adsorbents, for example, kaolin; and

[0132] (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0133] The solid dosage forms can also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0134] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0135] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0136] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0137] The compounds of the present invention may be administered alone or in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's route of administration and dosage remain unchanged, while the compound of Formula I or Formula II is administered simultaneously or subsequently. When a compound of Formula I or Formula II is administered concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and a compound of Formula I or Formula II is preferably used. Combination administration also includes administering a compound of Formula I or Formula II with one or more other known drugs during overlapping time periods. When a compound of Formula I or Formula II is administered in combination with one or more other drugs, the dosage of the compound of Formula I or Formula II or the known drug may be lower than when administered alone.

[0138] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0139] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0140] 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.

[0141] The abbreviations of the raw materials and reagents used in the following examples are described as follows:

[0142] NIS: N-iodosuccinimide;

[0143] TEA: triethylamine;

[0144] DMF: N,N-dimethylformamide;

[0145] THF: tetrahydrofuran;

[0146] TFA: trifluoroacetic acid;

[0147] DIPEA: N,N-diisopropylethylamine;

[0148] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0149] DMSO: dimethyl sulfoxide;

[0150] NMP: N-methylpyrrolidone;

[0151] NBS: N-bromosuccinimide;

[0152] NCS: N-chlorosuccinimide;

[0153] NaHMDS: sodium bis(trimethylsilyl)amide;

[0154] DMAc: N,N-dimethylacetamide;

[0155] LAH: lithium aluminum hydride.

[0156] Example 1 Preparation of Compound 1

[0157]

[0158] Step 1: Synthesis of 4-iodo-5-amino-1,3-dihydroisobenzofuran (Intermediate 1-1)

[0159] 5-Amino-1,3-dihydroisobenzofuran (10 g, 0.074 mol) and NIS (16.6 g, 0.074 mol) were added to acetonitrile (200 ml), and the mixture was stirred at 25°C for 4 hours. After concentration, water was added to the reaction mixture, and dichloromethane was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then passed through a column to obtain a yellowish solid product (4.4 g, 23%).

[0160] 1 H NMR (400MHz, CDCl3) δ6.95 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.19 (s, 2H), 4.96 (s, 2H).

[0161] Step 2: Synthesis of 4-trimethylsilylene-5-amino-1,3-dihydroisobenzofuran (Intermediate 1-2)

[0162] 4-Iodo-5-amino-1,3-dihydroisobenzofuran (2.0 g, 7.66 mmol), trimethylsilylene (2.7 ml, 19.16 mmol), CuI (1.46 g, 7.66 mmol), and Pd(dppf)Cl2 (1.1 g, 1.53 mmol) were added to triethylamine (25 ml). The reaction was then allowed to react at 80°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 (0.9 g, 51.5%).

[0163] 1H NMR (400MHz, CDCl3) δ6.95 (d, J = 8.4Hz, 1H), 6.61 (d, J = 8.4Hz, 1H), 5.08 (s, 2H), 5.03 (s, 2H), 0.26 (s, 9H).

[0164] Step 3: Synthesis of 3,6-dihydro-1H-furo[3,4-e]indole (Intermediate 1-3)

[0165] 4-Trimethylsilylene-5-amino-1,3-dihydroisobenzofuran (4.4 g, 19.02 mmol) and CuI (7.24 g, 38 mmol) were added to DMF (70 ml). The reaction was then allowed to react at 120°C for 2 hours. After concentration, the reaction mixture was treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain a yellow solid product (1.79 g, 59%).

[0166] MS(ESI)calcd for C 10 H9NO:159.07; found:160.00[M+1].

[0167] 1 H NMR (400MHz, CDCl3) δ8.32(brs,1H),7.34(d,J=8.0Hz,1H),7.27(s,1H),7.07(d,J=8.0Hz,1H),6.42(s,1H),5.37-5.36(m,2H),5.25-5.24(m,2H).

[0168] Step 4: Synthesis of 8-formyl-3,6-dihydro-1H-furo[3,4-e]indole (Intermediate 1-4)

[0169] 3,6-Dihydro-1H-furo[3,4-f]indole (600 mg, 3.77 mmol) and POCl3 (694 mg, 4.53 mmol) were added to DMF (10 ml). The mixture was allowed to react at room temperature for 3 hours. A 2.0 M aqueous NaOH solution was then added and the mixture was heated to 70°C and reacted for 0.5 hours. The mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and spun down to dryness to obtain the product as a red solid (449 mg, 64%).

[0170] MS(ESI)calcd for C 11 H9NO2:187.06; found:188.15[M+1].

[0171] 1H NMR (400MHz, DMSO-D6) δ12.26(brs,1H),9.78(s,1H),8.28(s,1H),7.41(d,J=8.0Hz,1H),7.18(d,J=8.4Hz,1H),5.39-5.38(m,2H),5.09-5.07(m,2H).

[0172] Step 5: Synthesis of 8-cyano-3,6-dihydro-1H-furo[3,4-e]indole (Intermediate 1-5)

[0173] 8-Formyl-3,6-dihydro-1H-furo[3,4-e]indole (449 mg, 2.43 mmol), hydroxylamine hydrochloride (337 mg, 4.85 mmol), and pyridine (770 mg) were added to THF (5 ml). The reaction was then allowed to react at 80°C for 12 hours. Acetic anhydride (2.3 ml) was then added and allowed to react for 12 hours. A 2.0 M aqueous NaOH solution was then added at room temperature, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and spun down to dryness to obtain the product as a yellow solid (450 mg, 100%).

[0174] MS(ESI)calcd for C 11 H8N2O:184.06; found:183.00[M-1].

[0175] Step 6: Synthesis of tert-butyl 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-benzoate (Intermediate 1-6)

[0176] 8-Cyano-3,6-dihydro-1H-furo[3,4-e]indole (50 mg, 0.27 mmol), Cs2CO3 (132 mg, 0.4 mmol), and tert-butyl 4-fluorobenzoate (80 mg, 0.4 mmol) were added to DMF (1 ml). The reaction was then incubated at 80°C for 12 hours and cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (30 mg, 31%).

[0177] MS(ESI)calcd for C 22 H 20 N2O2:360.15; found:361.15[M+1].

[0178] 1H NMR (400MHz, CDCl3) δ8.20(d,J=8.4Hz,2H),7.84(s,1H),7.55(d,J=8.4Hz,2H),7.45 (d,J=8.4Hz,1H),7.23(d,J=8.4Hz,1H),5.57(s,1H),5.23-5.24(m,1H),1.64(s,9H)

[0179] Step 7: Synthesis of 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-benzoic acid (Compound 1)

[0180] To TFA (1 ml), tert-butyl 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-benzoate (30 mg, 0.08 mmol) was added. The reaction was then allowed to react at 60°C for 3 hours. Water was then added to the reaction mixture, and the off-white solid product was filtered and dried to obtain the desired product (24 mg, 95%).

[0181] MS(ESI)calcd for C 18 H 12 N2O3:304.08; found:303.05[M-1].

[0182] 1 H NMR (400MHz, DMSO-D6) δ13.28(s,1H),8.71(s,1H),8.17(d,J=8.4Hz,2H),7.80(d,J =8.4Hz,2H),7.61(d,J=8.4Hz,1H),7.35(d,J=8.4Hz,1H),5.40(s,2H),5.14(s,2H).

[0183] Example 2 Preparation of Compound 6

[0184]

[0185] Step 1: Synthesis of ethyl 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 6-1)

[0186] 8-Cyano-3,6-dihydro-1H-furo[3,4-e]indole (520 mg, 2.83 mmol), Cs2CO3 (1.4 g, 4.34 mmol), and ethyl 4-fluoro-2-(methoxymethyleneoxy)benzoate (968 mg, 4.34 mmol) were added to DMF (10 ml). The reaction was then allowed to react at 85°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (258 mg, 23%).

[0187] MS(ESI)calcd for C 22 H 20 N2O5:392.14; found:393.05[M+1].

[0188] Step 2: Synthesis of ethyl 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-hydroxybenzoate (Intermediate 6-2)

[0189] To THF (20 ml), add ethyl 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoate (1.4 g, 3.57 mmol), EtOH (10 ml), and HCl (2.0 M, 14 ml). The mixture was reacted at 70°C for 12 hours, then cooled to room temperature. The product was filtered, washed with EtOH and H2O, and dried to give an off-white solid (1.1 g, 88%).

[0190] MS(ESI)calcd for C 20 H 16 N2O4:348.11; found:349.10[M+1].

[0191] Step 3: Synthesis of 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-hydroxybenzoic acid (Compound 6)

[0192] To THF (2 ml), ethyl 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-hydroxybenzoate (60 mg, 0.17 mmol), H₂O (0.6 ml), and LiOH (43 mg) were added. The mixture was allowed to react at room temperature for 24 hours, and then acidified with HCl (2.0 M). The off-white solid product was filtered and washed with H₂O and EtOH, and dried to obtain the desired product (50 mg, 91%).

[0193] MS(ESI)calcd for C18 H 12 N2O4:320.08; found:319.00[M-1].

[0194] 1 H NMR (400MHz, DMSO-D6) δ8.68(s,1H),8.00(d,J=8.4Hz,1H),7.63(d,J=8.4Hz,1H),7.35(d,J=8.4Hz,1H),7.27-7.22(m,2H),5.40(s,2H),5.14(s,2H).

[0195] Example 3 Preparation of Compound 12

[0196]

[0197] Step 1: Synthesis of 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoic acid (Intermediate 12-1)

[0198] To a mixed solvent of THF (3 ml) and ethanol (3 ml) was added ethyl 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoate (200 mg, 0.51 mmol), H₂O (1.0 ml), and LiOH (107 mg). The mixture was allowed to react at room temperature for 12 hours, and then acidified with HCl (2.0 M). The off-white solid product was filtered, washed with H₂O and EtOH, and dried to yield the desired product (159 mg, 85%).

[0199] MS(ESI)calcd for C 20 H 16 N2O5:364.11; found:363.00[M-1].

[0200] Step 2: Synthesis of 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)-N-(OTHP)benzamide (Compound 12-2)

[0201] 4-(8-Cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoic acid (157 mg, 0.43 mmol), DIPEA (166 mg), HATU (327 mg, 0.86 mmol), and NH2OTHP (114 mg, 0.65 mmol) were added to DMF (3 ml). The reaction was allowed to react at room temperature for 12 hours. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain a yellow solid product (120 mg, 60%).

[0202] MS(ESI)calcd for C 25 H 25 N3O6:463.17; found:464.05[M+1].

[0203] 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),8.68(s,1H),7.70(d,J=8.0Hz,1H),7.59(d,J=8.8Hz,1H),7.47(d,J=2.0Hz,1H),7.39(dd,J=8.0and 2.0Hz,1H),7.35(d,J=8.4Hz,1H),5.41(s,2H),5.39(s,2H),5.14(s,2H),5.06(s,1H),4 .05-4.00(m,1H),3.56-3.53(m,1H),3.44(s,3H),1.75-1.73(m,3H),1.57-1.55(m,3H).

[0204] Step 3: Synthesis of 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-N,2-dihydroxybenzamide (Compound 12)

[0205] To a mixed solvent of THF (1 ml) and EtOH (0.5 ml) was added 4-(8-cyano-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)-N-(OTHP)benzamide (30 mg, 0.26 mmol) and HCl (2.0 M, 0.3 ml). The mixture was then reacted at 70°C for 12 hours and cooled to room temperature. The resulting solid was filtered, washed with EtOH and H2O, and dried to yield the product as an off-red solid (20 mg, 83%).

[0206] MS(ESI)calcd for C 18 H 13N3O4:335.09; found:336.00[M+1].

[0207] 1 H NMR (400MHz, DMSO-d6) δ12.71(brs,1H),11.62(brs,1H),9.53(s,1H),8.70(s,1H),7.96(d,J=8.8 Hz,1H),7.66(d,J=8.4Hz,1H),7.40(d,J=8.4Hz,1H),7.23-7.24(m,2H),5.44(s,2H),5.18(s,2H).

[0208] Example 4 Preparation of Compound 5

[0209]

[0210] Step 1: Synthesis of 4-(8-formyl-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-benzonitrile (Intermediate 5-1)

[0211] 8-Formyl-3,6-dihydro-1H-furo[3,4-e]indole (300 mg, 1.6 mmol), Cs2CO3 (1.0 g, 3.2 mmol), and 4-fluorobenzonitrile (310 mg, 2.6 mmol) were added to DMSO (5.0 ml). The reaction was then incubated at 80°C for 12 hours and cooled to room temperature. Water was then added to the reaction mixture, and the resulting filter cake was washed with water and ethanol and dried to yield an off-white solid product (390 mg, 84%).

[0212] MS(ESI)calcd for C 18 H 12 N2O2:288.09; found:289.30[M+1].

[0213] 1 H NMR (400MHz, DMSO-D6) δ9.91(s,1H),8.73(s,1H),8.15(d,J=8.8Hz,2H),7.94(d,J= 8.8Hz,2H),7.54(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),5.45(s,2H),5.13(s,2H).

[0214] Step 2: Synthesis of 8-formyl-6-(4-(1H-tetrazol-5-yl)phenyl)-3,6-dihydro-1H-furo[3,4-e]indole (Intermediate 5-2)

[0215] To NMP (6.0 ml), add 4-(8-formyl-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)-benzonitrile (390 mg, 1.35 mmol), NaN3 (308 mg, 4.74 mmol), and triethylamine hydrochloride (372 mg). The mixture was then reacted at 120°C in a sealed tube for 12 hours, then cooled to room temperature. Hydrochloric acid (2.0 M) was then added to adjust the pH of the reaction mixture to 3, and the mixture was stirred for half an hour. The filter cake was filtered, washed with methanol, and dried to yield a brown solid product (420 mg, 95%).

[0216] MS(ESI)calcd for C 18 H 13 N5O2:331.11; found:332.25[M+1].

[0217] 1 H NMR (400MHz, DMSO-D6) δ9.91(s,1H),8.71(s,1H),8.29(d,J=8.4Hz,2H),7.95(d,J= 8.4Hz,2H),7.55(d,J=8.8Hz,1H),7.31(d,J=8.8Hz,1H),5.45(s,2H),5.13(s,2H).

[0218] Step 3: Synthesis of 8-cyano-6-(4-(1H-tetrazol-5-yl)phenyl)-3,6-dihydro-1H-furo[3,4-e]indole (Compound 5)

[0219] 8-Formyl-6-(4-(1H-tetrazol-5-yl)phenyl)-3,6-dihydro-1H-furo[3,4-e]indole (320 mg, 0.97 mmol), hydroxylamine hydrochloride (100 mg, 1.45 mmol), and sodium formate (197 mg) were added to formic acid (5.0 ml). The reaction was then incubated at 105°C for 4 hours. Water was then added to the reaction mixture, and the resulting filter cake was filtered and thoroughly washed with methanol. The methanol solution was collected, concentrated under reduced pressure, and then spun down to dryness to yield the desired product (50 mg, 15%).

[0220] MS(ESI)calcd for C 18 H 12 N6O:328.11; found:327.35[M-1].

[0221] 1H NMR (400MHz, DMSO-D6) δ8.72(s,1H),8.27(d,J=8.4Hz,2H),7.92(d,J=8.8Hz ,2H),7.63(d,J=8.4Hz,1H),7.36(d,J=8.4Hz,1H),5.40(s,2H),5.14(s,2H).

[0222] Example 5 Preparation of Compound 49

[0223]

[0224] Step 1: Synthesis of 5-amino-4,6-dibromo-2,3-dihydroindene (Intermediate 49-1)

[0225] 5-Amino-2,3-dihydroindene (10.0 g, 75 mmol) and NBS (33.4 g, 188 mmol) were added to acetonitrile (400 ml), and the mixture was stirred at room temperature for 4 hours. After concentration, water was added to the reaction mixture, and dichloromethane was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then passed through a column to obtain a yellow liquid product (8.7 g, 40%).

[0226] Step 2: Synthesis of 5-amino-4-bromo-2,3-dihydro-1H-indene (Intermediate 49-2)

[0227] 5-Amino-4,6-dibromo-2,3-dihydroindene (4.0 g, 14 mmol) and SnCl2 dihydrate (3.8 g, 17 mmol) were added to a mixed solvent of concentrated hydrochloric acid (15 ml) and HOAc (18 ml). The mixture was stirred at 120°C for half an hour. Then, a NaOH aqueous solution (2.0 M) was added at room temperature to adjust the pH of the reaction solution to 9. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then passed through a column to obtain a yellow liquid product (2.5 g, 84%).

[0228] 1 H NMR (400MHz, CDCl3) δ6.94(d,J=7.6Hz,1H),6.59(d,J=8.0Hz,1H),4.34(br,2H),2.92(t,J=8.0Hz,2H),2.90(t,J=8.0Hz,2H),2.11-2.03(m,2H).

[0229] Step 3: Synthesis of 4-trimethylsilylene-5-amino-2,3-dihydro-1H-indene (Intermediate 49-3)

[0230] 5-Amino-4-bromo-2,3-dihydro-1H-indene (100 mg, 0.47 mmol), trimethylsilylene (70 mg, 0.71 mmol), CuI (9.0 mg, 0.05 mmol), and Pd(dppf)Cl2 (34 mg, 0.05 mmol) were added to triethylamine (6 ml). The reaction was then allowed to react at 80°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 (28 mg, 26%) as a pale yellow liquid.

[0231] MS(ESI)calcd for C 14 H 19 NSi:229.13; found:230.35[M+1].

[0232] Step 4: Synthesis of 3,6,7,8-tetrahydrocyclopenta[e]indole (Intermediate 49-4)

[0233] 4-Trimethylsilylene-5-amino-2,3-dihydro-1H-indene (28 mg, 0.12 mmol) and CuI (47 mg, 0.24 mmol) were added to DMF (1 ml). The mixture was then reacted at 120°C for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness and then filtered through a column to obtain the product as a white solid (10 mg, 53%).

[0234] MS(ESI)calcd for C 11 H 11 N:157.09;found:158.30[M+1].

[0235] 1 H NMR (400MHz, CDCl3) δ8.14(br,1H),7.22(d,J=8.8Hz,1H),7.21-7.20(m,1H),7.10(d,J=8.4 Hz,1H),6.47-6.45(m,1H),3.11(t,J=7.6Hz,2H),3.02(t,J=7.2Hz,2H),2.23-2.16(m,2H).

[0236] Step 5: Synthesis of 1-formyl-3,6,7,8-tetrahydrocyclopenta[e]indole (Intermediate 49-5)

[0237] To DMF (4.0 ml), add 3,6,7,8-tetrahydrocyclopenta[e]indole (200 mg, 1.28 mmol) and POCl3 (197 mg, 1.28 mmol). The mixture was allowed to react at room temperature for 12 hours. Aqueous NaOH (2.0 M) was then added to adjust the pH to 9-12, and the mixture was heated to 70°C for 1 hour. Extraction with dichloromethane was performed, and the organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield the product as a yellow solid (176 mg, 75%).

[0238] MS(ESI)calcd for C 12 H 11 NO:185.08; found:186.35[M+1].

[0239] 1 H NMR (400MHz, DMSO-d6) δ12.11(brs,1H),9.84(s,1H),8.19(d,J=1.6Hz,1H),7.25(d,J=8.0Hz ,1H),7.12(d,J=8.4Hz,1H),3.33(t,J=7.6Hz,2H),2.92(t,J=7.6Hz,2H),2.10-2.03(m,2H).

[0240] Step 6: Synthesis of 1-cyano-3,6,7,8-tetrahydrocyclopenta[e]indole (Intermediate 49-6)

[0241] To THF (5.0 ml), add 1-formyl-3,6,7,8-tetrahydrocyclopenta[e]indole (176 mg, 0.96 mmol), hydroxylamine hydrochloride (133 mg, 1.91 mmol), and pyridine (300 mg). The mixture was allowed to react at 80°C for 12 hours. Acetic anhydride (985 mg) was then added and allowed to react for 7 hours. A 2.0 M aqueous sodium hydroxide solution was then added at room temperature to adjust the pH to 10-12. The mixture was stirred for half an hour and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (82 mg, 47%).

[0242] Step 7: Synthesis of tert-butyl 4-(1-cyano-7,8-dihydrocyclopenta[e]indol-3(6H)-yl)benzoate (Intermediate 49-7)

[0243] To DMF (3.0 ml), add 1-cyano-3,6,7,8-tetrahydrocyclopenta[e]indole (82 mg, 0.45 mmol), Cs2CO3 (295 mg, 0.91 mmol), and tert-butyl 4-fluorobenzoate (134 mg, 0.68 mmol). The reaction mixture was then allowed to react at 100°C for 12 hours, then cooled to room temperature. 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 yield the product as a colorless oil (77 mg, 48%).

[0244] MS(ESI)calcd for C 23 H 22 N2O2:358.17; found:359.30[M+1].

[0245] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.12(d,J=8.8Hz,2H),7.78(d,J=8.8Hz,2H),7.45(d,J=8.4Hz,1H ),7.27(d,J=8.8Hz,1H),3.25(t,J=7.6Hz,2H),2.98(t,J=7.6Hz,2H),2.23-2.15(m,2H),1.58(s,9H).

[0246] Step 8: Synthesis of 4-(1-cyano-7,8-dihydrocyclopenta[e]indol-3(6H)-yl)benzoic acid (Compound 49)

[0247] To TFA (1 ml), tert-butyl 4-(1-cyano-7,8-dihydrocyclopenta[e]indol-3(6H)-yl)benzoate (77 mg, 0.22 mmol) was added. The mixture was allowed to react at room temperature for 2 hours, then concentrated under reduced pressure to dryness, washed with ethyl acetate, and dried to afford the desired product as a white solid (37 mg, 56%).

[0248] MS(ESI)calcd for C 19 H 14 N2O2:302.11; found:303.25[M+1].

[0249] 1H NMR (400MHz, DMSO-d6) δ13.26(s,1H),8.63(s,1H),8.16(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H),7.46( d,J=8.4Hz,1H),7.28(d,J=8.4Hz,1H),3.25(t,J=7.6Hz,2H),2.98(t,J=7.6Hz,2H),2.23-2.16(m,2H).

[0250] Example 6 Preparation of Compound 97

[0251]

[0252] Step 1: Synthesis of 8-chloro-3,6-dihydro-1H-furo[3,4-e]indole (Intermediate 97-1)

[0253] 3,6-Dihydro-1H-furo[3,4-e]indole (150 mg, 0.94 mmol) and NCS (126 mg, 0.94 mmol) were added to acetonitrile (6.0 ml). The mixture was allowed to react at room temperature for 4 hours. Water was then added to the reaction mixture, and ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a yellow solid (158 mg, 85%).

[0254] MS(ESI)calcd for C 10 H8ClNO:193.03; found:192.40[M-1].

[0255] 1 H NMR (400MHz, CDCl3) δ11.47(s,1H),7.52(d,J=2.8Hz,1H),7.34(d,J=8.4Hz,1H),7.09(d,J=8.0Hz,1H),5.38(s,2H),5.06(s,2H).

[0256] Step 2: Synthesis of tert-butyl 4-(8-chloro-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)benzoate (Intermediate 97-2)

[0257] 8-Chloro-3,6-dihydro-1H-furo[3,4-e]indole (155 mg, 0.8 mmol), Cs2CO3 (419 mg, 1.28 mmol), and tert-butyl 4-fluorobenzoate (252 mg, 0.128 mmol) were added to DMF (5.0 ml). The reaction was then allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a white solid (210 mg, 71%).

[0258] 1 H NMR (400MHz, CDCl3) δ8.08(d,J=8.4Hz,2H),8.02(s,1H),7.74(d,J=8.4Hz,2H),7. 60(d,J=8.4Hz,1H),7.25(d,J=8.4Hz,1H),5.44(s,2H),5.10(s,2H),1.58(s,9H).

[0259] Step 3: Synthesis of 4-(8-chloro-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)benzoic acid (Compound 97)

[0260] To TFA (2.0 ml), tert-butyl 4-(8-chloro-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)benzoate (210 mg, 0.57 mmol) was added. The mixture was allowed to react at room temperature for 1 hour, then concentrated under reduced pressure to dryness, slurried with methanol, and filtered to dryness to obtain the desired product as a white solid (150 mg, 84%).

[0261] MS(ESI)calcd for C 17 H 12 ClNO3:313.05; found:312.30[M-1].

[0262] 1 H NMR (400MHz, CDCl3) δ13.16(s,1H),8.12(d,J=8.4Hz,2H),8.04(s,1H),7.75(d,J= 8.8Hz,2H),7.62(d,J=8.8Hz,1H),7.25(d,J=8.4Hz,1H),5.45(s,2H),5.11(s,2H).

[0263] Example 7 Preparation of Compound 193

[0264]

[0265] Step 1: Synthesis of 8-bromo-3,6-dihydro-1H-furo[3,4-e]indole (Intermediate 193-1)

[0266] 3,6-Dihydro-1H-furo[3,4-e]indole (500 mg, 3.14 mmol) and NBS (448 mg, 2.5 mmol) were added to acetonitrile (10.0 ml). The mixture was allowed to react at room temperature for 3 hours. Water was then added to the reaction mixture, and ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain a brown solid product (70 mg, 10%).

[0267] MS(ESI)calcd for C 10 H8BrNO:236.98,238.98; found:236.30,238.30[M-1].

[0268] Step 2: Synthesis of tert-butyl 4-(8-bromo-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)benzoate (Intermediate 193-2)

[0269] 8-Bromo-3,6-dihydro-1H-furo[3,4-e]indole (70 mg, 0.3 mmol), Cs2CO3 (192 mg, 0.6 mmol), and tert-butyl 4-fluorobenzoate (86 mg, 0.45 mmol) were added to DMF (1.5 ml). The mixture was allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction mixture was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a white solid (10 mg, 8%).

[0270] Step 3: Synthesis of 4-(8-bromo-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)benzoic acid (Compound 193)

[0271] To TFA (0.5 ml), tert-butyl 4-(8-bromo-1,3-dihydro-6H-furo[3,4-e]indol-6-yl)benzoate (5 mg, 0.02 mmol) was added. The mixture was allowed to react at room temperature for 0.5 hour, then concentrated under reduced pressure to dryness, washed with ethyl acetate, and dried to give the desired product as a brown solid (4 mg, 92%).

[0272] MS(ESI)calcd for C 17 H 11 BrNO3:357.00,359.00; found:356.20,358.20[M-1].

[0273] 1H NMR (400MHz, DMSO-D6) δ8.11(s,1H),8.01(d,J=8.4Hz,2H),7.70(d,J=8.4Hz ,2H),7.60(d,J=8.4Hz,1H),7.25(d,J=8.4Hz,1H),5.48(s,2H),5.09(s,2H).

[0274] Example 8 Preparation of Compound 25

[0275]

[0276] Step 1: Synthesis of 5-amino-4,6-dibromo-2,3-dihydrobenzofuran (Intermediate 25-1)

[0277] 5-Amino-2,3-dihydrobenzofuran (5.0 g, 37.03 mmol) and bromine (17.8 g, 111.1 mmol) were added to acetic acid (100 ml), and the reaction was stirred at room temperature for 12 hours. The reaction solution was then treated with saturated Na2SO3 solution until it turned yellow. Aqueous sodium hydroxide solution (4.0 M) was added until the pH of the reaction solution reached 10. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered to obtain an off-white solid product (4.3 g, 40%).

[0278] 1 HNMR (400MHz, DMSO-d6) δ6.92(s,1H),4.76(s,2H),4.50(t,J=8.8Hz,2H),3.10(t,J=8.8Hz,2H).

[0279] Step 2: Synthesis of 5-amino-4-bromo-2,3-dihydrobenzofuran (Intermediate 25-2)

[0280] 5-Amino-4,6-dibromo-2,3-dihydrobenzofuran (11.8 g, 40.41 mmol) and SnCl2 dihydrate (10.0 g, 44.45 mmol) were added to concentrated hydrochloric acid (20 ml) and HOAc (60 ml), and the reaction was stirred at 120 ° C for 2 hours. Then, NaOH aqueous solution (2.0 M) was added at room temperature until the pH of the reaction solution reached 10. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then passed through a column to obtain a white solid product (7.5 g, 87%).

[0281] 1HNMR (400MHz, DMSO-d6) δ6.55(d,J=8.4Hz,1H),6.52(d,J=8.4Hz,1H),4.73(br,2H),4.50(t,J=8.4Hz,2H),3.08(t,J=8.8Hz,2H).

[0282] Step 3: Synthesis of tert-butyl (4-bromo-2,3-dihydrobenzofuran-5-yl)carbamate (Intermediate 25-3)

[0283] 5-Amino-4-bromo-2,3-dihydrobenzofuran (7.8 g, 36.45 mmol) was added to THF (60 ml), and then NaHMDS (146 ml, 0.5 M toluene solution) was added at 0°C, and the reaction was stirred for 1 hour. Boc2O (8.6 g, 40.1 mmol) was added, and the reaction was stirred at 25°C for 12 hours. Saturated NH4Cl aqueous solution was added until neutral, and ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then passed through a column to obtain a yellow solid product (9.8 g, 82%).

[0284] 1 HNMR (400MHz, DMSO-d6) δ8.48(s,1H),7.05(d,J=8.4Hz,1H),6.71(d,J=8.4Hz,1H),4.59(t,J=8.4Hz,2H),3.17(t,J=8.4Hz,2H),1.43(s,9H).

[0285] Step 4: Synthesis of tert-butyl (4-trimethylsilylene-2,3-dihydrobenzofuran-5-yl)carbamate (Intermediate 25-4)

[0286] To a mixed solvent of 1,4-dioxane (25 ml) and water (2.5 ml) were added tert-butyl 4-bromo-2,3-dihydrobenzofuran-5-yl)carbamate (1.8 g, 5.75 mmol), 2-ethynyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.6 g, 11.5 mmol), Cs2CO3 (5.6 g, 17.25 mmol), Pd(dppf)Cl2 (417 mg, 0.57 mmol), and Xphos (547 mg, 1.15 mmol). The mixture was then reacted at 110°C in a sealed tube under a nitrogen atmosphere for 4 hours. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain a light yellow liquid product (1.3 g).

[0287] Step 5: Synthesis of 1,6-dihydro-2H-furo[3,2-e]indole (Intermediate 25-5)

[0288] To NMP (7 ml), add tert-butyl (4-trimethylsilylene-2,3-dihydrobenzofuran-5-yl)carbamate (1.3 g) and t-BuOK (880 mg, 7.85 mmol). The mixture was then reacted at 80°C for 1 hour. After cooling to room temperature, saturated aqueous NH4Cl was added until the reaction mixture was neutral. The mixture was then extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid product (332 mg, 36% yield over two steps).

[0289] MS(ESI)calcd for C 10 H9NO:159.07; found:160.35[M+1].

[0290] 1 HNMR(400MHz,DMSO-d6)δ10.94(s,1H),7.30(t,J=2.8Hz,1H),7.11(d,J=8.4Hz,1H),6 .60(d,J=8.4Hz,1H),6.23-6.21(m,1H),4.52(t,J=8.4Hz,2H),3.26(t,J=8.4Hz,2H).

[0291] Step 6: Synthesis of 8-formyl-1,6-dihydro-2H-furo[3,2-e]indole (Intermediate 25-6)

[0292] POCl3 (450 mg, 2.94 mmol) and 1,6-dihydro-2H-furo[3,2-e]indole (332 mg, 2.09 mmol) were added to DMF (1.5 ml). The mixture was allowed to react at room temperature for 2 hours. Aqueous NaOH (2.0 M) was then added to bring the pH of the reaction mixture to 9-12, and the mixture was heated to 70°C for 1 hour. The mixture was cooled to room temperature and filtered to yield the product as a yellow solid (270 mg, 69%).

[0293] 1 HNMR(400MHz,DMSO-d6)δ12.04(s,1H),9.78(s,1H),8.20(s,1H),7.21(d,J=8 .4Hz,1H),6.75(d,J=8.4Hz,1H),4.53(t,J=8.8Hz,2H),3.57(t,J=8.8Hz,2H).

[0294] Step 7: Synthesis of 8-cyano-1,6-dihydro-2H-furo[3,2-e]indole (Intermediate 25-7)

[0295] 8-Formyl-1,6-dihydro-2H-furo[3,2-e]indole (270 mg, 1.44 mmol), hydroxylamine hydrochloride (186 mg, 2.90 mmol), and pyridine (456 mg) were added to DMF (3.0 ml). The reaction was then allowed to react at 80°C for 2 hours. Acetic anhydride (750 mg) was then added and allowed to react for 12 hours. A 2.0 M aqueous NaOH solution was then added at room temperature until the pH of the reaction solution reached 10-12. The mixture was stirred for half an hour 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 brown solid (180 mg, 67%).

[0296] MS(ESI)calcd for C 11 H8N2O:184.06; found:183.45[M-1].

[0297] 1 HNMR (400MHz, DMSO-d6) δ12.06(s,1H),8.17(s,1H),7.27(d,J=8.8Hz,1H),6.78(d,J=8.8Hz,1H),4.61(t,J=8.8Hz,2H),3.43(t,J=8.4Hz,2H).

[0298] Step 8: Synthesis of tert-butyl 4-(8-cyano-1,2-dihydro-6H-furo[3,2-e]indol-6-yl)benzoate (Intermediate 25-8)

[0299] 8-Cyano-1,6-dihydro-2H-furo[3,2-e]indole (100 mg, 0.54 mmol), Cs2CO3 (353 mg, 1.09 mmol), and tert-butyl 4-fluorobenzoate (213 mg, 1.09 mmol) were added to DMAc (1.5 ml). The reaction was then incubated at 100°C for 5 hours and cooled to room temperature. The reaction mixture was treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a white solid (98 mg, 47%).

[0300] MS(ESI)calcd for C 22 H 20 N2O3:360.15; found:361.30[M+1].

[0301] 1HNMR(400MHz,DMSO-d6)δ8.61(s,1H),8.10(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.42(d,J =8.8Hz,1H),6.89(d,J=8.8Hz,1H),4.68(t,J=8.8Hz,2H),3.51(t,J=8.8Hz,2H),1.58(s,9H).

[0302] Step 9: Synthesis of 4-(8-cyano-1,2-dihydro-6H-furo[3,2-e]indol-6-yl)benzoic acid (Compound 25)

[0303] To TFA (2 ml), tert-butyl 4-(8-cyano-1,2-dihydro-6H-furo[3,2-e]indol-6-yl)benzoate (98 mg, 0.27 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. After addition of water, the reaction mixture was filtered and the filter cake was washed with water and dried to afford the desired product as an off-white solid (64 mg, 77%).

[0304] MS(ESI)calcd for C 18 H 12 N2O3:304.08; found:305.25[M+1].

[0305] 1 HNMR(400MHz,DMSO-d6)δ8.62(s,1H),8.14(d,J=8.8Hz,2H),7.76(d,J=8.8Hz,2H),7.4 2(d,J=9.2Hz,1H), 6.89(d,J=9.2Hz,1H), 4.67(t,J=8.8Hz,2H), 3.51(t,J=8.4Hz,2H).

[0306] Example 9 Preparation of Compound 61

[0307]

[0308] Step 1: Synthesis of tert-butyl 4-iodo-5-aminoisoindoline-2-carboxylate (Intermediate 61-1)

[0309] In a mixed solvent of dichloromethane (23 ml) and acetic acid (46 ml), tert-butyl 5-aminoisoindoline-2-carboxylate (5.0 g, 21.35 mmol) and NIS (4.32 g, 19.22 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Sodium sulfite solution (1.0 M) was added to the reaction mixture until it turned light yellow. After neutralization with sodium carbonate, ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered to obtain a yellow solid product (2.7 g, 35%).

[0310] 1 H NMR (400MHz, CDCl3) δ7.01-6.93(m,1H),6.67-6.61(m,1H),4.72-4.68(m,2H),4.55-4.48(m,2H),1.53-1.51(m,9H).

[0311] Step 2: Synthesis of tert-butyl 4-trimethylsilylene-5-aminoisoindoline-2-carboxylate (Intermediate 61-2)

[0312] To triethylamine (34 ml), add tert-butyl 4-iodo-5-aminoisoindoline-2-carboxylate (2.7 g, 9.89 mmol), trimethylsilylene (4.9 g, 49.45 mmol), CuI (3.8 g, 19.78 mmol), and Pd(dppf)Cl2 (2.2 g, 2.97 mmol). The reaction was then allowed to react at 80°C for 24 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated and treated with water. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered to dryness. A brown solid product (2.0 g, 61%) was obtained.

[0313] 1 H NMR (400MHz, DMSO-d6) δ7.02-6.98(m,1H),6.63(d,J=8.4Hz,1H),5.36(s,2H),4.44(s,2H),4.42(s,2H),1.44(s,9H),0.24(s,9H).

[0314] Step 3: Synthesis of tert-butyl 3,6-dihydropyrrolo[3,4-e]indole-2(1H)-carboxylate (Intermediate 61-3)

[0315] To DMF (28 ml), add tert-butyl 4-trimethylsilylene-5-aminoisoindoline-2-carboxylate (2.0 g, 6.05 mmol) and CuI (1.73 g, 9.09 mmol). The reaction was then allowed to react at 110°C for 2 hours. After cooling to room temperature, the mixture was filtered, treated with water, and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield the product as a yellow solid (784 mg, 50%).

[0316] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),7.38-7.32(m,2H),7.04-7.01(m,1H),6.40-6.38(m,1H),4.75-4.62(m,4H),1.48-1.47(m,9H).

[0317] Step 4: Synthesis of 2-methyl-1,2,3,6-tetrahydropyrrolo[3,4-e]indole (Intermediate 61-4)

[0318] To THF (13 ml), add tert-butyl 3,6-dihydropyrrolo[3,4-e]indole-2(1H)-carboxylate (684 mg, 2.65 mmol) and LAH (202 mg). The mixture was then reacted at 60°C for 2 hours. After cooling to room temperature, the reaction mixture was treated with water and sodium hydroxide (4.0 M). The filtrate was filtered, concentrated under reduced pressure, and then filtered through a column to obtain a yellow solid product (411 mg, 90%).

[0319] LCMS calculation for C 11 H 12 N2:172.10; found:173.35[M+1].

[0320] 1 H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 7.32-7.31 (m, 1H), 7.22 (d, J = 8.4Hz, 1H), 6.93(d,J=8.4Hz,1H),6.28-6.27(m,1H),4.00(s,2H),3.89(s,2H),2.54(s,3H).

[0321] Step 5: Synthesis of 8-formyl-2-methyl-1,2,3,6-tetrahydropyrrolo[3,4-e]indole (Intermediate 61-5)

[0322] 2-Methyl-1,2,3,6-tetrahydropyrrolo[3,4-e]indole (200 mg, 1.16 mmol) and POCl3 (271 mg) were added to DMF (4.0 ml). The mixture was allowed to react at room temperature for 3 hours. Aqueous NaOH (4.0 M) was then added until the pH reached 13, and the mixture was heated to 70°C for 0.5 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then spin-dried to give a brown crude product (163 mg).

[0323] LCMS calculation for C 12 H 12N2O:200.09; found:201.30[M+1].

[0324] Step 6: Synthesis of 8-cyano-2-methyl-1,2,3,6-tetrahydropyrrolo[3,4-e]indole (Intermediate 61-6)

[0325] 8-Formyl-2-methyl-1,2,3,6-tetrahydropyrrolo[3,4-e]indole (163 mg, 0.82 mmol), hydroxylamine hydrochloride (114 mg, 1.64 mmol), and pyridine (0.4 ml) were added to THF (4 ml). The reaction was then allowed to react at 80°C for 5 hours. Acetic anhydride (0.7 ml) was then added and the reaction was allowed to react for 12 hours. Aqueous NaOH (4.0 M) was then added at room temperature until the pH of the reaction solution reached 10. The reaction was stirred for 0.5 hours, and ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product (65 mg, 40%).

[0326] LCMS calculation for C 12 H 11 N3:197.10; found:198.35[M+1].

[0327] Step 7: Synthesis of tert-butyl 4-(8-cyano-2-methyl-2,3-dihydropyrrolo[3,4-e]indol-6(1H)-yl)benzoate (Intermediate 61-7)

[0328] To DMF (1.5 ml), add 8-cyano-2-methyl-1,2,3,6-tetrahydropyrrolo[3,4-e]indole (60 mg, 0.3 mmol), Cs2CO3 (195 mg, 0.6 mmol), and tert-butyl 4-fluorobenzoate (88 mg, 0.45 mmol). The reaction was then allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction mixture was treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (15 mg, 13%).

[0329] LCMS calculation for C 23 H 23 N3O2:373.18; found:374.30[M+1].

[0330] Step 8: Synthesis of 4-(8-cyano-2-methyl-2,3-dihydropyrrolo[3,4-e]indol-6(1H)-yl)benzoic acid trifluoroacetate (Compound 61)

[0331] To TFA (0.3 ml), tert-butyl 4-(8-cyano-2-methyl-2,3-dihydropyrrolo[3,4-e]indol-6(1H)-yl)benzoate (15 mg, 0.04 mmol) was added. The mixture was allowed to react at room temperature for 2 hours, then concentrated under reduced pressure to dryness, slurried with ethanol, and dried to afford the desired product as an off-white solid (10 mg, 51%).

[0332] LCMS calculation for C 19 H 15 N3O2:317.12; found:318.30[M+1].

[0333] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.80(s,1H),8.18(d,J=8Hz,2H),7.81(d,J=8.4Hz, 2H),7.71(d,J=8.4Hz,1H),7.44(d,J=8.8Hz,1H),5.06(s,2H),4.75(s,2H),3.16(s,3H).

[0334] Referring to the preparation methods of Examples 1-9, Compounds 1-193 were prepared. The examples to which their preparation methods refer, as well as their structural formulas and characterization data are shown in Table 1.

[0335] Table 1 Structural formula, characterization data and preparation methods of Compounds 1 to 193

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342] Example 10 Inhibition of Xanthine Oxidase Activity by Compounds

[0343] 3 mg of the test compound, including the positive control febuxostat, was weighed and dissolved in DMSO to a 10 mM stock solution, and then gradiently diluted with 5% DMSO aqueous solution to form 8 concentration gradients containing the same DMSO concentration (500 uM, 50 uM, 5 uM, 500 nM, 250 nM, 50 nM, 5 nM, 0.5 nM).

[0344] The xanthine oxidase activity assay kit (MAK078-1KT) was purchased from the official website of Merck. Mouse liver tissue (500 μl / 30 mg) was homogenized with the kit's assay buffer to obtain a tissue homogenate containing mouse xanthine oxidase. The homogenate was centrifuged at 10,000 rpm for 10 minutes at 4°C. The supernatant was transferred to a new centrifuge tube and placed on ice until ready to use.

[0345] Add 50ul of tissue homogenate to a 96-well plate, add 2ul of the test compound at the corresponding concentration, and then add 48ul of the mixture containing the other components of the kit, with a total volume of 100ul / well. Incubate at 25°C for 3 minutes, excite at 535nm, and read the excited fluorescence intensity at 587nm (the more superoxide radicals generated in the reaction system due to the oxidation of hypoxanthine and xanthine by xanthine oxidase, the more resorufin will react with 10-acetyl-3,7-dihydroxyphenoxazine in the system, and the higher the excited fluorescence intensity, indicating higher xanthine oxidase activity). At 25°C, read the results kinetically every 3 minutes for 15 minutes. The wells without inhibitor are considered 100% xanthine oxidase activity, and the wells without enzyme are considered zero activity (background). After reading the plate, perform QC to confirm that the 12-minute point is in the linear range. Analyze the inhibition efficiency at the 12-minute point to obtain the IC value of the test compound. 50 .

[0346] The test results are shown in Table 2: The indole and saturated ring compounds or their derivatives of the present invention have a strong inhibitory effect on the activity of xanthine oxidase, and the inhibitory activity of some compounds is better than that of the positive drug febuxostat.

[0347] Table 2. Inhibition results of compounds on xanthine oxidase activity

[0348] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> 1 9.78 49 14.93 2 30.56 50 6.97 3 43.31 51 6.37 4 28.23 52 2.65 5 31.28 54 31.3 6 1.69 55 5.58 7 17.69 61 1651 8 2.33 97 778 10 45.3 98 2139 12 38.62 99 636 13 15.60 100 664 25 5.42 102 3.79 26 9.60 103 26.3 27 8.73 193 431 Febuxostat 11.25

[0349] Example 11 Inhibition of uric acid transporter by the compound

[0350] Concentration gradients of the test compound and the positive control (lesinurad) were prepared as in Example 10.

[0351] All cell culture media were purchased from Invitrogen, and plastics from Corning. Because renal tubular epithelial cells express Urat1 and Glut9, they can be used to assay urate transporter activity. Mouse renal tubular epithelial cells were seeded onto 0.4 μm pore size cell culture transwell membranes and cultured until the cells completely confluently filled the transwell, forming a monolayer. Prior to testing the test compound, the transwell chamber was replaced with DMEM basal medium containing the test compound at the specified concentration and 4.5 mg / dL uric acid. The bottom layer of the multiwell plate was replaced with DMEM basal medium without uric acid. After incubation at 37°C for 60 minutes, 100 μl of medium was removed from the bottom layer of the multiwell plate, and uric acid concentrations were read at 290 nm using a microplate reader. Wells without uric acid served as blank controls, and wells without compound were considered 100% transport. The uric acid concentrations in the wells corresponding to the test compound were compared with those in the wells with 100% transport to determine the inhibition efficiency.

[0352] The results showed that lesinurad at a concentration of 1000 nM exhibited an inhibition rate of 23.63% on uric acid transporter activity, while compound 6 exhibited an inhibition rate of 64% at a concentration of 250 nM. This indicates that the compounds of the present invention exhibited significant inhibitory activity against uric acid transporter activity, with their inhibitory activity at a concentration of 250 nM being higher than that of lesinurad at a concentration of 1000 nM.

[0353] Example 12 Inhibition of uric acid transporter by the compound

[0354] In this example, a third party (Beijing Kanglong Chemical Co., Ltd.) was commissioned to use HEK-293 cells (HEK293-hURAT1) that stably overexpress the human urate transporter (protein name URAT1, gene name SLC22A12) as a cell model for studying urate transport to determine the inhibitory activity of candidate compounds against the human urate transporter. Concentration gradients of the test compound and the positive control (Lesinurad) were prepared as in Example 10. All cell culture media were purchased from Invitrogen, and plastics were purchased from Corning. C14-labeled uric acid was from VWR, USA. The specific procedures were as follows:

[0355] Cells were pre-plated in 96-well plates. The next day, the culture medium was replaced with culture medium pre-mixed with C14-labeled uric acid and varying concentrations of a positive control or other test compound. After a 5-minute incubation, the culture medium was removed, the cells were lysed with 0.1N NaOH, and the supernatant was read using a Revvity liquid scintillation counter (Model MicroBeta2). The reading for wells containing C14-labeled uric acid but no compound was considered 100% uric acid transport, while the reading for wells without C14-labeled uric acid was considered background reading. The inhibitory efficacy of the positive control compound or test compound at varying concentrations on the uric acid transporter was calculated to obtain the IC50.

[0356] The test results are shown in Table 3: The activity of compound 6 in inhibiting uric acid transporter is comparable to that of the positive control (Lesinurad) under the same experimental conditions. It can be seen that the compound of the present invention has good inhibitory activity on uric acid transporter.

[0357] Table 3 Inhibition results of compounds on uric acid transporter

[0358] Compound IC50(nM) 6 46313 Lesinurad 48431

[0359] Example 13: Pharmacological Efficacy Test of Compounds in Lowering Uric Acid in the Body

[0360] In this example, Balb / c wild-type adult male mice aged 8-12 weeks, provided by Weitonglihua, were divided into a baseline group (baseline), a control group (vehicle), and a treatment group (compounds 1 and 6). The baseline group received no treatment. During oral gavage, the control group received 0.5 ml of a 1.2% aqueous solution of 2-BP-β-CD (cyclodextrin), while the treatment group received 0.5 ml of a solution of the test compound prepared in a 1.2% aqueous solution of 2-BP-β-CD (cyclodextrin). Seven hours after administration, hyperuricemia was induced by oral administration of 0.5 ml of a mixed solution containing 60 mg / ml potassium oxonate (a uricase inhibitor) and 6.67 mg / ml hypoxanthine (a substrate for xanthine oxidase) prepared in a 0.5% aqueous methylcellulose solution. One hour later, 100 μl of peripheral blood was collected from the inner orbit, and serum uric acid concentration was measured using a conventional phosphotungstic acid method.

[0361] The results are as follows Figure 1 As shown, 8 hours after administration, compound 1 and compound 6 could effectively reduce the blood uric acid concentration to about half compared with the control group.

[0362] The technical features of the above-described embodiments can be combined arbitrarily. To make the description concise, 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, they should be considered to be within the scope of this specification.

[0363] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. An indole-containing saturated ring compound having a structure as shown in Formula I or Formula II, 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 deuterated compound thereof, or a tritiated compound thereof, in, X is selected from: -O-, -S-, -CH2-, -NR 2 -; Y is selected from: -O-, -S-, -NR 2 -; m and n are independently selected from: 0, 1, 2, and m+n is 2; Z and W are independently selected from: CR 3 ; Q 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; 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, X 1 、X 2 are 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 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen; Each R 2 are independently selected from: hydrogen, C1-C6 alkyl; Each R 3 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen; 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; Each R 5 are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl; Each R 6 are independently selected from the group consisting of 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 5-10 membered heteroaryl; Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and C1-C6 alkylamino.

2. The indole-saturated ring compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 1, characterized in that: The indole saturated ring compound or its derivative has a structure as shown in Formula III or Formula IV:

3. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 1, characterized in that: The indole saturated ring compound or its derivative has a structure as shown in Formula V-1, Formula V-2, Formula V-3, Formula V-4, Formula V-5, Formula V-6, Formula V-7 or Formula V-8:

4. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Each R 2 Selected from: hydrogen, C1-C3 alkyl; preferably, each R 2 Selected from: hydrogen, methyl, ethyl.

5. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: X 1 、X 2 are 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 Each is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, and bromine; Each R 2 are independently selected from: hydrogen, C1-C3 alkyl; Each R 3 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen; Preferably, X 1 Selected from: -O-, -S-, X 2 -NR 2 -, R 2 Selected from: hydrogen, methyl, ethyl, propyl; Preferably, Z 1 , Z 2 and Z 3 0 or 1 of them are N, and the others are CR 3 , R 3 Selected from: hydrogen, methyl, ethyl, propyl.

6. The indole-saturated cyclic 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 to 3, characterized in that: Each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl; and / or, each R 5 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl; Preferably, each R 4 Each of the following groups is independently selected from the group consisting of 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, tetrahydropyrrolyl, and tetrahydrothiophenyl; Preferably, each R 5 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

7. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Each R 6 are independently selected from the group consisting of 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 a substituted or unsubstituted 5-6 membered heteroaryl group; Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino; Preferably, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, 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, furyl, thienyl, pyrrolyl, and imidazolyl.

8. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: 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, carboxyl, nitro, hydroxyl; Preferably, Q is selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, and hydroxyl; Preferably, Q is selected from the group consisting of: cyano, chlorine, and bromine; more preferably, cyano.

9. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: 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 R 4 Substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C6 cycloalkyl, one or more R 5 a 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, X 1 、X 2 are 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 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen; Each R 2 are independently selected from: hydrogen, C1-C3 alkyl; Each R 3 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen; Each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl; Each R 5 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl; Each R 6 are independently selected from the group consisting of 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 the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

10. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 9, characterized in that: L is selected from the group consisting of 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, oxane, tetrahydropyrrolyl, tetrahydrothienyl, halogen-substituted tetrahydropyrrolyl, hydroxy-substituted tetrahydropyrrolyl, 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, Among them, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, 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, furyl, thienyl, pyrrolyl, and imidazolyl.

11. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 10, characterized in that: L is selected from: Preferably, L is selected from:

12. The indole-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Q is selected from: halogen, cyano; L is selected from: 1 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 pyridazinyl, Among them, each R 6 Each is independently selected from the group consisting of hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, and -C(=O)NHOH.

13. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 12, characterized in that: Q is selected from: chlorine, bromine, cyano; L is selected from:

14. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: The indole saturated ring compound or its derivative has a structure as shown in Formula V-1, Wherein, Q is cyano; L is selected from: 1 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 pyridazinyl; each R 6 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, -C(=O)NHOH; Preferably, L is selected from: More preferably, L is selected from:

15. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: The indole saturated ring compound or its derivative has a structure as shown in Formula V-3, Wherein, Q is cyano; L is selected from: 1 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 pyridazinyl; each R 6 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, -C(=O)NHOH; Preferably, L is selected from: More preferably, L is selected from:

16. The indolo-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: The indole saturated ring compound or its derivative has a structure as shown in Formula V-5, Wherein, Q is cyano; L is selected from: 1 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 pyridazinyl; each R 6 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, -C(=O)NHOH; Preferably, L is selected from: More preferably, L is selected from:

17. The indole-saturated cyclic compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: The indole saturated ring compound or its derivative has a structure as shown in Formula V-1, Wherein, Q is chlorine or bromine; L is selected from: 1 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 pyridazinyl; each R 6 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolyl, -C(=O)NHOH; Preferably, L is selected from: More preferably, L is selected from:

18. The indole saturated ring compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 1, characterized in that: The indole and saturated ring compound or its derivative is selected from the following compounds:

19. Use of the indolo-saturated cyclic compound according to any one of claims 1 to 18 or its derivative, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug molecule, deuteride, or tritium in the preparation of an XOR inhibitor and / or a URAT1 inhibitor.

20. Use of the indole-saturated cyclic compound or its derivative, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug molecule, deuteride, or tritium according to any one of claims 1 to 18 in the preparation of a uric acid-lowering drug.

21. Use of the indole-saturated cyclic compound according to any one of claims 1 to 18 or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product in the preparation of a medicament for preventing and / or treating gout or hyperuricemia.

22. A XOR / URAT1 dual inhibitor, characterized in that The active ingredient contains the indole and saturated ring compound or its derivative according to any one of claims 1 to 18, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritium.

23. A uric acid-lowering drug, characterized in that: The active ingredient is prepared from an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient includes the indole saturated ring compound or its derivative according to any one of claims 1 to 18, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide.

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