Indolosaturated ring compounds or derivatives thereof and their use

Abstract

The application provides an indole saturated ring compound 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 compound thereof, and an application thereof. The indole saturated ring compound or the derivative thereof provided by the application is a novel compound, the compound has good inhibitory activity on uric acid oxidase and uric acid transporter, is XOR / URAT1 dual inhibition, has good uric acid reducing effect, has good safety, has good pharmacokinetics, has high drug property, and can be used for preparing a uric acid reducing drug and used for preventing and / or treating gout or hyperuricemia.

Description

[0001] The present application claims priority to the Chinese patent application No. 2024104935740, filed on April 23, 2024, and entitled "Indole and saturated ring compound or its derivative and application thereof", the entire content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the field of pharmaceutical chemistry, in particular to a class of indole and saturated ring compounds or its derivatives and application thereof. BACKGROUND

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

[0004] Currently, the drugs used to reduce uric acid mainly include the following: allopurinol or febuxostat inhibits xanthine oxidase to reduce the generation of uric acid; benzbromarone interferes with the reabsorption of uric acid in the kidneys to promote the excretion of uric acid; or for patients with refractory hyperuricemia, exogenous recombinant, modified uricase (even combined with immunosuppressants) is used to degrade uric acid; or some single-target drugs targeting uric acid transport proteins, such as Lesinurad approved in the United States in 2015 and withdrawn from the market in 2019, and Dotinurad approved in Japan.

[0005] Current drugs and therapeutic approaches have their limitations, and there is a huge unmet clinical need for hyperuricemia and gout patients, so it is necessary to develop safe and effective new uric acid-lowering drugs. From the mechanism of action and pharmacokinetics, the strategy of attacking the pathways of uric acid generation (xanthine oxidase) and uric acid reabsorption (uric acid transporter URAT1, gene name SLC22A12) at the same time with a single molecule is more advantageous than the strategy of attacking them separately. Pfizer developed a XOR / URAT1 dual inhibitor, a dual-target molecule PF-06743649, but it stopped at the clinical phase I because a few patients developed acute kidney injury. Therefore, it is necessary to develop a new dual-target uric acid-lowering drug to benefit hyperuricemia patients. SUMMARY

[0006] In view of the above problems, the present application provides an indole and saturated ring compound or its derivative, which has good inhibitory activity on xanthine oxidase (XOR) and uric acid transporter (URAT1), is a XOR / URAT1 dual inhibitor, and has good uric acid-lowering effect.

[0007] The present application comprises the following technical solutions:

[0008] The indole and 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, having the structure shown in formula I or formula II,

[0009]

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

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

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

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

[0014] Q is selected from: hydrogen, 1 or more R 4 substituted or unsubstituted C1-C6 alkyl, 1 or more R 4 substituted or unsubstituted C1-C6 alkoxy, 1 or more R 4 substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, aldehyde group, carboxyl, nitro, hydroxyl;

[0015] L is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C6 alkyl groups, one or more R 4 Substituted or unsubstituted C1-C6 alkoxy groups, one or more R groups 4 Substituted or unsubstituted C1-C6 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, hydroxyl groups, one or more R groups 5 Substituted or unsubstituted C3-C8 cycloalkyl groups, one or more R 5 Substituted or unsubstituted 3-8 membered heterocyclic group, one or more R 6 Replaced or not replaced C6-C 10 aryl, one or more R 6 Substituted or unsubstituted 5-10 heteroaryl groups

[0016] X 1 X 2 Each of the following can be independently selected from: -O-, -S-, -C(R) 1 )2-、-NR 2 -;

[0017] Z 1 Z 2 and Z 3 Each was selected independently from: CR 3 N;

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

[0019] Each R 2 Each of the following is independently selected from: hydrogen and C1-C6 alkyl groups;

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

[0021] Each R 4 Each group is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclic groups;

[0022] Each R 5 Each of the following is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

[0023] Each R 6Each group is independently selected from: hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxyl, mercapto, amino, R 5 Replaced or not replaced C6-C 10 Aryl, R 5 Substituted or unsubstituted 5-10 heteroaryl groups;

[0024] Each R is independently selected from: 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 cyclic compound or its derivative has a structure as shown in Formula III or Formula IV:

[0026]

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

[0028]

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

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

[0031] In some of these embodiments, X 1 X 2 Each of the following can be independently selected from: -O-, -S-, -C(R) 1 )2-、-NR 2 -;

[0032] Z 1 Z 2 and Z 3 Each was selected independently from: CR 3 N;

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

[0034] Each R 2 Each of the following is independently selected from: hydrogen and C1-C3 alkyl groups;

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

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

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

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

[0039] In some of these embodiments, each R 4 Each of the following is independently selected: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, tetrahydrofuranyl, oxecyclohexyl, tetrahydropyrroleyl, tetrahydrothiopheneyl.

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

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

[0042] In some of these embodiments, each R 6Each group is independently selected from: hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxyl, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5 Substituted or unsubstituted 5-6 membered heteroaryl groups;

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

[0044] In some of these embodiments, each R 6 Each of the following is independently selected from: 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, hydroxy, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thiophene, pyrroleyl, imidazolyl.

[0045] In some embodiments, Q is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C3 alkyl groups, one or more R 4 Substituted or unsubstituted C1-C3 alkoxy groups, one or more R groups 4 Substituted or unsubstituted C1-C3 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, and hydroxyl groups.

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

[0047] In some of these embodiments, Q is selected from: chlorine, bromine, or cyano.

[0048] In some embodiments, L is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C3 alkyl groups, one or more R 4 Substituted or unsubstituted C1-C3 alkoxy groups, one or more R groups 4Substituted or unsubstituted C1-C3 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, hydroxyl groups, one or more R groups 5 Substituted or unsubstituted C3-C6 cycloalkyl groups, one or more R 5 Substituted or unsubstituted 3-6 membered heterocyclic group, one or more R 6 Substituted or unsubstituted phenyl groups, one or more R groups 6 Substituted or unsubstituted naphthyl group, one or more R 6 Substituted or unsubstituted 5-6 heteroaryl groups

[0049] X 1 X 2 Each of the following can be independently selected from: -O-, -S-, -C(R) 1 )2-、-NR 2 -;

[0050] Z 1 Z 2 and Z 3 Each was selected independently from: CR 3 N;

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

[0052] Each R 2 Each of the following is independently selected from: hydrogen and C1-C3 alkyl groups;

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

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

[0055] Each R 5 Each group is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

[0056] Each R 6 Each of the following is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxyl, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R5 Substituted or unsubstituted naphthyl, R 5 Substituted or unsubstituted 5-6 membered heteroaryl groups;

[0057] Each R is independently selected from: 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, oxacyclobutyl, tetrahydrofuranyl, oxacyclohexyl, tetrahydropyrroleyl, tetrahydrothiopheneyl, halogen-substituted tetrahydropyrroleyl, hydroxyl-substituted tetrahydropyrroleyl, aziridine, halogen-substituted aziridine, hydroxyl-substituted aziridine, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl group, one or more R groups 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl group, one or more R 6 Substituted or unsubstituted pyrimidine groups

[0059] Among them, each R 6 Each of the following is independently selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyyl, ethoxyyl, 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, furanyl, thiophene, pyrroleyl, imidazolyl.

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

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

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

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

[0064] L is selected from:

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

[0066]

[0067] Where Q is a cyano group;

[0068] L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; each R 6 Each group is independently selected from: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH;

[0069] Preferably, L is selected from:

[0070] More preferably, L is selected from:

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

[0072]

[0073] Where Q is a cyano group;

[0074] L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; each R 6Each group is independently selected from: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH;

[0075] Preferably, L is selected from:

[0076] More preferably, L is selected from:

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

[0078]

[0079] Where Q is a cyano group;

[0080] L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; each R 6 Each group is independently selected from: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH;

[0081] Preferably, L is selected from:

[0082] More preferably, L is selected from:

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

[0084]

[0085] Where Q is chlorine or bromine;

[0086] L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; each R 6 Each group is independently selected from: hydrogen, methyl, ethyl, carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH;

[0087] Preferably, L is selected from:

[0088] More preferably, L is selected from:

[0089] This invention also provides applications of the aforementioned indole-saturated cyclic compounds or their derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, including the following technical solutions:

[0090] The use of the indole-saturated cyclic compounds or their derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, or their deuterates, or their tritides in the preparation of XOR inhibitors and / or URAT1 inhibitors.

[0091] The application of the indole-saturated cyclic compounds or their derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, or their deuterates, or their tritides in the preparation of uric acid-lowering drugs.

[0092] The use of the indole-saturated cyclic compounds or their derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, or their deuterates, or their tritides in the preparation of medicaments for the prevention and / or treatment of gout or hyperuricemia.

[0093] The present invention also provides an XOR / URAT1 dual inhibitor, the active ingredient of which contains 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 as described in the present invention.

[0094] The present invention also provides a uric acid-lowering drug, characterized in that it is prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes the indole-saturated cyclic compounds or their derivatives, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, or their deuterates, or their tritides as described in the present invention.

[0095] The indole-saturated cyclic compounds or their derivatives provided by this invention are a class of novel compounds. These compounds have good inhibitory activity against both uricase and urate transporter proteins, exhibiting dual XOR / URAT1 inhibition. They have good uric acid-lowering effects, good safety profile, excellent pharmacokinetic properties, and high drug-likeness. They can be used to prepare uric acid-lowering drugs for the prevention and / or treatment of gout or hyperuricemia. Attached Figure Description

[0096] Figure 1 Serum uric acid concentration in mice 8 hours after administration of compounds 1 and 6. Detailed Implementation

[0097] To facilitate understanding of the present invention, a more complete description will be provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0098] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the examples are commercially available products.

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

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

[0101] In the compounds described in this invention, when any variable (e.g., R) 4 R 5 If a component (e.g., a substituent) appears more than once in any component, the definition of each occurrence is independent of the definition of each subsequent occurrence. Similarly, combinations of substituents and variables are permitted, provided such combinations stabilize the compound. A line drawn from a substituent into the ring system indicates that the bond referred to can be attached to any substituted ring atom. If the ring system is polycyclic, it means that such a bond is attached only to any suitable carbon atom of a neighboring ring. It should be understood that those skilled in the art can select the substituents and substitution patterns of the compounds of this invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques in the art and the methods described below. If a substituent is itself substituted by more than one group, it should be understood that these groups can be on the same carbon atom or on different carbon atoms, as long as the structure is stable.

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

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

[0104] The term "alkoxy" as used in this article 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 "heterocyclic alkyl" or "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic substituent in which one or more ring atoms are selected from heteroatoms of N, O, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Bicyclic or polycyclic groups include spirocyclic, fused, and bridged rings. Examples include: oxoheterobutyl, azaheterobutyl, morpholino, piperidinyl, tetrahydropyrrolyl, pyrrolylalkyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazoleyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiopheneyl, dihydrotriazolyl, dihydroazacyclobutane, tetrahydrofuranyl, tetrahydrothiopheneyl. And so on, and their N-oxides. The connection of heterocyclic substituents can be achieved through carbon atoms or through heteroatoms.

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

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

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

[0109] Therefore, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting an alkaline compound of the present invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid, etc.

[0110] If the compounds of this invention are acidic, then a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary, and tertiary amines, wherein substituted amines include 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, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.

[0111] Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci. '1977: 66: 1–19, describe in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

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

[0113] The present invention provides a uric acid-lowering drug, as well as a drug or method for preventing and / or treating gout or hyperuricemia, comprising (administered to a patient or subject) an active ingredient (i.e., the indole-saturated cyclic compound or its derivatives, or its stereoisomers, or its pharmaceutically acceptable salts, or its solvates, or its prodrug molecules, or its deuterates, or its tritides) within a safe and effective range, and pharmaceutically acceptable excipients. When administering the drug, a safe and effective amount of the active ingredient is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. Of course, the specific dose should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0114] The "active ingredient" as described in this invention refers to the compound of formula I or formula II, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide.

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

[0116] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0117] "Pharmaceutical acceptable excipients" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0118] "Compatibility" here refers to the ability of the components in the composition to interact with and blend with the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.

[0119] Pharmaceutically acceptable examples of 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, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as...). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, 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 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 chemical bonds. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0121] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[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 the following components:

[0124] (a) Fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silica;

[0125] (b) Adhesives, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0126] (c) Moisturizers, such as glycerin;

[0127] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginate, certain complex silicates, and sodium carbonate;

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

[0129] (f) Absorption accelerators, such as quaternary ammonium compounds;

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

[0131] (h) Adsorbents, such as kaolin; and

[0132] (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer.

[0133] The solid dosage form can also be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient from this composition can be delayed in a portion of the digestive tract. Examples of suitable encapsulating components are polymers and waxes.

[0134] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides 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 ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol 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 this invention can be administered alone or in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage remain unchanged, while the compound of formula I or II is taken simultaneously or subsequently. When the compound of formula I or II is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I or II is preferred. Drug combination also includes taking the compound of formula I or II with one or more other known drugs during overlapping time periods. When the compound of formula I or II is used in combination with one or more other drugs, the dosage of the compound of formula I or II or the known drug may be lower than the dosage when they are taken alone.

[0138] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

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

[0140] The raw materials used in the following examples may be commercially available, or prepared by methods known in the art, or prepared according to the methods described herein.

[0141] The abbreviations for the raw materials and reagents used in the following examples are explained below:

[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'-tetramethylurea hexafluorophosphate;

[0149] DMSO: Dimethyl sulfoxide;

[0150] NMP: N-methylpyrrolidone;

[0151] NBS: N-bromosuccinimide;

[0152] NCS: N-chlorosuccinimide;

[0153] NaHMDS: Sodium bis(trimethylsilyl)amino;

[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] In acetonitrile (200 ml), 5-amino-1,3-dihydroisobenzofuran (10 g, 0.074 mol) and NIS (16.6 g, 0.074 mol) were added. The mixture was stirred at 25 °C for 4 hours. After concentration, the reaction was treated with water, and then extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and evaporated to dryness before being passed through a column to obtain a yellow 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-trimethylsilyne-5-amino-1,3-dihydroisobenzofuran (intermediates 1-2)

[0162] In triethylamine (25 ml), 4-iodo-5-amino-1,3-dihydroisobenzofuran (2.0 g, 7.66 mmol), trimethylsilyne (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. The reaction was then carried out at 80 °C for 12 hours. After concentration, the reaction was treated with water, extracted with dichloromethane, and the organic phase was dried, concentrated under reduced pressure, and purified by column chromatography to give a yellow solid product (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-furan[3,4-e]indole (intermediates 1-3)

[0165] In DMF (70 ml), 4-trimethylsilyne-5-amino-1,3-dihydroisobenzofuran (4.4 g, 19.02 mmol) and CuI (7.24 g, 38 mmol) were added. The reaction was then carried out at 120 °C for 2 hours. After concentration, the reaction was treated with water, extracted with ethyl acetate, dried, concentrated under reduced pressure, and purified by column chromatography to give 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-aldehyde-3,6-dihydro-1H-furan[3,4-e]indole (intermediates 1-4)

[0169] In DMF (10 ml), 3,6-dihydro-1H-furan[3,4-f]indole (600 mg, 3.77 mmol) and POCl3 (694 mg, 4.53 mmol) were added. The mixture was then reacted at room temperature for 3 hours. NaOH aqueous solution (2.0 M) was then added, and the mixture was heated to 70 °C and reacted for 0.5 hours. The mixture was extracted with ethyl acetate, dried over dryness, concentrated under reduced pressure, and evaporated to dryness to give a red solid product (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-furan[3,4-e]indole (intermediates 1-5)

[0173] In THF (5 ml), 8-aldehyde-3,6-dihydro-1H-furan[3,4-e]indole (449 mg, 2.43 mmol), hydroxylamine hydrochloride (337 mg, 4.85 mmol), and pyridine (770 mg) were added. The reaction was then carried out at 80 °C for 12 hours. Acetic anhydride (2.3 ml) was then added and the reaction was carried out for another 12 hours. NaOH aqueous solution (2.0 M) was then added at room temperature, followed by extraction with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and evaporated to dryness to give a yellow solid product (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-furan[3,4-e]indol-6-yl)benzoate (intermediates 1-6)

[0176] In DMF (1 ml), 8-cyano-3,6-dihydro-1H-furan[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. The reaction was then carried out at 80 °C for 12 hours and cooled to room temperature. The reaction was then treated with water, extracted with ethyl acetate, dried, concentrated under reduced pressure, and purified by column chromatography to give a white solid product (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-furan[3,4-e]indol-6-yl)-benzoic acid (compound 1)

[0180] To TFA (1 ml), tert-butyl 4-(8-cyano-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)benzoate (30 mg, 0.08 mmol) was added. The mixture was then reacted at 60 °C for 3 hours, followed by the addition of water to treat the reaction. The product was filtered to obtain a white solid, which was then dried to give the target 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-furan[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoate (intermediate 6-1)

[0186] In DMF (10 ml), 8-cyano-3,6-dihydro-1H-furan[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. The reaction was then carried out at 85 °C for 12 hours and cooled to room temperature. The reaction was then treated with water, extracted with ethyl acetate, dried, concentrated under reduced pressure, and purified by column chromatography to give a white solid product (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-furan[3,4-e]indol-6-yl)-2-hydroxybenzoate (intermediate 6-2)

[0189] In THF (20 ml), ethyl 4-(8-cyano-1,3-dihydro-6H-furan[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) were added. The mixture was then reacted at 70 °C for 12 hours and cooled to room temperature. After filtration, the product was washed with EtOH and H2O and dried to give a white solid product (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-furan[3,4-e]indol-6-yl)-2-hydroxybenzoic acid (compound 6)

[0192] In THF (2 ml), ethyl 4-(8-cyano-1,3-dihydro-6H-furan[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 then reacted at room temperature for 24 hours, followed by acidification with HCl (2.0 M). The product was filtered to obtain a white solid, washed with H2O and EtOH, and dried to obtain the target 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-furan[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoic acid (intermediate 12-1)

[0198] Ethyl 4-(8-cyano-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoate (200 mg, 0.51 mmol), H2O (1.0 ml), and LiOH (107 mg) were added to a mixed solvent of THF (3 ml) and ethanol (3 ml). The mixture was then reacted at room temperature for 12 hours, followed by acidification with HCl (2.0 M). The product was filtered to obtain a white solid, washed with H2O and EtOH, and dried to obtain the target 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-furan[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)-N-(OTHP)benzamide (compound 12-2)

[0201] 4-(8-cyano-1,3-dihydro-6H-furan[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 mixture was then reacted at room temperature for 12 hours, followed by water treatment, extraction with ethyl acetate, drying of the organic phase, concentration under reduced pressure, and rotary evaporation 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-furan[3,4-e]indol-6-yl)-N,2-dihydroxybenzamide (compound 12)

[0205] 4-(8-cyano-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)-N-(OTHP)benzamide (30 mg, 0.26 mmol) and HCl (2.0 M, 0.3 ml) were added to a mixed solvent of THF (1 ml) and EtOH (0.5 ml). The mixture was then reacted at 70 °C for 12 hours and cooled to room temperature. The mixture was filtered, and the resulting solid was washed with EtOH and H₂O and dried to give a reddish solid product (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-aldehyde-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-benzonitrile (intermediate 5-1)

[0211] In DMSO (5.0 mL), 300 mg (1.6 mmol) of 8-aldehyde-3,6-dihydro-1H-furan[3,4-e]indole, 1.0 g (3.2 mmol) of Cs₂CO₃, and 310 mg (2.6 mmol) of 4-fluorobenzonitrile were added. The reaction was then carried out at 80 °C for 12 hours and cooled to room temperature. The reaction was then treated with water, and the resulting filter cake was washed with water and ethanol and dried to give a 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-aldehyde-6-(4-(1H-tetrazol-5-yl)phenyl)-3,6-dihydro-1H-furan[3,4-e]indole (intermediate 5-2)

[0215] In NMP (6.0 ml), 4-(8-aldehyde-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-benzonitrile (390 mg, 1.35 mmol), NaN3 (308 mg, 4.74 mmol), and triethylamine hydrochloride (372 mg) were added. The reaction mixture was then sealed in a tube and reacted at 120 °C for 12 hours, followed by cooling to room temperature. The pH of the reaction mixture was then adjusted to 3 with hydrochloric acid (2.0 M), and the mixture was stirred for half an hour. The resulting filter cake was washed with methanol and dried to give 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-furan[3,4-e]indole (compound 5)

[0219] In formic acid (5.0 ml), 8-aldehyde-6-(4-(1H-tetrazol-5-yl)phenyl)-3,6-dihydro-1H-furan[3,4-e]indole (320 mg, 0.97 mmol), hydroxylamine hydrochloride (100 mg, 1.45 mmol), and sodium formate (197 mg) were added. The mixture was then reacted at 105 °C for 4 hours, followed by the addition of water to treat the reaction. The resulting filter cake was thoroughly washed with methanol, and the methanol solution was collected, concentrated under reduced pressure, and evaporated to dryness to obtain the target 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] In acetonitrile (400 ml), 5-amino-2,3-dihydroindene (10.0 g, 75 mmol) and NBS (33.4 g, 188 mmol) were added, and the mixture was stirred at room temperature for 4 hours. After concentration, the reaction was treated with water, extracted with dichloromethane, dried the organic phase, concentrated under reduced pressure, and passed through a column to give 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] In a mixture of concentrated hydrochloric acid (15 ml), HOAc (18 ml), and a mixed solvent, 5-amino-4,6-dibromo-2,3-dihydroindene (4.0 g, 14 mmol) and SnCl2 dihydrate (3.8 g, 17 mmol) were added. The mixture was stirred at 120 °C for half an hour. Then, at room temperature, NaOH aqueous solution (2.0 M) was added 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 column chromatography was performed 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-trimethylsilyne-5-amino-2,3-dihydro-1H-indene (intermediate 49-3)

[0230] In triethylamine (6 ml), 5-amino-4-bromo-2,3-dihydro-1H-indene (100 mg, 0.47 mmol), trimethylsilyne (70 mg, 0.71 mmol), CuI (9.0 mg, 0.05 mmol), and Pd(dppf)Cl2 (34 mg, 0.05 mmol) were added. The reaction was then carried out at 80 °C for 12 hours. After concentration, the reaction was treated with water, extracted with dichloromethane, dried over a vacuum, concentrated to dryness, and column chromatography to give a pale yellow liquid product (28 mg, 26%).

[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-tetrahydrocyclopentano[e]indole (intermediate 49-4)

[0233] In DMF (1 ml), 28 mg (0.12 mmol) of 4-trimethylsilyne-5-amino-2,3-dihydro-1H-indene and 47 mg (0.24 mmol) of CuI were added. The mixture was then reacted at 120 °C for 2 hours. After cooling to room temperature, the mixture was filtered, concentrated, evaporated to dryness, and passed through a column chromatography to give a white solid product (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-aldehyde-3,6,7,8-tetrahydrocyclopentano[e]indole (intermediate 49-5)

[0237] In DMF (4.0 mL), 3,6,7,8-tetrahydrocyclopentano[e]indole (200 mg, 1.28 mmol) and POCl3 (197 mg, 1.28 mmol) were added. The reaction mixture was then reacted at room temperature for 12 hours. The pH of the reaction mixture was adjusted to 9-12 with NaOH aqueous solution (2.0 M), and the mixture was heated to 70 °C for 1 hour. The mixture was extracted with dichloromethane, dried over reduced pressure, concentrated to dryness, and then column-secreted to give a yellow solid product (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-tetrahydrocyclopentano[e]indole (intermediate 49-6)

[0241] In THF (5.0 mL), 1-aldehyde-3,6,7,8-tetrahydrocyclopentanoid[e]indole (176 mg, 0.96 mmol), hydroxylamine hydrochloride (133 mg, 1.91 mmol), and pyridine (300 mg) were added. The reaction was then carried out at 80 °C for 12 hours. Acetic anhydride (985 mg) was then added and the reaction was carried out for 7 hours. The pH of the solution was then adjusted to 10⁻¹² with NaOH aqueous solution (2.0 M) at room temperature, and the mixture was stirred for half an hour. Dichloromethane was added for extraction, the organic phase was dried, concentrated under reduced pressure, and then purified by column chromatography to give an off-white solid product (82 mg, 47%).

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

[0243] In DMF (3.0 mL), 1-cyano-3,6,7,8-tetrahydrocyclopentano[e]indole (82 mg, 0.45 mmol), Cs₂CO₃ (295 mg, 0.91 mmol), and tert-butyl 4-fluorobenzoate (134 mg, 0.68 mmol) were added. The reaction was then carried out at 100 °C for 12 hours, followed by cooling to room temperature. The reaction was treated with water, extracted with dichloromethane, dried over a vacuum, concentrated to dryness, and column chromatography to give a colorless oily product (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-dihydrocyclopentano[e]indole-3(6H)-yl)benzoic acid (compound 49)

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

[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-furan[3,4-e]indole (intermediate 97-1)

[0253] In acetonitrile (6.0 mL), 3,6-dihydro-1H-furan[3,4-e]indole (150 mg, 0.94 mmol) and NCS (126 mg, 0.94 mmol) were added. The reaction was then carried out at room temperature for 4 hours. The reaction was then treated with water, extracted with ethyl acetate, dried over a vacuum, concentrated to dryness, and column-secreted to give a yellow solid product (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-furan[3,4-e]indol-6-yl)benzoate (intermediate 97-2)

[0257] In DMF (5.0 mL), 8-chloro-3,6-dihydro-1H-furan[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. The reaction mixture was then reacted at 80 °C for 12 hours and cooled to room temperature. The reaction was then treated with water, extracted with ethyl acetate, dried over a vacuum, concentrated to dryness, and column-secreted to give a white solid product (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-furan[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-furan[3,4-e]indol-6-yl)benzoate (210 mg, 0.57 mmol) was added. The mixture was then reacted at room temperature for 1 hour, concentrated under reduced pressure, evaporated to dryness, slurried with methanol, filtered, and dried to give the target 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-furan[3,4-e]indole (intermediate 193-1)

[0266] In acetonitrile (10.0 ml), 3,6-dihydro-1H-furan[3,4-e]indole (500 mg, 3.14 mmol) and NBS (448 mg, 2.5 mmol) were added. The reaction was then carried out at room temperature for 3 hours. The reaction was then treated with water, extracted with ethyl acetate, dried over a vacuum, concentrated to dryness, and column-secreted to give 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-furan[3,4-e]indol-6-yl)benzoate (intermediate 193-2)

[0269] In DMF (1.5 mL), 8-bromo-3,6-dihydro-1H-furan[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. The reaction mixture was then reacted at 80 °C for 12 hours and cooled to room temperature. The reaction was then treated with water, extracted with ethyl acetate, dried over reduced pressure, concentrated under reduced pressure, and purified by column chromatography to give a white solid product (10 mg, 8%).

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

[0271] In TFA (0.5 ml), tert-butyl 4-(8-bromo-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)benzoate (5 mg, 0.02 mmol) was added. The reaction was carried out at room temperature for 0.5 h, then concentrated under reduced pressure, evaporated to dryness, washed with ethyl acetate, and dried to give the target product (4 mg, 92%) as a brown solid.

[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 mixture was stirred at room temperature for 12 hours. The reaction solution was then treated with saturated Na2SO3 solution until it turned yellow. Sodium hydroxide aqueous solution (4.0 M) was added to adjust the pH of the reaction solution to 10. Ethyl acetate was added for extraction, the organic phase was dried, concentrated under reduced pressure, and then column chromatography was performed 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] In concentrated hydrochloric acid (20 ml) and HOAc (60 ml), 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. The mixture 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 was 10. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and column chromatography was performed to give 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 (4-bromo-2,3-dihydrobenzofuran-5-yl)tert-butyl carbamate (intermediate 25-3)

[0283] 5-Amino-4-bromo-2,3-dihydrobenzofuran (7.8 g, 36.45 mmol) was added to THF (60 ml), followed by the addition of NaHMDS (146 ml, 0.5 M toluene solution) at 0 °C. The mixture was stirred for 1 hour, then Boc₂O (8.6 g, 40.1 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. Saturated NH₄Cl aqueous solution was added until neutral, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and column chromatography was performed to give 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 (4-trimethylsilyne-2,3-dihydrobenzofuran-5-yl)carbamate tert-butyl ester (intermediate 25-4)

[0286] In a mixed solvent of 1,4-dioxane (25 ml) and water (2.5 ml), tert-butyl 4-bromo-2,3-dihydrobenzofuran-5-yl)carbamate (1.8 g, 5.75 mmol), 2-acetylene-4,4,5,5-tetramethyl-[1,3,2]dioxborane (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) were added. The reaction was then carried out in a sealed tube at 110 °C for 4 hours under a nitrogen atmosphere. The reaction was then treated with water, extracted with ethyl acetate, dried over a vacuum, concentrated to dryness, and column chromatography to give a pale yellow liquid product (1.3 g).

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

[0288] In NMP (7 ml), tert-butyl (4-trimethylsilyne-2,3-dihydrobenzofuran-5-yl)carbamate (1.3 g) and t-BuOK (880 mg, 7.85 mmol) were added. The reaction was then carried out at 80 °C for 1 hour. After cooling to room temperature, saturated NH4Cl aqueous solution was added until the reaction solution was neutral. The mixture was then extracted with ethyl acetate, dried over reduced pressure, concentrated to dryness, and column chromatography to give a white solid product (332 mg, two-step yield 36%).

[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-aldehyde-1,6-dihydro-2H-furan[3,2-e]indole (intermediate 25-6)

[0292] In DMF (1.5 ml), POCl3 (450 mg, 2.94 mmol) and 1,6-dihydro-2H-furan[3,2-e]indole (332 mg, 2.09 mmol) were added. The mixture was then reacted at room temperature for 2 hours. NaOH aqueous solution (2.0 M) was then added to adjust the pH of the reaction solution to 9-12, and the mixture was heated to 70 °C for 1 hour. After cooling to room temperature, the mixture was filtered to give a yellow solid product (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-furan[3,2-e]indole (intermediate 25-7)

[0295] In DMF (3.0 ml), 270 mg (1.44 mmol) of 8-aldehyde-1,6-dihydro-2H-furan[3,2-e]indole, 186 mg (2.90 mmol) of hydroxylamine hydrochloride, and 456 mg of pyridine were added. The reaction was then carried out at 80 °C for 2 hours. Acetic anhydride (750 mg) was then added and the reaction was carried out for 12 hours. NaOH aqueous solution (2.0 M) was then added at room temperature to adjust the pH of the reaction solution to 10-12, and the mixture was stirred for half an hour. Dichloromethane was added for extraction, the organic phase was dried, concentrated under reduced pressure, and then purified by column chromatography to give a brown solid product (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-furan[3,2-e]indol-6-yl)benzoate (intermediate 25-8)

[0299] In DMAc (1.5 ml), 8-cyano-1,6-dihydro-2H-furan[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. The reaction was then carried out at 100 °C for 5 hours, followed by cooling to room temperature. The reaction was treated with water, extracted with ethyl acetate, dried over reduced pressure, concentrated under reduced pressure, and purified by column chromatography to give a white solid product (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-furan[3,2-e]indol-6-yl)benzoic acid (compound 25)

[0303] To TFA (2 ml), tert-butyl 4-(8-cyano-1,2-dihydro-6H-furan[3,2-e]indol-6-yl)benzoate (98 mg, 0.27 mmol) was added. The mixture was then reacted at room temperature for 1 hour. After treatment with water, the mixture was filtered, and the filter cake was washed with water and dried to give the target product (64 mg, 77%) as a white solid.

[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. The reaction was then treated with sodium sulfite solution (1.0 M) until the product turned pale yellow. After neutralization with sodium carbonate, the product was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and column chromatography was performed to give 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-trimethylsilyne-5-aminoisoindoline-2-carboxylate (intermediate 61-2)

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

[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] In DMF (28 ml), tert-butyl 4-trimethylsilyne-5-aminoisoindoline-2-carboxylate (2.0 g, 6.05 mmol) and CuI (1.73 g, 9.09 mmol) were added. The mixture was then reacted at 110 °C for 2 hours. After cooling to room temperature, the mixture was filtered, the reaction was treated with water, extracted with ethyl acetate, dried over reduced pressure, concentrated to dryness, and column chromatography was performed to give a yellow solid product (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] In 13 ml of THF, tert-butyl 3,6-dihydropyrrolo[3,4-e]indole-2(1H)-carboxylate (684 mg, 2.65 mmol) and LAH (202 mg) were added. The reaction was then carried out at 60 °C for 2 hours. After cooling to room temperature, water and sodium hydroxide (4.0 M) were added to treat the reaction. The mixture was filtered, concentrated under reduced pressure, evaporated to dryness, and then passed through a column to give a yellow solid product (411 mg, 90%).

[0319] LCMS calcd 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-aldehyde-2-methyl-1,2,3,6-tetrahydropyrrolo[3,4-e]indole (intermediate 61-5)

[0322] In DMF (4.0 mL), 2-methyl-1,2,3,6-tetrahydropyrrolo[3,4-e]indole (200 mg, 1.16 mmol) and POCl3 (271 mg) were added. The mixture was then reacted at room temperature for 3 hours. NaOH aqueous solution (4.0 M) was then added to adjust the pH to 13, and the mixture was heated to 70 °C for 0.5 hours. After cooling to room temperature, ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and evaporated to dryness to give a brown crude product (163 mg).

[0323] LCMS calcd 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] In THF (4 ml), 8-aldehyde-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. The reaction was then carried out at 80 °C for 5 hours. Acetic anhydride (0.7 ml) was then added and the reaction was carried out for 12 hours. NaOH aqueous solution (4.0 M) was then added at room temperature to adjust the pH of the reaction solution to 10, and the reaction was stirred for 0.5 hours. Ethyl acetate was added for extraction, the organic phase was dried, concentrated under reduced pressure, and then purified by column chromatography to give the product (65 mg, 40%).

[0326] LCMS calcd 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] In 1.5 ml of DMF, 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) were added. The reaction was then carried out at 80 °C for 12 hours, followed by cooling to room temperature. The reaction was treated with water, extracted with ethyl acetate, dried over a vacuum, concentrated to dryness, and column chromatography to give a white solid product (15 mg, 13%).

[0329] LCMS calcd 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 then reacted at room temperature for 2 hours, concentrated under reduced pressure, evaporated to dryness, and then slurried with ethanol. After drying, a white solid (10 mg, 51%) was obtained.

[0332] LCMS calcd 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] Compounds 1-193 were prepared according to the preparation methods of Examples 1-9. The preparation methods of these compounds, as well as their structural formulas and characterization data, are shown in Table 1.

[0335] Table 1. Structural formulas, characterization data, and preparation methods of compounds 1-193

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342] Example 10: Inhibition of xanthine oxidase activity by the compound

[0343] Weigh 3 mg of the test compound, including the positive control febuxostat, dissolve it in DMSO to prepare a 10 mM stock solution, and then serially dilute it with 5% DMSO aqueous solution to prepare 8 concentration gradients containing the same concentration of DMSO (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 Merck website. Mouse liver tissue (500 μL / 30 mg) was homogenized using the kit's assay buffer to obtain a tissue homogenate containing mouse xanthine oxidase. After centrifugation at 10,000 rpm for 10 min at 4°C, the supernatant was transferred to a new centrifuge tube and placed on ice for later use.

[0345] Add 50 μL of tissue homogenate to each well of a 96-well plate, followed by 2 μL of the corresponding concentration of the test compound, and then 48 μL of the mixture containing the other components of the kit, for a total volume of 100 μL / well. Incubate at 25°C for 3 minutes, then excite at 535 nm. Read the fluorescence intensity at 587 nm (the more superoxide radicals generated by xanthine oxidase oxidizing hypoxanthine and xanthine in the reaction system, the more Resorufin is produced through chemical reaction with 10-acetyl-3,7-dihydroxyphenoxazine in the system, resulting in higher fluorescence intensity and indicating higher xanthine oxidase activity). Dynamically read the fluorescence every 3 minutes over 15 minutes at 25°C. Wells without inhibitors represent 100% xanthine oxidase activity, while wells without enzymes represent zero activity (background). After reading the plate, perform QC to confirm that the 12-minute mark is within the linear range. Analyze the inhibition efficiency at the 12-minute mark to obtain the IC50 of the test compound. 50 .

[0346] The test results are shown in Table 2: The indole-saturated cyclic 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 control drug febuxostat.

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

[0348] Compound IC 50 (nM) Compound 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 protein by compound

[0350] As in Example 10, a concentration gradient of the test compound and the positive control (lesinurad) was prepared.

[0351] All cell culture media were purchased from Invitrogen, and plastic products from Corning. Because renal tubular epithelial cells express Urat1 and Glut9, these cells can be used to detect uric acid transporter activity. Mouse renal tubular epithelial cells were seeded on cell culture transwell membranes with 0.4 μm pores and cultured until the cells completely covered the transwell, forming a monolayer. Before detecting the test compound, the transwell cuvettes were replaced with DMEM basal medium containing a specific concentration of the test compound and 4.5 mg / dL uric acid. The bottom layer of the multi-well plate was replaced with DMEM basal medium without uric acid. After incubation at 37°C for 60 min, 100 μL of medium was removed from the bottom layer of the multi-well plate, and the uric acid concentration was read at 290 nm using a microplate reader. Using wells without uric acid as a blank control and wells without the compound as 100% transport, the uric acid concentration in the wells corresponding to the test compound was compared with the concentration in the wells with 100% transport to obtain the inhibition efficiency.

[0352] The results showed that lesinurad inhibited uric acid transporter protein by 23.63% at a concentration of 1000 nM, while compound 6 inhibited uric acid transporter protein by 64% at a concentration of 250 nM. Therefore, the compounds of this invention exhibit good inhibitory activity against uric acid transporter protein, with higher inhibitory activity at 250 nM than that of lesinurad at 1000 nM.

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

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

[0355] Cells were pre-coated in 96-well plates. The following day, the medium was replaced with a mixture of C14-labeled uric acid and different concentrations of positive controls or other test compounds. After incubation for 5 minutes, the medium was removed, and the cells were lysed with 0.1N NaOH. The supernatant was then read using a Revvity liquid scintillation counter (MicroBeta2). The readings of wells with C14-labeled uric acid but no other compound were considered 100% uric acid transport, while the readings of wells without C14-labeled uric acid were considered background readings. The inhibitory efficiency of different concentrations of positive control compounds or test compounds on uric acid transporters was calculated to obtain the IC50.

[0356] The test results are shown in Table 3: The inhibitory activity of compound 6 of the present invention against uric acid transporters is comparable to that of the positive control (Lesinurad) under the same experimental conditions. This demonstrates that the compound of the present invention exhibits good inhibitory activity against uric acid transporters.

[0357] Table 3 shows the inhibitory effects of the compounds on uric acid transporters.

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

[0359] Example 13: Pharmacological test of the compound in lowering uric acid levels in the body.

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

[0361] The results are as follows Figure 1 As shown, 8 hours after administration of compounds 1 and 6, serum uric acid concentration was effectively reduced to about half that of the control group.

[0362] The technical features of the above embodiments can be combined in any way. For the sake of brevity, 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 embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. An indole-saturated cyclic compound having the structure shown in Formula I, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide. I in, X is selected from: -O-, -CH2-, -NR 2 -; m and n are independently selected from 0, 1, and 2 respectively, 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 groups, one or more R 4 Substituted or unsubstituted C1-C6 alkoxy groups, one or more R groups 4 Substituted or unsubstituted C1-C6 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, and hydroxyl groups; L is selected from: one or more R 6 Replaced or not replaced C6-C 10 aryl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl group, one or more R 6 Substituted or unsubstituted pyrimidine group; Each R 2 Each of the following is independently selected from: hydrogen and C1-C6 alkyl groups; Each R 3 Each of the following is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen; Each R 4 Each of the following is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl. Each R 5 Each of the following is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl. Each R 6 Each of the following is independently selected from: -C(=O)R, hydroxyl group, R 5 Substituted or unsubstituted tetrazolium group; Each R is independently selected from: hydroxyl, hydroxyamino, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino.

2. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 1, characterized in that... The indole-saturated cyclic compound has the structure shown in Formula III: III.

3. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 1, characterized in that... The indole-saturated cyclic compounds have structures as shown in formulas V-1, V-2, V-3, V-5, or V-6: 。 4. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, Each R 2 Selected from: hydrogen, C1-C3 alkyl.

5. The indole-saturated cyclic compound or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 4, characterized in that, Each R 2 Selected from: hydrogen, methyl, ethyl.

6. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, Each R 4 Each of the following groups is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl. And / or, each R 5 Each of the following is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

7. The indole-saturated cyclic compound or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide according to claim 6, characterized in that, Each R 4 Each of the following groups is independently selected: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

8. The indole-saturated cyclic compound or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide according to claim 6, characterized in that, Each R 5 Each of the following groups is independently selected: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

9. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, Each R 6 Each of the following is independently selected from: -C(=O)R, hydroxyl group, R 5 Substituted or unsubstituted tetrazolium group; Each R is independently selected from: hydroxyl, hydroxyamino, amino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

10. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 9, characterized in that... Each R 6 Each group is independently selected from: carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, hydroxyl, and tetrazolium.

11. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, Q is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C3 alkyl groups, one or more R 4 Substituted or unsubstituted C1-C3 alkoxy groups, one or more R groups 4 Substituted or unsubstituted C1-C3 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, and hydroxyl groups.

12. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 11, characterized in that... Q is selected from: hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxyl.

13. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 12, characterized in that... Q is selected from: cyano, chlorine, bromine.

14. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, L is selected from: one or more R 6 Substituted or unsubstituted phenyl groups, one or more R groups 6 Substituted or unsubstituted naphthyl group, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl group, one or more R 6 Substituted or unsubstituted pyrimidine group; Each R 5 Each of the following groups is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl. Each R 6 Each of the following is independently selected from: C(=O)R, hydroxyl group, R 5 Substituted or unsubstituted tetrazolium group; Each R is independently selected from: hydroxyl, hydroxyamino, amino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino.

15. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 14, characterized in that... L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl group, one or more R groups 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl group, one or more R 6 Substituted or unsubstituted pyrimidine group; Among them, each R 6 Each group is independently selected from: carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, hydroxyl, and tetrazolium.

16. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 15, characterized in that... L is selected from: , , , , , , , , , , , , , , , , , , , , , , .

17. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 16, characterized in that, L is selected from: , , , , , , , , , , , .

18. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, Q is selected from: halogen, cyano; L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; wherein each R 6 Each group is independently selected from: carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH.

19. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 18, characterized in that, Q is selected from: chlorine, bromine, cyano; L is selected from: , , , , , , , , , , , , .

20. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, The indole-saturated cyclic compounds have the structure shown in Formula V-1. Where Q is a cyano group; L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; each R 6 Each group is independently selected from: carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH.

21. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 20, characterized in that... L is selected from: , , , , , , , , , , , .

22. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 21, characterized in that... L is selected from: , , .

23. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, The indole-saturated cyclic compounds have the structure shown in Formula V-3. Where Q is a cyano group; L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; each R 6 Each group is independently selected from: carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH.

24. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 23, characterized in that... L is selected from: , , , , , , , , , , , .

25. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 24, characterized in that... L is selected from: , , .

26. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, The indole-saturated cyclic compounds have the structure shown in Formula V-5. Where Q is a cyano group; L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; each R 6 Each group is independently selected from: carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH.

27. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 26, characterized in that... L is selected from: , , , , , , , , , , , .

28. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 27, characterized in that... L is selected from: , , , .

29. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to any one of claims 1-3, characterized in that, The indole-saturated cyclic compounds have the structure shown in Formula V-1. Where Q is chlorine or bromine; L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridinyl group, one or more R 6 Substituted or unsubstituted pyrazinyl group, one or more R 6 Substituted or unsubstituted pyridazinyl groups; each R 6 Each group is independently selected from: carboxyl, hydroxyl, tetrazolium, and -C(=O)NHOH.

30. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 29, characterized in that... L is selected from: , , , , , , , , , , , .

31. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 30, characterized in that... L is selected from: .

32. The indole-saturated cyclic compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide, according to claim 1, characterized in that... The indole-saturated cyclic compounds are selected from the following compounds: 。 33. The use of the indole-saturated cyclic compound of any one of claims 1-32, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide in the preparation of XOR inhibitors and / or URAT1 inhibitors.

34. The use of the indole-saturated cyclic compound of any one of claims 1-32, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide in the preparation of a uric acid-lowering drug.

35. The use of the indole-saturated cyclic compound of any one of claims 1-32, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide in the preparation of a medicament for the prevention and / or treatment of gout or hyperuricemia.

36. An XOR / URAT1 dual inhibitor, characterized in that, Its active ingredient contains an indole-saturated cyclic compound as described in any one of claims 1-32, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide.

37. A uric acid-lowering drug, characterized in that, It is prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes an indole-saturated cyclic compound as described in any one of claims 1-32, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuteride, or its tritide.

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