Aryl-substituted indole compound or derivative thereof and use thereof

Abstract

The present invention provides an aryl-substituted indole compound having a structure as shown in formula I or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof, and a use thereof. The aryl-substituted indole compound or a derivative thereof provided by the present invention is a compound having a novel structure. The compound has good inhibitory activity on both urate oxidase and a urate transporter, is a dual inhibitor of XOR / URAT1, exhibits good uric acid-lowering effect, good safety, good pharmacokinetic properties, and high potential to be manufactured as a drug, and can be used for preparing a uric acid-lowering drug for preventing and / or treating gout or hyperuricemia.

Description

Aryl-substituted indole compounds or their derivatives and their applications

[0001] This invention claims priority to two Chinese patent applications filed on March 20, 2025, with application number 2025103352354, entitled "Aryl-substituted indole compounds or their derivatives and their applications", and on June 13, 2025, with application number 2025107934405, entitled "Aryl-substituted indole compounds or their derivatives and their applications", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, specifically to a class of aryl-substituted indole compounds or their derivatives and their applications. Background Technology

[0003] Uric acid is the final product of purine metabolism in humans and non-human primates, formed by the catalysis of xanthine oxidase. Humans lack uricase, and uric acid can only be excreted through the intestines and kidneys. Due to the prevalence of Western diets, excessive purine intake can lead to massive cell death in a short period (tumor lysis syndrome). Inefficient uric acid excretion pathways caused by genetic or environmental factors can also result in hyperuricemia. Extensive basic and clinical medical data indicate that, regardless of whether uric acid crystals form, high uric acid is an independent high-risk factor, associated with the pathogenesis of various diseases, such as diabetic nephropathy, other chronic kidney diseases, and cardiovascular diseases. The normal range for uric acid in the human body is 3-6.0 mg / dl (180-360 μmol). Uric acid solubility is <6.5 mg / dl (37℃, pH 7.0). Exceeding this concentration can lead to crystal formation. Decreasing pH and temperature promote crystallization, causing deposits in joints at the extremities or other parts of the body (such as blood vessels and kidneys), resulting in cell damage and inflammation, causing significant pain and severely impacting the patient's quality of life. Hyperuricemia affects 8% of the total population, and gout affects 4%. More than 10% of people over 60 years of age will experience a gout attack.

[0004] Currently, the main drugs used to lower uric acid include: allopurinol or febuxostat inhibiting xanthine oxidase, thereby reducing uric acid production; benzbromarone interfering with the reabsorption of uric acid in the kidneys, thereby promoting uric acid excretion; or for patients with refractory hyperuricemia, using exogenous recombinant or modified uricase (even in combination with immunosuppressants) to degrade uric acid; or some single-target drugs targeting uric acid transport proteins, such as Lesinurad, which was approved in the United States in 2015 and withdrawn from the market in 2019, and Dotinurad, which was launched in Japan.

[0005] Existing drugs and treatments have limitations, and there is a significant unmet clinical need among patients with hyperuricemia and gout. Therefore, there is a need to develop safe and effective new uric acid-lowering drugs. From a mechanism of action and pharmacokinetic perspective, targeting both the uric acid production pathway (xanthine oxidase) and the uric acid reabsorption pathway (uric acid transporter URAT1, gene name SLC22A12) with a single molecule is more advantageous than a single-target strategy. Pfizer developed a dual XOR / URAT1 inhibitor, namely the dual-target molecule PF-06743649, but its clinical trials were halted in Phase I due to acute kidney injury in a small number of patients. Therefore, it is necessary to develop a new dual-target uric acid-lowering drug to benefit patients with hyperuricemia and reduce the burden on national healthcare payments. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides an aryl-substituted indole compound or its derivative and its applications. This type of compound exhibits good inhibitory activity against both uricase and uricase transporter, and is a dual inhibitor of XOR / URAT1, thus possessing a good uric acid-lowering effect.

[0007] This invention includes the following technical solutions:

[0008] This invention provides aryl-substituted indole compounds or derivatives thereof having the structure shown in Formula I, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their prodrug molecules, or their deuterates, or their tritides.

[0009] Where X is selected from: -O-, -S-, -C(R1R2)-, -N(R3)-;

[0010] Y is selected from: -O-, -S-, -N(R3)-;

[0011] Z and W are each independently selected from: CR4;

[0012] m and n are independently selected from 0, 1, 2, and 3 respectively, y1 and y2 are independently selected from 0 and 1 respectively, and m+n+y1+y2 is 2, 3 or 4;

[0013] Q is selected from: hydrogen, halogen, cyano;

[0014] L is selected from: one or more R5-substituted or unsubstituted C6-C 10 Aryl, one or more R5-substituted or unsubstituted 5-10 heteroaryl groups;

[0015] Each R1 and R2 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C8 alkyl, one or more R6-substituted or unsubstituted C1-C8 alkoxy, one or more R6-substituted or unsubstituted C1-C8 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R6-substituted or unsubstituted C3-C8 cycloalkyl, or R1 and R2 on the same carbon are connected to form R6-substituted or unsubstituted C3-C8 cycloalkyl;

[0016] Each R3 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C8 alkyl groups, one or more R6-substituted or unsubstituted C3-C8 cycloalkyl groups, and one or more R6-substituted or unsubstituted C1-C8 alkyl acyl groups;

[0017] Each R4 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C8 alkyl groups, one or more R6-substituted or unsubstituted C1-C8 alkoxy groups, one or more R6-substituted or unsubstituted C1-C8 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, hydroxyl groups, one or more R6-substituted or unsubstituted C3-C8 cycloalkyl groups, and one or more R6-substituted or unsubstituted C6-C4 alkyl groups. 14 Aryl;

[0018] Each R5 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, R6 substituted or unsubstituted C6-C 10 Aryl, R6-substituted or unsubstituted 5-10 heteroaryl groups;

[0019] Each R6 is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, and C3-C8 cycloalkyl;

[0020] Each R is independently selected from: hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino.

[0021] In the aryl-substituted indole compounds or their derivatives described in this invention, when m+n+y1+y2 is 2, at least one of R1, R2 and R4 is not hydrogen.

[0022] In some implementations, m+n+y1+y2 is 3.

[0023] In some of these implementations, m+n+y1+y2 is 2, and at least one of R1, R2, and R4 is not hydrogen.

[0024] In some embodiments, the aryl-substituted indole compound has a structure as shown in Formula II:

[0025] Where m and n are independently selected from 0, 1, 2, and 3 respectively, and m+n is 2, 3, or 4.

[0026] In some implementations, m and n are independently selected from 0, 1, 2, and 3, respectively, and m+n is 3.

[0027] In some of these embodiments, m and n are independently selected from 0, 1, and 2, respectively, and m+n is 2, and at least one of R1, R2, and R4 is not hydrogen.

[0028] In some of these embodiments, m and n are independently selected from 0, 1, and 2, respectively, and m+n is 2; at least one of R1 and R2 is not hydrogen.

[0029] In some embodiments, m and n are independently selected from 0, 1, and 2, respectively, and m+n is 2; there is a pair of R1 and R2 on the same carbon that are not hydrogen, while the other R1 and R2 are all hydrogen.

[0030] In some embodiments, m and n are independently selected from 0, 1, and 2, respectively, and m+n is 2; Z and W are both CH; and at least one of R1 and R2 is not hydrogen.

[0031] In some embodiments, m and n are independently selected from 0, 1, and 2, respectively, and m+n is 2; Z and W are CH; there is a pair of R1 and R2 on the same carbon that are not hydrogen, while the other R1 and R2 are all hydrogen.

[0032] In some of these implementations, m and n are independently selected from 0, 1, and 2, respectively, and m+n is 2; at least one of R4 is not hydrogen.

[0033] In some embodiments, the aryl-substituted indole compound has a structure as shown in Formula III:

[0034] a is selected from: 1, 2.

[0035] In some implementations, a is 2.

[0036] In some of these embodiments, a is 1, and at least one of R1 and R2 is not hydrogen, preferably neither of them is hydrogen.

[0037] In some of these implementations, a is 1, and at least one of R1, R2, and each of R4 is not hydrogen.

[0038] In some embodiments, a is 1, Z and W are CH, and at least one of R1 and R2 is not hydrogen, preferably neither of them is hydrogen.

[0039] In some of these implementations, a is 1, and at least one of R4 is not hydrogen.

[0040] In some embodiments, the aryl-substituted indole compound or its derivative has a structure as shown in formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8 or III-9:

[0041] Among them, at least one of R1, R2 and R4 is not hydrogen, or at least one of R1 and R2 is not hydrogen, or at least one of R4 is not hydrogen.

[0042] In some of these embodiments, one set of R1 and R2 on the same carbon atom is not hydrogen, while the other R1 and R2 are hydrogen.

[0043] In some of these embodiments, Z and W are CH, and at least one of R1 and R2 is not hydrogen.

[0044] In some embodiments, Z and W are CH; there is a pair of R1 and R2 on the same carbon that are not hydrogen, while the other R1 and R2 are all hydrogen.

[0045] In some embodiments, the aryl-substituted indole compound or its derivative has a structure as shown in formula II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, II-23, III-10, III-11, III-12, III-13, III-14, III-15, III-16, III-17 or III-18:

[0046] In some of these embodiments, all R4 in the compounds represented by formulas II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, II-23, III-10, III-11, III-12, III-13, III-14, III-15, III-16, III-17, or III-18 are H.

[0047] In some of these embodiments, in the compounds shown by formula II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, II-23, III-10, III-11, III-12, III-13, III-14, III-15, III-16, III-17 or III-18, all R1 and R2 are H.

[0048] In some of these embodiments, in the compounds represented by formulas II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, II-23, III-10, III-11, III-12, III-13, III-14, III-15, III-16, III-17, or III-18, one pair of R1 and R2 on the same carbon atom are not hydrogen, while the other R1 and R2 are hydrogen.

[0049] In some embodiments, each R1 and R2 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C4 alkyl groups, one or more R6-substituted or unsubstituted C1-C4 alkoxy groups, one or more R6-substituted or unsubstituted C1-C4 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, hydroxyl groups, one or more R6-substituted or unsubstituted C3-C6 cycloalkyl groups, or R1 and R2 on the same carbon atom are linked together to form R6-substituted or unsubstituted C3-C6 cycloalkyl groups.

[0050] In some embodiments, each of R6 in R1 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, and C3-C6 cycloalkyl.

[0051] In some embodiments, each of R6 in R1 is independently selected from: hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluorine, chlorine, bromine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0052] In some embodiments, each R1 and R2 is independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, isopropylthio, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or R1 and R2 on the same carbon atom are linked together to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0053] In some of these implementations, R1 and R2 on the same carbon atom are identical.

[0054] In some embodiments, each R3 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C4 alkyl groups, one or more R6-substituted or unsubstituted C3-C6 cycloalkyl groups, and one or more R6-substituted or unsubstituted C1-C4 alkyl acyl groups.

[0055] In some embodiments, each of the R6 in R3 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, and C3-C6 cycloalkyl.

[0056] In some embodiments, each of the R6 groups in R3 is independently selected from: hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluorine, chlorine, bromine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0057] In some embodiments, each R3 is independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetyl, n-propionyl, and isopropionyl.

[0058] In some embodiments, each R4 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C4 alkyl groups, one or more R6-substituted or unsubstituted C1-C4 alkoxy groups, one or more R6-substituted or unsubstituted C1-C4 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, hydroxyl groups, one or more R6-substituted or unsubstituted C3-C6 cycloalkyl groups, and one or more R6-substituted or unsubstituted C6-C4 cycloalkyl groups. 10 Aryl.

[0059] In some embodiments, each of the R6 in R4 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, and C3-C6 cycloalkyl.

[0060] In some embodiments, each of the R6 in R4 is independently selected from: hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluorine, chlorine, bromine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0061] In some embodiments, each R4 is independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, isopropylthio, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroisopropyl, phenyl, naphthyl.

[0062] In some implementations, W is CH.

[0063] In some implementations, W is CH when all R1 and R2 are hydrogen.

[0064] In some of these embodiments, Q is selected from: hydrogen, bromine, chlorine, fluorine, and cyano.

[0065] In some embodiments, each R5 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, R6-substituted or unsubstituted phenyl, R6-substituted or unsubstituted naphthyl, R6-substituted or unsubstituted 5-6 heteroaryl;

[0066] Each R is independently selected from: hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

[0067] In some of the actual examples, each R5 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.

[0068] In some embodiments, L is selected from: one or more R5-substituted or unsubstituted phenyl groups, one or more R5-substituted or unsubstituted naphthyl groups, and one or more R5-substituted or unsubstituted 5-6 heteroaryl groups.

[0069] In some embodiments, L is selected from: one or more R5-substituted or unsubstituted phenyl groups, one or more R5-substituted or unsubstituted naphthyl groups, one or more R5-substituted or unsubstituted pyridyl groups, one or more R5-substituted or unsubstituted pyrazinyl groups, one or more R5-substituted or unsubstituted pyridazinyl groups, and one or more R5-substituted or unsubstituted pyrimidinyl groups.

[0070] Preferably, each R5 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, 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.

[0071] In some of these real modes, L is selected from:

[0072] The present invention also provides the use of the aryl-substituted indole 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.

[0073] The present invention also provides the use of the aryl-substituted indole 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.

[0074] The present invention also provides the use of the aryl-substituted indole 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.

[0075] The present invention also provides an XOR / URAT1 dual inhibitor, the active ingredient of which contains an aryl-substituted indole 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.

[0076] The present invention also provides a uric acid-lowering drug, which is prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes aryl-substituted indole 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.

[0077] The present invention also provides a method for preventing and / or treating gout or hyperuricemia, comprising:

[0078] Administering safe and effective amounts of the aryl-substituted indole 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 this invention to patients with gout or hyperuricemia; and / or,

[0079] The present invention provides a safe and effective dose of the uric acid-lowering drug for patients with gout or hyperuricemia.

[0080] The aryl-substituted indole compounds or their derivatives provided by this invention are a class of novel compounds. These compounds exhibit good inhibitory activity against both uricase and uricase transporter proteins, and are a dual inhibitor of XOR / URAT1, thus possessing excellent uric acid-lowering effects. Furthermore, they have good safety profiles, excellent pharmacokinetic properties, and high drug-likeness, and can be used to prepare uric acid-lowering drugs for the prevention and / or treatment of gout or hyperuricemia. Attached Figure Description

[0081] Figure 1 shows the serum uric acid concentration in mice with hyperuricemia 24 hours after a single administration of the compound. Detailed Implementation

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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."

[0086] In the compounds of this invention, when any variable (e.g., R1, R2, etc.) appears more than once in any component, the definition of each occurrence is independent of the definitions of other occurrences. Similarly, combinations of substituents and variables are permitted, provided such combinations stabilize the compound. Lines drawn from a substituent into the ring system indicate 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 will 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 different carbon atoms, as long as structural stability is achieved.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] This invention includes the free form of compounds of Formula I, 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. The free forms 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective range, and pharmaceutically acceptable excipients.

[0098] The "active ingredient" as described in this invention refers to the compound of formula I described in this invention, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate.

[0099] "Safe and effective amount" refers to an amount of active ingredient sufficient to significantly improve the condition without causing serious side effects. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is the pharmaceutically considered effective dose. Of course, the specific dosage 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.

[0100] "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.

[0101] "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.

[0102] Pharmaceutically acceptable examples of 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 Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0103] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or polymer through non-bonding interaction. In another preferred embodiment, the compound of formula I 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.

[0104] 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.

[0105] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0106] 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:

[0107] (a) Fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silica;

[0108] (b) Adhesives, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0109] (c) Moisturizers, such as glycerin;

[0110] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginate, certain complex silicates, and sodium carbonate;

[0111] (e) Slow solvents, such as paraffin;

[0112] (f) Absorption accelerators, such as quaternary ammonium compounds;

[0113] (g) Wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0114] (h) Adsorbents, such as kaolin; and

[0115] (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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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 administration method and dosage of the original drug remain unchanged, while the compound of Formula I is taken simultaneously or subsequently. When the compound of Formula I is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of Formula I is preferred. Drug combination also includes taking the compound of Formula I with one or more other known drugs during overlapping time periods. When the compound of Formula I is used in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than the dosage when they are taken alone.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] Example 1: Preparation of intermediate 1-Int

[0125] Step 1: Synthesis of 7-(N-benzyl)amine-3,4-dihydro-1H-isochromanine (intermediate 1-Int-1)

[0126] In toluene (50 ml), 7-bromo-3,4-dihydro-1H-isochromanone (2.0 g, 9.43 mmol), Cs₂CO₃ (9.2 g, 28.3 mmol), Pd(OAc)₂ (214 mg, 0.94 mmol), RuPhos (440 mg, 0.94 mmol), and BnNH₂ (2.0 g, 18.87 mmol) were added. The mixture was then stirred at 100 °C for 12 hours. After concentration, the reaction mixture was treated with water, extracted with ethyl acetate, dried over reduced pressure, concentrated under reduced pressure, and column chromatography to give a yellow solid product (1.9 g, 84%).

[0127] Step 2: Synthesis of 7-amino-3,4-dihydro-1H-isochromanol (intermediate 1-Int-2)

[0128] 7-(N-benzyl)amine-3,4-dihydro-1H-isochromanol (2.7 g, 11.29 mmol) and Pd / C-Pd(OH)₂ (300 mg) were added to methanol (60 ml). The mixture was then hydrogenated at 40 °C under normal pressure for 12 hours. After filtration and concentration, the product was column-secured to give a white solid product (1.5 g, 89%).

[0129] Step 3: Synthesis of 8-iodo-7-amino-3,4-dihydro-1H-isochromanol (intermediate 1-Int)

[0130] In acetonitrile (20 ml), 7-amino-3,4-dihydro-1H-isochromanol (1.4 g, 9.39 mmol) and N-iodosuccinimide (NIS) (2.1 g, 9.39 mmol) were added. The mixture was stirred at 0 °C for 2 hours. After concentration, the reaction was treated with water, extracted with dichloromethane, dried, concentrated under reduced pressure, and column filtered to give a yellow liquid product (543 mg, 21%).

[0131] 1 H NMR (400MHz, CDCl3) δ6.92(d,J=8.0Hz,1H),6.64(d,J=8.0Hz,1H),4.56(s,2H),3.89(t,J=5.6Hz,2H),2.73(t,J=5.6Hz,2H).

[0132] Example 2 Preparation of intermediate 11-Int

[0133] Step 1: Synthesis of diethyl 2-(4-nitro-2-(methoxycarbonyl)phenyl)-malonate (intermediate 11-Int-1)

[0134] In DMF (5.0 ml), methyl 2-fluoro-5-nitrobenzoate (500 mg, 2.5 mmol), diethyl malonate (600 mg, 3.7 mmol), and Cs₂CO₃ (1.2 g, 3.7 mmol) were added. The mixture was then stirred at 25 °C for 6 hours. Water was added and ethyl acetate was added for extraction. The extract was dried, concentrated under reduced pressure, and evaporated to dryness to obtain an oily crude product (0.7 g).

[0135] 1 HNMR(400MHz, CDCl3)δ8.86(d,J=2.8Hz,1H),8.37(dd,J=8.8and 2.8Hz,1H),7.69(d,J=8.8Hz,1H),5.82(s,1H),4.30-4.22(m,4H),3.96(s,3H),1.28(t,J=6.8Hz,6H).

[0136] Step 2: Synthesis of (4-nitro-2-(methoxycarbonyl)phenyl)-ethyl acetate (intermediate 11-Int-2)

[0137] In dimethyl sulfoxide (DMSO) (160 ml), diethyl 2-(4-nitro-2-(methoxycarbonyl)phenyl)-malonate (23.5 g, 69.3 mmol), water (32 ml), and LiCl (5.9 g, 138.6 mmol) were added. The mixture was then stirred at 110 °C for 12 hours. Water was added, followed by extraction with ethyl acetate. The extract was dried, concentrated under reduced pressure, and evaporated to dryness before being column-secured to give a yellow oily product (12.6 g, 68%).

[0138] 1 HNMR(400MHz,DMSO-d6)δ8.62(d,J=2.4Hz,1H),8.41(dd,J=8.4and 2.8Hz,1H),7.72(d,J=8.4Hz,1H),4.15(s,2H),4.08(q,J=7.2Hz,2H),3.86(s,3H),1.18(t,J=7.2Hz,3H).

[0139] Step 3: Synthesis of ethyl 2-(4-nitro-2-(methoxycarbonyl)phenyl)-2-methylpropionate (intermediate 11-Int-3)

[0140] In N-methylpyrrolidone (NMP) (90 ml), ethyl (4-nitro-2-(methoxycarbonyl)phenyl)-acetate (8.0 g, 29.9 mmol) and NaH (6.0 g, 60%, 149.5 mmol) were added. The mixture was then stirred at 0 °C for 0.5 h, followed by the addition of MeI (3.0 eq), and the reaction was stirred at room temperature for 4 h. Water was added, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated under reduced pressure, and evaporated to dryness before being column-secured to give a yellow oily product (2.7 g, 35%).

[0141] 1 HNMR(400MHz,DMSO-d6)δ8.49(d,J=2.4Hz,1H),8.38(dd,J=8.8and 2.8Hz,1H),7.91(d,J=4.8Hz,1H),4.01(t,J=6.8Hz,2H),3.81(s,3H),1.59(s,6H),1.10(t,J=7.2Hz,3H).

[0142] Step 4: Synthesis of 2-(4-nitro-2-(hydroxymethyl)phenyl)-2-methylpropanol (intermediate 11-Int-4)

[0143] LiAlH4 (9.3 g, 231 mmol) was added to tetrahydrofuran (THF) (100 ml), followed by a 20 ml solution of ethyl 2-(4-nitro-2-(methoxycarbonyl)phenyl)-2-methylpropionate (12.0 g, 46.3 mmol) in THF at 0 °C. The mixture was stirred at 0 °C for 2 hours, and water was added until no gas was produced. The mixture was then filtered. The filter cake was washed several times with ethyl acetate and THF. All filtrates and extracts were combined, the organic phase was dried, concentrated under reduced pressure, and evaporated to dryness before column chromatography to give a yellow oily product (3.4 g, 33%).

[0144] 1 HNMR(400MHz,DMSO-d6)δ8.11(d,J=2.4Hz,1H),7.69(dd,J=8.4and 2.4Hz,1H),7.55(d,J=8.4Hz,1H),5.35(t,J=5.6Hz,1H),4.80-4.78(m,3H),3.59(d,J=5.2Hz,2H),1.34(s,6H).

[0145] Step 5: Synthesis of 4,4-dimethyl-7-nitro-3,4-dihydro-1H-isochromanol (intermediate 11-Int-5)

[0146] In toluene (80 ml), 7.3 g (32.43 mmol) of 2-(4-nitro-2-(hydroxymethyl)phenyl)-2-methylpropanol was added, followed by 11.2 g of p-toluenesulfonic acid (P-TSA). The mixture was heated to 100 °C and reacted for 1 hour. After cooling to 0 °C, water was added, followed by extraction with ethyl acetate. The ethyl acetate extracts were combined, dried, concentrated under reduced pressure, and purified by column chromatography to give a yellowish liquid product (4.1 g, 61%).

[0147] 1 HNMR (400MHz, DMSO-d6) δ7.72(d,J=8.4Hz,1H),7.61(d,J=8.4Hz,1H),7.52(s,1H),4.82(s,2H),3.59(s,2H),1.26(s,6H).

[0148] Step 6: Synthesis of 7-amino-4,4-dimethyl-3,4-dihydro-1H-isochromanol (intermediate 11-Int-6)

[0149] In MeOH (40 ml) and ethyl acetate (40 ml), 4,4-dimethyl-7-nitro-3,4-dihydro-1H-isochromanol (4.1 g, 19.8 mmol), Pd / C (10%, 0.4 g), and Pd(OH)₂ / C (10%, 0.4 g) were added. The mixture was then hydrogenated at 25 °C for 4 hours, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness to give a yellowish solid product (3.6 g).

[0150] MS(ESI)calcd for C 11 H 15 ON:177.12; found:178.10[M+1].

[0151] 1 HNMR (400MHz, DMSO-d6) δ7.00(d,J=8.4Hz,1H),6.42(d,J=8.4Hz,,1H),6.13(s,1H),4.83(s,2H),4.54(s,2H),3.45(s,2H),1.12(s,6H).

[0152] Step 7: Synthesis of 8-iodo-7-amino-4,4-dimethyl-3,4-dihydro-1H-isochromanol (intermediate 11-Int)

[0153] In HOAc (50 ml), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isochromanol (3.9 g, 22 mmol) and NIS (4.95 g, 22 mmol) were added. The mixture was stirred at 25 °C for 1 hour. Water was then added, followed by extraction with ethyl acetate. The extracts were combined, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a white solid product (4.3 g, 64%).

[0154] MS(ESI)calcd for C 11 H 14 OIN:303.01; found:304.00[M+1].

[0155] 1 HNMR (400MHz, DMSO-d6) δ7.12(d,J=8.4Hz,1H),6.68(d,J=8.4Hz,1H),5.10(s,2H),4.42(s,2H),3.45(s,2H),1.14(s,6H).

[0156] Example 3: Preparation of intermediate 625-Int

[0157] Step 1: Synthesis of 2-(4-bromo-2-(hydroxymethyl)phenyl)-prop-2-ol (intermediate 625-Int-1)

[0158] Add 20 g (0.09 mol) of 5-bromo-isobenzofuran-3-one to THF (200 ml), then add methyl magnesium bromide (3 M, 78 ml, 0.23 mol) dropwise at 0 °C. Stir the reaction at 25 °C for 12 hours, cool to 0 °C, and add 300 ml of saturated ammonium chloride solution dropwise. Separate the aqueous phase and extract with ethyl acetate. Combine the extract with the original THF solution, dry, concentrate under reduced pressure, and evaporate to dryness to obtain the crude product (25.85 g).

[0159] Step 2: Synthesis of 5-bromo-1,1-dimethyl-1,3-dihydroisobenzofuran (intermediate 625-Int-2)

[0160] In toluene (300 ml), add the above-mentioned 2-(4-bromo-2-(hydroxymethyl)phenyl)-prop-2-ol (25.85 g), then add phosphoric acid (85%, 77 ml), and heat to 85°C for 3 hours. Cool to 0°C, add water (300 ml), then neutralize the pH of the reaction solution to 7 with NaOH aqueous solution (2.0 M), add ethyl acetate for extraction (3 x 200 ml), combine the ethyl acetate extracts, dry, concentrate under reduced pressure, evaporate to dryness, and pass through a column to give a yellowish liquid product (21 g, 98%).

[0161] 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.0Hz,1H),7.31(s,1H),6.97(d,J=8.0Hz,1H),5.01(s,2H),1.46(s,6H).

[0162] Step 3: Synthesis of 5-benzylamino-1,1-dimethyl-1,3-dihydroisobenzofuran (intermediate 625-Int-3)

[0163] In a dioxane (460 ml) solution, 5-bromo-1,1-dimethyl-1,3-dihydroisobenzofuran (21 g, 0.09 mol), benzylamine (19.9 g, 0.19 mol), Cs₂CO₃ (60.5 g, 0.19 mol), RuPhos (4.3 g, 9.28 mmol), and Pd(OAc)₂ (2.1 g, 9.28 mmol) were added. The mixture was then reacted at 100 °C for 12 hours. After cooling to room temperature, the mixture was filtered, concentrated under reduced pressure, evaporated to dryness, and then column-secreted to give a yellow liquid product (22.16 g, 94%).

[0164] MS(ESI)calcd for C 17 H 19 NO:253.15; found:254.35[M+1].

[0165] 1 H NMR (400MHz, CDCl3) δ7.37-7.31(m,4H),7.28-7.24(m,1H),6.90(d,J=8.0Hz,1H),6.56(dd,J=8.0and 2.0Hz,1H),6.46(s,1H),4.96(s,2H),4.30(s,2H),1.44(s,6H).

[0166] Step 4: Synthesis of 5-amino-1,1-dimethyl-1,3-dihydroisobenzofuran (intermediate 625-Int-4)

[0167] In methanol (150 ml), 22.16 g (0.087 mol) of 5-benzylamino-1,1-dimethyl-1,3-dihydroisobenzofuran, 1.1 g of Pd / C (10%), and 1.1 g of Pd(OH)₂ / C (10%) were added. The mixture was then hydrogenated at 25 °C for 12 hours, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness. The filtrate was then slurried with n-hexane and filtered to obtain a white solid product (12.79 g, 90%).

[0168] MS(ESI)calcd for C 10 H 13NO:163.10; found:164.40[M+1].

[0169] 1 H NMR (400MHz, CDCl3) δ6.89 (d, J = 8.0 Hz, 1H), 6.58 (dd, J = 8.0 and 2.0 Hz, 1H), 6.50 (s, 1H), 4.97 (s, 2H), 3.66 (brs, 2H), 1.45 (s, 6H).

[0170] Step 5: Synthesis of 4-iodo-5-amino-1,1-dimethyl-1,3-dihydroisobenzofuran (intermediate 625-Int)

[0171] In a mixed solvent of dichloromethane (120 ml) and water (120 ml), 5-amino-1,1-dimethyl-1,3-dihydroisobenzofuran (10.25 g, 0.075 mol) and I2 (19.92 g, 0.079 mol) were added. The mixture was stirred at 25 °C for 12 hours. The aqueous phase was then separated and extracted with dichloromethane. The extract was combined with the original dichloromethane solution, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a yellow solid product (5.58 g, 26%).

[0172] MS(ESI)calcd for C 10 H 12 INO:289.00; found:290.30[M+1].

[0173] 1 H NMR (400MHz, CDCl3) δ6.85 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.90 (s, 2H), 1.45 (s, 6H).

[0174] Example 4: Preparation of intermediate 635-Int

[0175] Step 1: Synthesis of 2-(5-bromo-2-(hydroxymethyl)phenyl)-prop-2-ol (intermediate 635-Int-1)

[0176] To THF (80 mL), 6-bromo-isobenzofuran-1-one (2.0 g, 9.38 mmol) was added, followed by dropwise addition of methyl magnesium bromide (3 M, 24 mL, 23.47 mmol) at 0 °C. The mixture was then stirred at 25 °C for 12 hours, cooled to 0 °C, and saturated ammonium chloride aqueous solution (30 mL) was added dropwise. The aqueous phase was then separated and extracted with ethyl acetate. The extract was combined with the original THF solution, dried, concentrated under reduced pressure, and purified by column chromatography to give a white solid product (1.8 g, 79%).

[0177] 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 2.4Hz, 1H), 7.38 (dd, J = 10.4 and 2.8Hz, 1H), 7.17 (d, J = 10.0Hz, 1H), 4.17 (s, 2H), 0.28 (s, 6H).

[0178] Step 2: Synthesis of 6-bromo-1,1-dimethyl-1,3-dihydroisobenzofuran (intermediate 635-Int-2)

[0179] In toluene (24 ml), 1.8 g (7.38 mmol) of the above-mentioned 2-(5-bromo-2-(hydroxymethyl)phenyl)-prop-2-ol was added, followed by phosphoric acid (85%, 13.4 g). The mixture was heated to 85 °C and reacted for 3 hours. After cooling to 0 °C, 30 ml of water was added, and the organic phase was separated. The aqueous phase was neutralized to pH 7.0 with NaOH aqueous solution (2.0 M), and extracted with ethyl acetate (3 x 200 ml). The ethyl acetate extracts and the separated organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to give a yellowish liquid product (1.53 g, 92%).

[0180] 1 H NMR (400MHz, CDCl3) δ7.36(dd,J=8.4and 2.0Hz,1H),7.35(d,J=1.6Hz,1H),7.06(d,J=8.0Hz,1H),5.00(s,2H),1.48(s,6H).

[0181] Step 3: Synthesis of 6-benzylamino-1,1-dimethyl-1,3-dihydroisobenzofuran (intermediate 635-Int-3)

[0182] In a 16.5 mL solution of dioxane, 6-bromo-1,1-dimethyl-1,3-dihydroisobenzofuran (0.75 g, 3.32 mmol), benzylamine (0.71 g, 6.64 mmol), Cs₂CO₃ (2.2 g, 6.64 mmol), RuPhos (155 mg, 0.33 mmol), and Pd(OAc)₂ (75 mg, 0.33 mmol) were added. The mixture was then reacted at 100 °C for 12 hours. After cooling to room temperature, the mixture was filtered, concentrated under reduced pressure, evaporated to dryness, and then passed through a column chromatography to give a yellow liquid product (0.6 g, 71%).

[0183] MS(ESI)calcd for C 17 H 19 NO:253.15; found:254.35[M+1].

[0184] 1 H NMR (400MHz, CDCl3) δ7.39-7.28(m,5H),6.97(d,J=8.0Hz,1H),6.53(dd,J=8.0and2. 4Hz,1H),6.39(d,J=2.0Hz,1H),4.97(s,2H),4.33(s,2H),4.04(s,1H),1.46(s,6H).

[0185] Step 4: Synthesis of 5-amino-3,3-dimethyl-1,3-dihydroisobenzofuran (intermediate 635-Int-4)

[0186] In methanol (20 ml), 0.6 g (3.16 mmol) of 6-benzylamino-1,1-dimethyl-1,3-dihydroisobenzofuran, Pd / C (10%, 40 mg), and Pd(OH)₂ / C (10%, 40 mg) were added. The mixture was then hydrogenated at 25 °C for 12 hours, filtered, and the filtrate was concentrated under reduced pressure, evaporated to dryness, and passed through a column chromatography to give a white solid product (469 mg, 90%).

[0187] MS(ESI)calcd for C 10 H 13 NO:163.10; found:164.40[M+1].

[0188] 1 H NMR (400MHz, CDCl3) δ6.96(d,J=8.0Hz,1H),6.59(dd,J=8.0and 2.4Hz,1H),6.44(d,J=2.0Hz,1H),4.97(s,2H),3.67(s,2H),1.46(s,6H).

[0189] Step 5: Synthesis of 4,6-dibromo-5-amino-3,3-dimethyl-1,3-dihydroisobenzofuran (intermediate 635-Int-5)

[0190] In acetonitrile (3 ml), 5-amino-3,3-dimethyl-1,3-dihydroisobenzofuran (100 mg, 0.61 mmol) and N-bromosuccinimide (NBS) (217 mg, 1.22 mmol) were added. The mixture was stirred at 25 °C for 2 hours, then concentrated under reduced pressure and evaporated to dryness before being column filtered to give a yellowish liquid product (162 mg, 83%).

[0191] 1 H NMR (400MHz, CDCl3) δ7.21(s,1H),4.94(s,2H),4.61(s,2H),1.60(s,6H).

[0192] Step 6: Synthesis of 4-bromo-5-amino-3,3-dimethyl-1,3-dihydroisobenzofuran (intermediate 635-Int)

[0193] In a dioxane solution (5 ml), 4,6-dibromo-5-amino-3,3-dimethyl-1,3-dihydroisobenzofuran (0.7 g, 2.18 mmol), SnCl2 dihydrate (540 mg, 2.4 mmol), and hydrochloric acid (0.91 ml, 12.0 M) were added, and the mixture was reacted at 110 °C for 6 hours. After cooling to room temperature, NaOH (15%) was added to adjust the pH of the reaction solution to 10–11, followed by extraction with ethyl acetate. The extract was dried, concentrated under reduced pressure, and evaporated to dryness. The solution was then column chromatography to give a yellow liquid product (194 mg, 35%).

[0194] 1 H NMR (400MHz, DMSO-d6) δ6.93(d,J=8.0Hz,1H),6.72(d,J=8.0Hz,1H),5.28(s,2H),4.81(s,2H),1.50(s,6H).

[0195] Example 5: Preparation of intermediate 754-Int

[0196] Step 1: Synthesis of 6-nitro-4-(isopropen-2-yl)-1,3-dihydroisobenzofuran (intermediate 754-Int-1)

[0197] In a dioxane (25 ml), 4-bromo-6-nitro-1,3-dihydroisobenzofuran (2.0 g, 8.23 ​​mmol), pinacol isopropenylboronic acid (3.0 ml, 16.5 mmol), K₂CO₃ (1.0 M, 16 ml), and PdCl₂ (dppf) (0.6 g, 0.8 mmol) were added. The mixture was then reacted at 90 °C for 6 hours. After cooling to room temperature, the reaction was treated with water, and the mixture was extracted with ethyl acetate. The extracts were combined, dried, concentrated under reduced pressure, and evaporated to dryness before being column-secured to give a brown solid product (1.4 g, 83%).

[0198] 1 H NMR (400MHz, DMSO-D6) δ8.14(s,1H),8.08(s,1H),5.39(s,1H),5.17(s,1H),5.16(s,2H),5.09(s,2H),2.14(s,3H),.

[0199] Step 2: Synthesis of 5-amino-7-isopropyl-1,3-dihydroisobenzofuran (intermediate 754-Int-2)

[0200] In a mixed solvent of ethyl acetate (20 ml) and methanol (20 ml), 6-nitro-4-(isopropen-2-yl)-1,3-dihydroisobenzofuran (1.4 g, 6.8 mmol), Pd / C (10% , 100 mg), and Pd(OH)₂ / C (10% , 100 mg) were added. The mixture was then hydrogenated at 25 °C for 6 hours, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness to give a brown solid product (1.2 g, 100%).

[0201] 1 H NMR (400MHz, DMSO-D6) δ6.36(s,1H),6.28(s,1H),4.97(brs,2H),4.88(s,2H),4.83(s,2H),2.63(pent,J=7.2Hz,1H),1.12(d,J=7.2Hz,6H).

[0202] Step 3: Synthesis of 4-iodo-5-amino-7-isopropyl-1,3-dihydroisobenzofuran (intermediate 754-Int)

[0203] In acetonitrile (15 ml), 5-amino-7-isopropyl-1,3-dihydroisobenzofuran (1.0 g, 5.65 mmol) and NIS (1.27 g, 5.65 mmol) were added, and the mixture was stirred at 25 °C for 1 hour. The reaction was then treated with water, and the mixture was extracted with ethyl acetate. The extracts were combined, dried, concentrated under reduced pressure, and purified by column chromatography to give a yellowish liquid product (1.06 g, 62%).

[0204] 1 H NMR (400MHz, DMSO-D6) δ6.56 (s, 1H), 5.14 (brs, 2H), 5.10 (s, 2H), 4.77 (s, 2H), 2.63 (pent, J = 6.8Hz, 1H), 1.11 (d, J = 6.8Hz, 6H).

[0205] Example 6: Preparation of intermediate F1-Int

[0206] Step 1: Synthesis of methyl 4-bromo-2-bromomethyl-6-fluorobenzoate (intermediate F1-Int-1)

[0207] In acetonitrile (350 ml), methyl 4-bromo-6-methyl-2-fluorobenzoate (22.0 g, 90 mmol), NBS (21.39 g, 120 mmol), and AIBN (1.46 g, 9 mmol) were added. The mixture was then stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was concentrated and treated with n-hexane. The mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain a yellowish liquid crude product (32.19 g).

[0208] Step 2: Synthesis of methyl 4-bromo-2-acetoxymethyl-6-fluorobenzoate (intermediate F1-Int-2)

[0209] In N,N-dimethylacetamide (DMAC) (190 ml), methyl 4-bromo-2-bromomethyl-6-fluorobenzoate (32.19 g) and KOAc (38.43 g) were added. The mixture was then stirred at 85 °C for 12 hours, cooled to room temperature, and treated with water. The mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and column chromatography was performed to give a yellow liquid product (15.17 g, 56%).

[0210] 1 H NMR (400MHz, CDCl3) δ7.40(s,1H),7.29(dd,J=9.2and 2.0Hz,1H),5.22(s,2H),3.93(s,3H),2.12(s,3H).

[0211] Step 3: Synthesis of 5-bromo-2-hydroxymethyl-3-fluorobenzyl alcohol (intermediate F1-Int-3)

[0212] In ethanol (360 ml), methyl 4-bromo-2-acetoxymethyl-6-fluorobenzoate (17.95 g, 59 mmol) and NaBH4 (5.56 g, 150 mmol) were added. The mixture was stirred at 45 °C for 3 hours. After concentration, the reaction was treated with water, extracted with ethyl acetate, dried the organic phase, concentrated under reduced pressure, and then slurried in n-hexane to give an off-white solid product (13.6 g, 98%).

[0213] 1 H NMR (400MHz, DMSO-d6) δ7.47(s,1H),7.38(dd,J=9.2and 2.0Hz,1H),5.39(t,J=5.6Hz,1H),5.07(t,J=5.6Hz,1H),4.67(d,J=5.6Hz,2H),4.45(dd,J=5.2and 1.6Hz,2H).

[0214] Step 4: Synthesis of 6-bromo-4-fluoro-1,3-dihydroisobenzofuran (intermediate F1-Int-4)

[0215] In dichloromethane (500 ml), 5-bromo-2-hydroxymethyl-3-fluorobenzyl alcohol (13.6 g, 57.86 mmol) and manganese dioxide (25.15 g, 290 mmol) were added, and the mixture was stirred at 40 °C for 12 hours. The mixture was filtered, and the filter cake was washed several times with dichloromethane. All the resulting dichloromethane solutions were combined, concentrated, and then dichloromethane (300 ml), triethylsilane (20.18 g), and trifluoroacetic acid (33.0 g) were added. The mixture was then reacted at room temperature for 1 hour. After concentration, 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 (8.7 g, 69%).

[0216] 1 H NMR (400MHz, DMSO-d6) δ7.45-7.42(m,2H),5.04(s,2H),5.03(s,2H).

[0217] Step 5: Synthesis of 5-(N-benzyl)amine-7-fluoro-1,3-dihydroisobenzofuran (intermediate F1-Int-5)

[0218] In toluene (200 ml), 6-bromo-4-fluoro-1,3-dihydroisobenzofuran (8.7 g, 40 mmol), Cs₂CO₃ (26.1 g, 80 mmol), Pd(OAc)₂ (910 mg, 4 mmol), RuPhos (1.86 g, 4 mmol), and BnNH₂ (8.1 g, 80 mmol) were added. The mixture was then stirred at 110 °C for 4 hours, filtered, and the filter cake was washed several times with dichloromethane. The filtrates were combined, concentrated, and column chromatography to give an off-white solid product (8.6 g, 88%).

[0219] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.30(m,4H),7.22(t,J=6.4Hz,1H),6.56(t,J=6.4Hz,1H),6.35(s,1H),6.25(dd,J=12and 1.6Hz,1H),4.89(s,2H),4.86(s,2H),4.26(d,J=6.0Hz,2H).

[0220] Step 6: Synthesis of 5-amino-7-fluoro-1,3-dihydroisobenzofuran (intermediate F1-Int-6)

[0221] In methanol (400 ml), 10.24 g of 5-(N-benzyl)amine-7-fluoro-1,3-dihydroisobenzofuran (42.14 mmol), 1.0 g of Pd / C, and 1.0 g of Pd(OH)₂ / C were added. The mixture was then hydrogenated at 25 °C and atmospheric pressure for 12 hours. After filtration and concentration, the product was column chromatography to give a white solid product (6.0 g, 93%).

[0222] 1 H NMR (400MHz, DMSO-d6) δ6.29 (s, 1H), 6.23 (d, J = 11.6Hz, 1H), 5.36 (s, 2H), 4.89 (s, 2H), 4.86 (s, 2H).

[0223] Step 7: Synthesis of 5-amino-7-fluoro-4-iodine-1,3-dihydroisobenzofuran (intermediate F1-Int)

[0224] In acetic acid (60 ml), 5-amino-7-fluoro-1,3-dihydroisobenzofuran (5.69 g, 37.15 mmol) and NIS (9.19 g, 40.87 mmol) were added, and the mixture was stirred at 25 °C for 2 hours. Water was then added, the mixture was filtered, the filter cake was dissolved in dichloromethane, dried, concentrated under reduced pressure, evaporated to dryness, and then passed through a column to obtain a white solid product (7.2 g, 69%).

[0225] 1 H NMR (400MHz, DMSO-d6) δ6.46 (d, J = 11.6Hz, 1H), 5.50 (s, 2H), 5.10 (s, 2H), 4.81 (s, 2H).

[0226] The intermediate compounds shown in Table 1 were prepared according to the preparation methods of Examples 1-6. The preparation methods of the examples, their structural formulas and characterization data are shown in Table 1.

[0227] Table 1. Structural formulas, characterization data, and preparation methods of the main intermediate compounds.

[0228] Example 7: Preparation of Compound 1

[0229] Step 1: Synthesis of 8-trimethylsilyne-7-amino-3,4-dihydro-1H-isochromanol (Intermediate 1-1)

[0230] In triethylamine (3 ml), 8-iodo-7-amino-3,4-dihydro-1H-isocyanate (200 mg, 0.73 mmol), trimethylsilyne (179 mg, 1.82 mmol), CuI (7.0 mg, 0.04 mmol), and Pd(dppf)Cl2 (16 mg, 0.04 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 yellow liquid product (154 mg, 86%).

[0231] 1 H NMR (400MHz, CDCl3) δ6.89(d,J=8.0Hz,1H),6.58(d,J=8.0Hz,1H),4.78(s,2H),3.90(t,J=5.6Hz,2H),2.70(t,J=5.6Hz,2H),0.25(s,9H).

[0232] Step 2: Synthesis of 1,3,4,7-tetrahydropyrano[3,4-e]indole (intermediates 1-2)

[0233] In N,N-dimethylformamide (DMF) (3 ml), 8-trimethylsilyne-7-amino-3,4-dihydro-1H-isocyanate (154 mg, 0.63 mmol) and CuI (239 mg, 1.26 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 dichloromethane, dried over reduced pressure, concentrated under reduced pressure, and purified by column chromatography to give the product (50 mg, 46%).

[0234] 1 H NMR (400MHz, CDCl3) δ8.19(brs,1H),7.24(d,J=8.4Hz,1H),7.19-7.18(m,1H),6.94(d,J= 8.4Hz,1H),6.39-6.37(m,1H),5.05(s,2H),4.05(t,J=5.6Hz,1H),2.93(t,J=5.6Hz,1H).

[0235] Step 3: Synthesis of 9-aldehyde-1,3,4,7-tetrahydropyrano[3,4-e]indole (intermediates 1-3)

[0236] In DMF (1.5 mL), 1,3,4,7-tetrahydropyrano[3,4-e]indole (50 mg, 0.29 mmol) and POCl3 (49 mg, 0.32 mmol) were added. The reaction mixture was then reacted at room temperature for 12 hours. NaOH aqueous solution (2.0 M) was then added to adjust the pH of the reaction mixture to 12, and the mixture was heated to 70 °C for 0.5 hours. The mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and evaporated to dryness to give a white solid product (47 mg, 79%).

[0237] MS(ESI)calcd for C 12 H 11 NO2:201.08; found:202.30[M+1].

[0238] 1 H NMR (400MHz, DMSO-d6) δ12.17(brs,1H),9.69(s,1H),8.20(d,J=2.0Hz,1H),7.26(d,J=8. 4Hz, 1H), 6.98 (d, J = 8.4Hz, 1H), 5.20 (s, 2H), 3.89 (t, J = 5.6Hz, 2H), 2.85 (t, J = 5.6Hz, 2H).

[0239] Step 4: Synthesis of 9-cyano-1,3,4,7-tetrahydropyrano[3,4-e]indole (intermediates 1-4)

[0240] In THF (1.3 mL), 9-aldehyde-1,3,4,7-tetrahydropyrano[3,4-e]indole (47 mg, 0.23 mmol), hydroxylamine hydrochloride (33 mg, 0.47 mmol), and pyridine (74 mg) were added. The reaction was then carried out at 80 °C for 12 hours. Acetic anhydride (192 mg) was then added and the reaction was carried out for 4 hours. NaOH aqueous solution (2.0 M) was then added at room temperature to adjust the pH of the reaction solution to 8-10. Ethyl acetate was added for extraction, the organic phase was dried, concentrated under reduced pressure, and evaporated to dryness. The solution was then column-secreted to give an off-white solid product (15 mg, 17%).

[0241] MS(ESI)calcd for C 12 H 10 N2O:198.08; found:196.90[M-1].

[0242] Step 5: Synthesis of tert-butyl 4-(9-cyano-3,4-dihydro-pyrano[3,4-e]indole-7(1H)-yl)benzoate (intermediates 1-5)

[0243] In DMF (0.5 mL), 9-cyano-1,3,4,7-tetrahydropyrano[3,4-e]indole (15 mg, 0.08 mmol), Cs₂CO₃ (74 mg, 0.23 mmol), and tert-butyl 4-fluorobenzoate (30 mg, 0.15 mmol) were added. The mixture was then reacted at 80 °C for 12 hours and cooled to room temperature. After concentration under reduced pressure and rotary evaporation, the product was purified by column chromatography to give a white solid product (25 mg, 88%).

[0244] Step 6: Synthesis of 4-(9-cyano-3,4-dihydro-pyrano[3,4-e]indol-7(1H)-yl)benzoic acid (compound 1)

[0245] In trifluoroacetic acid (TFA) (1 ml), tert-butyl 4-(9-cyano-3,4-dihydro-pyrano[3,4-e]indol-7(1H)-yl)benzoate (25 mg, 0.07 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 as a white solid (11 mg, 49%).

[0246] MS(ESI)calcd for C 19 H 14 N2O3:318.10; found:317.30[M-1].

[0247] 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.16(d,J=8.8Hz,2H),7.78(d,J=8.4Hz,2H),7.50(d,J= 8.8Hz,1H),7.17(d,J=8.8Hz,1H),5.20(s,2H),3.96(t,J=5.6Hz,2H),2.90(t,J=5.6Hz,2H).

[0248] Example 8: Preparation of Compound 625

[0249] Step 1: Synthesis of 4-trimethylsilyne-5-amino-1,1-dimethyl-1,3-dihydroisobenzofuran (intermediate 625-1)

[0250] In triethylamine (60 ml), 4-iodo-5-amino-1,1-dimethyl-1,3-dihydroisobenzofuran (5.58 g, 19.31 mmol), trimethylsilyne (3.79 g, 38.62 mmol), CuI (0.74 g, 3.86 mmol), and Pd(dppf)Cl2 (1.41 g, 1.93 mmol) were added. The mixture was then reacted 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 brown liquid product (4.13 g, 82%).

[0251] MS(ESI)calcd for C 15 H 21 NOSi:259.14; found:260.35[M+1].

[0252] 1 H NMR (400MHz, CDCl3) δ6.84(d,J=8.0Hz,1H),6.63(d,J=8.4Hz,1H),5.02(s,2H),1.42(s,6H),0.23(s,9H).

[0253] Step 2: Synthesis of 3,3-dimethyl-3,6-dihydro-1H-furan[3,4-e]indole (intermediate 625-2)

[0254] In DMF (80 ml), 4-trimethylsilyn-5-amino-1,1-dimethyl-1,3-dihydroisobenzofuran (4.13 g, 15.94 mmol) and CuI (6.07 g, 31.87 mmol) were added. The mixture was then reacted at 120 °C for 1 hour. After concentration, the reaction mixture was treated with water, extracted with ethyl acetate, dried, concentrated under reduced pressure, and purified by column chromatography to give a yellow solid product (1.8 g, 60%).

[0255] 1 H NMR (400MHz, DMSO-d6) δ11.16(brs,1H),7.34-7.32(m,1H),7.26(d,J=8.4Hz,1H),6.90(d,J=8.0Hz,1H),6.26-6.25(m,1H),5.08(s,2H),1.39(s,6H).

[0256] Step 3: Synthesis of 8-aldehyde-3,3-dimethyl-3,6-dihydro-1H-furan[3,4-e]indole (intermediate 625-3)

[0257] In DMF (3 ml), 3,3-dimethyl-3,6-dihydro-1H-furan[3,4-f]indole (300 mg, 1.6 mmol) and POCl3 (295 mg, 1.92 mmol) were added. The reaction mixture was then reacted at room temperature for 12 hours. NaOH aqueous solution (2.0 M) was then added to adjust the pH of the reaction mixture to 11-12, and the mixture was heated to 70 °C 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 yellow solid product (271 mg, 78%).

[0258] MS(ESI)calcd for C 13 H 13 NO2:215.09; found:214.40[M-1].

[0259] 1 H NMR (400MHz, DMSO-d6) δ12.20(brs,1H),9.73(s,1H),8.26(s,1H),7.35(d,J=8.0Hz,1H),7.08(d,J=8.0Hz,1H),5.29(s,2H),1.39(s,6H).

[0260] Step 4: Synthesis of 8-cyano-3,3-dimethyl-3,6-dihydro-1H-furan[3,4-e]indole (intermediate 625-4)

[0261] In THF (5 ml), 265 mg (1.23 mmol) of 8-aldehyde-3,3-dimethyl-3,6-dihydro-1H-furan[3,4-e]indole, 171 mg (2.45 mmol) of hydroxylamine hydrochloride, and 388 mg of pyridine were added. The reaction was then carried out at 80 °C for 12 hours. Acetic anhydride (1.35 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 to adjust the pH of the reaction solution to 11-12. After stirring for half an hour, dichloromethane was added for extraction. The organic phase was dried, concentrated under reduced pressure, and evaporated to dryness. The product was then slurried with ethyl acetate and filtered to obtain a white solid product (100 mg, 38%).

[0262] MS(ESI)calcd for C 13 H 12 N2O:212.09; found:213.30[M+1].

[0263] 1H NMR (400MHz, DMSO-d6) δ12.27(brs,1H),8.23(s,1H),7.42(d,J=8.4Hz,1H),7.12(d,J=8.4Hz,1H),5.23(s,2H),1.41(s,6H).

[0264] Step 5: Synthesis of tert-butyl 4-(8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)benzoate (intermediate 625-5)

[0265] In DMF (4 ml), 8-cyano-3,3-dimethyl-3,6-dihydro-1H-furan[3,4-e]indole (100 mg, 0.47 mmol), Cs₂CO₃ (307 mg, 0.94 mmol), and tert-butyl 4-fluorobenzoate (185 mg, 0.94 mmol) were added. The mixture was then reacted at 80 °C for 12 hours and cooled to room temperature. After treatment with water, the mixture was filtered, and the resulting filter cake was slurried with methanol to give a white solid product (107 mg, 58%).

[0266] 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.08(d,J=8.8Hz,2H),7.76(d,J=8.8Hz,2H),7 .54(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),5.30(s,2H),1.54(s,9H),1.44(s,6H).

[0267] Step 6: Synthesis of 4-(8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-benzoic acid (compound 625)

[0268] To TFA (0.5 ml), tert-butyl 4-(8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)benzoate (100 mg, 0.26 mmol) was added. The mixture was then reacted at room temperature for 2 hours. After concentration under reduced pressure and rotary evaporation, the product was slurried with methanol, filtered, and the resulting off-white solid product was dried to obtain the target product (70 mg, 76%).

[0269] MS(ESI)calcd for C 20 H 16 N2O3:332.12; found:330.85[M-1].

[0270] 1H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.12(d,J=8.4Hz,2H),7.76(d,J=8.8Hz,2H),7.55(d,8.8Hz,1H),7.26(d,J=8.8Hz,1H),5.30(s,2H),1.44(s,6H).

[0271] Example 9: Preparation of Compound 141

[0272] Step 1: Synthesis of 1-iodo-2-amino-5,6,7,8-tetrahydronaphthalene (intermediate 141-1)

[0273] In dichloromethane (10 ml) and acetic acid (100 ml), 2-amino-5,6,7,8-tetrahydronaphthalene (4.0 g, 27.17 mmol) and NIS (6.1 g, 27.17 mmol) were added. The mixture was stirred at 0 °C for 2 hours. After concentration, the reaction was treated with water, and then extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and passed through a column to obtain a yellow liquid product (4.2 g, 57%).

[0274] LCMS calcd for C 10 H 12 IN:273.00; found:274.20[M+1].

[0275] 1 H NMR (400MHz, CDCl3) δ6.86 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.07 (brs, 2H), 2.68-2.57 (m, 4H), 1.82-1.65 (m, 4H).

[0276] Step 2: Synthesis of 1-trimethylsilyne-2-amino-5,6,7,8-tetrahydronaphthalene (intermediate 141-2)

[0277] In triethylamine (76 ml), 1-iodo-2-amino-5,6,7,8-tetrahydronaphthalene (6.0 g, 21.98 mmol), trimethylsilyne (10.8 g, 0.11 mol), CuI (8.4 g, 43.9 mmol), and Pd(dppf)Cl2 (4.9 g, 6.59 mmol) were added. The reaction was then carried out 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 evaporated to dryness before column chromatography to give a yellow liquid product (4.0 g, 75%).

[0278] LCMS calcd for C 15 H21 NSi:243.14; found:244.35[M+1].

[0279] 1 H NMR (400MHz, DMSO-d6) δ6.76(d,J=8.0Hz,1H),6.49(d,J=8.0Hz,1H),5.05(s,2H),2.65-2.51(m,4H),1.66-1.62(m,4H),0.23(s,9H).

[0280] Step 3: Synthesis of 6,7,8,9-tetrahydro-3H-benzo[e]indole (intermediate 141-3)

[0281] In DMF (75 ml), 1-trimethylsilyne-2-amino-5,6,7,8-tetrahydronaphthalene (4.0 g, 16.45 mmol) and CuI (4.7 g, 24.68 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 under reduced pressure, and purified by column chromatography to obtain an oily product (920 mg, 33%).

[0282] LCMS calcd for C 12 H 13 N:171.10; found:172.40[M+1].

[0283] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.25(brs,1H),7.10(d,J=8.0Hz,1H),6.76(d,J=8.4H z,1H),6.333-6.319(m,1H),2.85(t,J=6.2Hz,2H),2.75(t,J=6.2Hz,2H),1.85-1.72(m,4H).

[0284] Step 4: Synthesis of 1-aldehyde-6,7,8,9-tetrahydro-3H-benzo[e]indole (intermediate 141-4)

[0285] In DMF (6.0 mL), 6,7,8,9-tetrahydro-3H-benzo[e]indole (300 mg, 1.75 mmol) and POCl3 (409 mg, 2.63 mmol) were added. The mixture was then reacted at room temperature for 3 hours. NaOH aqueous solution (2.0 M) was then added to adjust the pH of the reaction solution to 9, and the mixture was heated to 70 °C and reacted for 0.5 hours. After cooling to room temperature, HCl aqueous solution (2.0 M) was added to adjust the pH of the reaction solution to 2. Ethyl acetate was added for extraction, and the organic phase was dried, concentrated under reduced pressure, and evaporated to dryness to obtain an oily crude product (482 mg).

[0286] Step 5: Synthesis of 1-cyano-6,7,8,9-tetrahydro-3H-benzo[e]indole (intermediate 141-5)

[0287] In THF (7 ml), 1-aldehyde-6,7,8,9-tetrahydro-3H-benzo[e]indole (482 mg, 1.75 mmol), hydroxylamine hydrochloride (244 mg, 3.51 mmol), and pyridine (0.7 ml) were added. The reaction was then carried out at 80 °C for 5 hours. Acetic anhydride (1.5 ml) 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 8-10, 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 (290 mg, 84%).

[0288] Step 6: Synthesis of tert-butyl 4-(1-cyano-6,7,8,9-tetrahydro-3H-benzo[e]indol-3-yl)benzoate (intermediate 141-6)

[0289] In DMF (5 ml), 1-cyano-6,7,8,9-tetrahydro-3H-benzo[e]indole (184 mg, 0.94 mmol), Cs₂CO₃ (613 mg, 1.88 mmol), and tert-butyl 4-fluorobenzoate (203 mg, 1.03 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 the product (130 mg, 37%).

[0290] Step 7: Synthesis of 4-(1-cyano-6,7,8,9-tetrahydro-3H-benzo[e]indol-3-yl)benzoic acid (compound 141)

[0291] To TFA (0.6 ml), tert-butyl 4-(1-cyano-6,7,8,9-tetrahydro-3H-benzo[e]indol-3-yl)benzoate (130 mg, 0.35 mmol) was added. The mixture was then reacted at room temperature for 2 hours, concentrated under reduced pressure, evaporated to dryness, slurried with MeOH, and dried to give the target product (69 mg, 63%) as a pale pink solid.

[0292] LCMS calcd for C 20 H 16 N2O2:316.12; found:315.40[M-1].

[0293] 1 H NMR (400MHz, DMSO-d6) δ13.23(s,1H),8.60(s,1H),8.15(d,J=8.8Hz,2H),7.76(d,J=8.4Hz,2H),7.40( d,J=8.4Hz,1H),7.08(d,J=8.8Hz,1H),3.19(t,J=6.4Hz,2H),2.82(t,J=6.4Hz,2H),1.89-1.75(m,4H).

[0294] Example 10: Preparation of Compound 630

[0295] Step 1: Synthesis of methyl 4-(8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoate (intermediate 630-1)

[0296] In DMF (3.0 mL), 8-cyano-3,3-dimethyl-3,6-dihydro-1H-furan[3,4-e]indole (150 mg, 0.71 mmol), Cs₂CO₃ (369 mg, 1.13 mmol), and methyl 4-fluoro-2-(methoxymethyleneoxy)benzoate (226 mg, 1.13 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 over the organic phase, concentrated under reduced pressure, and purified by column chromatography to give a white solid product (160 mg, 56%).

[0297] MS(ESI)calcd for C 23 H 22 N2O5:406.15; found:407.30[M+1].

[0298] 1H NMR (400MHz, DMSO-d6) δ8.70(s,1H),7.90(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,1H),7.51(d,J=2.0Hz,1H),7.39(dd,J=8.4and 2.0Hz,1H),7.31(d,J=8.4Hz,1H),5.39(s,2H),5.34(s,2H),3.86(s,3H),3.44(s,3H),1.49(s,6H).

[0299] Step 2: Synthesis of methyl 4-(8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-2-hydroxybenzoate (intermediate 630-2)

[0300] In dichloromethane (3.0 ml), methyl 4-(8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-2-(methoxymethyleneoxy)benzoate (60 mg, 0.15 mmol) and TFA (0.1 ml) were added. The mixture was then reacted at 25 °C for 2 hours. After concentration under reduced pressure and rotary evaporation, the mixture was slurried with methanol and filtered to obtain a white solid product (39 mg, 73%).

[0301] MS(ESI)calcd for C 21 H 18 N2O4:362.13; found:361.35[M-1].

[0302] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.70(s,1H),7.99(d,J=8.4Hz,1H),7.61( d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),7.29(d,J=2.0Hz,1H),7.26(dd,J=8.4and 2.4Hz,1H),5.34(s,2H),3.94(s,3H),1.48(s,6H).

[0303] Step 3: Synthesis of 4-(8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-2-hydroxybenzoic acid (compound 630)

[0304] In a mixed solvent of THF (2 ml) and ethanol (0.5 ml), methyl 4-(8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-2-hydroxybenzoate (39 mg, 0.11 mmol), H2O (6.0 ml), and LiOH (2.0 M, 0.38 ml) were added. The reaction was then carried out at room temperature for 48 hours. HCl aqueous solution (2.0 M) was added to adjust the pH of the reaction solution to 1-3. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then evaporated to dryness. The mixture was then slurried with methanol and filtered to obtain a white solid product (20 mg, 53%).

[0305] MS(ESI)calcd for C 20 H 16 N2O4:348.11; found:347.30[M-1].

[0306] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.01(d,J=8.4Hz,1H),7.61(d,J=8.4Hz,1H),7.30(d,J=8.4Hz,1H),7.26(d,J=2.0Hz,1H),7.24(dd,J=8.4and 2.0Hz,1H),5.34(s,2H),1.48(s,6H).

[0307] Example 11: Preparation of Compound 754

[0308] Step 1: Synthesis of 4-trimethylsilyne-5-amino-7-isopropyl-1,3-dihydroisobenzofuran (intermediate 754-1)

[0309] In triethylamine (12 ml), 4-iodo-5-amino-7-isopropyl-1,3-dihydroisobenzofuran (1.06 g, 3.5 mmol), trimethylsilyne (0.68 g, 7 mmol), CuI (33 mg, 0.17 mmol), and Pd(dppf)Cl2 (77 mg, 0.1 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 brown solid product (0.9 g, 94%).

[0310] 1H NMR (400MHz, DMSO-D6) δ6.53(s,1H),5.27(s,2H),4.95(s,2H),4.88(s,2H),2.64(pent,J=6.8Hz,1H),1.11(d,J=6.8Hz,6H),0.22(s,9H).

[0311] Step 2: Synthesis of 4-isopropyl-3,6-dihydro-1H-furan[3,4-e]indole (intermediate 754-2)

[0312] In DMF (8 ml), 0.9 g (3.3 mmol) of 4-trimethylsilyn-5-amino-7-isopropyl-1,3-dihydroisobenzofuran and 1.3 g (6.6 mmol) of CuI were added. The mixture was then reacted at 120 °C for 3 hours. After cooling to room temperature, the mixture was filtered, the filtrate was treated with water, extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and evaporated to dryness before column chromatography to give a white solid product (275 mg, 41%).

[0313] 1 H NMR (400MHz, CDCl3) δ8.24 (brs 1H), 7.21 (s, 1H), 7.20 (s, 1H), 6.38 (s, 1H), 5.37 (2, 2H), 5.28 (s, 2H), 2.90 (pent, J = 7.2Hz, 1H), 1.29 (d, J = 7.2Hz, 6H).

[0314] Step 3: Synthesis of 8-aldehyde-4-isopropyl-3,6-dihydro-1H-furan[3,4-e]indole (intermediate 754-3)

[0315] In DMF (3 ml), 270 mg (1.34 mmol) of 4-isopropyl-3,6-dihydro-1H-furan[3,4-e]indole and 247 mg (1.6 mmol) of POCl3 were added. The reaction was then carried out at room temperature for 12 hours. NaOH aqueous solution (2.0 M) was then added to adjust the pH of the reaction solution to 11-12, and the mixture was heated to 70 °C for 0.5 hours. HCl (1.0 M) was then added to adjust the pH of the reaction solution to 3, followed by extraction with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and evaporated to dryness to obtain a solid product (287 mg, 93%).

[0316] MS(ESI)calcd for C 14 H 15 NO2:229.11found:230.30[M+1].

[0317] 1H NMR(400MHz,DMSO-D6)δ12.13(brs,1H),9.75(s,1H),8.24(s,1H),7.24(s,1H ),5.40(s,2H),5.14(s,2H),2.86(pent,J=6.8Hz,1H),1.22(d,J=6.8Hz,6H).

[0318] Step 4: Synthesis of 8-cyano-4-isopropyl-3,6-dihydro-1H-furan[3,4-e]indole (intermediate 754-4)

[0319] In THF (8 ml), 285 mg (1.24 mmol) of 8-aldehyde-4-isopropyl-3,6-dihydro-1H-furan[3,4-e]indole, 173 mg (2.45 mmol) of hydroxylamine hydrochloride, and 0.7 ml of pyridine were added. The reaction was then carried out at 80 °C for 6 hours. Acetic anhydride (1.0 ml) 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 11-12. After stirring for half an hour, ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and evaporated to dryness to give a brown solid product (280 mg, 99%).

[0320] MS(ESI)calcd for C 14 H 14 N2O:226.11; found:224.90[M-1].

[0321] Step 5: Synthesis of tert-butyl 4-(8-cyano-4-isopropyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)benzoate (intermediate 754-5)

[0322] In DMF (4 ml), 8-cyano-4-isopropyl-3,6-dihydro-1H-furan[3,4-e]indole (280 mg, 1.24 mmol), Cs₂CO₃ (807 mg, 2.5 mmol), and tert-butyl 4-fluorobenzoate (364 mg, 1.86 mmol) were added. The reaction was then carried out at 80 °C for 12 hours and cooled to room temperature. After water treatment, the reaction was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and evaporated to dryness before column chromatography to give a white solid product (280 mg, 56%).

[0323] MS(ESI)calcd for C 25 H 26 N2O3:402.19; found:402.90[M+1].

[0324] 1H NMR (400MHz, CDCl3) δ8.22(d,J=8.4Hz,2H),7.77(s,1H),7.54(d,J=8.4Hz,2H),7.28(s,1H ),5.58(s,2H),5.27(s,2H),2.90(pent,J=6.8Hz,1H),1.64(s,9H),1.24(d,J=6.8Hz,6H).

[0325] Step 6: Synthesis of 4-(8-cyano-4-isopropyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-benzoic acid (compound 754)

[0326] To TFA (1.5 ml), tert-butyl 4-(8-cyano-4-isopropyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)benzoate (280 mg, 0.7 mmol) was added. The mixture was then reacted at room temperature for 2 hours, followed by the addition of water (3 ml). The reaction was filtered to obtain a white solid product, which was dried to give the target product (224 mg, 93%).

[0327] MS(ESI)calcd for C 21 H 18 N2O3:346.13; found:344.90[M-1].

[0328] 1 H NMR(400MHz,DMSO-D6)δ8.64(s 1H),8.18(d,J=8.8Hz,2H),7.80(d,J=8.4Hz,2H),7.40(s,1H),5.40(s,2H),5.20(s,2H),2.90(pent,J=6.8Hz,1H),1.20(d,J=6.8Hz,6H).

[0329] Example 12: Preparation of Compound 161

[0330] Step 1: Synthesis of tert-butyl 4-(3-cyano-5-benzyloxy-1H-indole-1-yl)benzoate (Intermediate 161-1)

[0331] In DMAC (85 ml), 3-cyano-5-benzyloxy-1H-indole (12.7 g, 51.2 mmol), Cs₂CO₃ (25.1 g, 76.81 mmol), and tert-butyl 4-fluorobenzoate (15.1 g, 76.81 mmol) were added. The reaction mixture was then reacted at 100 °C for 4 hours and cooled to room temperature. Water (85 ml) was added to treat the reaction, and the mixture was filtered to obtain a filter cake. After washing with water, the cake was dried at 50 °C and then slurried with ethyl acetate / petroleum ether (1 / 5, 72 ml) to give a brown solid product (18.9 g, 85%).

[0332] 1 HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.12-8.09(m,2H),7.81-7.78(m,2H),7.62(d,J=9.2Hz,1H),7.52-7.48(m,2H), 7.44-7.39(m,2H),7.37-7.33(m,1H),7.32(d,J=2.4Hz,1H),7.10(dd,J=9.2Hz,2.4Hz,1H),5.23(s,2H),1.58(s,9H).

[0333] Step 2: Synthesis of tert-butyl 4-(4-bromo-3-cyano-5-benzyloxy-1H-indol-1-yl)benzoate (intermediate 161-2)

[0334] In acetonitrile (240 ml), tert-butyl 4-(3-cyano-5-benzyloxy-1H-indol-1-yl)benzoate (16.3 g, 38.39 mmol) and NBS (7.5 g, 42.23 mmol) were added. The mixture was stirred at 70 °C for 4 hours. After concentration, the reaction was treated with water, extracted with dichloromethane, dried, concentrated under reduced pressure, and then slurried with acetonitrile (120 ml). The slurry was filtered to obtain a brown solid product (15.7 g, 81%).

[0335] 1 HNMR(400MHz,DMSO-d6)δ8.68(s,1H),8.11(d,J=8.8Hz,2H),7.90(s,1H),7.80(d,J=8.4Hz,2H),7.54 (d,J=7.2Hz,2H),7.50(s,1H),7.43(t,J=7.2Hz,2H),7.35(t,J=7.2Hz,1H),5.34(s,2H),1.58(s,9H).

[0336] Step 3: Synthesis of 4-(4-((E)-3-(tert-butyldimethylsiloxy)propen-1-yl)-3-cyano-5-benzyloxy-1H-indole-1-yl)-tert-butyl benzoate (intermediate 161-3)

[0337] In dioxane (1 ml), tert-butyl 4-(4-bromo-3-cyano-5-benzyloxy-1H-indol-1-yl)benzoate (50 mg, 0.12 mmol), (E)-3-(tert-butyldimethylsiloxy)propen-1-yl-boronic acid pinacol ester (72 mg, 0.24 mmol), K₂CO₃ (2.0 M, 0.12 ml) and PdCl₂ (dppf) (20 mg, 0.03 mmol) were added. The reaction was then carried out at 90 °C for 12 hours. After cooling to room temperature, the product was concentrated under reduced pressure, evaporated to dryness, and then column-sected to give a yellow liquid product (91 mg, 99%).

[0338] Step 4: Synthesis of 4-(4-(3-(tert-butyldimethylsiloxy)propane-1-yl)-3-cyano-5-hydroxy-1H-indol-1-yl)-tert-butyl benzoate (intermediate 161-4)

[0339] In methanol (1 ml), tert-butyl benzoate (91 mg, 0.18 mmol), 10% Pd / C (5 mg), and 10% Pd(OH)2 / C (5 mg) were added. The mixture was then hydrogenated at 25 °C for 4 hours. After filtration, the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain a yellow liquid product (83 mg, 91%).

[0340] MS(ESI)calcd for C 29 H 38 N2O4Si:506.26; found:507.25[M+1].

[0341] Step 5: Synthesis of tert-butyl 4-(4-(3-(hydroxy)propane)-3-cyano-5-hydroxy-1H-indol-1-yl)-benzoate (intermediate 161-5)

[0342] To THF (1 ml), tert-butyl benzoate (83 mg, 0.16 mmol) and a THF solution of TBAF (0.32 ml, 1.0 M, 0.32 mmol) were added. The reaction was then carried out at 25 °C for 2 hours. The solution was then concentrated under reduced pressure, evaporated to dryness, and column chromatography to give a pale yellow solid product (32 mg, 50%). MS (ESI) calcd for C23 H 24 N2O4:392.17; found:391.35[M-1].

[0343] 1 H NMR (400MHz, CDCl3) δ8.18(d,J=8.4Hz,2H),7.79(s,1H),7.52(d,J=8.8Hz,2H),7.30(d,J=8.8Hz,1H ),6.99(d,J=9.2Hz,1H),3.72(t,J=6Hz,2H),3.33(t,J=6.4Hz,2H),2.18-2.12(m,2H),1.63(s,9H).

[0344] Step 6: Synthesis of tert-butyl 4-(1-cyano-8,9-dihydro-7H-pyran[3,2-e]indol-3-yl)benzoate (intermediate 161-6)

[0345] In THF (1 ml), tert-butyl 4-(4-(3-(hydroxy)propyl)-3-cyano-5-hydroxy-1H-indol-1-yl)-benzoate (50 mg, 0.13 mmol), triphenylphosphine (44 mg, 0.17 mmol), and diisopropyl azodicarboxylate (DIAD) (34 mg, 0.17 mmol) were added. The mixture was then stirred at 25 °C for 3 hours, concentrated under reduced pressure, evaporated to dryness, and column chromatography to give a white solid product (44 mg, 90%).

[0346] MS(ESI)calcd for C 23 H 22 N2O3:374.16; found:375.25[M+1].

[0347] 1 H NMR (400MHz, CDCl3) δ8.17(d,J=8.4Hz,2H),7.76(s,1H),7.51(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,1H) ,6.85(d,J=8.8Hz,1H),4.24(t,J=5.2Hz,2H),3.32(t,J=6.4Hz,2H),2.17-2.11(m,2H),1.63(s,9H).

[0348] Step 7: Synthesis of 4-(1-cyano-8,9-dihydro-7H-pyran[3,2-e]indol-3-yl)-benzoic acid (compound 161)

[0349] To TFA (1.0 ml), tert-butyl 4-(1-cyano-8,9-dihydro-7H-pyran[3,2-e]indol-3-yl)benzoate (44 mg, 0.11 mmol) was added. The mixture was then reacted at room temperature for 2 hours. After concentration under reduced pressure and evaporation to dryness, the product was slurryed with ethyl acetate, filtered to obtain a white solid product, and dried to obtain the target product (33 mg, 92%).

[0350] MS(ESI)calcd for C 19 H 14 N2O3:318.1; found:317.30[M-1].

[0351] 1 H NMR (400MHz, DMSO-d6) δ13.21(brs,1H),8.57(s,1H),8.14(d,J=8Hz,2H),7.75(d,J=8.4Hz,2H),7.38( d,J=9.2Hz,1H),6.83(d,J=8.8Hz,1H),4.18(t,J=5.2Hz,2H),3.17(t,J=6.4Hz,2H),2.08-2.02(m,2H).

[0352] Example 13: Preparation of compound F8

[0353] Step 1: Synthesis of 4-fluoro-8-cyano-3,3-dimethyl-3,6-dihydro-1H-furan[3,4-e]indole (intermediate F8-1)

[0354] In DMSO (3 ml), 5-amino-1,1-dimethyl-7-fluoro-4-iodide-1,3-dihydroisobenzofuran (100 mg, 0.33 mmol), isoxazol-4-boronic acid (48 mg, 0.42 mmol), potassium fluoride (0.2 ml, 4.7 M aqueous solution), and Pd(dtbpf)Cl2 (6 mg) were added. The reaction was then carried out at 100 °C for 12 hours. Water (10 ml) was then added at room temperature, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and purified by column chromatography to give a pale yellow solid product (62 mg, 83%).

[0355] MS(ESI)calcd for C 13 H 11 OFN2:230.09; found:229.00[M-1].

[0356] 1H NMR (400MHz, DMSO-d6) δ12.33(s,1H),8.27(d,J=2.4Hz,1H),7.27(d,J=10.4Hz,1H),5.32(s,2H),1.53(s,6H).

[0357] Step 2: Synthesis of tert-butyl 4-(4-fluoro-8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)benzoate (intermediate F8-2)

[0358] In DMF (3 ml), 100 mg (0.43 mmol) of 4-fluoro-8-cyano-3,3-dimethyl-3,6-dihydro-1H-furan[3,4-e]indole, 283 mg (0.87 mmol) of Cs₂CO₃, and 170 mg (0.87 mmol) of tert-butyl 4-fluorobenzoate were added. The mixture was then reacted at 80 °C for 12 hours and cooled to room temperature. After treatment with water, the mixture was filtered, and the resulting filter cake was slurried with methanol to give an off-white solid product (81 mg, 46%).

[0359] Step 3: Synthesis of 4-(4-fluoro-8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)-benzoic acid (compound F8)

[0360] To TFA (1.0 ml), tert-butyl 4-(4-fluoro-8-cyano-3,3-dimethyl-1,3-dihydro-6H-furan[3,4-e]indol-6-yl)benzoate (81 mg, 0.2 mmol) was added. The mixture was then reacted at room temperature for 1 hour. After concentration under reduced pressure and rotary evaporation, the product was slurried with methanol, filtered, and the resulting off-white solid product was dried to obtain the target product (55 mg, 73%).

[0361] MS(ESI)calcd for C 20 H 15 O3FN2:350.11; found:349.15[M-1].

[0362] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.16(d,J=8.4Hz,2H),7.80(d,J=8.8Hz,2H),7.42(d,J=10.4Hz,1H),5.40(s,2H),1.56(s,6H).

[0363] The following compounds were prepared according to the preparation methods described in Examples 7-13. The preparation methods described in the examples, as well as their structural formulas and characterization data, are shown in Table 2.

[0364] Table 2. Compound structural formulas, characterization data, and preparation methods.

[0365] Example 14: Inhibition of xanthine oxidase activity by the compound

[0366] Weigh approximately 3 mg of the test compound, including the positive controls febuxostat and topiprostat. Calculate the required solvent volume based on the molecular weight, 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 μM, 50 μM, 5 μM, 500 nM, 250 nM, 50 nM, 5 nM, 0.5 nM).

[0367] 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.

[0368] 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, excite at 535 nm, and 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, and obtain the IC50 of the test compound. 50 .

[0369] The test results are shown in Table 3: The compounds 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 drugs febuxostat and topiprostat.

[0370] Table 3. Inhibition results of compounds on xanthine oxidase activity

[0371] Example 15: Inhibition of uric acid transporter protein by compound

[0372] As in Example 14, different concentration dilutions of the test compound and the positive control compound Lesinurad stock solution were prepared.

[0373] All cell culture media were sourced from Invitrogen, and plastic products from Corning. 14 The labeled uric acid was obtained from American Radiolabeled Chemicals (CAT#ARC 0513-250 μCi). The human embryonic kidney cell line HEK293 (from ATCC.org) was used as the starting cell line for transient transfection. A plasmid overexpressing human URAT1 cDNA, which was independently cloned, was transiently transfected into HEK293 cells to serve as a cell model for studying uric acid transport by overexpressing human uric acid transporter proteins. Twenty-four hours after transfection, 300,000 cells / well were seeded into 48-well plates, with three replicates for each test condition. The following day, cells were washed with 200 μl of chloride-free HBSS buffer pre-warmed at 37°C, and then replaced with a plate pre-mixed with 10 μM C. 14 Labeled uric acid and culture media containing different concentrations of the test compounds were incubated at 37°C in a CO2 incubator for 30 minutes. After incubation, the culture medium was removed, and the cells were washed three times with 200 μl of chloride-free HBSS pre-cooled to 4°C buffer. Cells were then lysed with 100 μl of 0.1N NaOH, and the cell lysis buffer was mixed with 100 μl of Ultima Gold scintillation buffer. TM Mix well and take a reading using a Revvity liquid scintillation counter (model MicroBeta2). Add C 14 The reading of the well labeled with uric acid, but without any added compound, is 100% uric acid transport, without added C. 14 The readings of the labeled uric acid wells were used as background readings, and then the inhibitory efficiency of different concentrations of the analyte on the uric acid transporter 1 (URAT1) was calculated. This assay employed multiple concentration gradients to test the inhibition rate of URAT1 and calculated the IC50. 50 .

[0374] As shown in Table 4, compound F1 of the present invention has good inhibitory activity against uric acid transporter protein.

[0375] Table 4 shows the half-maximal inhibitory concentration (IC50) of the compounds against the uric acid transporter (Urat1). 50

[0376] Example 16: Pharmacological test of the compound in lowering blood uric acid.

[0377] In this embodiment, adult male Balb / c wild-type mice aged 8-12 weeks provided by Vital Rivers were divided into a model group (con), a control group (ref), and a treatment group (compound 1, F8, F1). The model group was administered 0.5 mL of a 1.2% 2-BP-β-CD (cyclodextrin) aqueous solution by gavage, the control group was administered 0.5 mL of febuxostat (40 mg / kg) prepared with a 1.2% 2-BP-β-CD (cyclodextrin) aqueous solution, and the treatment group was administered 0.5 mL of the test compound solution (40 mg / kg) prepared with a 1.2% 2-BP-β-CD (cyclodextrin) aqueous solution. 23 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% methylcellulose aqueous solution was administered by gavage 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.

[0378] As shown in Figure 1, 24 hours after a single administration, compared with the model group, the febuxostat group reduced serum uric acid by 36.4%, while compounds 1, F8, and F1 reduced serum uric acid by 79.5%, 71.7%, and 84.1%, respectively. This indicates that the compounds of the present invention can effectively reduce serum uric acid concentration, and their effect is significantly better than that of the positive control drug febuxostat.

[0379] 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.

[0380] 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 aryl-substituted indole 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 having the structure shown in Formula I. in, X is selected from: -O-, -S-, -C(R1R2)-, -N(R3)-; Y is selected from: -O-, -S-, -N(R3)-; Z and W are each independently selected from: CR4; m and n are independently selected from 0, 1, 2, and 3 respectively, y1 and y2 are independently selected from 0 and 1 respectively, and m+n+y1+y2 is 2, 3 or 4; Q is selected from: hydrogen, halogen, cyano; L is selected from: one or more R5-substituted or unsubstituted C6-C 10 Aryl, one or more R5-substituted or unsubstituted 5-10 heteroaryl groups; Each R1 and R2 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C8 alkyl, one or more R6-substituted or unsubstituted C1-C8 alkoxy, one or more R6-substituted or unsubstituted C1-C8 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R6-substituted or unsubstituted C3-C8 cycloalkyl, or R1 and R2 on the same carbon are connected to form R6-substituted or unsubstituted C3-C8 cycloalkyl; Each R3 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C8 alkyl groups, one or more R6-substituted or unsubstituted C3-C8 cycloalkyl groups, and one or more R6-substituted or unsubstituted C1-C8 alkyl acyl groups; Each R4 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C8 alkyl groups, one or more R6-substituted or unsubstituted C1-C8 alkoxy groups, one or more R6-substituted or unsubstituted C1-C8 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, hydroxyl groups, one or more R6-substituted or unsubstituted C3-C8 cycloalkyl groups, and one or more R6-substituted or unsubstituted C6-C4 alkyl groups. 14 Aryl; Each R5 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, R6-substituted or unsubstituted C6-C 10 Aryl, R6-substituted or unsubstituted 5-10 heteroaryl groups; Each R6 is independently selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, and C3-C8 cycloalkyl; Each R is independently selected from: hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino.

2. The aryl-substituted indole 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 claim 1, is characterized in that... The sum of m+n+y1+y2 is 3.

3. The aryl-substituted indole 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 claim 1, is characterized in that... The sum of m+n+y1+y2 is 2, and at least one of R1, R2, and R4 is not hydrogen.

4. The aryl-substituted indole 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 claim 1, characterized in that, The aryl-substituted indole compounds have the structure shown in Formula II: Where m and n are independently selected from 0, 1, 2, and 3 respectively, and m+n is 2, 3, or 4.

5. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 4, characterized in that, m and n are independently selected from 0, 1, 2, and 3 respectively, and m+n is 3.

6. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 4, characterized in that, m and n are independently selected from 0, 1, and 2 respectively, and m+n is 2. At least one of R1, R2, and R4 is not hydrogen.

7. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 4, characterized in that, m and n are independently selected from 0, 1, and 2 respectively, and m+n is 2; at least one of R1 and R2 is not hydrogen.

8. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 4, characterized in that, m and n are independently selected from 0, 1, and 2 respectively, and m+n is 2; there is a pair of R1 and R2 on the same carbon that are not hydrogen, and all other R1 and R2 are hydrogen.

9. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 4, characterized in that, m and n are independently selected from 0, 1, and 2 respectively, and m+n is 2; Z and W are CH; at least one of R1 and R2 is not hydrogen.

10. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 4, characterized in that, m and n are independently selected from 0, 1, and 2 respectively, and m+n is 2; Z and W are CH; there is a pair of R1 and R2 on the same carbon that are not hydrogen, and all other R1 and R2 are hydrogen.

11. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 4, characterized in that, m and n are independently selected from 0, 1, and 2 respectively, and m+n is 2; at least one of each R4 is not hydrogen.

12. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 1, characterized in that, The aryl-substituted indole compounds have the structure shown in Formula III: a is selected from: 1, 2.

13. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 12, characterized in that, a is 1, and at least one of R1 and R2 is not hydrogen, preferably neither of them is hydrogen; Alternatively, a is 1, and at least one of R1, R2, and each of R4 is not hydrogen; Alternatively, a is 1, Z and W are CH, and at least one of R1 and R2 is not hydrogen, preferably neither of them is hydrogen; Alternatively, a is 1, and at least one of the R4 groups is not hydrogen.

14. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 1, characterized in that, The aryl-substituted indole compounds or their derivatives have structures as shown in formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-10, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9: Among them, at least one of R1, R2 and R4 is not hydrogen, or at least one of R1 and R2 is not hydrogen, or at least one of R4 is not hydrogen.

15. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 14, characterized in that, There is a pair of R1 and R2 on the same carbon atom that are not hydrogen, while all other R1 and R2 are hydrogen.

16. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 14, characterized in that, Z and W are CH, and at least one of R1 and R2 is not hydrogen.

17. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 14, characterized in that, Z and W are CH; there is a pair of R1 and R2 on the same carbon that are not hydrogen, while the other R1 and R2 are all hydrogen.

18. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 1, characterized in that, The aryl-substituted indole compounds or their derivatives have structures as shown in formulas II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, II-23, III-10, III-11, III-12, III-13, III-14, III-15, III-16, III-17 or III-18:

19. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 18, characterized in that, All R4 are H; and / or, all R1 and R2 are H.

20. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 18, characterized in that, There is a pair of R1 and R2 on the same carbon atom that are not hydrogen, while all other R1 and R2 are hydrogen.

21. An aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-18 or 20, characterized in that, Each R1 and R2 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C4 alkyl groups, one or more R6-substituted or unsubstituted C1-C4 alkoxy groups, one or more R6-substituted or unsubstituted C1-C4 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, hydroxyl groups, one or more R6-substituted or unsubstituted C3-C6 cycloalkyl groups, or R1 and R2 on the same carbon atom are linked together to form R6-substituted or unsubstituted C3-C6 cycloalkyl groups.

22. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 21, characterized in that, Each R6 in R1 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, and C3-C6 cycloalkyl. Preferably, each R6 in R1 is independently selected from: hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluorine, chlorine, bromine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

23. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 21, characterized in that, Each R1 and R2 is independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, isopropylthio, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or R1 and R2 on the same carbon atom are linked together to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

24. An aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-18 or 20, characterized in that, R1 and R2 on the same carbon atom are identical.

25. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-20, characterized in that, Each R3 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C4 alkyl groups, one or more R6-substituted or unsubstituted C3-C6 cycloalkyl groups, and one or more R6-substituted or unsubstituted C1-C4 alkyl acyl groups; Preferably, each R6 in R3 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, and C3-C6 cycloalkyl. Preferably, each R6 in R3 is independently selected from: hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluorine, chlorine, bromine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferably, each R3 is independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetyl, n-propionyl, and isopropionyl.

26. An aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-18 or 20, characterized in that, Each R4 is independently selected from: hydrogen, one or more R6-substituted or unsubstituted C1-C4 alkyl groups, one or more R6-substituted or unsubstituted C1-C4 alkoxy groups, one or more R6-substituted or unsubstituted C1-C4 alkylthio groups, halogens, cyano groups, aldehyde groups, carboxyl groups, nitro groups, hydroxyl groups, one or more R6-substituted or unsubstituted C3-C6 cycloalkyl groups, and one or more R6-substituted or unsubstituted C6-C4 alkyl groups. 10 Aryl.

27. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 26, characterized in that, Each R6 in R4 is independently selected from: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, and C3-C6 cycloalkyl. Preferably, each R6 in R4 is independently selected from: hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluorine, chlorine, bromine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

28. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 27, characterized in that, Each R4 is independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, isopropylthio, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroisopropyl, phenyl, and naphthyl.

29. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-20, characterized in that, W stands for CH.

30. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-20, characterized in that, When all R1 and R2 are hydrogen, W is CH.

31. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-20, characterized in that, Q is selected from: hydrogen, bromine, chlorine, fluorine, and cyano.

32. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-20, characterized in that, Each R5 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, R6-substituted or unsubstituted phenyl, R6-substituted or unsubstituted naphthyl, R6-substituted or unsubstituted 5-6 heteroaryl; Each R is independently selected from: hydrogen, hydroxyl, hydroxylamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino; Preferably, each R5 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.

33. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to any one of claims 1-20, characterized in that, L is selected from: one or more R5-substituted or unsubstituted phenyl groups, one or more R5-substituted or unsubstituted naphthyl groups, and one or more R5-substituted or unsubstituted 5-6-membered heteroaryl groups.

34. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 33, characterized in that, L is selected from: one or more R5-substituted or unsubstituted phenyl groups, one or more R5-substituted or unsubstituted naphthyl groups, one or more R5-substituted or unsubstituted pyridyl groups, one or more R5-substituted or unsubstituted pyrazinyl groups, one or more R5-substituted or unsubstituted pyridazinyl groups, and one or more R5-substituted or unsubstituted pyrimidinyl groups. Preferably, each R5 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, 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.

35. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 34, characterized in that, L is selected from:

36. The aryl-substituted indole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide, according to claim 1, characterized in that, The aryl-substituted indole compounds or their derivatives are selected from the following compounds: Preferably, the aryl-substituted indole compound or its derivative is selected from the following compounds:

37. The use of the aryl-substituted indole 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 any one of claims 1-36 in the preparation of XOR inhibitors and / or URAT1 inhibitors.

38. The use of the aryl-substituted indole 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 any one of claims 1-36, in the preparation of a uric acid-lowering drug.

39. The use of the aryl-substituted indole 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 any one of claims 1-36, in the preparation of a medicament for the prevention and / or treatment of gout or hyperuricemia.

40. An XOR / URAT1 dual inhibitor, characterized in that, Its active ingredient contains an aryl-substituted indole 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 any one of claims 1-36.

41. 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 aryl-substituted indole 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 any one of claims 1-36.

42. A method for preventing and / or treating gout or hyperuricemia, characterized in that, include: Administering to patients with gout or hyperuricemia a safe and effective amount of any one of the aryl-substituted indole 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 any one of the 1-37 examples; and / or, Administering a safe and effective amount of the uric acid-lowering drug as described in claim 41 to patients with gout or hyperuricemia.

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